Conditions: COVID-19
Keywords: Adults COVID-19 Multicenter Putative Therapeutics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 527
Healthy volunteers: no

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 Coronavirus Disease 2019 (COVID-19). Big Effect Trial (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-B stage will evaluate the combination of remdesivir with lenzilumab vs remdesivir with a lenzilumab placebo. The primary objective is to evaluate the clinical efficacy of different investigational therapeutics relative to the control arm in adults hospitalized with COVID-19 according to clinical status (8-point ordinal 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 Coronavirus Disease 2019 (COVID-19). Big Effect Trial (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-B stage will evaluate the combination of remdesivir with lenzilumab vs remdesivir with a lenzilumab 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 and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Day 1 (prior to study product administration) and Days 3, 5, 8, and 11 while hospitalized. OP swabs (oropharyngeal swabs are preferred, but if these are not obtainable, saliva or nasopharyngeal or nasal swabs may be substituted) and 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 different investigational therapeutics 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 to 1) evaluate the clinical efficacy of different investigational therapeutics as assessed by time to recovery compared to the control arm, and 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: 200-mg intravenous (IV) remdesivir loading dose on Day 1, followed by a 100-mg once-daily IV maintenance dose up to a 10-day total course while hospitalized and 600-mg IV lenzilumab infusion every 8 hours starting on Day 1 for a total of 3 doses. N=275. arm 2: 200-mg intravenous (IV) remdesivir loading dose on Day 1, followed by a 100-mg once-daily IV maintenance dose up to a 10-day total course while hospitalized and 600-mg IV lenzilumab placebo infusion every 8 hours starting on Day 1 for a total of 3 doses. N=275.

Interventions: intervention 1: Lenzilumab intervention 2: Placebo intervention 3: Remdesivir
Intervention descriptions: intervention 1: Lenzilumab is a first-in-class recombinant monoclonal antibody targeting soluble human GM-CSF, with potential immunomodulating activity, high binding affinity in the pM range, and 94% specificity to the human germline, which reduces immunogenicity. intervention 2: Placebo for lenzilumab is commercially sourced 0.9% sodium chloride. intervention 3: Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524.

Protocol document:
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 B 
 
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: 
 
20-0013 
 
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 
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). 


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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) and one swab (throughout this form swab collections can mean 
swabs can be collected from deep inside your nose, the middle of your nose, or your throat) from 
you about 5 times, depending on how long you remain in the hospital. 
 
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 and swab samples collected on this study for research and safety tests. 
Swab samples will be tested for SARS-CoV-2. 
 
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 contraception. If a hormonal method of contraception is used (for 
example, an implant, a hormone-releasing intrauterine device [IUD], injections, pills, a vaginal 
ring, or a skin patch) a barrier method must also be used at the same time (for example, male 
condom, diaphragm, cervical cap) while taking part in this study and for 5 months after your last 
dose of the study drug or placebo. Please speak to the study doctor or 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, also only while you are in the hospital. 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 not receive any more study drugs. If you are readmitted to 
the hospital before Day 11, you may receive the rest of your remdesivir infusions, up to Day 10. 
 
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 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) and one swab from you on Days 1, 3, 5, 8, and 11 as long as you remain in 
the hospital.  
 


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You will have follow-up visits on Days 8 (if you have already been discharged from the 
hospital), 15, 22, 29 and 60. 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, Day 22, and 
Day 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. If you 
have in-person visits on Days 15 and 29, we will also take one or more blood sample(s) and one 
swab.  
 
The total amount of blood that we will collect from you for this study is up to about 31 
tablespoons. We will use the blood samples and swabs collected on this study for research and 
safety tests. Swabs will be tested for SARS-CoV-2. Swabs will be collected from deep in your 
nose. If this is not possible, the swab will be taken from the middle or front of your nose or 
throat. 
 
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 United States Food and Drug Administration (FDA) recently 
approved remdesivir as a treatment for COVID-19, which means it can be given to COVID-19 
patients as standard treatment. 
 
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 


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• 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 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. 
 
Lenzilumab 
Description: Lenzilumab is a drug that is under investigation as a treatment for COVID-19. It is 
a type of drug called a monoclonal antibody, and it works by attaching to natural proteins in the 
body that can cause inflammation. It ultimately reduces inflammation inside the body. Because 
inflammation seems to be one of the most serious problems during COVID-19 illness, we think 
that this drug may helpful as a treatment. Lenzilumab is not approved by the FDA to treat 
COVID-19, but they have given us permission to test it in this study. 
 
Lenzilumab 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 three times over 24 hours by infusion, and 
each infusion takes about 60 minutes. 
 
Risks: The most common side effects seen in people receiving lenzilumab include: 


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• Infusion-related reactions (nausea, headache, chest pressure, palpitations, shortness of 
breath, fever, chills, heart rate changes, low blood pressure, difficulty breathing, low 
blood oxygen, flushing, rash, itching, and hives). 
• Upper respiratory tract infection 
• Headache 
 
Less common side effects include: 
• Diarrhea 
• Reflux 
• Vomiting 
• Obstructive abdominal hernia (“pinched” intestine) 
• Arthralgia (joint pain) 
• Muscle spasms 
• Extremity pain 
• Urinary tract infection 
• Appendicitis (inflammation of the appendix) 
• Pneumonia (lung infection) 
• Hypertension (high blood pressure) 
• Acute myocardial infarction (heart attack) 
• Transient ischemic attack (mini stroke) 
• Insomnia (trouble falling or staying asleep) 
• Depression 
• Suicide attempt 
 
If you are having suicidal thoughts call the study doctor at the telephone number listed on the 
first page of this form. If you feel in crisis, you can call 911 and/or a Nationwide Suicide Hotline 
that is answered 24 hours a day with a skilled, trained counselor. One example is the National 
Suicide Prevention Lifeline at 1-800-273-TALK (8255). 
 
Because of the way lenzilumab works, it may increase the risk of serious infections. However, 
the chance that this would happen with the doses of lenzilumab that is being given in this study is 
very low. 
 
Lenzilumab can cause an allergic reaction, which may include fever, chills, nausea, hives, 
itching, decreased blood pressure, swelling, decreased oxygen supply, wheezing, difficulty 
breathing, and an abnormal heartbeat. Severe allergic reactions (called anaphylaxis) can cause 
heart attacks and, if untreated, even death. We cannot always predict in advance who might 
develop this serious reaction. 
 
We will monitor you closely for side effects while you are getting the lenzilumab and will have 
medicine and equipment available to treat side effects, including severe effects, if needed. If you 
have a severe side effect that does not improve with treatment, we will stop the infusion. 
 


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Placebo 
Description: The placebo for this study is an inactive liquid that is similar to lenzilumab, but 
does not have any active drug in it. It is given three times over 24 hours by infusion, and each 
infusion takes about 60 minutes.  
 
Risks: The main risks of a placebo infusion are those associated with IV line placement described 
below (see Section 4). 
 
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. 
 
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.  
 
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. 
 
Swab collection 
Throat swab: This procedure may be uncomfortable, and it causes many people to gag. 
 
Middle nose swab: This procedure may tickle and be slightly uncomfortable. 
 
Deep nose swab: Most people feel pressure and discomfort during this procedure, and it can 
cause a nosebleed. 
 
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. 
 
 Alert System 
 has an electronic system that lets your study doctors know if you are admitted to a 
 hospital, or if you visit a 
 hospital Emergency Department.   


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 hospitals want to make sure the study doctors know about any possible problems or side 
effects you experience while you are taking part in the study. If you obtain emergency medical 
care at another hospital or clinic, please let your study doctor or study staff know as soon as 
possible. 
 
Study Information Included in Your Electronic Medical Record 
A notation that you are taking part in this research study may be made in your electronic medical 
record. Information from the research that relates to your general medical care may be included 
in the record (for example: list of allergies, results of standard blood tests done at the hospital 
labs). 
 
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 
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. 
 


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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 
abstinent or use birth control while you are on this study and for 5 months 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 and cannot 
use one of these birth control methods. Some methods of birth control will not work when you 
are taking certain drugs. Be aware that women can still become pregnant even if using an 
acceptable birth control method.  
 
If you think or know you have become pregnant during the study, please contact the research 
team member. You will not receive any more study drug. The team will ask your permission to 
follow-up with you about your health and the health of your baby until 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, you must agree to remain abstinent or use birth control while you are on this 
study for up to 5 months. 
 
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. 


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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 
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. 


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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.    
 
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. 
What will I have to pay for if I take part in this study? 
 
It will not cost you anything to be in this study. 
 
Study funds will pay for certain study-related items and services that are being done only for 
research. However, we may bill your health insurer for, among other things, routine items and 
services you would have received even if you did not take part in the research. You will be 
responsible for payment of any deductibles and co-payments required by your insurer for this 
routine care or other billed care. 
 
If you have any questions about costs to you that may result from taking part in the research, 
please speak with the study doctors and study staff. If necessary, we will arrange for you to 
speak with someone in Patient Financial Services about these costs.  Before you agree to be in 
this study, you should contact your health insurer to see if your plan will cover the costs 
required as part of your participation. 
 
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 


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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 lenzilumab by Humanigen, 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 
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. 
 
 


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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.  
 
If I take part in this research study, how will you protect my privacy? 
During this research, identifiable information about your health will be collected. In the rest of 
this section, we (
) refer to this information simply as “health information”. 
Under federal law, health information is private. However, there are exceptions to this rule, and 
you should know who may be able to see, use, and share your health information for research 
and why they may need to do so. 
 
In this study, we may collect health information about you from: 
• Past, present, and future medical records 
• Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable health information and why they may need 
to do so: 
• 
 research staff involved in this study in order to conduct the research 
• The sponsor(s) of this study, and the people or groups it hires to help perform this 
research or audit the research 
• Other researchers and medical centers that are part of this study and their ethics boards 
• A group that oversees the data (study information) and safety of this research 
• Non-research staff within 
 who need this information to do their jobs (such as for 
treatment, payment (billing), or health care operations) 
• Advarra IRB Review a group of people who review research studies to protect the rights 
and safety of research participants 
• People from organizations that provide independent accreditation and oversight of 
hospitals and research 
• People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers 
• Federal and state agencies (such as the Food and Drug Administration (FDA), the 
Department of Health and Human Services, the National Institutes of Health, and other 
US or foreign government bodies that oversee or review research) 
• Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law) 
 


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Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form. For example, we understand that the 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
and to oversee and improve its products’ performance. We share your health information only 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy. The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list. However, once your information 
is shared outside 
, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information. Your permission to use and share your 
identifiable information does not expire.  
 
The results of this research study may be published in a medical book or journal, or used to teach 
others. However, your name or other identifying information will not be used for these purposes 
without your specific permission. 
 
Your Privacy Rights 
You have the right not to sign and date this form that allows us to use and share your health 
information for research; however, if you don’t sign and date it, you can’t take part in this 
research study. 
 
You have the right to withdraw your permission for us to use or share your health information 
for this research study. If you want to withdraw your permission, you must notify the person in 
charge of this research study in writing at the address listed on the first page of this form. Once 
permission is withdrawn, you cannot continue to take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others, and such information may continue to be used for certain 
purposes, such as to comply with the law or maintain the reliability of the study. 
 
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment. To ask for this information, please contact the person in charge of this 
research study, listed on page 1 of this form. You may only get such information after the 
research is finished. 
 
 
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, as 
required by U.S. Law.  This Web site will not include information that can identify you. At 


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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. Humanigen, Inc., the company that makes lenzilumab, is 
providing lenzilumab 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 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00046406. 
 


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D. What happens if I am injured as a result of taking part in this research study? 
 
We (
) will offer you the care needed to treat any injury that directly results 
from taking part in this research study. We reserve the right to bill your insurance company 
or other third parties, if appropriate, for the care you get for the injury. We will try to have 
these costs paid for, but you may still be responsible for some of them.  For example, if the 
care is billed to your insurer, you will be responsible for payment of any deductibles and co-
payments required by your insurer.  To ask questions about this, talk to the study doctor or 
study staff.  Be aware that your health care payer/insurer might not cover the costs of 
study-related injuries or illnesses. 
 
 Injuries sometimes happen even when no one is at fault. There are no plans to pay you or 
give you other compensation for an injury, should one occur.  However, you are not giving 
up any of your legal rights by signing and dating this form. If you think you have been 
injured or have experienced a medical problem as a result of taking part in this research 
study, tell the person in charge of this study as soon as possible.  The researcher's name and 
phone number are listed on the first page of this consent form. 
In general, no long-term medical care or financial compensation for research-related injuries 
will be provided by the NIH or the Federal Government.  
 
A Declaration under the Public Readiness and Emergency Preparedness (PREP) Act was 
issued by the Secretary of the United States Department of Health and Human Services on 
March 10, 2020.  This Declaration limits the legal rights of a subject participating in clinical 
studies utilizing COVID-19 countermeasures. 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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Informed Consent and Authorization 
Statement of Person Giving Informed Consent and Authorization 
• I have read this consent form. 
• This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
• I have had the opportunity to ask questions. 
• I understand the information given to me. 
• By signing and dating this form, I do not give up any of my legal rights. 
• I will get a signed and dated copy of this consent form. 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
Printed Name of Subject 
 
 
 
 
 
Signature of Subject 
 
Date/Time 
 
 
Statement of Study Doctor or Person Obtaining Consent: 
• I have explained the research to the study subject. 
• I have answered all questions about this research study to the best of my ability. 
 
 
 
Printed Name of Person Obtaining Consent 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
Date/Time 
 
 


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Signature of Authorized Representative for Adult: 
I give my consent for the person I am authorized to represent to take part in this research study 
and agree to allow his/her health information to be used and shared as described above. 
 
 
 
 
 
Print Name (check applicable box below) 
 Court-appointed Guardian 
 Health Care Proxy 
 Durable Power of Attorney 
 Family Member/Next-of-Kin 
 
 
 
 
 
Signature 
 
Date/Time 
 
If Family Member or Next-of-Kin, Describe Relationship to Subject: _____________________ 
 
 
Adult Assent 
Signature of Assenting Adult: 
I agree to take part in this research study and agree to allow my health information to be used 
and shared as described above. 
 
 
 
 
 
 
 
 
 
 
Printed Name of Assenting Adult 
 
 
 
 
 
Signature of Assenting Adult  
 
 
 
 
Date/Time 
 
 
Statement of Witness: 
I represent that the consent form was presented orally to the subject in the subject’s own 
language, that the subject was given the opportunity to ask questions, and that the subject has 
indicated his/her consent and authorization for participation by (check one box as applicable): 
 Making his/her mark above 
 Other means ______________________________________________________________ 
(fill in above) 
 
 
 
Printed Name of Witness 
 
 
 
 
 
Signature of Witness  
 
 
 
 
 
Date/Time 
 

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 6 BET-B: 
Lenzilumab/Remdesivir vs. Placebo/Remdesivir  
 
NCT04583969  
 
Version 3.0 
 
DATE: 23-MAY-2022 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
Appendix 6 BET-B 
23MAY2022 
- 2 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 20-0013 
Development Phase: 
Phase 2/3 
Products: 
Lenzilumab + Remdesivir 
IV Placebo + Remdesivir 
Form/Route: 
IV  
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: 
October 19, 2020 
Clinical Trial Estimated 
Completion Date: 
TBD 
Date of the Analysis Plan: 
May 23, 2022 
Version Number: 
3.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is 
confidential. This information may not be disclosed to third parties without written authorization from Division of Microbiology 
and Infectious Diseases. This report may not be reproduced, stored in a retrieval system or transmitted in any form or by any 
means - electronic, mechanical, recording or otherwise - without the prior authorization from Division of Microbiology and 
Infectious Diseases. This document must be returned to Division of Microbiology and Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
Appendix 6 BET-B 
23MAY2022 
- 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 ..........................................................................................10 
3.1.2.2. 
Other Secondary and Exploratory Objective(s) ..........................................................10 
3.1.2.3. 
Stage Specific Objective(s) .........................................................................................10 
3.2. 
Endpoints ....................................................................................................................10 
3.2.1. 
Primary Endpoint ........................................................................................................10 
3.2.2. 
Secondary Endpoints ..................................................................................................11 
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) .....................12 
4.4.4. 
Selection of Doses in the Study ..................................................................................12 
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 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
Appendix 6 BET-B 
23MAY2022 
Table of Contents (continued) 
 
- 4 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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 ...............................................................................................................19 
6.5.1. 
Multiple Imputation ....................................................................................................20 
6.5.1.1. 
Imputation Strategy for Subjects Lost to Follow-up with no Post-Baseline 
Data .............................................................................................................................20 
6.5.1.2. 
Imputation Strategy for Subjects Lost to Follow-up while Discharged .....................21 
6.5.1.3. 
Imputation Strategy for Subjects Lost to Follow-up while Hospitalized or 
Transferred ..................................................................................................................22 
6.5.2. 
Targeted Maximum Likelihood Method (TMLE) ......................................................26 
6.6. 
Interim Analyses and Data Monitoring ......................................................................30 
6.7. 
Multicenter Studies .....................................................................................................32 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................32 
7. 
STUDY SUBJECTS ...................................................................................................33 
7.1. 
Disposition of Subjects ...............................................................................................33 
7.2. 
Protocol Deviations ....................................................................................................33 
8. 
EFFICACY EVALUATION ......................................................................................34 
8.1. 
Primary Efficacy Analysis ..........................................................................................34 
8.1.1. 
Primary Analysis for the Primary Endpoint ...............................................................34 
8.1.2. 
Sensitivity Analysis for the Primary Endpoint ...........................................................35 
8.1.3. 
Secondary Analysis for the Primary Endpoint ...........................................................35 
8.2. 
Key Secondary Efficacy Analyses ..............................................................................38 
8.2.1. 
Time to Mechanical Ventilation or Death Up to and Including Day 29 for 
Primary Endpoint Subgroup and All Subjects in ITT Population ..............................38 
8.2.2. 
Time to Sustained Recovery Up to and Including Day 60 for Primary 
Endpoint Subgroup in the ITT Population ..................................................................39 
8.2.3. 
Survival without Mechanical Ventilation up to and Including Day 29 for All 
Subjects in the ITT and mITT Populations.................................................................40 


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8.2.4. 
Time to Sustained Recovery up to and including Day 60 for ITT Population ...........40 
8.3. 
Other Secondary Efficacy Analyses ...........................................................................40 
9. 
SAFETY EVALUATION ..........................................................................................41 
9.1. 
Demographic and Other Baseline Characteristics ......................................................41 
9.2. 
Measurements of Treatment Compliance ...................................................................41 
9.3. 
Adverse Events ...........................................................................................................41 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................41 
9.5. 
Pregnancies .................................................................................................................41 
9.6. 
Clinical Laboratory Evaluations .................................................................................41 
9.7. 
Vital Signs and Physical Evaluations .........................................................................41 
9.8. 
Concomitant Medications ...........................................................................................41 
9.9. 
Other Safety Measures ................................................................................................41 
10. 
PHARMACOKINETICS ...........................................................................................42 
11. 
IMMUNOGENICITY ................................................................................................43 
12. 
OTHER ANALYSES .................................................................................................44 
13. 
REPORTING CONVENTIONS ................................................................................45 
14. 
TECHNICAL DETAILS ............................................................................................46 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................47 
15.1. 
Changes from v1.0 to v2.0 of the BET-B SAP...........................................................47 
15.2. 
Changes from v2.0 to v3.0 of the BET-B SAP...........................................................47 
16. 
REFERENCES ...........................................................................................................48 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................49 
APPENDICES ...............................................................................................................................50 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................51 
APPENDIX 2. FIGURE MOCK-UPS ........................................................................................72 
 


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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 
TMLE 
Targeted Maximum Likelihood Estimate 
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 primary and key secondary endpoints that 
are specific to the BET-B study only. 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 
Concurrent with the implementation and enrollment of BET-B under the objectives described in Section 5 of 
the master SAP, the lenzilumab manufacturer, Humanigen, sponsored the LIVE-AIR, a phase 3 randomized, 
double-blind, placebo-controlled trial in hospitalized patients with COVID-19 with survival without 
ventilation as the primary endpoint. Based on the results from the LIVE-AIR trial (and with no knowledge of 
unblinded interim results from this trial), consideration was made to expanding BET-B from a phase 2 to a 
phase 2/3 trial to serve as a confirmatory pivotal trial. This could be accomplished with a larger sample size. 
These changes were implemented in version 5.0 of the protocol. 
3.1.1. 
Primary Objectives 
The primary objective for BET-B is to evaluate the clinical efficacy of lenzilumab as assessed by survival 
without invasive mechanical ventilation or ECMO through Day 29 in subjects who are < 85 years old with a 
baseline ordinal score 5 or 6 and a baseline CRP<150 mg/L. 
3.1.2. 
Secondary Objectives 
3.1.2.1. 
Key Secondary Objectives 
1. To evaluate the clinical efficacy of lenzilumab as assessed by time to mechanical ventilation or death 
through Day 29 in subjects < 85 years old with baseline clinical ordinal scores 5 or 6 and baseline 
CRP<150 mg/L. 
2. To evaluate the clinical efficacy of lenzilumab as assessed by time to sustained recovery in subjects 
who are < 85 years old with a baseline ordinal score 5 or 6 and a baseline CRP<150 mg/L. 
3. To evaluate the clinical efficacy of lenzilumab as assessed by survival without mechanical ventilation 
through Day 29. 
4. To evaluate the clinical efficacy of lenzilumab as assessed by time to sustained recovery. 
3.1.2.2. 
Other Secondary and Exploratory Objective(s) 
See the other secondary objectives listed in Section 3.1.2 and exploratory objectives listed in Section 3.1.3 of 
the master SAP. 
3.1.2.3. 
Stage Specific Objective(s) 
1. To evaluate lenzilumab pharmacokinetics (PK) in subjects with COVID-19. 
a. Measures: Serum samples for PK (at pre-dose, Day 5, Day 15, and Day 29). 
Details regarding this exploratory PK endpoint will be covered in a separate SAP addendum. 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
The primary endpoint for stage BET-B is whether the subject did not satisfy one of the following two 
categories from the ordinal scale up to and including Study Day 29: 
• Hospitalized, on invasive mechanical ventilation or ECMO (ordinal score 7); or 


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• Death (ordinal score 8).  
The analysis will only include subjects < 85 years old with a baseline ordinal score of 5 or 6 and baseline CRP 
< 150. 
3.2.2. 
Secondary Endpoints 
1. Time to mechanical ventilation or death up to and including Study Day 29 for subjects < 85 years old 
with baseline ordinal score of 5 or 6 and baseline CRP <150mg/L. That is time to a clinical status of:  
• Hospitalized, on invasive mechanical ventilation or ECMO (ordinal score 7); or 
• Death (ordinal score 8). 
2. Time to sustained recovery as defined as the first day on which the subject who is < 85 years old with 
baseline ordinal score of 5 or 6 and baseline CRP < 150 mg/L satisfies 1 of the following 3 categories 
from the clinical status ordinal scale (and does not return to a score of ≥ 4 up to and including Study 
Day 60): 
• Not hospitalized, no new or increased limitations on activities (ordinal score 1); 
• Not hospitalized, but new or increased limitation on activities and/or requiring new or increased 
home oxygen, CPAP, or BiPAP (ordinal score 2); 
• Hospitalized, not requiring new or increased supplemental oxygen - no longer requires ongoing 
medical care (ordinal score 3). 
3. Proportion of subjects at Day 29 that did not satisfy the following criteria up to and including Study 
Day 29: 
• For subject with baseline clinical status of 5 or 6:  
o Hospitalized, on invasive mechanical ventilation or ECMO (ordinal score 7); 
o Death (ordinal score 8); or 
• For subjects with baseline clinical status of 7: 
o Death (ordinal score 8). 
This is similar to the primary endpoint but will be analyzed including all subjects randomized to 
BET-B including any shared controls from other stages.  
4. Time to sustained recovery will be analyzed including all subjects randomized to BET-B including 
any shared controls from other stages. 
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 550 (275 Lenzilumab + RDV and 275 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.  
In addition to receiving remdesivir, subjects in the BET-B trial will be randomized to receive lenzilumab or 
placebo as follows:  
• Lenzilumab 600-mg IV infusion starting on Day 1 for a total of 3 doses.  
• Placebo will be given at an equal volume at the same schedule.  
4.4.2. 
Identity of Investigational Product(s) 
Refer to Section 6.1.1 of the Appendix B - BET-B protocol. 
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 are the US FDA approved doses. The duration of dosing may be adjusted by the site 
according to clinical severity. The maximum number of doses to be given during hospitalization is ten doses.  
This includes the loading dose and all maintenance doses given during the study and pre-study if applicable. 
For lenzilumab, the dosing strategy of 600 mg every 8 hours for three doses will be used. Previous studies 
using this dosing regimen have shown this regimen to maintain adequate lung tissue levels of lenzilumab for 


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at least seven days and did not show any evidence of an increase in infections or development of pulmonary 
alveolar proteinosis (PAP). 
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. 
Lenzilumab will be administered as a 600-mg IV infusion starting on Day 1 for a total of 3 doses. 
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 3 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 
The LIVE-AIR trial estimated a HR of about 1.5 in its overall population, and a HR of above 3 in the 
identified subgroup. The corresponding relative risks for the primary endpoint were in the 2.5 or 2.6 range, 
and the corresponding odds ratios were around 3. Because the treatment effect in the post hoc subgroup may 
be overly optimistic, the BET-B updated sample size assumes an intermediate odds ratio of 2.5 for the 
subgroup. The LIVE-AIR trial also observed a 21% event rate in the placebo group in the subgroup, which is 
likely higher than expected in this trial.  
A sample size of 400 in the subgroup will yield 80% power if the control event rate is 16% and 89% power if 
the control rate is 21%, if the odds ratio is 2.5 and a two-sided alpha=.049. (An odds ratio of 2.5 is defined 
such that if the control event rate is 16%, the treated rate would be 7%.) At most 550 participants (that is, 
subjects randomized into BET-B and relevant shared controls) will be randomized. Based on early BET 
baseline estimates, roughly 75% of subjects are expected to fall in the primary analysis subgroup at baseline 
(CRP<150mg/L, age<85, and baseline ordinal score < 7). The trial will enroll subjects until 400 are 
randomized in the subgroup or 550 overall, whatever comes first. These calculations are not inflated for 
missing data, as little missing data are expected. 


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Several statistical features were modified at the time BET-B was changed to a Phase 2/3 design including an 
increase in sample size, change to the primary endpoint, and new futility analysis. Refer to Section 6.1 of the 
master SAP for additional details of general principles applied in this study. Some of the deviations from the 
main SAP are noted below: 
• The Day 8 ordinal score will be analyzed without multiple imputation.  
• The primary endpoint of progression to mechanical ventilation or death will be analyzed using 
multiple imputation for missing event using the pseudocode provided in Section 6.5. After imputation, 
odds ratio and risk difference can be obtained using the following pseudocode: 
6.2. 
Timing of Analyses 
See Section 6.2.1 of the master SAP. An additional futility analysis will take place after approximately 280 
subjects eligible for the primary analysis subgroup have been enrolled and randomized. 
6.3. 
Analysis Populations 
The primary analysis will be based on the intention-to-treat (ITT) population, including all subjects who were 
randomized and will use randomized arm. The primary analysis and key secondary endpoints will be repeated 
using the mITT analysis population which includes all randomized subjects who received at least one dose of 
study product and is analyzed as randomized. Safety analyses will be based on the safety population and will 
use actual treatment received. An enrolled population will include all consented participants and will be used 
to compute disposition, baseline characteristics, and similar summaries based on randomized treatment group. 
For all populations, actual ordinal score at baseline will be used to classify subjects into baseline ordinal score 
category.  
See Section 6.3.1 through Section 6.3.4 of the master SAP for full definitions of analyses populations to be 
used for this stage. 
6.4. 
Covariates and Subgroups 
The primary analysis of survival without mechanical ventilation uses baseline ordinal score, baseline CRP, 
age, and baseline dexamethasone use as covariates in the logistic regression model. This primary analysis will 
be repeated for the following subgroups: severity of disease, baseline steroid use, baseline use of emerging 
COVID-19 treatments, duration of symptoms, race, comorbidities (binary 2+ vs less than or equal to 1), age, 
baseline CRP, and sex. Table 1 provides details of covariates to be used for all analyses of primary, secondary 
or exploratory endpoints. 


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Table 1: 
Covariates and Subgroup Analyses for Each Endpoint 
Endpoint 
Analysis 
Covariates/Subgroups 
Primary Endpoint 
Survival without mechanical 
ventilation in subjects who 
are < 85 years old, have 
baseline clinical status of 5 
or 6, and baseline CRP < 
150 mg/L. 
[Note: baseline CRP must 
be available for inclusion in 
this analysis.] 
Primary and main 
sensitivity analysis 
1. 
Adjust for the following covariates in the ITT Population 
• 
Baseline dexamethasone use 
• 
Actual baseline ordinal score  
• 
Baseline CRP (continuous) 
• 
Age (continuous) 
Additional sensitivity 
1. 
Repeat primary analysis with the following covariates in the ITT Population: 
• 
Baseline dexamethasone use 
• 
Actual baseline ordinal score  
• 
Baseline CRP (continuous) 
• 
Age (categorical)  
• 
Geographical regions 
2. 
Repeat primary analysis on mITT population using actual baseline ordinal 
score and adjusting for the following covariates: 
• 
Baseline dexamethasone use 
• 
Actual baseline ordinal score  
• 
Baseline CRP (continuous) 
• 
Age (continuous) 
3. 
Repeat primary analysis on mITT population adjusting for the following 
covariates: 
• 
Baseline dexamethasone use 
• 
Actual baseline ordinal score  
• 
Baseline CRP (continuous) 
• 
Age (categorical) 
• 
Geographical regions 
Subgroup 
Repeat the primary analysis for this endpoint within each of the following 
subgroups using the ITT population:  
• 
Actual baseline ordinal score  
• 
Baseline steroid use  
• 
Baseline use of emerging COVID-19 treatments   
• 
Duration of symptoms prior to enrollment  
• 
Race 
• 
Ethnicity 
• 
Comorbidities  
• 
Age (categorical) 
• 
Sex 
• 
Baseline CRP (≤ median, >median) 
• 
Baseline CRP (<150, ≥150) 
Baseline dexamethasone use, baseline CRP (continuous), age (continuous), and 
baseline ordinal score will be included in the subgroup analysis as covariates 
unless the covariate is the subgroup. 


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Endpoint 
Analysis 
Covariates/Subgroups 
Key Secondary Endpoints  
[Note: All key secondary endpoint analyses in the ITT population will be repeated in the mITT population.] 
1. 
Time to mechanical 
ventilation or death up 
to and including Day 
29 in subjects who are 
< 85 years old, have 
baseline clinical status 
of 5 or 6, and baseline 
CRP < 150 mg/L.  
[Note: baseline CRP 
must be available for 
inclusion in this 
analysis.] 
Primary 
1. 
Adjust for the following covariates using ITT population: 
• 
Baseline Dexamethasone use 
• 
Actual baseline ordinal score  
• 
Baseline CRP (continuous) 
• 
Age (continuous) 
Subgroup 
Repeat the primary analysis for this endpoint within each of the following 
subgroups using the ITT population:  
• 
Actual baseline ordinal score  
• 
Baseline use of emerging COVID-19 treatments   
• 
Duration of symptoms prior to enrollment  
• 
Race 
• 
Ethnicity 
• 
Comorbidities  
• 
Age (categorical) 
• 
Sex 
• 
Baseline CRP (≤ median, >median)  
• 
Baseline CRP (<150, ≥150) 
Baseline dexamethasone use, baseline CRP (continuous), age (continuous), and 
baseline ordinal score will be included in the subgroup analysis as covariates 
unless the covariate is the subgroup. 
2. 
Time to Sustained 
Recovery up to Day 60 
in subjects who are < 
85 years old, have 
baseline clinical status 
of 5 or 6, and baseline 
CRP < 150 mg/L. 
Primary 
1. 
Adjust for the following covariates using ITT population: 
• 
Baseline Dexamethasone use 
• 
Actual baseline ordinal score 
• 
Baseline CRP (continuous) 
• 
Age (continuous)  
Supplementary 
1. 
Adjust for the following covariates using ITT population: 
• 
Baseline Dexamethasone use 
• 
Actual baseline ordinal score  
• 
Age (continuous) 
• 
Duration of symptoms prior to enrollment (continuous) 
Subgroup 
Repeat the primary analysis for this endpoint within each of the following 
subgroups: 
• 
Actual baseline ordinal score  
• 
Baseline steroid use   
• 
Baseline use of emerging COVID-19 treatments   
• 
Duration of symptoms prior to enrollment  
• 
Race 
• 
Ethnicity 
• 
Comorbidities  
• 
Age (categorical) 
• 
Sex 
• 
Baseline CRP (≤ median, >median)  
• 
Baseline CRP (<150, ≥150) 


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Endpoint 
Analysis 
Covariates/Subgroups 
Baseline dexamethasone use, and baseline ordinal score, baseline CRP, and age 
will be included in the subgroup analysis as covariates unless the covariate is the 
subgroup. 
3. 
Survival without 
invasive mechanical 
ventilation/ECMO for 
all subjects in ITT 
population 
Primary 
1.Adjust for the following covariates 
• 
Baseline Dexamethasone use 
• 
Actual baseline ordinal score  
• 
Baseline CRP (continuous) 
• 
Age (continuous) 
Sensitivity 
1. Repeat primary analysis with the following covariates: 
• 
Baseline Dexamethasone use 
• 
Actual baseline ordinal score  
• 
Baseline CRP (continuous) 
• 
Age (categorical)  
• 
Geographic regions (categorical)  
Subgroup   
Repeat the primary analysis for this endpoint within each of the following 
subgroups using the ITT population:  
• 
Actual baseline ordinal score  
• 
Baseline use of emerging COVID-19 treatments   
• 
Duration of symptoms prior to enrollment  
• 
Race 
• 
Ethnicity 
• 
Comorbidities  
• 
Age (categorical) 
• 
Sex 
• 
Baseline CRP (≤ median, >median)  
• 
Baseline CRP (<150, ≥150) 
Baseline dexamethasone use, baseline CRP (continuous), age (continuous), and 
baseline ordinal score will be included in the subgroup analysis as covariates 
unless the covariate is the subgroup. 
4. 
Time to Sustained 
Recovery up to Day 60 
for all subjects in ITT 
population 
Primary 
Adjust for the following covariates using ITT population: 
• 
Baseline Dexamethasone use 
• 
Actual baseline ordinal score   
• 
Baseline CRP (continuous) 
• 
Age (continuous)  
Supplementary 
Repeat the primary analysis adjusting for the following covariates: 
• 
Baseline Dexamethasone use 
• 
Actual baseline ordinal score   
• 
Baseline CRP (continuous) 
• 
Age (continuous) 
• 
Duration of symptoms prior to enrollment (continuous) 
Subgroup 
Repeat the primary analysis for this endpoint within each of the following 
subgroups: 
• 
Actual baseline ordinal score  
• 
Baseline steroid use   
• 
Baseline use of emerging COVID-19 treatments   
• 
Duration of symptoms prior to enrollment  


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Endpoint 
Analysis 
Covariates/Subgroups 
• 
Race 
• 
Ethnicity 
• 
Comorbidities  
• 
Age (categorical) 
• 
Sex 
• 
Baseline CRP (≤ median, >median)  
• 
Baseline CRP (<150, ≥150) 
Baseline dexamethasone use, baseline ordinal score, baseline CRP (continuous), 
and age (continuous) will be included in the subgroup analysis as covariates 
unless the covariate is the subgroup. 
Other Secondary Endpoints and Exploratory Endpoints 
The analysis described for the other secondary efficacy and safety endpoints and exploratory endpoints in the Master SAP will be followed. 
Refer to Table 6 in the master SAP for addition details regarding covariates and subgroups to be used for those endpoints.  
6.5. 
Missing Data 
For the primary endpoint of incidence of mechanical ventilation or death, subjects who are lost to follow-up 
before Day 29 prior to having an event and have their last assessment within window for Day 29 (i.e., Day 26, 
27, 28) will be considered as non-events by Day 29 regardless of their discharge status at that time. 
Remaining missing data for subjects lost to follow-up after discharge, while still hospitalized, or with no post 
baseline data will be imputed using multiple imputation. The main sensitivity analysis will consider subjects 
missing data while discharged as non-events and use a similar multiple imputation as the primary analysis for 
remaining missingness. Additional sensitivity analyses of the primary endpoint will use the same imputation 
approach as the primary analysis on different analysis populations and using different covariates in the final 
model.  
Two secondary analyses of the primary endpoint will be conducted: the first is based on targeted maximum 
likelihood estimation (TMLE), and the second is a multiple imputation approach that uses TMLE for analysis 
of each imputed dataset. These approaches are described in Section 6.5.2. 
Analysis of time to event endpoints (i.e., sustained recovery, time to improvement, time to mechanical 
ventilation or death) will be based on observed ordinal score along with discharge and death information. 
Refer to Table 2 for additional details regarding censoring and handling of missing data for all endpoints. 
 Some analyses of ordinal score such as ordinal scores over time described in Section 6.5.1 of the master SAP 
will be performed based on the complete dataset of ordinal score created using the following steps: 
• All planned timepoints after death are assigned a score of 8 
• Intermittent missingness: 
o Impute the intermittent missing ordinal score as 1 if the scores reported before and after the 
missing value are both 1 and no change in oxygen use or hospitalization status after discharge to a 
location other than hospice, long term acute care or other hospital. 
o Impute the intermittent missing ordinal score as 2 after discharge to a location other than hospice, 
long term acute care or other hospital if the subject doesn’t fall into the category above and subject 
is not hospitalized at the time point. 
o Remaining intermittently missing data imputed using last observation carried forward. 


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• All remaining missing ordinal scores after last assessment imputed using last observation carried 
forward.  
6.5.1. 
Multiple Imputation 
The multiple imputation approach will classify subjects with missing event into 3 categories as listed below 
and will apply different imputation models for each as detailed in this section. 
6.5.1.1. 
Imputation Strategy for Subjects Lost to Follow-up with no Post-Baseline Data 
This group includes subjects randomized but who withdrew from the study soon after randomization without 
any post-baseline data. Missing incidence of mechanical ventilation or death data for these subjects will be 
imputed using multiple imputation model implemented using PROC MI procedure in SAS based on the 
monotone logistic regression model. The imputation model will include the following covariates: Randomized 
treatment group (trtvar), baseline dexamethasone use (basedexafl), actual baseline ordinal score 
(baseordscorevar), age, indicator for black or Hispanic ethnicity (blackhispfl), presence of 2 or more 
comorbidities (comorb2fl), and baseline CRP (basecrp). 
Since missing data in any of these baseline characteristics may cause issues with the monotone missing data 
patterns, the following methods will be used to fill in missing baseline covariates data: 
• For continuous baseline covariates (age, CRP), mean imputation will be used to replace missing values 
with the overall mean value from all randomized subjects for the given covariate. Note that there will 
not be any missing data for age and baseline CRP for subjects in the primary subgroup, but there will 
be some missingness in either of these variables for some of the subjects in the full ITT population. 
• For indicator variables of baseline dexamethasone use, black or Hispanic ethnicity, presence or two or 
more comorbidities, subjects with missing values will be given the value with the greatest number of 
subjects among all randomized subjects. 
• We do not anticipate any missing data for actual baseline ordinal score. 
In the case that more than 1% of subjects have missing baseline covariates and the overall p-value for the 
primary endpoint is < 0.1, a sensitivity analysis will be performed that uses a fully conditional specification 
(FCS) to impute missing baseline covariates.  This is implemented by replacing the monotone logistic line 
in the PROC MI pseudocode shown below with the following line: 
 
fcs logistic(eventD29= trtvar baseordscorevar basedexausevar age blackhispfl comorb2fl 
basecrp ); 
For most of the modeling, the reference group for categorical variables will be ‘No’ for indicator variables, 
‘Placebo + RDV’ for treatment group, and ‘6 or 7’ for actual baseline ordinal score. As an exception, analyses 
based on the primary subgroup will use ordinal score '6' as the reference group for actual baseline ordinal 
score. 
Pseudocode: 
• DEFINE eventD29 as the binary variable for death or progression to mechanical ventilation or death 
by Day 29 (1=Yes, 0=No, .=Missing)  
• DEFINE input1 as the full analysis dataset containing all baseline covariates and event indicator for 
complete data subjects as well as subjects with no post-baseline data with missing event indicator to be 
imputed.  


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• DEFINE imp_out1 as the output dataset containing the 20 imputed datasets  
  
 
proc mi data=input1  out= imp_out1 nimpute=20 seed = 837405 noprint; 
class trtvar baseordscorevar basedexausefl blackhispfl comorb2fl eventD29;  
var trtvar baseordscorevar basedexausefl age blackhispfl comorb2fl basecrp eventD29; 
monotone logistic(eventD29= trtvar baseordscorevar basedexausevar age blackhispfl 
comorb2fl basecrp ); 
run; 
 
The above procedure will output imp_out1 dataset which contains 20 replicates for each subject. Update the 
dataset to remove subjects with complete data and only keep the 20 imputed datasets for subjects with no 
post-baseline data. 
6.5.1.2. 
Imputation Strategy for Subjects Lost to Follow-up while Discharged  
This group includes subjects with post-baseline data available who were lost to follow-up or terminated early 
from the study prior to Day 29 and prior to death or progression to mechanical ventilation and were 
discharged to a location other than LTAC, hospice care or other hospital at the time of their last assessment. 
Imputation Approach if Less than 10 Events are Observed 
If, as expected, less than 10 post-discharge events are observed in the discharged group, missing incidence of 
mechanical ventilation or death data for these subjects will be imputed from a simple binomial distribution 
with the event rate calculated as the proportion of discharged subjects with known outcome (i.e., discharged 
to a location other than LTAC, hospice care or other hospital) who died or progressed to mechanical 
ventilation after discharge, without adjusting for any covariates in this group.   
If no event is observed in a given analysis such as in subgroup analyses, the event rate of 0.5/total number of 
discharged subjects with outcome in the subgroup will be used instead of 0. 
Pseudocode: 
• DEFINE eventD29 as the binary variable for death or progression to mechanical ventilation or death 
by Day 29 (1=Yes, 0=No, .=Missing)  
• DEFINE input2 as the analysis dataset containing discharged subjects with missing event.    
• Define evntrate as the event rate among subjects discharged to a location other than LTAC, hospice 
care or other hospital who have known outcome. 
• DEFINE imp_out2 as the output dataset containing the 20 imputed datasets 
  data imp_out2; 
set input2;  
subid=input(substr(usubjid,5,4),best12.); 
seed=3849+subid; 
call streaminit(seed); 
p=&evntrate; 
do i=1 to 20; 
_imputation_ = i;  
 
eventd29=rand("Binomial",p,1);  
output; 
end; 
drop p i; 
run; 


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imp_out2 contains 20 imputed values for each subject discharged to a location other than LTAC, hospice care 
or other hospital who had missing event. 
Imputation Approach if 10 Events or More are Observed 
In the case that 10 post-discharge events or more are observed in this group of discharged subjects, missing 
events will be imputed using PROC MI adjusting for baseline ordinal score as shown in the below 
pseudocode.  
Pseudocode: 
• DEFINE input2 as the analysis dataset containing all discharged subjects including those with missing 
event to be imputed and those with known outcome.    
 
proc mi data=input2 out= imp_out2 nimpute=20 seed = 748485 noprint; 
class baseordscorevar eventD29;  
var eventD29; 
monotone logistic(eventD29= baseordscorevar); 
run; 
6.5.1.3. 
Imputation Strategy for Subjects Lost to Follow-up while Hospitalized or Transferred 
This group includes subjects with post-baseline data available who were lost to follow-up or terminated early 
from the study prior to Day 29 and prior to death or progression to mechanical ventilation and were still 
hospitalized or discharged to LTAC, hospice care or other hospital at the time of their last assessment.  
Missing incidence of mechanical ventilation or death data for these subjects will be imputed using the 
algorithm described below that takes into account each subject’s baseline covariates and time of last 
assessment. For each of these subjects with missing event, the first step will be to estimate the probability of 
having an event between their last assessment date and Day 29 which will be estimated from a Cox model as 
described below: 
Step 1: Define a dataset including all subjects regardless of missingness except those that have no post 
baseline data. For all subjects who terminated early without event, consider them as non-events and censor 
them at the time of last assessment.  
Step 2: Fit a Cox proportional hazards model for all subjects in step 1 using the following covariates: 
randomized treatment group (trtvar), baseline dexamethasone use (basedexavar), baseline actual ordinal score 
(baseordscorevar), age, indicator for black or Hispanic ethnicity (blackhispfl), presence of 2 or more 
comorbidities(comorb2fl), and baseline CRP (basecrp). The resulting Cox proportional hazards model will be 
of this form: 
ℎ(𝑡) = ℎ0(𝑡)exp⁡(𝑏1𝑋1 + 𝑏2𝑋2 + ⋯+ 𝑏𝑝𝑋𝑝) 
where  
ℎ(𝑡): Expected hazard at time t. 
ℎ0(𝑡): Baseline hazard function and represent the hazard when all the covariates are zero. 
𝑋1, 𝑋2, … , 𝑋𝑝 : Covariates in the cox model 
𝑏1, 𝑏2, … , 𝑏𝑝 : Model coefficients. 
Pseudocode: 


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• aval: time variable. All subjects except those with no post-baseline data are included. Subjects missing 
endpoint are censored at their last assessment day in this cox model. 
• cnsr: Event indicator variable (1=No event, 0=event). Subjects with missing outcome are censored. 
• Subjects_miss: Dataset with subjects lost to follow-up while discharged or transferred whose endpoint 
needs to be imputed.  
• Outset: Output dataset containing survival estimates for all subjects in subject_miss dataset given their 
covariates for all timepoints specified in timelist.  
proc phreg data = analysis;  
class trtvar (ref = "Placebo + RDV") basedexavar(ref="No"); baseordscorevar (ref="5") 
blackhispfl(ref="No") comorb2fl(ref="No"); 
model aval * cnsr(1) = trtvar basedexavar baseordscorevar blackhispfl comorb2fl basecrp 
age / ties=efron; 
baseline out = outset survival = survival covariates=subjects_miss timelist=1 to 29 by 1 
/ method = emp; 
run;  
 
Step 3: For each subject to be imputed (i.e., those lost to follow-up while hospitalized/transferred), estimate 
the survival probability at their last assessment (SL) and the survival probability at Day 29 (S29). Then, the 
probability that this subject will have an event between their last assessment day and Day 29 is given by: 
Pe = Prob (Event by Day 29|no event through last assessment) = 1 – S29/SL 
Step 4: For each subject lost to follow-up while discharged or transferred to another hospital, impute the 
event from a binomial distribution using the event probability calculated in Step 3. 
Pseudocode:  
• DEFINE eventD29 as the binary variable for death or progression to mechanical ventilation or death 
by Day 29 (1=Yes, 0=No, .=Missing)  
• DEFINE input3 as the analysis dataset containing subjects lost to follow-up while hospitalized or 
transferred with missing event. Add the variable for the probability of an event between last 
assessment and Day 29 (pe) calculated in step 3 to the dataset for subjects with missing data to be 
imputed.  
• DEFINE imp_out2 as the output dataset containing the 20 imputed datasets 
  
 
data imp_out3; 
set input3; 
subid=input(substr(usubjid,5,4),best12.); 
seed=7564+subid; 
call streaminit(seed); 
p=&pe.; 
do i=1 to 20; 
_imputation_ = i;  
 
eventd29=rand("Binomial",p,1);  
output; 
end;   
drop p I ; 
run; 


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imp_out3 will have 20 imputed values for each subject who was lost to follow-up while hospitalized or 
transferred and had missing event. 
 
Combine the 3 output datasets from the three different imputations. 
 
data imp_out_all; 
 
set imp_out1 imp_out2 imp_out3;  
run; 
 
Create 20 replicates for each subject with non-missing event: 
  data complete_all; 
set complete;  
do i=1 to 20; 
_imputation_ = i;  
output; 
end; 
drop  i; 
run; 
The final dataset to be used for analysis will be created by combined imputed data and complete data: 
 
data imp_out; 
 
set imp_out_all complete; 
 
proc sort; by subject_imputation_; 
run; 
 
Using this imp_out dataset, calculate odds ratio follow: 
Odds ratios from logistic regression using multiple imputation: 
 
proc logistic data=imp_out out=imp_parms; 
 
by _imputation_; 
  
class baseordscorevar (param=ref ref=5) basedexausevar (param=ref ref=no steroid 
use) trtvar (param=ref ref=placebolabel); 
 
 model eventd29 (eventd29=’1’) = trtvar baseordscorevar basedexausevar age 
baseCRP; 
ods output oddsratioswald = orest parameterestimates=pars;   
run; 
 
*Keep only estimates for the treatment variable; 
data pars1;set pars;where Variable='Treatment variable';run; 
*Combine estimates; 
PROC MIANALYZE DATA=pars1;  
 
ODS OUTPUT PARAMETERESTIMATES= logor;  
 
MODELEFFECTS estimate ;  
 
STDERR stderr ;  
RUN;  
*Transform estimates from the log(OR) scale to the OR scale; 
data OR;  
  
SET logor;  
 
OR_estimate = EXP(ESTIMATE);  


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OR_LCL_95 =OR_estimate*EXP(-1.96*STDERR);  
 
OR_UCL_95 =OR_estimate*EXP(+1.96*STDERR);  
OR_LCL_80 =OR_estimate*EXP(-1.28*STDERR);  
 
OR_UCL_80 =OR_estimate*EXP(+1.28*STDERR);  
 
RUN;run; 
 
To estimate risk differences from logistic regression, the approach from Ge et. al [1] as described below: 
  
proc logistic data = dataset outmodel=pout; 
 
class trtvar ; 
 
model surv(event=’1’) = trtvar othercovariates  ; 
run; 
 
*Create dataset tempa to contain all subjects and assign them the active Lenzilumab + 
RDV and dataset tempp which include all subjects assigned the placebo treatment; 
 
proc logistic inmodel=pout; 
  score data = tempa out=preda(keep=id P_a rename= (P_1=P_a))) ; 
run; 
 
proc logistic inmodel=pout; 
  score data = tempp out=predp(keep=id P_1 rename= (P_1=P_p)) ; 
run; 
  
proc sort data=preda;by subjectid;run; 
proc sort data=predp;by subjectid;run; 
 
*Combine to obtain risk differences in probabilities for each subject; 
 
data comb; 
 
merge predp preda; 
 
by subjectid; 
 
diff=P_a-P_p; 
run; 
 
proc means data=comb; var diff; run; 
To obtain the CI for the risk difference, use bootstrap with the following steps: 
1. Sample with replacement from the dataset. 
2. Obtain risk difference estimate for each bootstrap sample. 
3. Repeat this step the above step 1000 times and use the 2.5th and 97.5th percentiles of the risk 
estimates as the limits for the 95% CI for the risk difference. The risk difference from bootstrap should 
be equal to the risk difference obtained prior to performing bootstrap.  
To generate bootstrap CI for risk difference using multiple imputation, repeat steps 1 and 2 for each imputed 
dataset. The final risk difference will be calculated as the mean risk difference across all imputed datasets, and 
the 95% CI will be obtained as the 2.5th and 97.5th percentile of risk difference estimates across all imputed 
datasets and bootstrap samples [2].  


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6.5.2. 
Targeted Maximum Likelihood Method (TMLE) 
Missingness in the outcome is easily accounted for in the estimation procedure of TMLE using the missing 
indicator as shown in the below pseudocode provided that only baseline covariate and treatment information 
is used in the adjustment for missing data. Because of this requirement, we consider two approaches:  
First approach: 
The first approach uses TMLE with only baseline covariates to adjust for missing data and does not make use 
of discharge or transfer data for this adjustment. All subjects missing outcome data due to being terminated 
early from the study or being lost to follow-up before having an event and before Day 29 will be considered 
as having a missing outcome data and be imputed using the missing indicator in TMLE.  
Second approach: 
The second uses a multiple imputation approach that, as in the multiple imputation analyses described in 
Section 6.5.1, does make use of the discharge and transfer data. TMLE is used to analyze the individual 
imputed data sets. Standard methods are then used to combine across results across the imputed data sets. We 
note that this approach cannot be considered formally to be a TMLE analysis. The reason for the second 
approach is to assess the impact of not using the post-baseline data in the first approach. 
Assumptions for the second approach:  
• Discharged subjects missing event will be considered non-events. 
• For participants who are censored while hospitalized or after transfer, the multiple imputation 
approach described in Section 6.5.1.3 will be used. 
• Event for subjects with no post-baseline data will be missing and handled using TMLE  
Each imputed dataset will be analyzed using TMLE. For patients with no post-baseline follow-up, no 
imputation is required. We will use the feature in TMLE that permits use of baseline data as part of 
adjustment for these patients. 
The estimates of treatment effects , 𝜃,̂⁡are obtained by taking the mean of risk difference estimates across 
imputations. The variance of these estimates is estimated by the sum of the average variances of estimates 
within each imputation and (m+1)/m multiplied by the empirical variance across of the estimates of interest 
across imputations, where m is the number of imputations. 
The within imputation variance, 𝑉𝑊, is the average variance of risk difference estimates within each 
imputation and is calculated as:𝑉𝑊=
1
𝑚⁡⁡∑
𝑆𝐸
𝑚
𝑖=1
2 
The between imputation variance, 𝑉𝐵, reflects the extra variance due to imputation and is obtained by 
taking the variance of risk difference over imputed datasetsis the average variance of risk difference estimates 
within each imputation and is calculated as:⁡𝑉𝐵=
1
𝑚−1⁡⁡∑
(𝜃̂ −𝜃𝑖)
𝑚
𝑖=1
2 where 
 𝜃̂⁡is the overall mean estimate for risk difference 
 𝜃𝑖 is the risk difference estimate for each imputed dataset. 
The total variance, 𝑽𝑩, is then calculated as: 𝑉𝑇=⁡⁡𝑉𝑊+⁡
(𝑚+1)
⁡𝑚
𝑉𝐵 
The 95% CI for risk difference can then be obtained by ( 𝜃̂ −1.96√𝑉𝑇, 𝜃̂ −1.96√𝑉𝑇 ) 


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The same approach will be followed for combining odds ratio estimates from TMLE version with MI and 
their 95% CI. First, odds ratio will first be transformed on the log scale before calculating the mean log-OR 
(mlog_OR) and total variance for for log (OR) (VlogORT ). The final OR estimate is then obtained as  
𝑂𝑅= exp(𝑚𝑙𝑜𝑔𝑂𝑅)  and the 95% CI is obtained as (𝑂𝑅∗exp⁡(−1.96 ∗√VlogORT⁡ , 𝑂𝑅∗exp⁡(1.96 ∗
√VlogORT⁡) 
These estimates can also be obtained in SAS for risk difference and ORs as shown below: 
Pseudocode in SAS: 
Risk difference calculation in SAS after TMLE: 
1. Combine transformed estimates from multiple imputed datasets; 
• rd_t is a dataset that has columns for imputation number, risk difference estimates and standard 
error for risk difference calculated from each imputation dataset 
• comb_rd_t contains the  final combined estimates and standard errors for risk difference 
 
PROC MIANALYZE DATA=rd_t;  
ODS OUTPUT PARAMETERESTIMATES= comb_rd_t;  
MODELEFFECTS rd_value ; #risk difference estimates; 
STDERR rd_se; ; #risk difference standard error; 
RUN;  
2. Back-transform combined values to obtain final estimate and 95% CI;  
DATA comb_rd_bt; 
  
SET comb_rd_t;  
RD_Estimate = ESTIMATE; *Pooled risk difference;  
RD_LCL =ESTIMATE -1.96*STDERR; *Pooled lower limit; 
 RD_UCL =ESTIMATE +1.96*STDERR; *Pooled upper limit;  
RUN; 
Odds ratio calculation in SAS after TMLE: 
3. Combine transformed estimates from multiple imputed datasets; 
• logsodds_t is a dataset that has columns for imputation number, log(OR) estimates and standard 
error for log(OR) calculated from each imputation dataset 
• comb_logsodds_t contains the  final combined estimates and standard errors for log (OR) 
PROC MIANALYZE DATA=logsodds_t;  
ODS OUTPUT PARAMETERESTIMATES= comb_logsodds_t;  
MODELEFFECTS log_or_value ; #log_OR estimates; 
STDERR log_or_se; ; #log_OR standard error; 
RUN;  
4. Back-transform combined values to obtain final estimate for OR  and its 95% CI; 
DATA comb_lgsodds_bt; 
  
SET comb_logsodds_t;  
OR_estimate = EXP(ESTIMATE); *Pooled odds ratio;  
OR_LCL =OR_estimate*EXP(-1.96*STDERR); *Pooled lower limit; 


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OR_UCL =OR_estimate*EXP(+1.96*STDERR); *Pooled upper limit;  
RUN; 
For both of these approaches, TMLE will be implemented using the tmle R package (https://cran.r-
project.org/web/packages/tmle/index.html). For the second approach of TMLE that includes MI, final 
estimates will be combined across the different imputation datasets using either SAS pseudocode provided 
above or using formulas provides in either R or SAS. 
Pseudo code: 
Y = binary outcome variable (that can include missing values) 
trt = treatment information coded as 0, 1 
BaselineCov = Dataframe of baseline covariates (numerical) of each 
patient. 
MissingIndicator = Vector with 1 indicating that outcome was missing, 0 
otherwise 
SL.library = c("SL.glm", "SL.gam", "SL.glmnet")  
 
tmResult = tmle(Y = Y, A = trt, Delta = MissingIndicator, W = 
BaselineCov, family = "binomial", Q.SL.library  = SL.library, 
g.SL.library = SL.library, Delta.SL.library = SL.library) 
 
 


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Table 2: 
Imputation Method for Each Endpoint and Analysis Type 
Endpoint 
Analysis 
Imputation/Censoring Method 
Primary Endpoint 
Survival without 
mechanical ventilation in 
subjects who are < 85 
years old, have baseline 
clinical status of 5 or 6, 
and baseline CRP < 150 
mg/L. 
Primary, additional 
sensitivity and subgroup 
• 
Subjects who complete follow-up without mechanical ventilation or death 
or who have the event after Day 29 will be considered non-events. 
• 
Subjects who die or progress to mechanical ventilation after Day 29 will be 
considered non-events.  
• 
Subjects whose last assessment in the study is before Day 29 and before 
experiencing death or progression to mechanical ventilation will have 
missing event data for this endpoint and multiple imputation will be used to 
impute the missing data. See Section 6.5 for details. 
• 
Subjects whose last assessment in the study is before Day 29 but within 
window for Day 29 (i.e., Day 26, 27, 28) and before experiencing death or 
progression to mechanical ventilation will be considered non-events 
regardless of their discharge status. 
Sensitivity 1 
• 
Subjects who complete follow-up without mechanical ventilation or death 
or who have the event after Day 29 will be considered non-events. 
• 
Subjects who die or progress to mechanical ventilation after Day 29 will be 
considered non-events.  
• 
Subjects whose last assessment in the study is before Day 29 and before 
experiencing death or progression to mechanical ventilation and were 
discharged to a location other than LTAC, hospice care, or other hospital 
will be considered non-events. 
• 
Subjects whose last assessment in the study is before Day 29 and before 
experiencing death or progression to mechanical ventilation and either had 
no post-baseline data or were still hospitalized or were discharged to 
LTAC, hospice care, or other hospital will have missing event data for this 
endpoint and multiple imputation will be used to impute the missing data. 
See Section 6.5 for details. 
• 
Subjects whose last assessment in the study is before Day 29 but within 
window for Day 29 (i.e., Day 26, 27, 28) and before experiencing death or 
progression to mechanical ventilation will be considered non-events 
regardless of their discharge status. 
Sensitivity 2 
• 
Subjects who complete follow-up without mechanical ventilation or death 
or who have the event after Day 29 will be considered non-events. 
• 
Subjects who die or progress to mechanical ventilation after Day 29 will be 
considered non-events.  
• 
Subjects whose last assessment in the study is before Day 29 and before 
experiencing death or progression to mechanical ventilation will have 
missing event data for this endpoint and multiple imputation will be used to 
impute the missing data. See Section 6.5 for details. 
• 
Subjects whose last assessment in the study is before Day 29 but within 
window for Day 29 (i.e., Day 26, 27, 28) and before experiencing death or 
progression to mechanical ventilation will be considered missing and 
imputed using multiple imputation as described in Section 6.5. 
Key Secondary Endpoints 
Time to mechanical 
ventilation or death up to 
and including Day 29 in 
subjects who are < 85 
years old, have baseline 
clinical status of 5 or 6, 
and baseline CRP < 150 
Primary and subgroup 
• 
Use the complete data for ordinal score to define survival without 
mechanical ventilation. 
• 
All subjects whose last assessment in the study is before Day 29 and before 
progression to mechanical ventilation or death will be considered non-
events and censored at the date of their last observed assessment. 
• 
Subjects who complete follow-up without mechanical ventilation or death 
will be censored at the expected study Day 29.  


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Endpoint 
Analysis 
Imputation/Censoring Method 
mg/L. 
Sensitivity 
• 
Use the complete data for ordinal score to define survival without 
respiratory failure. 
• 
Subjects whose last assessment in the study is before Day 29 and were 
discharged to a location other than LTAC, hospice care or other hospital, or 
progressed to mechanical ventilation or death after Day 29 will be 
considered non-events and censored at Day 29. 
• 
Subjects whose last assessment in the study is before Day 29 and before 
progression to mechanical ventilation or death and without being 
discharged to a location other than LTAC, hospice care or other hospital at 
their last assessment will be considered non-events and censored at the date 
of their last observed assessment. 
• 
Subjects who complete follow-up without mechanical ventilation or death 
will be censored at the expected study Day 29.  
Time to Sustained 
Recovery up to Day 60 in 
subjects who are < 85 
years old, have baseline 
clinical status of 5 or 6, 
and baseline CRP < 150 
mg/L. 
Primary and subgroup 
• 
Use the complete data for ordinal score to derive sustained recovery.  
• 
Subjects whose last assessment in the study is prior to Day 60 prior to 
recovery will be considered not recovered and censored at the date of last 
follow-up. 
• 
Death prior to recovery will be considered not recovered and censored at 
expected study Day 60.  
Sensitivity  
• 
Use the complete data for ordinal score to derive sustained recovery.  
• 
Subjects whose last assessment in the study is prior to Day 60 after 
discharge from the hospital to a location other than LTAC, hospice care or 
other hospital will be treated as recovered by Day 60. Their time to 
recovery will be the day the time of their first observed/imputed recovery 
score (i.e; 1, 2, 3) or the day of discharge, whichever comes first. 
• 
Subjects whose last assessment in the study is prior to Day 60 without 
being discharged from the hospital to a location other than LTAC, Hospice 
care or other hospital at their last assessment will be considered not 
recovered and censored at the date of last follow-up. 
• 
Death prior to recovery will be considered not recovered and censored at 
expected study Day 60. 
Survival without 
mechanical ventilation for 
all subjects in ITT 
population 
Primary, sensitivity, and 
subgroup 
• 
Use the same imputation methods as those used for the primary endpoint of 
BET-B 
Time to Sustained 
Recovery up to Day 60 for 
all subjects in ITT 
population 
Primary, sensitivity, and 
subgroup 
• 
Use the same imputation methods as those used for the analysis of time to 
recovery endpoint based on the primary subgroup of BET-B 
Other Secondary Endpoints and Exploratory Endpoints 
The analysis described for the other secondary efficacy and safety endpoints along with exploratory endpoints in the Master SAP will be 
followed. Refer to Table 7 in the master SAP for addition details regarding imputation methods to be used for those endpoints.  
6.6. 
Interim Analyses and Data Monitoring 
Refer to Section 6.6 of the master SAP for details of interim analyses. The details of the futility analysis are 
provided below. If enrollment is nearing completion at the timepoint of interim futility analysis (study 
enrollment projected to be completed within weeks), the below futility analysis will not be completed. 
A futility analysis will take place after approximately 280 subjects eligible for the primary analysis subgroup 
have been enrolled and randomized. If protocol version 6.0 is implemented after the 280th subject is 
randomized, then the futility analysis will be based on data observed by the implementation date. Subjects 
discharged to locations other than LTAC, Hospice care or other hospital, and with no other follow-up data 


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indicating death or mechanical ventilation will be treated as non-events and censored at Day 29 for futility 
analysis. Subjects that are lost to follow-up or terminated early before Day 29 prior mechanical ventilation or 
death but were hospitalized at their last assessment will be considered non-events and censored at the date of 
their last observed assessment. Subjects that are lost to follow-up or terminated early after discharge or after 
Day 29 prior mechanical ventilation or death will be considered non-events and censored at Day 29. Subjects 
who complete follow-up without mechanical ventilation or death will be considered non-events and censored 
at Day 29. Mechanical ventilation or death that occur after Day 29 are considered non-events and censored at 
Day 29. No other imputation methods will be applied for the futility analysis. 
For the futility analysis, the conditional power (the probability of rejecting the hypothesis that the proportion 
who survive without mechanical ventilation is the same between subjects who received active treatment 
versus those subjects who received placebo given the data observed) will be computed for the randomized 
subjects eligible for the primary analysis subgroup. The conditional power will be computed under the 
hypothesized treatment effect (a relative risk of 2.2). If the conditional power under the hypothesized 
treatment effect is less than 20%, the DSMB could recommend stopping the study for futility.  
To consider all accumulated data properly, the interim Z value for the conditional power calculation will be 
based on a test of difference in the Kaplan-Meier (KM) estimates at Day 29, as some subjects will be in the 
middle of their follow-up. The alpha used in the conditional power calculation will be 0.049 to account for the 
spending of alpha= 0.001 during the first interim analysis. The hypothesized drift parameter will be updated 
by the lumped event rate and will be based on the overall interim event rate and the assumed relative risk 
rather than the interim relative risk. The unconditional power will be updated for a z-test (unpooled variance) 
of the difference in KM estimates using the current overall event rate and the hypothesized relative risk of 2.2. 
Based on these assumptions the following formula will be used to calculate conditional power (CP): 
𝐶𝑃=
𝑡𝜃̂𝑡+ 𝜃𝐹(1 −𝑡) −𝑍1−𝛼/2⁡
√1 −𝑡
 
where 𝜃̂𝑡 is the estimated drift parameter at information time t.  𝜃̂𝑡 can be estimated using  
𝜃̂𝑡= 𝐵𝑡
𝑡⁡, 𝐵𝑡= 𝑍𝑡√𝑡 
where 𝑍𝑡 is the interim Z statistic of difference in KM estimates using an unpooled variance estimate.  𝜃𝐹 is 
the drift parameter at the final time and can be estimated as 
𝜃𝐹= 𝑍1−𝛼/2⁡ + 𝑍1−𝛽 
where Z is the standard normal with α=0.49 and 1-β is the recalculated unconditional power using the pooled 
event rate, 𝑝̅ =
𝑝̂1+𝑝̂2
2
, at information time, t and 𝑝̂1 and 𝑝̂2 are the KM estimates of each group. The updated 
conditional power can be estimated as 
1 −𝛽= Φ (𝑧−𝑍1−𝛼
2⁡
) + Φ (−𝑧−𝑍1−𝛼
2⁡
) , 𝑧=
𝑝𝐴−𝑝𝐵
√𝑝𝐴(1 −𝑝𝐴)
𝑛𝐴
+ 𝑝𝐵(1 −𝑝𝐵)
𝑛𝐵
 
where Φ is the standard normal distribution function and 𝑝𝐴 and 𝑝𝐵 are the group proportions that are 
consistent with a relative risk of 2.2 and 𝑝̅ at information t. 𝑝𝐴 and 𝑝𝐵 can be calculated as 
𝑝𝐵= 2𝑝̅
3.2⁡, 𝑝𝐴= 2.2𝑝𝐵⁡⁡ 
Finally, information time, t, can be estimated as 


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𝑡=
𝐸
400𝑝̅ 
where E is the total number of events at the time of the futility analysis. 
6.7. 
Multicenter Studies 
Refer to Section 6.7 of the master SAP. 
6.8. 
Multiple Comparisons/Multiplicity 
This protocol contains four key secondary endpoints. The key secondary endpoints will be tested in the order 
presented in the endpoint section using the following hierarchical hypothesis testing: If the primary analysis is 
significant at .049, then the first key secondary endpoint can be tested at .049. If this is significant, then the 
second key secondary endpoint can be tested at .049, and so forth. There is no hierarchical testing for other 
(non-key) secondary endpoints. 
The supplementary analyses (e.g., Westfall-Young and Hochberg) in Section 6.8 of the master SAP were 
intended for the proof-of-concept trials and thus will not be conducted for the BET-B study. 
 


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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 
For this phase 2/3 double-blind placebo controlled randomized trial two-sided p-value < 0.049 will be 
considered statistically significant at the final analysis. That is, an interim efficacy analysis done with 
alpha=.001, leads to alpha=.049 at the final test, using a Bonferroni approach to yield an overall .05 type I 
error rate. It is noted that since the endpoint and population are different between the interim test and final 
test, common interim analysis testing approaches such as O’Brien-Fleming would not apply, hence the use of 
Bonferroni which will be slightly conservative. 
8.1. 
Primary Efficacy Analysis 
8.1.1. 
Primary Analysis for the Primary Endpoint 
All efficacy analyses will be summarized and performed on the ITT and mITT population for both the 
primary subgroup and all subjects in the analysis population by treatment group and baseline ordinal score. 
The primary analysis of the primary endpoint, whether the subject did not satisfy one of the following two 
categories from the ordinal scale up to and including Study Day 29: 
7. Hospitalized, on invasive mechanical ventilation or ECMO or 
8. Death, 
will be analyzed as a logistic regression model to estimate adjusted odds ratios and adjusted risk differences 
adjusting for baseline dexamethasone use, baseline ordinal score, baseline CRP, age (continuous) for the pre-
specified subgroup (age < 85 years old, baseline clinical status of 5 or 6, and baseline CRP < 150 mg/L) in the 
ITT population. 
The null hypothesis is: 
H0: Odds ratio (treatment vs. placebo) = 1, 
and the alternative hypothesis is: 
HA: Odds ratio (treatment vs. placebo) ≠ 1 
where: 
Odds ratio (treatment vs. placebo) = Odds ratio comparing the odds of patients with treatment vs. placebo in 
terms of who survived without mechanical ventilation up to and including Study Day 29. 
The primary logistic model is defined as follow: 
 
𝑙𝑜𝑔𝑖𝑡⁡(𝑃(𝑌= 1)) = 𝛽0 + 𝛽1⁡𝑡𝑟𝑒𝑎𝑡+⁡𝛽2𝑏𝑎𝑠𝑒𝑜𝑟𝑑𝑠𝑐𝑜𝑟𝑒𝑣𝑎𝑟+⁡𝛽3𝑏𝑎𝑠𝑒𝑑𝑒𝑥𝑎𝑓𝑙+⁡𝛽3𝑏𝑎𝑠𝑒𝐶𝑅𝑃+⁡𝛽5⁡𝑎𝑔𝑒 
Where Y is the indicator for whether the subject progressed to mechanical ventilation or death. 
Missing data for the primary analysis will be imputed using multiple imputation. Details of the multiple 
imputation are provided in Section 6.5.1. 
Adjusted odds ratios, corresponding 95% CIs, and a p-value from an adjusted logistic regression [1] will be 
presented in Table 4 for subjects in the primary subgroup. Adjusted risk differences and corresponding 95% 
CI calculated using bootstrap will also be calculated. 


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8.1.2. 
Sensitivity Analysis for the Primary Endpoint 
The main sensitivity analysis for the primary endpoint will consider as non-events subjects who were missing 
event due to loss to follow-up but were discharged to a location other than LTAC, hospice care, or other 
hospital, and use same multiple imputation approach described in Section 6.5.1.1 and Section 6.5.1.3 for 
remaining missingness. The second sensitivity analysis will be added if the p-value from the primary analysis 
is less than <0.1 and will use the same imputation as the primary model but consider all subjects whose last 
assessment is in window for Day 29 but before Day 29 (Day 26, Day 27, Day 28) as censored on the actual 
day of the last assessment. Additional sensitivity analyses will use the same multiple imputation approach and 
functional form of the final model as the primary analysis with the addition of more covariates well as 
repeating the primary analysis on other analysis populations as listed in Table 1. Details of the multiple 
imputation are provided in Section 6.5.1. 
8.1.3. 
Secondary Analysis for the Primary Endpoint 
A secondary analysis of the primary endpoint will be performed using a targeted maximum likelihood 
estimate (TMLE) method for binary outcomes that estimates the average treatment effect among the entire 
population in terms of an odds ratio with corresponding p-value will be used. The test decision for this 
secondary analysis will be based on the p-value of the marginal odds ratio. 
For the underlying estimation of the binary outcome variable in each treatment arm, the following baseline 
covariates will be utilized: 
• Actual baseline ordinal score 
• Age (continuous) 
• Sex 
• Race and Ethnicity (Black or Hispanic indicator) 
• Baseline CRP 
• Baseline lymphocyte count 
• Baseline D-dimer 
• Baseline creatinine  
• Use of dexamethasone  
• Chronic respiratory disease 
• Chronic kidney disease 
• Cardiovascular disease 
• Comorbidities (Indicator for 2 or more comorbidities) 
The following super learner libraries with logistic link functions will be applied: 
• SL.glm (generalized linear model) 
• SL.gam (general additive model using smoothing splines of degree 2 for continuous variables) 
• SL.glmnet (generalized linear model with Lasso regularization, deviance as loss function and applying 
the lamba with minimal deviance for the prediction). 


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Categorical covariates with 90% of the subjects in one category will be dropped from the TMLE analysis. 
Mean imputation will be used for subjects missing values for continuous baseline variables. Missing values 
for categorical variables will be given a value of ‘No’. No missing data is expected for baseline ordinal score 
Odds ratio (treatment vs. placebo) = marginal odds ratio comparing the odds of patients with treatment vs. 
placebo in terms of who survived without ventilation up to and including Study Day 29. 
Marginal odds ratios, corresponding 95% CIs, and a p-value from an TMLE will be presented. Additionally, 
marginal risk differences with corresponding 95% CI will be presented.  
Missingness in the outcome is accounted for in the estimation procedure of TMLE using the missing indicator 
as shown in the below pseudocode. The TMLE approach will be implemented using the tmle R package 
(https://cran.r-project.org/web/packages/tmle/index.html). 
Pseudo code: 
Y = binary outcome variable (that can include missing values) 
trt = treatment information coded as 0, 1 
BaselineCov = Dataframe of baseline covariates (numerical) of each 
patient. 
MissingIndicator = Vector with 1 indicating that outcome was missing, 0 
otherwise 
SL.library = c("SL.glm", "SL.gam", "SL.glmnet")  
 
tmResult = tmle(Y = Y, A = trt, Delta = MissingIndicator, W = 
BaselineCov, family = "binomial", Q.SL.library  = SL.library, 
g.SL.library = SL.library, Delta.SL.library = SL.library) 
  
As a secondary analysis of the primary endpoint, marginal odds ratios, risk differences, and p-value calculated 
using TMLE will also be provided. If results from the primary analysis substantially differ between the 
logistic regression and TMLE, an assessment of the logistic regression model fit will be explored (including 
testing the model fit based on Nattino et al. [3]). 
The proportion of subjects with baseline ordinal score 5 or 6, who survived without mechanical ventilation 
including Study Day 29 will be presented by Lenzilumab + RDV long with 95% CIs obtained from logistic 
regression with bootstrap as described in Section 6.1 for the logistic regression rows or using TMLE for the 
TMLE row. 
Results of the sensitivity, secondary, and subgroup analyses for this endpoint will also be presented in Table 4 
for subjects in the primary subgroup.  
Refer to Table 1 for a list of covariates and subgroup analyses for this endpoint. Refer to Table 2 for 
imputation methods to be applied to this endpoint.  
A tipping point analysis that systematically and comprehensively varies assumptions about the missing 
outcomes on the two treatment arms will be performed. This tipping point analysis will vary assumptions 
about the missing outcomes on the two arms independently. The goal is to explore the plausibility of missing 
data assumptions under which the conclusions regarding efficacy change. Different scenarios will be explored 
that vary the assumed event rate among missing data to take values 1, 5, 10, 15, 20, 40% for the active 
treatment group (PT) and for the placebo group (PP). For each scenario, draws from the binomial distribution 
with parameter PT for subjects in the active treatment group with missing outcome and draws from the 
binomial distribution with parameter PP will be done for subjects in the placebo group missing outcome. This 


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process will be repeated 20 times to obtain 20 imputed datasets. For each scenario, the odds ratio and 
corresponding 95% CI will be obtained by fitting the same logistic regression model as the primary analysis 
for each imputation dataset and combining the estimates using PROC MIANALYZE in similar manner as was 
done for the primary analysis. The odds ratio and 95% CI will be presented in Table 17 for the primary 
subgroup and Table 18 for the ITT population. P-values from the tipping point analysis calculated using the 
same logistic regression described above are also provided in Figure 9 and Figure 10. Color shading will be 
used to show areas of the graph that show statistical significance. If significant shifts in conclusions regarding 
efficacy are observed in the tipping point analyses, additional tipping point analyses will be performed where 
additional assumptions regarding the event rate among discharged subjects will be explored. For example, 
scenarios where event rate in placebo missing discharged subjects are 1%, 2%, or 3% and event rate for the 
treated arm missing discharged subjects is the same as placebo or 3 times higher. Remaining missingness 
from non-discharged subjects will then be imputed in a similar manner as the main tipping point analysis.  
Pseudocode for Tipping Point analysis: 
• Define input dataset as the dataset of all subjects with a missing outcome. 
• Define PT as the proportion of subjects imputed as Event in the Lenzilumab + RDV. PT will take 
values 1, 5, 10, 15, 20, 40% 
• Define PP as the proportion of subjects imputed as Event in the Placebo + RDV. PP will take values 1, 
5, 10, 15, 20, 40% 
• For each combination of PT and PP, follow the below pseudocode to impute missing data and fit the 
final model to obtain odds ratio and its 95% CI along with the p-value.  
 
Data imp_tipping_&pp._&pt.; 
set input;  
subid=input(substr(usubjid,5,4),best12.); 
seed=645+subid; 
call streaminit(seed); 
pP= &pP.; 
pT= &pT.; 
do i=1 to 20; 
_imputation_ = i;  
If TRTVAR=’Placebo + RDV’ then 
eventd29=rand("Binomial",pP,1);  
Else if TRTVAR=’Lenzilumab + RDV’  then 
eventd29=rand("Binomial",pT,1);  
output; 
end; 
drop p i; 
run;  
 
For each of the 20 imputed datasets, combine imp_tipping_&pp._&pt. with the dataset of all subjects with 
complete outcome data to obtain the final dataset imp_tipping_final_&pp._&pt. 
Odds ratios from logistic regression using multiple imputation for each scenario: 
 
proc logistic data= imp_tipping_final_&pp._&pt. out=imp_parms_&pp._&pt.; 
 
by _imputation_; 
  
class baseordscorevar (param=ref ref=5) basedexausevar (param=ref ref=no steroid 
use) trtvar (param=ref ref=placebolabel); 
 
 model eventd29 (event=’1’) = trtvar baseordscorevar basedexausevar age baseCRP; 


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run; 
 
proc mianalyze data=parms_&pp._&pt.; 
 
class baseordscorevar (param=ref ref=5) basedexausevar (param=ref ref=no steroid 
use) trtvar (param=ref ref=placebolabel); 
 
modeleffects trtvar baseordscorevar basedexausevar age baseCRP; 
 
ods output parameterestimates=mianalyze_parms_&pp._&pt.; 
run; 
 
 
data OR_&pp._&pt.; 
set mianalyze_parms_&pp._&pt.; 
 
OR=exp(estimate); 
 
LCL_OR=exp(LCLMean); 
 
UCL_OR=exp(UCLMean); 
run; 
 
Repeat the above process for all combinations of PT and PP to obtain estimates and p-values for each 
scenario. 
8.2. 
Key Secondary Efficacy Analyses 
All analyses of key secondary endpoints on the ITT population outlined in Section 8.2.1, Section 8.2.2, 
Section 8.2.3 and Section 8.2.4 will be repeated for the mITT analysis population. For brevity, only the ITT 
analyses are described in the text and presented in output shells. The mITT analyses and their output will 
follow exactly what is provided for their ITT counterparts. 
8.2.1. 
Time to Mechanical Ventilation or Death Up to and Including Day 29 for Primary Endpoint 
Subgroup and All Subjects in ITT Population 
The time to mechanical ventilation or death up to and including Day 29 will be defined as the elapsed time (in 
days) from Study Day 1 to date of invasive mechanical ventilation/ECMO or death. For the primary analysis 
of this endpoint, all subjects lost to follow-up or terminated early prior to death or progression to invasive 
mechanical ventilation will be considered non-events and censored at the date of their last observed 
assessment. As sensitivity analysis of this endpoint, any subjects that are lost to follow-up or terminated early 
prior to death or progression to mechanical ventilation and were discharged to a location other than LTAC, 
hospice care or other hospital, or progress to invasive mechanical ventilation/ECMO or death after Day 29 
will be considered non-events and censored at Day 29 while subjects that are lost to follow-up or terminated 
early before Day 29 and before progression to invasive mechanical ventilation/ECMO or death and were 
either still hospitalized or discharged to LTAC, hospice care or other hospital at their last assessment will be 
considered non-events and censored at the date of their last observed assessment. If it is learned that a subject 
who terminated early had subsequently received ventilation or died prior to Day 29, then the subject will be 
classified as having the event. Subjects who complete follow-up without an event will be censored at the date 
of their expected Study Day 29 visit. Events that occur after Day 29 will be censored at the expected Study 
Day 29 date. 
Table 7 will present median time to event along with corresponding 95% confidence intervals for each 
Lenzilumab + RDV long with the hazard ratio estimate and p-value from a Cox proportional hazards model 
for subjects in the primary subgroup. Restricted mean survival time estimates (RMST) which do not rely on 
the proportionality assumption will be provided for each treatment group and actual baseline ordinal score 
stratum as well as the difference in restricted mean recovery time between treatment groups within each of the 


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baseline ordinal score strata for the primary subgroup (Table 9). For both the Cox proportional hazards model 
and the RMST method, tied event times will be handled using the Efron method. 
Kaplan-Meier curves for each Lenzilumab + RDV will be presented and supplemented with the hazard ratio 
estimate, p-value, and the number of subjects at risk in each Lenzilumab + RDV Study Day (not necessarily 
actual Study Days 1, 3, 5, 8, 11, 15, 22, 29) (Figure 1). A forest plot will be generated to display 95% CIs for 
hazard ratios from each of the subgroup analyses (Figure 5). These analyses will also be repeated for all 
subjects in the ITT population and results will be reported in Table 8, Figure 2, and Figure 6. 
Refer to Table 1 for a list of covariates and subgroup analyses for this endpoint. Refer to Table 2 for 
imputation methods to be applied to this endpoint.  
8.2.2. 
Time to Sustained Recovery Up to and Including Day 60 for Primary Endpoint Subgroup in 
the ITT Population  
Recovery will be defined as having a value of 1, 2, or 3 on the clinical status 8-point ordinal scale or 
discharge from the hospital to a location other than LTAC, hospice care, or other hospital. The time to 
sustained recovery will be defined as the elapsed time (in days) from Study Day 1 to the day prior to the 
earliest recorded day at which a subject reaches recovery and doesn’t worsen (ordinal score > 3) up to and 
including Study Day 60. This analysis will be conducted on the ITT population for those subjects who at 
baseline have a clinical status score of 5 or 6, CRP<150 mg/L, and age<85 years. For the primary analysis of 
this endpoint, all subjects lost to follow-up or terminated early prior recovery will be considered not recovered 
and censored at the date of their last observed assessment, regardless of their discharge status. As sensitivity 
analysis of this endpoint, any subjects that are lost to follow-up or terminated early prior to recovery and were 
discharged to a location other than LTAC, hospice care or other hospital will be considered recovered by 
study Day 60 with a time to recovery of time of discharge or time of first score of 1, 2, or 3, whichever comes 
first, while subjects that are lost to follow-up or terminated early before Day 60 before recovery, were still 
hospitalized or were discharged to LTAC, hospice care or other hospital at their last assessment will be 
considered not recovered and censored at the date of their last observed assessment.   
Refer to Table 1 for a list of covariates and subgroup analyses for this endpoint. Refer to Table 2 for 
imputation methods to be applied to this endpoint.  
The primary analysis time to sustained recovery up to and including Study Day 60 conducts a score test to 
compare treatment to control up to and including Study Day 60. The treatment median survival time, 
confidence intervals and p-value from the score test will be presented (Table 10). Restricted mean recovery 
time estimates will be provided for each treatment group and actual baseline ordinal score stratum as well as 
the difference in restricted mean recovery time between treatment groups within each of the baseline ordinal 
score strata (Table 12). 
Kaplan-Meier curves for each Lenzilumab + RDV will be presented and supplemented with the hazard ratio 
estimate, p-value, and the number of subjects at risk in each Lenzilumab + RDV Study Day (not necessarily 
actual Study Days 1, 3, 5, 8, 11, 15, 22, 29, and 60) (Figure 3). 
Each subgroup from Table 1 will be considered separately, and the tabular and graphical summaries described 
above will be replicated for each subgroup (Table 10). A forest plot will be generated to display 95% CIs for 
hazard ratios from each of the subgroup analyses (Figure 7). 


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8.2.3. 
Survival without Mechanical Ventilation up to and Including Day 29 for All Subjects in the 
ITT and mITT Populations 
The analysis for survival without mechanical ventilation for the primary endpoint described in Section 8.1 
will be repeated for all subjects in the ITT population without the restrictions in Table 5 and all subjects in 
mITT population in Table 6. 
8.2.4. 
Time to Sustained Recovery up to and including Day 60 for ITT Population 
The analysis for the time to sustained recovery for the primary endpoint subgroup described in Section 8.2.1 
will be repeated for all subjects in the ITT population without the restrictions. Results will be reported in 
Table 11, Table 12, Figure 4, and Figure 8. 
8.3. 
Other Secondary Efficacy Analyses 
The analysis described for the other secondary efficacy and safety endpoints in the Master SAP will be 
followed. However, analysis of secondary endpoints will be conducted for all subjects in the ITT Population 
and only 95% confidence intervals will be reported for efficacy and safety analyses. For the time to death and 
mortality endpoints, additional tables for the primary subgroup and full ITT population will be provided in 
Table 13 and Table 14, respectively. Results for time to death and mortality using subjects with baseline 
ordinal score of 5 or 6, CRP≥150 mg/L, and age<85 years are provided in Table 15. Results from analysis of 
time to death using a restricted mean survival approach are provided in Table 16. 


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9. 
SAFETY EVALUATION 
Safety evaluation for this study will be similar to that provided in the master SAP. However, additional safety 
summaries by baseline CRP<150 and CRP≥150 will be provided. 
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. 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
Refer to Section 9.4 of the master SAP. 
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 
15.1. 
Changes from v1.0 to v2.0 of the BET-B SAP 
• Change of the multiple imputation approach for the primary endpoint from a subject-specific 
imputation to an imputation method that imputes missing data depending on the discharge status of the 
subject at their last assessment or whether they have any post-baseline results or not. 
• A tipping point analysis for the primary endpoint was added. 
• Added a subgroup analysis of baseline CRP (< 150 vs ≥150) to the primary analysis using the ITT 
analysis population. 
• Change in the definition for censoring time for time to death or progression to mechanical ventilation. 
The original model considered subjects discharged missing outcome as non-events and censored at 
Day 29. The update analysis censors these subjects at last assessment and provides a sensitivity 
analysis that censors these subjects at Day 29. Similar updates were made to time to sustained 
recovery. 
• Analysis of time to death based on restricted mean survival time was added. 
15.2. 
Changes from v2.0 to v3.0 of the BET-B SAP 
• The tipping point analysis was updated to use the same methodology as the primary analysis. 
• A possible sensitivity analysis that considers as missing subjects without event whose last assessment 
is on Day 26, 27, or 28 was added and will be performed only if the p-value from the primary analysis 
is less than 0.1. 
• A possible sensitivity analysis using the fully conditional specification (FCS) logistic approach to 
impute missing data will be added if more than 1% of subjects have missing data in the baseline 
covariates used in the multiple imputation model and if the p-value from the primary analysis is <0.1. 
• The imputation procedure for discharged subjects was updated to estimate the event rate from the 
logistic regression model with baseline ordinal score as a covariate only if 10 or more events (after 
discharge) are observed in this group of discharged subjects with outcome. If less than 10 events are 
observed, the event rate will be estimated as the proportion of events among discharged subjects with 
outcome. Additionally, if 0 events are observed in a subgroup, the event rate will be calculated as 
0.5/total number of discharged subjects with outcome in that subgroup. 
 
 


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16. 
REFERENCES 
1. M. Ge, L. K. Durham, R. D. Meyer, W. Xie and N. Thomas, "Covariate-Adjusted difference in 
proportions from clincal trials using logistic regression and weighted risk differences.," Ther Innov 
Regul Sci, vol. 45, pp. 481-493, 2011. 
2. Schomaker M, Heumann C. Bootstrap inference when using multiple imputation. Stat Med. 
2018;37(14):2252-2266. doi:10.1002/sim.7654 
3. Nattino G, Pennell ML, Lemeshow S. Assessing the goodness of fit of logistic regression models in 
large samples: A modification of the Hosmer-Lemeshow test. Biometrics. 2020 Jun;76(2):549-560. 
doi: 10.1111/biom.13249. Epub 2020 Apr 6. PMID: 32134502.  
 


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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-B study. The rest of the 
tables will come from the master SAP. For endpoints such as time to sustained recovery and time 
to mechanical ventilation or death that have TFLs in both master and BET-B SAPs, the TFLs in 
BET-B will be used for analysis. In all TFLs, Treatment A will be replaced by Lenzilumab + 
RDV and Treatment B will be replaced by Placebo + RDV. Only 95% CIs will be reported for 
BET-B. 


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APPENDIX 1. TABLE MOCK-UPS 
LIST OF TABLES 
Table 1: 
Covariates and Subgroup Analyses for Each Endpoint ..............................................16 
Table 2: 
Imputation Method for Each Endpoint and Analysis Type ........................................29 
Table 3: 
Schedule of Study Procedures ....................................................................................53 
Table 4: 
Proportion of Subjects Alive and Without Mechanical Ventilation through 
Day 29 — ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 
mg/L, and age<85 years ..............................................................................................55 
Table 5: 
Proportion of Subjects Alive and Without Mechanical Ventilation through 
Day 29 — ITT Population ..........................................................................................56 
Table 6: 
Proportion of Subjects Alive and Without Mechanical Ventilation through 
Day 29 — mITT Population .......................................................................................56 
Table 7: 
Time to Mechanical Ventilation or Death through Day 29 — ITT Population 
with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years ...............57 
Table 8: 
Time to Mechanical Ventilation or Death through Day 29 — ITT Population ..........58 
Table 9: 
Time to Mechanical Ventilation or Death through Day 29 by Treatment 
Group, Actual Baseline Ordinal Score, and Analysis Population: Restricted 
Mean Survival Time Analysis ....................................................................................59 
Table 10: Time to Sustained Recovery through Day 60 — ITT Population with 
Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years .......................60 
Table 11: Time to Sustained Recovery through Day 60 — ITT Population ..............................64 
Table 12: Time to Sustained Recovery through Day 60 by Treatment Group, Actual 
Baseline Ordinal Score, and Analysis Population: Restricted Mean Survival 
Time Analysis .............................................................................................................65 
Table 13: Mortality Rates — ITT Population with Baseline Ordinal Score of 5 or 6, 
CRP<150 mg/L, and age<85 years .............................................................................66 
Table 14: Mortality Rates — ITT Population .............................................................................69 
Table 15: Mortality Rates — ITT Population with Baseline Ordinal Score of 5 or 6, 
CRP≥150 mg/L, and age<85 years .............................................................................69 
Table 16: Time to Death by Treatment Group, Actual Baseline Ordinal Score, and 
Analysis Population: Restricted Mean Survival Time Analysis .................................70 
Table 17: Summary Results of Tipping Point Analysis for the Proportion of Subjects 
Alive and Without Mechanical Ventilation through Day 29 — ITT 
Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and 
age<85 years ...............................................................................................................71 


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Table 18: Summary Results of Tipping Point Analysis for the Proportion of Subjects 
Alive and Without Mechanical Ventilation through Day 29 — ITT 
Population ...................................................................................................................71 
 


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9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart 
Table 3: 
Schedule of Study Procedures 
  
Screen 
Baseline  
Study Intervention Period 
Follow-up Visits 
Day +/- Window 
−1 or 1 
116 
Daily until hospital 
discharge (up to Day 29) 
811 
± 2 
156  
± 2 
2211 
± 3 
296 
± 3 
6011 
± 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 
 
• Lenzilumab or placebo: 3 infusions 
starting on Day 110 
• Remdesivir: IV daily for 5-10 days or 
until discharge.  
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
Vital signs and NEWS score 
1, 15 
 
X3 
 
 
 
 
 
 
Clinical data collection1  
 
X3 
Daily until discharge 
X 
X 
X 
X 
X14 
Adverse event evaluation 
 
X3 
Daily until discharge 
X 
X 
X 
X 
X 
Concomitant medication 
review13 
 
X3 
Day -7 until discharge 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
SAFETY LABORATORY 
 
 
 
 
 
 
 
 
Safety hematology, 
chemistry, and liver tests4,9 
X2 
X3 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized5 
 
X 
 
X 
 
Pregnancy test for females of 
childbearing potential 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH 
LABORATORY17  
 
 
 
 
 
 
 
 
Oropharyngeal swab7 
 
X3 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized 
 
X 
 
X 
 
Blood draw for serum and 
plasma.  
Specific testing is as follows: 
 
X3 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized  
 
X 
 
X 
 
PCR SARS-CoV-2 
 
X3 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized  
 
 
 
 
 
proteomic analysis 
(including specifically for 
lenzilumab 
GM-CSF, MCP-1, IP-10, 
IL-6, IL-1, TNF-a, G-CSF 
and MIPa) 
 
X3 
Day 3, 8, (all ± 1 day) if 
hospitalized 
 
X 
 
X 
 
lenzilumab 
pharmacokinetics12 
 
X8 
Day 5 (± 1 day) if 
hospitalized  
 
X 
 
X 
 
Serum for secondary 
research 
 
X3 
Day 3, 5, 8, 11 (all ± 1 day) 
if hospitalized 
 
X 
 
X 
 
Blood for RNA 
 
X3 
Day 3, 8 (all ± 1 day) if 
hospitalized 
 
X 
 
X 
 
Blood for PBMC12  
 
X3 
Day 3, 8 (all ± 1 day) if 
hospitalized 
 
X 
 
X 
 


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Notes: 
1 Refer to Section 8.1 of the protocol for details of clinical data to be collected including ordinal score, NEWS, oxygen requirement, mechanical 
ventilator requirement, etc. 
2 Screening laboratory tests include: ALT, AST, creatinine (and calculate an estimated glomerular filtration rate (eGFR) the formula used is 
determined by the sites, but should be consistent throughout the study), and 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. 
3 Baseline assessments should be performed prior to first infusion. Laboratory tests performed as part of routine clinical care in the 24 hours 
prior to first dose will be accepted for the baseline safety laboratory tests. Baseline may be the same as the screening laboratory tests if 
obtained in the 24 hours prior to first dose. 
4 Safety laboratory tests include WBC with differential, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, INR. 
5 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing.  
6 In-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability to return to the site for the visit. In 
this case, the visit may be performed by phone. 
• 
If still hospitalized at Day 15 and 29 or returns to the site for an in-person visit: assess adverse events, collect clinical data, vital 
signs, safety laboratory tests, and research laboratory samples (OP swab and 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 score), 
readmission to a hospital, and mortality only. 
7 Oropharyngeal swabs are preferred, but if these are not obtainable, saliva or nasopharyngeal or nasal swabs may be substituted.  
8 Pre-dose serum sample collections for PK.  
9 To include markers of inflammation and coagulation: CRP, ferritin, fibrinogen, d-dimer, and LDH.  
10 Approximately 1 hour prior to lenzilumab/placebo infusion, premedication with acetaminophen 500 to 1000 mg PO or IV, or 650 mg PR and 
diphenhydramine 12.5 to 25 mg IV, or 25 mg PO or equivalent is required. 
11 Day 8, 22 and 60 visits performed by phone or home visit if discharged from the site hospital: assess adverse events, clinical status (ordinal 
score), readmission to a hospital, and mortality only. 
12 Only collected at selected sites capable of processing. 
13 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. 
14 Ordinal score only. 
15 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. 
16 Day 1 is defined as the calendar day of randomization. 
17 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. 
 


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Table 4: 
Proportion of Subjects Alive and Without Mechanical Ventilation through Day 29 — ITT Population with Baseline Ordinal Score 
of 5 or 6, CRP<150 mg/L, and age<85 years 
[Implementation note: Sensitivity analysis 2 will be performed only if the p-value for the initial model of the primary endpoint is <0.1. 
Sensitivity analysis 4 that uses FCS logistic for multiple imputation will be performed only if more than 1% of subjects have missing baseline covariates 
and the overall p-value for the primary endpoint is < 0.1.] 
Analysis/Subgroup 
Category 
Lenzilumab + RDV  
(N=x) 
Placebo + RDV 
(N=x) 
Odds Ratio 
Risk Differencej 
P-valuek 
n 
% (95%CI)i 
n 
% (95%CI)i 
Estimate 
95% CI 
Estimate 95% CI 
Initial model, Baseline dexamethasone, Baseline OS, 
CRP, age (cont.), MIa  
- 
x 
x.x, x.x 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Sensitivity 
Sensitivity analysis 1: Baseline dexamethasone, 
Baseline OS, CRP, age (cont.), MIb 
- 
x 
x.x, x.x 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Sensitivity analysis 2: Baseline dexamethasone, 
Baseline OS, CRP, age (cont.), MIc 
- 
x 
x.x, x.x 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Sensitivity analysis 3: Baseline dexamethasone, 
Baseline OS, CRP, age (cat.), Geographical regions, 
MId 
- 
x 
x.x, x.x 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Sensitivity analysis 4: Baseline dexamethasone, 
Baseline OS, CRP, age (cont.), FCS MIe 
- 
x.x, x.x 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
x 
Secondary  
TMLE-Approach 1f 
- 
x 
x.x (x.x, x.x) 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
TMLE-Approach 2: MI combining TMLE analysis 
in imputed datasetsg 
- 
x 
x.x, x.x 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Subgroup Analysesh 
Baseline Ordinal Score 
5 
x 
x.x (x.x, x.x) 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
6 
x 
x.x (x.x, x.x) 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
7 
x 
x.x (x.x, x.x) 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
5 or 6 
x 
x.x (x.x, x.x) 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
P-value for interactioni 
 
 
 
 
 
 
 
 
0.xxx 
Repeat for all subgroups from Table 1 
 
x 
x.x (x.x, x.x) 
x 
x.x (x.x, x.x) 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 


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Analysis/Subgroup 
Category 
Lenzilumab + RDV  
(N=x) 
Placebo + RDV 
(N=x) 
Odds Ratio 
Risk Differencej 
P-valuek 
n 
% (95%CI)i 
n 
% (95%CI)i 
Estimate 
95% CI 
Estimate 95% CI 
CI=Confidence Internals. OR=Odds Ratios. NA=Not applicable. MI=Multiple Imputation. 
N=Number of subjects in the ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years . n=Number of subjects without mechanical ventilation or death through 
Day 29. 
a Odds Ratios of Active treatment vs Placebo calculated from the logistic regression model adjusted for baseline dexamethasone use, baseline OS, age (continuous), and baseline CRP. Missing data 
imputed using the 3-stage imputation procedure described in Section 6.5. 
b Sensitivity Analysis 1: Odds Ratios of Active treatment vs Placebo calculated from the logistic regression model adjusted for baseline dexamethasone use, baseline OS, age (continuous), and baseline 
CRP. Missing outcomes for subjects with a good discharge at last assessment are considered non-events for this analysis. 
c  Sensitivity Analysis 2: Odds Ratios of Active treatment vs Placebo calculated from the logistic regression model adjusted for baseline dexamethasone use, baseline OS, age (continuous), and baseline 
CRP. Subjects without event whose last assessment is in window for Day 29 (Day 26, 27, 28) are considered missing. Missing data imputed using the 3-stage imputation procedure described in Section 
6.5. 
d Sensitivity Analysis 3: Same imputation as initial model in a. The final model also includes categorical age and geographical regions as covariates. 
e Sensitivity Analysis 4: PROC MI part of the imputation model uses FCS logistic instead of monotone logistic. The rest of the imputation procedure and final covariates are similar to those in the initial 
model in a. 
f TMLE Approach 1: Estimates marginal ORs and risk differences using TMLE and adjusts for all missing data using the missing indicator functionality of TMLE. 
g TMLE Approach 2: Estimates marginal ORs and risk differences using MI combining TMLE analysis in imputed datasets. Missing events for discharged subjects are considered non-events, missing 
events for subjects with no post baseline data are handled using the missing indicator in TMLE, while a similar MI procedure as the primary analysis is used to impute missing event for subjects who 
were hospitalized or transferred to another hospital at their last assessment. 
h For the subgroup analyses, the model described in a was performed for each level of the subgroup without multiple imputation. P-value from the interaction between the subgroup variable and treatment 
group is also reported. 
i Estimate and 95% CI for the proportion are estimated using either logistic regression or TMLE. 
j Risk Differences calculated using the approach described in Ge.et al [1] or TMLE. CIs calculated using bootstrap or TMLE. 
k P-value from the logistic regression model or TMLE. For the interaction, P-value from interaction Type III test in subgroup analysis where the interaction between subgroup and treatment is being 
added to the logistic regression model. 
 
Tables with similar format: 
Table 5: 
Proportion of Subjects Alive and Without Mechanical Ventilation through Day 29 — ITT Population  
[Implementation note: Add subgroup analysis for baseline CRP < 150 mg/L vs baseline CRP ≥ 150 mg/L. Add footnote that analysis for this subgroup 
analysis will only include subjects in the ITT population with baseline ordinal score of 5 or 6 and age<85years.] 
Table 6: 
Proportion of Subjects Alive and Without Mechanical Ventilation through Day 29 — mITT Population  


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Table 7: 
Time to Mechanical Ventilation or Death through Day 29 — ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 
mg/L, and age<85 years 
Analysis/Subgroup 
Treatment 
Number of Subjects to Mechanical 
Ventilation or Deathd 
Median Time Until 
Event 
Hazard Ratio 
P-valuee 
n 
% 
Estimate 
95% CI 
Estimate 
95% CI 
Initial Modela 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x  
x.x 
x.x 
x.x,x.x 
Sensitivityb 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x  
x.x 
x.x 
x.x,x.x 
Subgroup Analysesc 
Baseline Ordinal Score 
5 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
6  
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
5 or 6 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
 
P-value for interactione 
 
 
 
 
 
 
x.xxx 
Repeat for the rest of the subgroups in Table 1. 
CI=Confidence Intervals.  
N= Number of subjects in ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years. n= Number of unique subjects who progressed to mechanical ventilation or death 
that satisfies the row criteria. 
a Hazard Ratio (HR) is the hazard ratio calculated from the Cox Proportional Hazard Model comparing Active treatment vs Placebo and adjusting for the baseline dexamethasone use (yes, no), Baseline 
Ordinal Score (5, 6 or 7), age, and baseline CRP as covariates. All subjects whose last assessment was before Day 29 and were missing the event were censored at the date of last assessment.  
b Same analysis as the initial model but subjects missing event and whose last assessment is before Day 29 are non-events for good discharges and censored at Day 29 or at last assessment for 
subjects still hospitalized or discharged to LTAC, hospice care, or other hospital. 
c For the subgroup analyses, the model described in a was performed for each level of the subgroup.  
d Number of subjects who progressed to a clinical status of 7 or 8 through Day 29. 
e P-value is based on the adjusted cox model or P-value from interaction Type III test in subgroup analysis where the interaction between subgroup and treatment is being added to the Cox Proportional 
Hazard Model. 
 


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Table with similar format: 
Table 8: 
Time to Mechanical Ventilation or Death through Day 29 — ITT Population 
[Implementation note: Add subgroup analysis for baseline CRP < 150 mg/L vs baseline CRP ≥ 150 mg/L. Add footnote that analysis for this subgroup 
analysis will only include subjects in the ITT population with baseline ordinal score of 5 or 6 and age<85years.] 


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Table 9: 
Time to Mechanical Ventilation or Death through Day 29 by Treatment Group, Actual Baseline Ordinal Score, and Analysis 
Population: Restricted Mean Survival Time Analysis 
Analysis Population 
Treatment Group 
Actual Baseline Ordinal Score 
n 
Taua 
Restricted Mean Time (Days) 
Difference 
Estimate 
95% CI 
Estimate 
95% CI 
ITT with BOS 5 or 6, 
CRP<150 mg/L, and 
age<85 years 
Lenzilumab + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
Any BOSb 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
ITT 
Lenzilumab + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
7 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
Any BOSb 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
N= Number of subjects in the specified treatment group, actual baseline ordinal score, and analysis population.  
n = Number of subjects who experiences a clinical status of 7 or 8 through Day 29. 
Difference is the difference in the restricted mean recovery time between active treatment to placebo. All subjects lost to follow-up before Day 29 and missing event were censored at last assessment. 
a Tau is the truncation time point for the Restricted Mean Survival Time analysis and is equal to the minimum of the largest observed times in each group. 
b There were X additional subjects with an Actual Baseline Ordinal Score of 4 that are included in the ‘Any BOS’ summaries. 
Programming  
Within an actual baseline ordinal score stratum: 
proc lifetest data=enrevent plots=(rmst) method=breslow rmst(cl); 
by stratum; 
time evntday * Censor(1); 
strata trtcode /diff=all; 
ods output  rmst=rmst; 
run; 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
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Table 10: 
Time to Sustained Recovery through Day 60 — ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and 
age<85 years 
Analysis/Subgroup 
Treatment 
Number of Recovered Subjects 
Median Time Until Recovery 
Hazard Ratio 
P-valuee 
n 
% 
Estimate 
95% CI 
Estimate 
95% CI 
Initial Modela 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x, x.x 
Sensitivity Analyses 
Sensitivity Analysis 1: Imputation for good dischargesb 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x, x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x, x.x 
Supplemental Analysis 1: Impact of age and duration of 
symptomsc 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x, x.x 
Subgroup Analysesd 
Baseline Ordinal Score 
5 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x, x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x, x.x 
6 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
7 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x, x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
Baseline Steroid Use 
Yes 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
No 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
Baseline Use of Emerging Covid-19 Treatments 
Yes 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Analysis/Subgroup 
Treatment 
Number of Recovered Subjects 
Median Time Until Recovery 
Hazard Ratio 
P-valuee 
n 
% 
Estimate 
95% CI 
Estimate 
95% CI 
No 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
Duration of Symptoms Prior to Enrollment Group 1 
≤ Median 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
> Median 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
Duration of Symptoms Prior to Enrollment Group 2 
< 25th percentile 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
25 ≤ 75th percentile 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
≥ 75th percentile 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
x 
x.x 
 
 
 
 
0.xxx 
Race 
White 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
Black/African American 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
Asian 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
Other 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
0.xxx 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
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Analysis/Subgroup 
Treatment 
Number of Recovered Subjects 
Median Time Until Recovery 
Hazard Ratio 
P-valuee 
n 
% 
Estimate 
95% CI 
Estimate 
95% CI 
Ethnicity 
Hispanic or Latino 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
Not Hispanic or Latino 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
Comorbidities Group 1 
None 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
Any 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
0.xxx 
Comorbidities Group 2 
One 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
Two or More 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
 
Comorbidities Group 3 
Obese 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
Non-obese 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
Age 
< 40 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
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Analysis/Subgroup 
Treatment 
Number of Recovered Subjects 
Median Time Until Recovery 
Hazard Ratio 
P-valuee 
n 
% 
Estimate 
95% CI 
Estimate 
95% CI 
41-64 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
65 and older 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
Sex 
Male 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
Female 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
Baseline CRP 
<= Median  
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
>Median 
Lenzilumab + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
x.x 
x.x,x.x 
0.xxx 
Placebo + RDV (N=X) 
x 
x.x 
x.x 
x.x,x.x 
 
P-value for interactione 
 
 
 
 
 
 
0.xxx 
CI=Confidence Intervals.   N=Number of subjects in the ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years. n= Number of unique recovered subjects that satisfies 
the row criteria.  
a Hazard Ratio (HR) is the hazard ratio calculated from the Cox Proportional Hazard Model comparing Active treatment vs Placebo.  All subjects lost to follow-up before recovery are censored at 
last assessment date. 
b Sensitivity Analysis 1: Subjects discharged to a location other than LTAC, hospice care, or other hospital are considered recovered and censored at Day 60. The rest of lost to follow-up subjects are 
censored at last assessment date. Model a was fit to estimate the HR, 95% CI and p-values. 
c Supplemental Analysis 1 (age and duration of symptoms prior to enrollment): In addition to the variable included in the model described in a, age and duration of symptoms prior to enrollment as 
additional covariates were added to the model when estimating the HR, 95% CI and p-values. Same censoring as in model a. 
d For the subgroup analyses, the model described in a was performed for each level of the subgroup.   
e P-value is based on the Cox adjusted model or P-value from interaction Type III test in subgroup analysis where the interaction between subgroup and treatment is being added to the Cox Proportional 
Hazard Model.  
 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
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Table with similar format: 
Table 11: 
Time to Sustained Recovery through Day 60 — ITT Population  
[Implementation note: Add subgroup analysis for baseline CRP < 150 mg/L vs baseline CRP ≥ 150 mg/L. Add footnote that analysis for this subgroup 
analysis will only include subjects in the ITT population with baseline ordinal score of 5 or 6 and age<85years.] 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
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Table 12: 
Time to Sustained Recovery through Day 60 by Treatment Group, Actual Baseline Ordinal Score, and Analysis Population: 
Restricted Mean Survival Time Analysis  
Analysis Population 
Treatment Group 
Actual Baseline 
Ordinal Score 
n 
Taua 
Restricted Mean Recovery 
Time (Days) 
Difference 
Estimate 
95% CI 
Estimate 
95% CI 
ITT with BOS 5 or 6, 
CRP<150 mg/L, and 
age<85 years 
Lenzilumab + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
Any BOSb 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
ITT 
Lenzilumab + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
7 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
Any BOSb 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
N= Number of subjects in the specified treatment group, actual baseline ordinal score, and analysis population.  
n = Number of recovered subjects.  
Difference is the difference in the restricted mean recovery time between active treatment to placebo. 
a Tau is the truncation time point for the Restricted Mean Survival Time analysis and is equal to the minimum of the largest observed times in each group. 
b There were X additional subjects with an Actual Baseline Ordinal Score of 4 that are included in the ‘Any BOS’ summaries. 
Programming notes: 
Within an actual baseline ordinal score stratum: 
proc lifetest data=enrevent plots=(rmst) method=breslow rmst(cl); 
by stratum; 
time evntday * Censor(1); 
strata trtcode /diff=all; 
ods output  rmst=rmst; 
run; 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
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Table 13: 
Mortality Rates — ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years 
Analysis Type 
Baseline 
Ordinal Score 
Treatment Group 
Number of 
Deaths 
Mortality Rate (CI)c 
Difference in Mortality Rates at the 
Specified Time Pointd 
HRe 
P-valuef 
n 
% 
Estimate 
80% CI 
95% 
CI 
Estimate 
80% CI 
95% CI 
Estimate 
80% CI 95% CI 
Time to Death by Day 15 
Primarya 
5 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
6 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
7 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Any BOS 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Primary with 
Sensitivity 
Imputationb 
5 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
6 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
7 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
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Analysis Type 
Baseline 
Ordinal Score 
Treatment Group 
Number of 
Deaths 
Mortality Rate (CI)c 
Difference in Mortality Rates at the 
Specified Time Pointd 
HRe 
P-valuef 
n 
% 
Estimate 
80% CI 
95% 
CI 
Estimate 
80% CI 
95% CI 
Estimate 
80% CI 95% CI 
 
Any BOS 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Time to Death by Day 29 
Primarya 
5 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
6 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
7 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Any BOS 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Primary with 
Sensitivity 
Imputationb 
5 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
6 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
7 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 


Statistical Analysis Plan - DMID Protocol: 20-0013 
Version 3.0 
Appendix 6 BET-B 
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Analysis Type 
Baseline 
Ordinal Score 
Treatment Group 
Number of 
Deaths 
Mortality Rate (CI)c 
Difference in Mortality Rates at the 
Specified Time Pointd 
HRe 
P-valuef 
n 
% 
Estimate 
80% CI 
95% 
CI 
Estimate 
80% CI 
95% CI 
Estimate 
80% CI 95% CI 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Any BOS 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Time to Death by Day 60 
Primarya 
5 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
6 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
7 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Any BOS 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Primary with 
Sensitivity 
Imputationb 
5 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
6 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 


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Analysis Type 
Baseline 
Ordinal Score 
Treatment Group 
Number of 
Deaths 
Mortality Rate (CI)c 
Difference in Mortality Rates at the 
Specified Time Pointd 
HRe 
P-valuef 
n 
% 
Estimate 
80% CI 
95% 
CI 
Estimate 
80% CI 
95% CI 
Estimate 
80% CI 95% CI 
7 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
Any BOS 
Lenzilumab + RDV 
(N=X) 
X 
x.x 
x.x 
x.x, x.x 
x.xxx 
x.x 
x.x, x.x 
x.x, x.x 
x.x 
x.x, x.x 
x.x, x.x 
0.xxx 
Placebo + RDV 
(N=X) 
X 
x.x 
x.xx 
x.x, x.x 
x.xxx 
 
 
 
 
 
 
 
CI= Confidence Intervals. N=Number of subjects in the Safety population. n= Number of unique subjects that satisfies the row criteria. 
a For the primary endpoint, all subjects whose last assessment was before the corresponding timepoint (Day 15 Visit, Day 29 Visit, Day 60 Visit) and were missing the event were censored at the date of 
last assessment.  
b Primary with Sensitivity Imputation: Same analysis as the initial model but subjects missing event and whose last assessment is before the corresponding timepoint (Day 15 Visit, Day 29 Visit, Day 60 
Visit) are non-events for good discharges and censored at Day 15, Day 29, Day 60 respectively or at last assessment for subjects still hospitalized or discharged to LTAC, hospice care, or other hospital. 
c Mortality Rates are the Kaplan-Meier estimates. 
d Difference in mortality rates (80%, 95% CI) obtained from Kaplan Meier. 
e HR is the hazard ratio from the Cox Proportional Hazard Model adjusted for baseline ordinal score and baseline steroid use. 
f P-value is based on the Cox adjusted model. 
Tables with similar format: 
Table 14: 
Mortality Rates — ITT Population 
Table 15: 
Mortality Rates — ITT Population with Baseline Ordinal Score of 5 or 6, CRP≥150 mg/L, and age<85 years 
  


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Table 16: 
Time to Death by Treatment Group, Actual Baseline Ordinal Score, and Analysis Population: Restricted Mean Survival Time 
Analysis  
Analysis Population 
Treatment Group 
Actual Baseline 
Ordinal Score 
n 
Taua 
Restricted Mean Time to 
Death (Days) 
Difference 
Estimate 
95% CI 
Estimate 
95% CI 
Time to Death through Day 15 
ITT with BOS 5 or 6, 
CRP<150 mg/L, and 
age<85 years 
Lenzilumab + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
Any BOSb 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
ITT 
Lenzilumab + RDV (N=X) 
5 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
6 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
7 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Lenzilumab + RDV (N=X) 
Any BOSb 
x 
x 
x.x 
x.x, x.x 
x.xx 
x.xx, x.xx 
Placebo + RDV (N=X) 
x 
x 
x.x 
x.x, x.x 
Time to Death through Day 29 
Time to Death through Day 60 
N= Number of subjects in the specified treatment group, actual baseline ordinal score, and analysis population.  
n = Number of subjects who died.  
Difference is the difference in the restricted mean time to death between active treatment to placebo. 
a Tau is the truncation time point for the Restricted Mean Survival Time analysis and is equal to the minimum of the largest observed times in each group. 
b There were X additional subjects with an Actual Baseline Ordinal Score of 4 that are included in the ‘Any BOS’ summaries. 


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Table 17: 
Summary Results of Tipping Point Analysis for the Proportion of Subjects Alive and Without Mechanical Ventilation through 
Day 29 — ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years 
 
Probability of event among nonresponders in Lenzilumab + RDV  
Probability of event among 
nonresponders in Placebo + RDV 
1% 
5% 
10% 
15% 
20% 
40% 
1% 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
5% 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
10% 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
15% 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
20% 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
40% 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Note: Values presented are odds ratios and their corresponding 95% CI calculated from the logistic regression model adjusting for Baseline dexamethasone, Baseline OS, CRP, and age (cont) with 
Placebo + RDV as the reference treatment arm. 
 
Table with similar format: 
Table 18: 
Summary Results of Tipping Point Analysis for the Proportion of Subjects Alive and Without Mechanical Ventilation through 
Day 29 — ITT Population 


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APPENDIX 2. FIGURE MOCK-UPS 
General Programming Notes for figures: 
• Treatment group labeling will be the following will vary by stage. Abbreviations will be 
used if the treatment group labels need to be abbreviated to improve fit.  
• Use the same color for a treatment on the different graphs (SAS standard colors): 
o Lenzilumab + RDV = Blue 
o Placebo + RDV = Red 
• For severity graphs (SAS standard colors): 
o 5 = green 
o 6 = blue 
o 7 = red 
o Death = black 
 
 


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LIST OF FIGURES 
Figure 1: 
Kaplan-Meier Plot for Time to Mechanical Ventilation or Death through 
Day 29 - ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 
mg/L, and age<85 years ..............................................................................................74 
Figure 2: 
Kaplan-Meier Plot for Time to Mechanical Ventilation or Death through 
Day 29 - ITT Population .............................................................................................74 
Figure 3: 
Kaplan-Meier Plot for Time to Sustained Recovery through Day 60 defined 
by 8-point Ordinal Scale - ITT Population with Baseline Ordinal Score of 5 
or 6, CRP<150 mg/L, and age<85 years ....................................................................75 
Figure 4: 
Kaplan-Meier Plot for Time to Sustained Recovery through Day 60 defined 
by 8-point Ordinal Scale - ITT Population .................................................................75 
Figure 5: 
Adjusted Hazard Ratios and 95% Confidence Intervals of Time to 
Mechanical Ventilation or Death through Study Visit Day 29 Using a Cox 
Proportional Hazard Model Overall and for each Subgroup - ITT Population 
with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years ...............76 
Figure 6: 
Adjusted Hazard Ratios and 95% Confidence Interval of Time to 
Mechanical Ventilation or Death through Study Visit Day 29 Using a Cox 
Proportional Hazard Model Overall and for each Subgroup – ITT Population .........76 
Figure 7: 
Adjusted Hazard Ratios and 95% Confidence Interval of Time to Sustained 
Recovery through Study Visit Day 60 Using a Cox Proportional Hazard 
Model Overall and for each Subgroup – ITT Population with Baseline 
Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years ......................................76 
Figure 8: 
Adjusted Hazard Ratios and 95% Confidence Interval of Time to Sustained 
Recovery through Study Visit Day 60 Using a Cox Proportional Hazard 
Model Overall and for each Subgroup – ITT Population ...........................................76 
Figure 9: 
P-values from Tipping Point Analysis for the Proportion of Subjects Alive 
and Without Mechanical Ventilation through Day 29 — ITT Population with 
Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years .......................77 
Figure 10: P-values from Tipping Point Analysis for the Proportion of Subjects Alive 
and Without Mechanical Ventilation through Day 29 — ITT Population .................77 
 


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Figure 1: 
Kaplan-Meier Plot for Time to Mechanical Ventilation or Death through Day 29 - ITT 
Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, and age<85 years  
[Implementation note: For time to mechanical ventilation or death, create individual figures 8A through 8F 
for all baseline dexamethasone use=Yes, No and Baseline ordinal score=5,6]  
 
 
Figure with Similar Format: 
Figure 2: 
Kaplan-Meier Plot for Time to Mechanical Ventilation or Death through Day 29 - ITT 
Population 
 


Statistical Analysis Plan - DMID Protocol: 20-0013 
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Figure 3: 
Kaplan-Meier Plot for Time to Sustained Recovery through Day 60 defined by 8-point 
Ordinal Scale - ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, 
and age<85 years 
[Implementation note: For time to sustained recovery, create individual figures 8A through 8F for all 
subjects, baseline steroid use=Yes, No and baseline ordinals score=5,6]  
 
 
Figure with Similar Format:  
Figure 4: 
Kaplan-Meier Plot for Time to Sustained Recovery through Day 60 defined by 8-point 
Ordinal Scale - ITT Population 


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Figure 5: 
Adjusted Hazard Ratios and 95% Confidence Intervals of Time to Mechanical 
Ventilation or Death through Study Visit Day 29 Using a Cox Proportional Hazard 
Model Overall and for each Subgroup - ITT Population with Baseline Ordinal Score of 5 
or 6, CRP<150 mg/L, and age<85 years 
[Implementation note: The figure below is a shell. The final figure will include all subgroups from Table 1.] 
 
 
Figures with Similar Format:  
Figure 6: 
Adjusted Hazard Ratios and 95% Confidence Interval of Time to Mechanical Ventilation 
or Death through Study Visit Day 29 Using a Cox Proportional Hazard Model Overall 
and for each Subgroup – ITT Population 
Figure 7: 
Adjusted Hazard Ratios and 95% Confidence Interval of Time to Sustained Recovery 
through Study Visit Day 60 Using a Cox Proportional Hazard Model Overall and for 
each Subgroup – ITT Population with Baseline Ordinal Score of 5 or 6, CRP<150 mg/L, 
and age<85 years 
Figure 8: 
Adjusted Hazard Ratios and 95% Confidence Interval of Time to Sustained Recovery 
through Study Visit Day 60 Using a Cox Proportional Hazard Model Overall and for 
each Subgroup – ITT Population 


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Figure 9: 
P-values from Tipping Point Analysis for the Proportion of Subjects Alive and Without 
Mechanical Ventilation through Day 29 — ITT Population with Baseline Ordinal Score 
of 5 or 6, CRP<150 mg/L, and age<85 years 
[Implementation note: Use the ‘TippingPoint’ R package to generate this figure following the example saved 
here: https://mran.microsoft.com/snapshot/2016-07-
08/web/packages/TippingPoint/vignettes/TippingPoint.html 
R code from this package will be updated to present p-values from logistic regressiont. Color shading will be 
added to illustrate which areas of the graph show significant statistical difference. The x and y axes will be 
added to present proportion of events among nonresponders instead of number of events. 
Update the x-axis label to be ‘Probability of event among nonresponders in Lenzilumab + RDV group’.  
Update the y-axis label to be ‘Probability of event among nonresponders in Placebo + RDV group’.] 
 
 
Figure with same format: 
Figure 10: 
P-values from Tipping Point Analysis for the Proportion of Subjects Alive and Without 
Mechanical Ventilation through Day 29 — ITT Population 

Prot_001.pdf: 
Protocol 20-0013B 
Version 7.0 
ACTIV-5/Big Effect Trial (BET) 
10 February 2022 
Appendix B – BET-B: Lenzilumab/Remdesivir vs. Placebo/Remdesivir 
1 
APPENDIX B – ACTIV-5/BET-B: LENZILUMAB/REMDESIVIR VS. 
PLACEBO/REMDESIVIR 
 
 
 
 
 
 


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Appendix B – BET-B: Lenzilumab/Remdesivir vs. Placebo/Remdesivir 
2 
TABLE OF CONTENTS  
Appendix B – ACTIV-5/BET-B: Lenzilumab/Remdesivir vs. Placebo/Remdesivir ..................... 1 
TABLE OF CONTENTS ................................................................................................................ 2 
LIST OF TABLES .......................................................................................................................... 4 
LIST OF FIGURES ........................................................................................................................ 4 
1. 
PROTOCOL SUMMARY ...................................................................................................... 5 
1.1 
Synopsis .......................................................................................................................... 5 
1.1.1 
Change in primary endpoint.................................................................................... 8 
1.2 
Schedule of Assessments .............................................................................................. 10 
2. 
INTRODUCTION ................................................................................................................ 11 
2.1 
Study Rationale ............................................................................................................. 11 
2.2 
Background ................................................................................................................... 11 
2.2.1 
Purpose of Study ................................................................................................... 11 
2.2.2 
Potential Therapeutic Agents ................................................................................ 11 
2.3 
Risk/Benefit Assessment .............................................................................................. 12 
2.3.1 
Known Overall Risks ............................................................................................ 12 
2.3.2 
Potential Risks of Remdesivir ............................................................................... 13 
2.3.3 
Potential Risks of Lenzilumab .............................................................................. 13 
2.3.4 
Known Potential Benefits ..................................................................................... 14 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 14 
4. 
STUDY DESIGN.................................................................................................................. 19 
4.1 
Overall Design .............................................................................................................. 19 
4.2 
Justification for Dose .................................................................................................... 19 
4.2.1 
Justification for Dose of Remdesivir .................................................................... 19 
4.2.2 
Justification for Dose of Lenzilumab .................................................................... 19 
5. 
STUDY POPULATION ....................................................................................................... 20 
5.1 
Inclusion Criteria .......................................................................................................... 20 
5.2 
Exclusion Criteria ......................................................................................................... 20 
5.2.1 
Exclusion of Specific Populations ........................................................................ 21 
5.3 
Inclusion of Vulnerable Subjects .................................................................................. 22 
5.4 
Lifestyle Considerations ............................................................................................... 22 
5.5 
Screen Failures .............................................................................................................. 23 
5.6 
Strategies for Recruitment and Retention ..................................................................... 23 
6. 
STUDY PRODUCT.............................................................................................................. 23 
6.1 
Study Product(s) and Administration –Remdesivir, Lenzilumab, and Placebo............ 23 
6.1.1 
Study Product Description .................................................................................... 23 
6.1.2 
Dosing and Administration ................................................................................... 23 
6.1.3 
Dose Escalation ..................................................................................................... 24 
6.1.4 
Dose Modifications ............................................................................................... 25 
6.1.5 
Overdosage ........................................................................................................... 25 


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Appendix B – BET-B: Lenzilumab/Remdesivir vs. Placebo/Remdesivir 
3 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 25 
6.2.1 
Acquisition and Accountability ............................................................................ 25 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................ 26 
6.2.3 
Product Storage and Stability................................................................................ 27 
6.2.4 
Preparation ............................................................................................................ 27 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 27 
6.4 
Study Intervention Compliance .................................................................................... 27 
6.5 
Concomitant Therapy.................................................................................................... 27 
6.5.1 
Permitted Concomitant Therapy and Procedures ................................................. 27 
6.5.2 
Prohibited Concomitant Therapy .......................................................................... 29 
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 ..................................................................................................... 34 
8.1.3 
Exploratory Assessments ...................................................................................... 34 
8.2 
Safety and Other Assessments ...................................................................................... 34 
8.3 
Adverse Events and Serious Adverse Events ............................................................... 34 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 34 
9.1 
Sample Size Determination........................................................................................... 35 
9.2 
Statistical Analyses ....................................................................................................... 35 
9.2.1 
General Approach ................................................................................................. 35 
9.2.2 
Analysis of the Primary Efficacy Endpoint .......................................................... 36 
9.2.3 
Futility Analysis .................................................................................................... 36 
9.2.4 
Hierarchical Testing .............................................................................................. 36 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....... 36 
11. REFERENCES ..................................................................................................................... 37 
 
 


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Appendix B – BET-B: Lenzilumab/Remdesivir vs. Placebo/Remdesivir 
4 
LIST OF TABLES 
Table 1. Change in CRP and ALC in patients treated with lenzilumab and controls ..................... 6 
Table 2. BET-B Schedule of Assessments ................................................................................... 10 
Table 3. Summary of Adverse Reaction Rates in Subjects with Mild, Moderate, or Severe 
COVID-19 in ACTT-1 .................................................................................................................. 13 
Table 4. BET-B Study Objectives ................................................................................................ 14 
 
LIST OF FIGURES 
Figure 1. Improvement in oxygenation and time to resolution of ARDS in patients treated with 
lenzilumab and controls .................................................................................................................. 6 
Figure 2. Clinical improvement in patients treated with lenzilumab and controls ......................... 7 
Figure 3. Kaplan-Meier plot of Survival Without Ventilation. A. Plot for mITT population. B. 
Plot for mITT population with baseline CRP<150 mg/L . ............................................................. 8 
 


Protocol 20-0013B 
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Appendix B – BET-B: Lenzilumab/Remdesivir vs. Placebo/Remdesivir 
5 
1. 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Rationale for Proposed Clinical Study 
COVID-19 has rapidly emerged as a life-threatening pandemic globally. Experience with SARS-
CoV-2 indicates that approximately 14% develop severe disease that requires hospitalization and 
oxygen support, and 5% require admission to an intensive care unit. In severe cases, COVID-19 
can be complicated by acute respiratory distress syndrome (ARDS), sepsis and septic shock, 
multiorgan failure, including acute kidney injury and cardiac injury. Although SARS-CoV-2 can 
infect the respiratory tract and cause direct cytolytic damage, these actions only partially explain 
the disease pathology. The majority of tissue damage appears to be driven by cytokine release 
syndrome (CRS) mediated host inflammatory response, which may occur even in patients who 
appear to be resolving infection by viral titers. Studies have shown that moderate to severe cases 
of COVID-19 are characterized by marked inflammation and cytokine storm.(1-5) These 
conditions may make it difficult to modify COVID-19 disease pathology solely with pathogen-
directed therapeutics such as remdesivir or viral neutralizing monoclonal antibodies. Therefore, 
it is imperative for any treatment strategy to consider host-directed mechanisms that mitigate 
CRS and the hyperinflammatory immune response. Thus, combining pathogen-directed and host-
directed therapeutics may have more utility and play a critical role in reducing the morbidity, 
mortality, need for invasive mechanical ventilation (IMV) and duration of hospitalization.  
 
Lenzilumab is a monoclonal antibody (mAb) that acts to reduce CRS through granulocyte-
macrophage colony-stimulating factor (GM-CSF) neutralization. Extensive data shows GM-CSF 
to be a key upstream cytokine in the initiation of CRS and neutralization of GM-CSF is expected 
to prevent or reduce the severity of CRS. In preclinical models of CRS induced by CAR-T and 
graft versus host disease, activated T cell production of GM-CSF licenses myeloid cells to 
expand and produce downstream inflammatory cytokines such as IL-1b, IL-6, MCP-1, MIP1a, 
IP-10, and TNFa. Neutralization of GM-CSF prevents the development of CRS and results in 
decreased levels of IL-6, MCP-1, MIP1a, IP-10, and TNFα and reduced levels of inflammatory 
myeloid cells. These and other data indicate that GM-CSF is a critical upstream regulator of 
many downstream inflammatory cytokines known to be important in the pathophysiology of 
CRS. 
 
In COVID-19, emerging clinical data point to the abundance of aberrant pathogenic GM-CSF+ 
T-cells in patients with severe disease and the frequency of GM-CSF+ CD8 T cells, GM-CSF+ 
CD4 T cells, IFNg+ GM-CSF+ CD4 T cells, and inflammatory CD14+CD16+ monocytes are 
correlated with severe disease and ICU admission. GM-CSF appears to play a role in the 
activation, expansion, and trafficking of inflammatory myeloid cells that make up the majority of 
the inflammatory cell infiltrate as measured by bronchoalveolar lavage in patients with severe 
COVID- 19. 
 
Lenzilumab has already been studied four phase I/II clinical trials across various indications, 
including patients with severe asthma, and has a favorable safety and tolerability profile. There 
have been no dose-limiting toxicities, no treatment-related severe adverse events or grade 3 or 4 
events, and no discontinuations due to adverse events reported to date with lenzilumab.  
 


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An initial cohort of patients with severe and critical COVID-19 pneumonia treated with 
lenzilumab under single use emergency INDs was conducted. Twelve patients were treated with 
lenzilumab, 600 mg IV every 8 hours for a total of three doses within a 24-hour period. It is 
important to note that this dosing regimen was specifically developed for the prevention and 
treatment of CRS (aka cytokine storm). The control cohort was identified from an electronic 
registry of more than 1,900 patients with confirmed COVID-19 in the same centers as 
lenzilumab cases. The control cohort is comprised of 27 patients who were not treated with 
lenzilumab, but were matched to cases in age, gender, comorbidity (at least 1 risk factor for poor 
outcome from COVID-19), as well as for being hospitalized with COVID-19 pneumonia, 
requiring oxygen supplementation without mechanical ventilation. At the time of their selection 
for the control cohort, the clinical outcomes of these patients were not known.  
  
Patients treated with lenzilumab demonstrated rapid improvement in oxygenation as determined 
by differences in mean SpO2/FiO2 ratios which were statistically significant (p<0.001, Figure 1). 
There was also a statistically significant difference in the time to resolution of ARDS 
(SpO2/FiO2 <315, p<0.001). 
 
Figure 1. Improvement in oxygenation and time to resolution of ARDS in patients treated 
with lenzilumab and controls 
 
 
 
Lenzilumab treated patients also showed a statistically significant improvement in CRP on day 3 
post treatment relative to controls (p=0.014; see Table 1). Absolute lymphocyte counts (ALC) 
also showed a statistically significant improvement post lenzilumab relative to control (p=0.04, 
Table 1).  
 
Table 1. Change in CRP and ALC in patients treated with lenzilumab and controls 
 
  
 


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Median time to 2-point clinical improvement on the 8-point clinical status ordinal scale was five 
days in the lenzilumab cohort vs. 11 days in the control group (x2=7.43, p=0.006; see Figure 2). 
Ventilator-free survival trended in favor of lenzilumab (x2=3.67, p=0.06, Figure 2B). 
Progression to invasive mechanical ventilation was 8.3% in the lenzilumab cohort vs. 37.0% in 
the control group (p=0.10). Mortality rate was 8% in the lenzilumab cohort vs. 19% in the 
control group (p=0.43).  
 
Figure 2. Clinical improvement in patients treated with lenzilumab and controls 
 
 
Concurrent with the implementation and enrollment of BET-B, the lenzilumab manufacturer, 
Humanigen, sponsored a phase 3 randomized, double-blind, placebo-controlled trial in 
hospitalized patients with COVID-19. Five hundred twenty subjects age >18 years, hospitalized 
with COVID-19 and with either oxygen saturation ≤94% on room air and/or requiring 
supplemental oxygen, were enrolled. (i.e., ordinal score 5 or 6 in the BET-B trial). The study 
excluded those on invasive mechanical ventilation (i.e. ordinal score 7 in the BET-B trial). 
Subjects were randomized to receive lenzilumab (1800 mg, n=261) or placebo (n=259) via three 
intravenous infusions administered 8 hours apart. As part of standard of care, 93.7% of subjects 
received corticosteroids, including dexamethasone, 72.4% received remdesivir, and 69.1% 
received both. Baseline demographics were comparable between the two treatment groups.  
 
The primary endpoint was survival without mechanical ventilation (SWOV) through day 28, 
using a time to event approach. The Kaplan-Meier (KM) estimate of failure to achieve SWOV by 
Day 28 was 15.6% (11.5-20.9) in the lenzilumab group compared to 22.1% (17.4-27.9) in the 
placebo group (Hazard Ratio [HR] =1.54, p=0. 0403, mITT; Figure 2A).(6) In a post hoc 
analysis, the subgroup of subjects with a CRP<150 mg/L and age<85 years, the KM estimate of 
failure to achieve SWOV was 8.5% (5.0-14.1) in the lenzilumab group compared to 21.2% 
(15.9-28.1) in the placebo group (HR=2.96, p=0.0003, mITT; Figure 2B). A similar treatment 
effect was observed when evaluating those that received remdesivir (15.6% vs 25.7%, HR=1.91, 
pp=0.0073, mITT) as well as remdesivir + steroids (16.3% vs 26.9%, HR=1.92, p=0.0067, 
mITT). Mortality in the full population did not reach a statistically significant difference (9.5 in 
lenzilumab arm vs 13.9% in placebo, HR=1.38, p=0.241), but in the subgroup of subjects with a 
CRP<150 mg/L and age<85 years this was statistically significant (6.5% vs 13.8%, HR=2.2, 
p=0.033, no adjustments for multiple comparisons).  
 


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Figure 3. Kaplan-Meier plot of Survival Without Ventilation. A. Plot for mITT population. 
B. Plot for mITT population with baseline CRP<150 mg/L .  
 
Based on the results from the LIVE-AIR trial (and with no knowledge of unblinded interim 
results from this trial), consideration was made to expanding BET-B from a phase 2 to a phase 
2/3 to serve as a confirmatory pivotal trial. This could be accomplished with a larger sample size. 
These changes were implemented in v5 of the protocol.  
1.1.1 
Change in primary endpoint 
The data from the Humanigen -sponsored LIVE-AIR trial also gave an opportunity to understand 
the performance of primary endpoint chosen for this trial. The ordinal score on Day 8 was 
previously chosen to reflect early improvement in disease. This endpoint had tested well using 
ACTT-1 data, a study conducted early in the pandemic. However, using the LIVE-AIR data, 
median ordinal score on Day 8 was 2 for both the lenzilumab and placebo arms in the subgroup, 
p = 0.156 (note: OS2 in the scale used in this trial was called OS7 in the LIVE-AIR trial). 
Approximately 75% of each arm was discharged by Day 8, which are very different trajectories 
for recovery and hospital discharge when compared to data obtained early in the pandemic 
(ACTT-1 data).  
 
Survival without ventilation (Cox proportional hazard model with proportions from using a time 
to event approach) was the primary endpoint in the LIVE-AIR study. This endpoint also tested 
well in ACTT-1 and ACTT-2 data and was chosen as the endpoint used in the ACTT-4 trial. 
Given the overall improvement in care in most patients before Day 8, coupled with the 
performance of survival without ventilation in several trials, changing the primary endpoint to 
survival without ventilation is justified.  Because the timing of ventilation and death within the 
29-day timeframe is less clinically important than its occurrence, the new endpoint is the binary 
version; that is, incidence of mechanical ventilation or death by Day 29. 
 
The subgroup ordinal scale 5 or 6 at baseline with a CRP<150 mg/L and age<85 years was a post 
hoc analysis in the LIVE-AIR trial. 78% of patients with a baseline CRP assessment in LIVE-
AIR had a CRP level of <150 mg/L. As noted above, this cutoff increased the ability to detect a 
difference in treatment arms and demonstrated a group of patients that may derive the greatest 
benefit. It is recognized that the treatment effect in the post hoc subgroup may be overly 
optimistic. However. the cutoff of CRP < 150 mg/L has been reported as a cutoff for subgroups 
that may benefit more from certain other COVID therapeutics (7), providing some albeit limited 
assurance that analysis in this subgroup may improve the power for detecting differences in 
efficacy between lenzilumab and placebo.  
  


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Study Design 
See the Master protocol document for a description of the study design. 
 
Study Objectives  
See Table 4 in Section 3. 
 
Study Population 
This trial will study lenzilumab in a hospitalized adult population (≥18 years old) with COVID-19. 
See Sections 5.1 and 5.2 for inclusion and exclusion criteria. 
 
Study Phase 
• Phase 2/3 
 
Study Sites 
There will be up to 70 domestic sites and 5 international sites. 
 
Study Interventions 
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.  
 
In addition to receiving remdesivir, subjects in the BET-B trial will be randomized to receive 
lenzilumab or placebo as follows:  
• Lenzilumab 600-mg IV infusion starting on Day 1 for a total of 3 doses.  
• Placebo will be given at an equal volume at the same schedule.  
  
Study Duration 
This stage is anticipated to enroll over approximately 12-18 months, with an additional 2 months 
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 
completion of 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 
Table 2. BET-B Schedule of Assessments 
  
Screen 
Baseline  Study Intervention Period 
Follow-up Visits 
Day +/- Window 
−1 or 1 
116 
Daily until hospital 
discharge (up to Day 29) 
811 
± 2 
156  
± 2 
2211 
± 3 
296 
± 3 
6011 
± 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 
 
• Lenzilumab or placebo: 3 infusions 
starting on Day 110 
• Remdesivir: IV daily for 5-10 days or 
until discharge.  
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
Vital signs and NEWS score 1, 15 
 
X3 
 
 
X6 
 
X6 
 
Clinical data collection1  
 
X3 
Daily until discharge 
X 
X 
X 
X 
X14 
Adverse event evaluation 
 
X3 
Daily until discharge 
X 
X 
X 
X 
X 
Concomitant medication review13 
 
X3 
Day -7 until discharge 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
SAFETY LABORATORY 
 
 
 
 
 
 
 
 
Safety hematology, chemistry, 
and liver tests4,9 
X2 
X3 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized5 
 
X 
 
X 
 
Pregnancy test for females of 
childbearing potential 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH LABORATORY17  
 
 
 
 
 
 
 
 
Oropharyngeal swab7 
 
X3 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
 
X 
 
X 
 
Blood draw for serum and plasma.  
Specific testing is as follows: 
 
X3 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized  
 
X 
 
X 
 
PCR SARS-CoV-2 
 
X3 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized  
 
 
 
 
 
proteomic analysis 
(including specifically for 
lenzilumab 
GM-CSF, MCP-1, IP-10, IL-
6, IL-1, TNF-a, G-CSF and 
MIPa) 
 
X3 
Day 3, 8, (all ± 1 day) if 
hospitalized 
 
X 
 
X 
 
lenzilumab 
pharmacokinetics12 
 
X8 
Day 5 (± 1 day) if 
hospitalized  
 
X 
 
X 
 
Serum for secondary 
research 
 
X3 
Day 3, 5, 8, 11 (all ± 1 
day) if hospitalized 
 
X 
 
X 
 
Blood for RNA 
 
X3 
Day 3, 8 (all ± 1 day) if 
hospitalized 
 
X 
 
X 
 
Blood for PBMC12  
 
X3 
Day 3, 8 (all ± 1 day) if 
hospitalized 
 
X 
 
X 
 


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Notes: 
1 Refer to Section 8.1 of the protocol for details of clinical data to be collected including ordinal score, NEWS, oxygen requirement, 
mechanical ventilator requirement, etc. 
2 Screening laboratory tests include: ALT, AST, creatinine (and calculate an estimated glomerular filtration rate (eGFR) the formula used 
is determined by the sites, but should be consistent throughout the study), and 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. 
3 Baseline assessments should be performed prior to first infusion. Laboratory tests performed as part of routine clinical care in the 24 
hours prior to first dose will be accepted for the baseline safety laboratory tests. Baseline may be the same as the screening laboratory 
tests if obtained in the 24 hours prior to first dose. 
4 Safety laboratory tests include WBC with differential, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, INR. 
5 Any laboratory tests performed as part of routine clinical care within the specified visit window can be used for safety laboratory testing.  
6 In-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability to return to the site for the 
visit. In this case, the visit may be performed by phone. 
• 
If still hospitalized at Day 15 and 29 or returns to the site for an in-person visit: assess adverse events, collect clinical data, vital 
signs, NEWS score, safety laboratory tests, and research laboratory samples (OP swab and 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 score), 
readmission to a hospital, and mortality only. 
7 Oropharyngeal swabs are preferred, but if these are not obtainable, saliva or nasopharyngeal or nasal swabs may be substituted.  
8 Pre-dose serum sample collections for PK.  
9 To include markers of inflammation and coagulation: CRP, ferritin, fibrinogen, d-dimer, and LDH.  
10 Approximately 1 hour prior to lenzilumab/placebo infusion, premedication with acetaminophen 500 to 1000 mg PO or IV, or 650 mg 
PR and diphenhydramine 12.5 to 25 mg IV, or 25 mg PO or equivalent is required. 
11 Day 8, 22 and 60 visits performed by phone or home visit if discharged from the site hospital: assess adverse events, clinical status 
(ordinal score), readmission to a hospital, and mortality only. 
12 Only collected at selected sites capable of processing. 
13 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. 
14 Ordinal score only. 
15 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. 
16 Day 1 is defined as the calendar day of randomization. 
17 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.  
 
2. 
INTRODUCTION 
2.1 
Study Rationale 
See Section 1.1 of this Appendix. 
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 


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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).(8) All subjects in the trial will be 
given remdesivir. 
 
Lenzilumab is a first-in-class Humaneered® monoclonal antibody targeting soluble human GM-
CSF, with potential immunomodulating activity, high binding affinity in the pM range, and 94% 
specificity to the human germline, which reduces immunogenicity. Upon administration, 
lenzilumab binds to and neutralizes GM-CSF. This prevents GM-CSF binding to the GM-CSF 
receptor, which is a heterodimeric protein expressed on myeloid progenitor cells and prevents 
GM-CSF-mediated signaling. 
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 lenzilumab (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.  
 
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 the 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 


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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 FDA approved antiviral and may be obtained as part of standard care outside 
the clinical trial. For the purpose of the BET-B study, 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 data in this trial was limited to severe (Grade 3) or 
potentially life-threatening (Grade 4) adverse events, serious adverse events, adverse events 
leading to study drug discontinuation, and moderate (Grade 2) severity or higher hypersensitivity 
reactions. Rates of adverse reactions (≥ Grade 3), serious adverse reactions, and adverse 
reactions leading to treatment discontinuation are presented in Table 3. 
 
Table 3. Summary of Adverse Reaction Rates in Subjects with Mild, Moderate, or Severe 
COVID-19 in ACTT-1 
Types of Adverse Reactions 
Remdesivir N=532 n (%) 
Placebo N=516 n (%) 
Adverse reactions, Grades ≥3 
41 (8%) 
46 (9%) 
Serious adverse reactions 
2 (0.4%)a 
3 (0.6%) 
Adverse reactions leading to 
treatment discontinuation 
11 (2%)b 
15 (3%)  
a Seizure (n=1), infusion-related reaction (n=1).  
b. Seizure (n=1), infusion-related reaction (n=1), transaminases increased (n=3), ALT increased and AST 
increased (n=1), GFR decreased (n=2), acute kidney injury (n=3). 
 
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 Lenzilumab 
As of July 2019, lenzilumab was administered to a total of 109 subjects who were either healthy 
or with specific disease entities including rheumatoid arthritis, asthma, and chronic 
myelomonocytic leukemia. Lenzilumab has been well tolerated, with only mild to moderate 
adverse effects reported in 109 subjects treated across four clinical trials. The most common 
adverse effects were upper respiratory tract infection, headache, and infusion reaction. These 


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adverse effects were no more likely to occur in patients treated with lenzilumab than those 
treated with a placebo injection.  
 
Uncommon adverse effects (occurred in fewer than 10% but in more than 2% of trial 
participants) include headache, infusion reaction, and upper respiratory tract infection. 
 
Rare adverse effects (occurred in < 2 % of trial participants) include diarrhea, reflux, vomiting, 
obstructive abdominal hernia, arthralgia, muscle spasms, extremity pain, urinary tract infection, 
appendicitis, pneumonia, hypertension, acute myocardial infarction (heart attack), transient 
ischemic attack, insomnia, depression, suicide attempt. 
 
One theoretical concern regarding GM-CSF neutralization as a therapeutic strategy was the 
potential for pulmonary alveolar proteinosis (PAP) development. Autoimmune PAP can be 
caused by a disruption of GM-CSF signaling in alveolar macrophages, leading to surfactant 
accumulation in the bronchioles and gas exchange impairment.(9) Patients with autoimmune 
PAP typically have high levels of polyclonal GM-CSF neutralizing auto-antibodies compared 
with healthy individuals.(10-12) Across the 4 studies of lenzilumab, no evidence of PAP was 
detected as assessed by surfactant protein D levels, lactate dehydrogenase levels, oxygen 
saturation, chest X-rays, and pulmonary function.  
2.3.4 
Known Potential Benefits 
Individual subjects with COVID-19 participating in this stage 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 4. BET-B Study Objectives 
 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary 
 
To evaluate the clinical efficacy of 
lenzilumab as assessed by survival without 
mechanical ventilation through Day 29 in 
subjects with ordinal scores 5 or 6 at baseline 
with a CRP<150 mg/L and age<85 years. 
 
 
Occurrence of mechanical ventilation or 
death at any point through Day 29 in subjects 
with ordinal scores 5 or 6 at baseline with a 
CRP<150 mg/L at baseline and age<85 years, 
where the event is one of these two 
categories: 
 
7. Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane 
oxygenation (ECMO); 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
8. Death. 
Key Secondary (in order of testing)* 
 
To evaluate the clinical efficacy of 
lenzilumab as assessed by: 
1. Survival without mechanical ventilation 
through Day 29 in subjects with ordinal 
scores 5 or 6 at baseline with a CRP<150 
mg/L and age<85 years. 
 
 
 
Time to ventilation or death Day 29 in 
subjects with ordinal scores 5 or 6 at baseline 
with a CRP<150 mg/L at baseline and age<85 
years, where the event is one of these two 
categories: 
 
7. Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane 
oxygenation (ECMO); 
8. Death. 
2. Time to sustained recovery compared to 
the control arm in subjects with ordinal scores 
5 or 6 at baseline with a CRP<150 mg/L and 
age<85 years. 
 
 
 
 
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. 
3. Survival without mechanical ventilation 
through Day 29. 
 
Occurrence of mechanical ventilation or 
death at any point through Day 29, where the 
event is one of these two categories: 
7. Hospitalized, on invasive mechanical 
ventilation or ECMO (OS5 or 6 only); 
8. Death. 
 
In those subjects who are at ordinal score 
7 at baseline, the event is defined as 
death through Day 29. 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
4. Time to sustained recovery  
 
 
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. 
Other Secondary  
 
1. To evaluate the clinical efficacy of 
lenzilumab as compared to the control arm as 
assessed by: 
o Ordinal scale: 
▪ Clinical status using ordinal scale at 
Days 8, 15, and 29. 
▪ Time to an improvement of one 
category and two categories from 
Day 1 (baseline) using an ordinal 
scale. 
▪ Mean change in the ordinal score 
from Day 1 to Days 3, 5, 8, 11, 15, 
22, and 29. 
 
• Clinical outcome assessed using ordinal 
scale daily while hospitalized and on Days 
8, 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/ 
 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
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).  
 
• Days of hospitalization up to Day 29. 
• Mortality: 
o 14-day mortality. 
o 29-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 
visit or still hospitalized). 
2. To evaluate the safety of lenzilumab 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 
 
 
• SAEs. 
 
• Grade 3 and 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). 
 


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OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
addition to AEs noted above).  
Exploratory  
 
1. To evaluate the virologic efficacy of 
lenzilumab as compared to the control arm as 
assessed by: 
• Percent of subjects with SARS-CoV-2 
detectable in saliva (or best technology) 
sample at Days 3, 5, 8, 11, 15, and 29.  
• Quantitative SARS-CoV-2 virus in 
saliva (or best technology) sample at 
Days 3, 5, 8, 11, 15, and 29. 
• Quantitative SARS-CoV-2 virus in 
blood at Days 3, 5, 8, and 11. 
 
 
• Qualitative and quantitative polymerase 
chain reaction (PCR) for SARS-CoV-2 in 
OP swab on Day 1; Days 3, 5, 8, and 11 
(while hospitalized); and Days 15 and 29 
(if attends in-person visit or still 
hospitalized). 
• Qualitative and quantitative PCR for 
SARS-CoV-2 in blood on Day 1; Days 3, 
5, 8, and 11 (while hospitalized). 
2. To evaluate the impact of study 
interventions on markers of inflammation and 
immune response. 
• Proteomic analysis of plasma cytokines 
and markers of inflammation including 
GM-CSF, MCP-1, IP-10, IL-6, IL-1, 
TNF-a, G-CSF, and MIPa.  
• Transcription, epigenetic, and molecular 
profiles of mRNA in peripheral blood 
mononuclear cells (PBMC). 
• Phenotypic and responsiveness markers in 
PBMC. 
3. 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.  
 
Stage-specific 
objective/endpoint 
4. To evaluate lenzilumab 
pharmacokinetics (PK) in 
subjects with COVID-19. 
• Serum samples for PK (at pre-dose, Day 
5, Day 15, and Day 29). 
* see Section 9.2.4Hierarchical Testing 
** “New or increased” is relative to pre-COVID status. 


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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 stage will be the same dose shown to be efficacious in the 
ACTT-1 clinical trial,(8) and are the US FDA approved doses. The duration of dosing may be 
adjusted by the site according to clinical severity. The maximum number of doses to be given 
during hospitalization is ten doses. This includes the loading dose and all maintenance doses 
given during the study and pre-study if applicable. 
4.2.2 
Justification for Dose of Lenzilumab 
Lenzilumab has been tested extensively in 109 human subjects from doses of 1 to 10 mg/kg, up 
to 600 mg. Following single-dose IV infusion, linear pharmacokinetic behavior was observed 
and the decline in serum concentrations was biexponential. After single-dose IV infusion at 600 
mg, serum concentrations declined below the therapeutic threshold 72 hours after administration. 
Steady-state pharmacokinetic data revealed a terminal half-life of 28 days and no Grade 3 or 
Grade 4 treatment-emergent AEs have been reported (see the Investigator Brochure for more 
details). There was no evidence of an increase in infections or the development of PAP at these 
doses. 
 
This initial rapid decline in serum concentrations and large volume of distribution of lenzilumab 
relative to plasma volume suggest that lenzilumab is distributed into tissues and repeat dosing is 
required to maintain tissue concentrations at a therapeutic level. In the setting of CRS, GM-CSF 
production by activated T cells in tissue initiates and sustains the inflammatory cascade. GM-
CSF is bound by extracellular matrix and receptors in the local environment and is rarely 
detectable in serum. Serum detection of GM-CSF is an indication of significant pathological 
production of this inflammatory cytokine. In the setting of COVID-19, patients have detectable 
levels of GM-CSF in their sera indicative of significant GM-CSF burst production by activated T 
cells. Given the significant tissue to serum concentration gradient, neutralization of pathological 
GM-CSF levels in tissue is required to blunt the inflammatory cascade. Inhibition of cytokine 
production from U937 cells (monocyte cell line) by lenzilumab has an IC50 of 0.048 ug/ml. It is 
known that serum antibody levels will exceed lung levels by several logs (500-1000x).(13) 
Targeting trough serum levels of lenzilumab at 50 ug/ml would result in lung levels of at least 
0.050 ug/ml which is above the IC50 to inhibit cytokine production from monocytes. Therefore, 
achieving adequate concentration of lenzilumab to fully neutralize receptor and matrix bound 
cytokine in tissue requires serum levels of lenzilumab greater than 50 ug/ml. These levels can be 
achieved with a dose of 600 mg of lenzilumab but repeat dosing will be necessary to maintain 
adequate tissue concentration of drug. The dosing strategy of 600 mg q8hrs for three doses is 
modeled to maintain adequate lung tissue levels of lenzilumab for at least seven days. 


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5. 
STUDY POPULATION 
Approximately 550 (275treatment and 275 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 any 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 
(experimental or licensed). 
5.1 
Inclusion Criteria 
1. Admitted to a hospital with symptoms suggestive of COVID-19 and requires ongoing 
medical care. 
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 score 5, 6, or 7).  
7. Women of childbearing potential must agree to either abstinence or use at least one 
acceptable method of contraception from the time of screening through 5 months post 
study IP dosing.  
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: 


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a. Subjects with an eGFR 20-30 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 <20 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. Received small -molecule tyrosine kinase inhibitors, including Janus kinase (JAK) 
inhibitors (e.g., baricitinib, ibrutinib, acalabrutinib, imatinib, gefitinib) in the 4 weeks 
prior to screening.* 
8. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-IL-1 [e.g., 
anakinra, canakinumab], anti-IL-6 [e.g., tocilizumab, sarilumab, sitlukimab]), or T-cells 
(e.g., abatacept) in the 4 weeks prior to screening.* 
9. Received monoclonal antibodies targeting B-cells (e.g., rituximab, and including any 
targeting multiple cell lines including B-cells) in the 3 months prior to screening.* 
10. Received GM-CSF agents (e.g., sargramostim) within 2 months prior to screening.* 
11. Received other immunosuppressants in the 4 weeks prior to screening and in the 
judgement of the investigator, the risk of immunosuppression with lenzilumab is larger 
than the risk of COVID-19.*  
12. Received any live vaccine in the 4 weeks prior to screening. 
13. Known active tuberculosis. 
14. Known history of HIV, Hepatitis B (HBV) or untreated hepatitis C (HCV) infection 
15. History of pulmonary alveolar proteinosis (PAP).* 
16. Has a malignancy currently receiving immunosuppressive chemotherapy, 
immunodeficiency, uncontrolled opportunistic infection, or uncontrolled cirrhosis. 
17. Has a medical condition that could, in the judgment of the investigator, limit the 
interpretation and generalizability of trial results. 
18. Positive test for influenza virus during the current illness (influenza testing is not 
required by protocol). 
19. Previous participation in an ACTIV-5/BET trial. 
 
* 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. The safety and efficacy of lenzilumab in pediatric patients less than 18 
years of age have not yet been established. Given significant gaps in knowledge in this 


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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 lenzilumab 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 lenzilumab is secreted in human milk. Because the effects 
of remdesivir and lenzilumab on the breastfeeding infant is not known, women who are breast 
feeding will not be eligible for the trial. 
5.3 
Inclusion of Vulnerable Subjects 
Certain human subjects are categorized as vulnerable populations and require special treatment 
with respect to safeguards of their well-being. For this clinical trial, examples include cognitively 
impaired or mentally disabled persons and intubated individuals who are sedated. When it is 
determined that a potential research subject is cognitively impaired, federal and institutional 
regulations permit researchers to obtain consent from a legally authorized representative (LAR). 
The study team will obtain consent from these vulnerable subjects using an IRB-approved 
protocol-specific process for consent using a LAR. 
 
For subjects for whom a LAR gave consent, during the course of the study, if the subject regains 
the capacity to consent, informed consent must be obtained from the subject and the subject 
offered the ability to leave the study if desired. 
5.4 
Lifestyle Considerations 
During this study, subjects are asked to: 
• Refrain from drinking alcohol through Day 15.  
• Avoid getting pregnant during the study from the time of screening through 5 months 
post study IP dosing. 
• 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, etc.) 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 
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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. 
6. 
STUDY PRODUCT 
6.1 
Study Product(s) and Administration –Remdesivir, Lenzilumab, 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. 
 
Lenzilumab Component: 
Lenzilumab is a first-in-class Humaneered® recombinant monoclonal antibody targeting soluble 
human GM-CSF, with potential immunomodulating activity, high binding affinity in the pM 
range, and 92% specificity to the human germline, which reduces immunogenicity. 
 
Placebo for lenzilumab will be commercially sourced 0.9% sodium chloride, USP injection. 
6.1.2 
Dosing and Administration 
All subjects will receive remdesivir as a 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 were administered prior to study 


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enrollment should be documented in on the 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 or 
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-B trial will be randomized to receive 
lenzilumab or placebo as follows:  
• Lenzilumab 600-mg IV infusion every 8 hours, infused in approximately 60 minutes, 
starting on Day 1 for a total of 3 doses.  
• Placebo will be given at an equal volume at the same schedule.  
 
Lenzilumab General Instructions: 
Lenzilumab 600 mg via IV infusion will be administered starting on Day 1 (within 12 hours of 
randomization). A total of three doses of lenzilumab will be administered within 8 hours (± 30 
minutes) between each dose. Doses may be delayed up to 12 hours as needed for patient’s 
clinical status, or for the research or medical teams schedule or workload, and this delayed 
dosing is not considered a protocol deviation. No two doses should be administered less than 4 
hours apart. 
 
The following pre-medications should be administered approximately 1 hour prior to each 
lenzilumab/placebo infusion to prevent infusion reactions. Any delays in premedication should 
not delay lenzilumab administration and is not considered a protocol deviation. Alternatives to 
the recommendations below should be discussed with the DMID Medical Officer. 
• Acetaminophen 500 to 1000 mg PO (includes liquid) or IV, or 650 mg PR.  
• Diphenhydramine 12.5 to 25 mg IV, or 25 mg PO or equivalent 
 
Since this is a blinded study, all subjects (active and placebo groups) should receive pre-
medication to prevent infusion reactions.  
 
At least 20 minutes between administration of remdesivir and lenzilumab or placebo are 
preferred if possible (to allow attribution of any infusion related adverse reactions). However, 
timely administration of both products is most important, and if the interval between products is 
likely to cause delays for either products, it can be omitted. See the Manual of Procedures (MOP) 
for details.  
 
If a dose of lenzilumab is delayed, it should be given as soon as practical. A total of 3 doses of 
lenzilumab should be given, even if delayed.  
6.1.3 
Dose Escalation 
Not Applicable 


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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 < 20 mL/min. 
o Remdesivir infusion will resume when the eGFR increases to ≥ 20 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 > 5 times upper limits of normal (ULN); resume remdesivir 
infusions when ALT and AST ≤ 5 times ULN. 
 
Lenzilumab component: No dosing adjustment needed. 
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. 
 
In the event of lenzilumab overdosage, monitor the patient for any signs or symptoms of adverse 
reactions and administer appropriate symptomatic treatment immediately. 
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, lenzilumab, and placebo.  
 
Accountability 
The site PI is responsible for study product distribution and disposition and has ultimate 
responsibility for study product accountability. The site PI may delegate to the participating 
site’s research pharmacist responsibility for study product accountability. The participating site’s 
research pharmacist will be responsible for maintaining complete records and documentation of 
study product receipt, accountability, dispensation, storage conditions, and final disposition of 
the study product(s). Time of study drug administration to the subject will be recorded on the 
appropriate data collection form (CRF). All study product(s), whether administered or not, must 
be documented on the appropriate study product accountability record or dispensing log. The 
Sponsor’s monitoring staff will verify the participating site’s study product accountability 
records and dispensing logs per the site monitoring plan. Refer to the protocol-specific MOP for 
details on storing study medications.  


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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 vials can be destroyed on-site 
following applicable site procedures with a second staff member observing and verifying the 
destruction.  
 
Unused vials at the end of the study should be saved until instructed by the Sponsor. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
Remdesivir component 
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. 
 
Lenzilumab component 
Lenzilumab is formulated as a sterile, clear, colorless liquid for IV administration and supplied in 
single-use, 10-mL vials. Each vial contains 100 mg of lenzilumab at a concentration of 10 
mg/mL. The drug product is formulated with sodium phosphate, sodium chloride, and 
polysorbate 80 at pH 7.0, as a concentrate for dilution prior to IV infusion. 
 
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.” 
 
Any unused investigational product should be handled as described in the MOP and waste 
material should be disposed of in accordance with local requirements. 
 


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Placebo  
Placebo for lenzilumab will not be supplied. Sites should use 0.9% Sodium Chloride Injection, 
USP which is a colorless, sterile, nonpyrogenic, isotonic solution of sodium chloride and water 
for injection (WFI) or pre-filled 0.9% Sodium Chloride pre-filled IV bags.  
Blinding instructions for lenzilumab/placebo are detailed in the MOP. 
6.2.3 
Product Storage and Stability 
Refer to the MOP for details regarding the stability and storage of remdesivir, lenzilumab, and 
placebo. 
6.2.4 
Preparation 
Refer to the MOP for details about preparation and handling of remdesivir, lenzilumab, and 
placebo.  
 
Remdesivir and lenzilumab 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. Patients will first be randomized to one of the stages 
to which they are eligible (e.g. lenzilumab or other interventions) with equal allocation. Then 
patients 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 backbone therapy comprising remdesivir. Patients randomized to 
lenzilumab in the first stage will be randomized to receive either lenzilumab/remdesivir or 
placebo/remdesivir 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 case report form (CRF). 
6.5 
Concomitant Therapy 
6.5.1 
Permitted Concomitant Therapy and Procedures 
For patients that are eligible for the study, other therapy received prior to enrollment with any 
other experimental treatment or off-label use of marketed medications that are intended as 
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[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 EDC system.  
Steroids for the treatment of COVID-19 may be used per the local institution’s written standard 
of care (i.e., not just an individual clinician decision) or National Institutes of Health (NIH) 
COVID-19 Treatment Guidelines (https://www.covid19treatmentguidelines.nih.gov/). NIH 
COVID-19 Treatment Guidelines provide current evidence-based information about the optimal 
management of COVID-19. NIH COVID-19 Treatment Guidelines were updated on June 25, 
2020 to include a Grade AI recommendation for using dexamethasone (6 mg per day for up to 10 
days) in patients with COVID-19 who are mechanically ventilated and a Grade B1 
recommendation for patients with COVID-19 who require supplemental oxygen but who are not 
mechanically ventilated based on preliminary data from the RECOVERY trial. The NIH 
Guidelines also recommend against using dexamethasone in COVID-19 patients who do not 
require supplemental oxygen.  
Steroid regimens for other standard indications including asthma exacerbation, ARDS, COPD, 
laryngeal edema, adrenal insufficiency, shock, etc. are allowable up to a maximum of prednisone 
60 mg daily or equivalent. All steroid use regardless of indication until Day 29 will be recorded 
in the EDC system.  
Small -molecule tyrosine kinase inhibitors, including JAK inhibitors (e.g., baricitinib) and 
monoclonal antibodies targeting cytokines (e.g., tocilizumab) may be used to prevent/treat 
progression of COVID-19 disease if used as described in the NIH COVID-19 Treatment 
Guidelines (https://www.covid19treatmentguidelines.nih.gov/). Progression of disease is defined 
as increase in ordinal score or increase in oxygen requirement from baseline.  
 
Subjects who are taking another antiviral for a concurrent infection (e.g., oseltamivir for an 
influenza virus) or another existing medical condition (e.g., hydroxychloroquine for lupus) may 
continue with the treatment. Note that these treatments may be thought of as an off-label 
medication for COVID-19, however, because they were being used prior to study enrollment for 
another indication, they are allowable. 
 
Outpatient experimental treatment or off-label use of marketed medications that are intended as 
specific treatment for COVID-19 do not need to be discontinued if there is a written policy or 
guideline for the local standard of care and treatment of COVID-19 patients or SARS-CoV-2 
infection (i.e., not just an individual clinician decision). In the absence of a local written standard 
of care, the National Institutes of Health (NIH) COVID-19 Treatment Guidelines may be used. If 
concomitant medications are used, there should be plans on how the concomitant drugs are 
stopped in case of additive toxicities. 
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, 
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with the exceptions listed in the bullets below. Administration of all biologics, convalescent 
plasma and steroids should be recorded from 7 days prior to enrollment to Day 29. 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; 
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, unless clinically indicated to 
prevent/treat progression of disease (as described above): 
• 
Small -molecule tyrosine kinase inhibitors, including JAK inhibitors (e.g., baricitinib, 
ibrutinib, acalabrutinib, imatinib, gefitinib).  
• 
Monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-IL-1 [e.g., anakinra, 
canakinumab], anti-IL-6 [e.g., tocilizumab, sarilumab, siltukimab]), or T-cells (e.g., 
abatacept). 
 
The following medications are prohibited at any time during this study: 


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• 
GM-CSF agents (e.g., sargramostim). 
• 
Lenzilumab outside of this trial (currently not available, but in case it becomes available 
during the study). 
• 
Other immunosuppressants which, in the judgment of the investigator, pose risk of 
immunosuppression in combination with lenzilumab that is larger than the risk of 
COVID-19. 
• 
Chloroquine or hydroxychloroquine use for the treatment of COVID-19. 
 
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.  
 
Overall, the risk of potential drug-drug interactions between lenzilumab and concomitant 
medications is low. As a monoclonal antibody, lenzilumab is not expected to undergo 
metabolism by hepatic enzymes or renal elimination. Drug interactions between lenzilumab and 
substrates/inhibitors/inducers of drug metabolizing enzymes are not expected.  
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 
criteria for grading “hypersensitivity” in the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adverse Events,(14) 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.  
 


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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).  
• 
Confirm that patient does not have a positive influenza test during the current illness for 
which they are being screened. (Influenza testing is not required per protocol.) 


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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 or BET. 
• History of vaccinations within 4 weeks prior to screening, including SARS-CoV-2 
vaccination. 
• Exclusionary vaccine history includes any live vaccine (that is, live attenuated) 
within 4 weeks prior to screening. 
• 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 5 months post study 
IP dosing.*  
*Note: Acceptable methods include barrier contraceptives (condoms or diaphragm) with spermicide, 
intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and surgical sterilization. 
• 
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 
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Study subjects who qualify will be randomized in the interactive response technology system 
(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 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 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 scale. 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.  
 
Ideally, the ordinal scale is completed concurrently with the NEW Score just prior to study 
product administration. 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. 


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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) 
8.1.3 
Exploratory Assessments 
See Section 8.1.2 of the Master protocol document. Additional exploratory assessments include: 
• Qualitative and quantitative polymerase chain reaction (PCR) for SARS-CoV-2 in OP 
swab on Day 1; Days 3, 5, 8, and 11 (while hospitalized); and Days 15 and 29 (if attends 
in-person visit or still hospitalized). 
• Qualitative and quantitative PCR for SARS-CoV-2 in blood on Day 1; Days 3, 5, 8, and 
11 (while hospitalized). 
• Plasma proteomic analysis of cytokines and markers of inflammation including GM-CSF, 
MCP-1, IP-10, IL-6, IL-1, TNF-a, G-CSF, and MIPa 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).  
• Serum samples for PK (at pre-dose, Day 5 (if hospitalized), Day 15, and Day 29). 
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 
evaluations (including samples for secondary research-defined in master protocol 10.1.1.2) is 
approximately 450 mL, with a maximum daily volume of approximately 73 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. However, there are important differences between 
BET-B and the Master protocol, and these are presented here.  
 
While the endpoints are ordered differently and BET-B's primary analysis, and some secondary 
analyses, are limited to a pre-specified subgroup, all BET stages will analyze the same endpoints. 
Furthermore, the method of analysis for any given endpoint will be conducted the same for BET-
B as for the other interventions. 
 
Several statistical features were modified at the time BET-B was changed to a Phase 2/3 design 
including an increase in sample size, change to the primary endpoint, and new futility analysis. 
 
Statistical Hypotheses 


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The primary null hypothesis being tested is that incidence the composite endpoint of mechanical 
ventilation or death is the same between the experimental and control arms within the following 
subgroup of (subjects with baseline CRP<150 mg/L, ordinal score<7, and age<85). The 
parameter estimated by the primary analysis is the odds ratio.  
 
These differences are study adaptations that were implemented mid-study. The changes were 
motivated entirely by the results of the LIVE-AIR study. Adapting BET-B to a Phase 2/3 trial 
was deemed a timely approach for replication of the LIVE-AIR results. At the time of this 
adaptation, the BET team involved in this decision had no knowledge of interim BET-B results 
broken down by active versus placebo groups. 
9.1 
Sample Size Determination 
The LIVE-AIR trial estimated a HR of about 1.5 in its overall population, and a HR of above 3 
in the identified subgroup. The corresponding relative risks for the primary endpoint were in the 
2.5 or 2.6 range, and the corresponding odds ratio were around 3. Because the treatment effect in 
the post hoc subgroup may be overly optimistic, the BET-B updated sample size assumes an 
intermediate odds ratio of 2.5 for the subgroup. The LIVE-AIR trial also observed a 21% event 
rate in the placebo group in the subgroup, which is likely higher than expected in this trial. (The 
primary analysis, logistic regression, will estimate an odds ratio. For the expected range of 
control event rates, the relative risk of 2.2 corresponds to an odds ratio of about 2.5; the relevant 
observed odds ratios in LIVE-AIR were about 3.)  
 
A sample size of 400 in the subgroup will yield 80% power if the control event rate is 16% and 
89% power if the control rate is 21%, if the odds ratio is 2.5 and a two-sided alpha=.049. (An 
odds ratio of 2.5 is defined such that if the control event rate is 16%, the treated rate would be 
7%). At most 550 participants (that is, subjects randomized into BET-B and relevant shared 
controls) will be randomized. Based on early BET baseline estimates, roughly 75% of subjects 
are expected to fall in the primary analysis subgroup at baseline (CRP<150, age<85, and OS<7). 
The trial will enroll subjects until 400 are randomized in the subgroup or 550 overall, whatever 
comes first. These calculations are not inflated for missing data, as little missing data are 
expected. 
 
9.2 
Statistical Analyses 
9.2.1 
General Approach 
The general approach follows the corresponding section in the Master Protocol (Section 9.3.1) 
with the following exception: 
 
The adapted study is now a Phase 2/3 double-blind, placebo- controlled, randomized trial testing 
a superiority hypothesis where the intervention will be considered statistically significant if the 
final two-sided p-value is < .05. The statements of declaring agents “promising” for a p-value 
<.20 as noted in the Master protocol are not applicable to BET-B. Only 95% confidence intervals 
will be computed for the treatment effect corresponding to the primary and key secondary 
endpoints.  


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Because of an interim analysis completed after 100 total subjects tested the original primary 
endpoint (Day 8 Ordinal Score) at alpha=.001, the primary analysis will be conducted at 
alpha=.049, for an overall two-sided .05 type I error rate (using a Bonferroni approach to 
multiplicity.) 
9.2.2 
Analysis of the Primary Efficacy Endpoint 
The primary analysis will be conducted as a logistic regression model (adjusted for severity 
level, baseline CRP, age, and baseline dexamethasone use), where the event is ventilation or 
death by Day 29, and will be limited to the pre-specified subgroup (age<85, CRP<150 mg/L, and 
ordinal score 5 or 6 at baseline). The main version of the primary analysis will be done in the 
ITT population; approaches to missing data will be detailed in the SAP.  The primary analysis 
will be repeated in the MITT population. 
 
 
Controls from other stages will be included in this analysis, as appropriate; this process is 
described in the primary efficacy endpoint analysis section in the Master Protocol. A sensitivity 
analysis will adjust for clinical site.  
 
9.2.3 
Futility Analysis 
A futility analysis will take place after 280 subjects in the primary analysis subgroup have been 
enrolled and randomized.  If Version 6.0 is implemented after the 280th subject is randomized, 
then the futility analysis will be based on data observed by the implementation date. If 
enrollment is nearing completion at the timepoint the interim futility analysis report would be 
anticipated to be available, a futility analysis will not be completed. The DSMB will continue to 
receive safety data weekly to ensure safety oversight.   
  
If conditional power under the hypothesized treatment effect is less than 20%, the DSMB could 
recommend stopping the study for futility. To properly consider all accumulated data, the interim 
Z-test for the conditional power calculation will be based on a test of difference in the Kaplan-
Meier estimates at Day 29, as some subjects will be in the middle of their follow-up. Further 
details in the SAP. 
 
9.2.4 
Hierarchical Testing 
This protocol contains three key secondary endpoints.  The key secondary endpoints will be 
tested in the order presented in the endpoint section.  If the primary analysis is significant at .049, 
then the first key secondary endpoint can be tested at .049.  If this is significant, then the second 
key secondary endpoint can be tested at .049, and so forth.  There is no hierarchical testing for 
other (non-key) secondary endpoints.  
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 


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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. 
REFERENCES 
1. 
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological 
features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9. 
2. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected 
with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 
3. 
Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune 
responses. J Med Virol. 2020;92(4):424-32. 
4. 
Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 
2020;368(6490):473-4. 
5. 
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm' in 
COVID-19. J Infect. 2020;80(6):607-13. 
6. 
Temesgen Z, Burger CD, Baker J, Polk C, Libertin C, Kelley C, et al. LENZILUMAB 
EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS 
FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-
CONTROLLED TRIAL. medRxiv. 2021:2021.05.01.21256470. 
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Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. 
Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med. 2020. 
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Trapnell BC, McCarthy C. The Alveolar Lipidome in Pulmonary Alveolar Proteinosis. A 
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Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, et al. Characteristics of a 
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Kitamura T, Tanaka N, Watanabe J, Uchida, Kanegasaki S, Yamada Y, et al. Idiopathic 
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Uchida K, Nakata K, Suzuki T, Luisetti M, Watanabe M, Koch DE, et al. 
Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune 
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Tabrizi M, Bornstein GG, Suria H. Biodistribution mechanisms of therapeutic 
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U.S. Department of Health and Human Services, National Institutes of Health, National 
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