Clinical trial NCT04315298
Conditions: COVID-19
Keywords: COVID-19 SARS-COV-2 coronavirus IL-6 sarilumab acute respiratory distress syndrome treatment
Sponsor: Regeneron Pharmaceuticals
Start date: 2020-03-18; Completion date: 2020-09-02
Enrollment: 1912 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 2:

The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with COVID-19 regardless of disease severity strata.

Phase 3 Cohort 1:

The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with critical COVID-19 receiving mechanical ventilation at baseline.

Phase 3 Cohort 2:

The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with COVID-19 receiving mechanical ventilation at baseline.

Detailed description:
Phase 2 and Phase 3 Cohort 1 completed. Cohorts 2 and 3 terminated early based on Phase 3 Cohort 1 results.

Arms: arm 1: Phase 2 arm 2: Phase 3: Cohort 1 arm 3: Phase 2 arm 4: Phase 3: Cohort 1 arm 5: Phase 3: Cohort 2 arm 6: Phase 3: Cohort 3
Interventions: intervention 1: Sarilumab intervention 2: Placebo
Intervention descriptions: intervention 1: Single or multiple intravenous (IV) doses of sarilumab. Additional doses may be administered if the patient meets protocol defined criteria. intervention 2: Single or multiple intravenous (IV) doses of placebo to match sarilumab administration

Protocol documents:
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GLOBAL STUDY LEVEL INFORMED CONSENT FORM 
(ICF) 
 
TITLE: 
An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-
Controlled Study Assessing Efficacy and Safety of Sarilumab for 
Hospitalized Patients with COVID-19 
 
PROTOCOL NO.: 
6R88-COV-2040 
WIRB® Protocol #20200610 
 
SPONSOR: 
Regeneron Pharmaceuticals, Inc. 
 
INVESTIGATOR: 
Name 
Address 
City, State  Zip 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Phone Number 
Phone Number (24 hours) 
[24 hour number is required] 
 
NCT  
NCT04315298 
Site Number 
[Site Number, if applicable] 
Participant’s Printed Name: 
 
Throughout this document, “you” and “your” includes the case where a 
Legally Authorized Representative is consenting on behalf of a patient. 
 
In medicine there are many unanswered questions. A research study is when scientists try to 
answer a question about something that we don’t know enough about.  Participation in a research 
study may or may not directly help you or others. Participation is entirely voluntary. It is 
completely up to you whether or not you take part. You can also change your mind at any time 
and it will not affect your ability to get medical care within the [Institution Name]. 
 
The purpose of this research study is to determine if the investigational study drug sarilumab is 
safe and if it can decrease the amount of time you have COVID-19 symptoms.  
 
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If you choose to participate, you will be in this study for up to 60 days or until discharge from 
the hospital, and you may receive the investigational study drug or a placebo. Your alternative is 
not to participate. 
 
The main risks to you if you choose to participate are infections. Common colds and urinary 
infections are the most common side effects reported in patients participating in sarilumab 
clinical studies. You can also experience oral herpes (cold sores), more serious infections, 
allergic reactions, and low white blood cell counts when using sarilumab. Unknown side effects 
may also occur. 
 
Participating in this research may or may not benefit you. 
 
If you are interested in learning more about this study, please continue to read below. 
 
THE INFORMED CONSENT PROCESS 
 
You are being asked to participate in a clinical research study sponsored by Regeneron 
Pharmaceuticals, Inc. (“Regeneron”). Your participation in this study is entirely voluntary. 
 
This study involves research and is conducted to determine the safety and effectiveness of a 
study drug called sarilumab. 
 
Sarilumab is currently being studied for treatment of COVID-19. You may be eligible to 
participate in this study if you meet certain requirements. Before you decide to participate, you 
need to understand the purpose of the study, the possible risks and benefits, and what would be 
expected of you. This process is called Informed Consent. 
 
This document is an Informed Consent Form. Please read this entire document carefully. Take 
time to ask the study doctor or study staff as many questions about the study as you would like. 
If there are any words or information in this document that you do not understand, please ask the 
study doctor or study staff to explain them to you. You can also ask for a copy of this unsigned 
form to review with your physician, friends, and family. 
 
If you agree to participate in this study, you must sign and date this consent form before any 
study-related tests or procedures are performed.  A copy of the signed and dated document will 
be given to you. 
 
To protect your safety, rights, wellbeing, and dignity, all information from the study is reviewed 
by an independent group of people called an Institutional Review Board (IRB). This study has 
been given a favorable opinion. 
 
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The Sponsor is paying for your care related specifically to this study and the study doctor will be 
paid by the Sponsor for those specific aspects of your care. 
 
WHAT DOES THIS INFORMED CONSENT FORM DESCRIBE? 
 
This document describes: 
 
• The purpose and procedures of the study. 
• Possible risks and side effects that you may experience. 
• Possible benefits that you may experience from participation in this study. 
• Other treatments or procedures (other than the procedure or treatment that is part of this 
study) that are available to you.  
• How your personal and health information will be used and disclosed in this study and 
requests your permission for that use and disclosure. 
• Your privacy rights in connection with the personal information collected from or shared 
by you in connection with the study. 
• What compensation and/or medical treatment is available to you if injury occurs.  
• Whom you can contact if you have questions about the study. 
• Your rights as a research participant. 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
You are being asked to participate in a research study of the investigational drug, sarilumab 
(study drug) sponsored by Regeneron Pharmaceuticals, Inc. (“Regeneron”) because you have 
the COVID-19 virus.  This research study will be referred to as the “study” throughout this form.  
 
Sarilumab (also known as Kevzara®) is considered an investigational drug in this study because 
it has not been approved for marketing by any health authority for the condition being studied 
but it has been approved in multiple countries for active rheumatoid arthritis.   
 
Sarilumab is a type of drug called a “monoclonal antibody”.  An antibody is a special kind of 
protein that your immune (defense) system normally makes to fight bacteria and viruses.  
Scientists can now make antibodies in the laboratory and produce them for the treatment of many 
different diseases.  Sarilumab has been specifically shown to block the action of a protein called 
interleukin-6 (IL-6) in your body. Interleukin-6 (IL-6) is a protein in the immune system that has 
been shown to play an important role in inflammation.  Inflammation may be associated with 
complications of COVID-19. 
 
The main purpose of this study is to determine if sarilumab is safe and if it can decrease the 
amount of time you have COVID-19 symptoms.  
 
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Regeneron, its collaborators or those developing the study drug; and their affiliates, 
representatives, agents and contractors (together, the “Regeneron Parties”), will use the 
information from the study to better understand the following:  
 
• Side effects that may be experienced by people taking sarilumab  
• How sarilumab works in the body 
• How much sarilumab is present in your blood 
• To see if sarilumab will decrease the amount of time you have COVID-19 symptoms  
 
This document describes what is known about the study drug and study tests at the time this 
consent form is signed. You will be told in a timely manner if any important new information is 
learned during the conduct of the study that may affect your decision to take part in the study.  
Your participation in this study is entirely voluntary and you may withdraw from the study at any 
time. You do not need to give a reason, and your medical care (outside of the study) will not be 
affected by your decision.   
 
After you sign this document, testing will be done to determine if you are eligible to participate 
in this study. You must meet certain requirements to be able to participate in this study. The 
study doctor will review all of the restrictions and requirements of the study with you to 
determine if you qualify for the study. There is a chance that you may not qualify.  There is also 
a chance that you may qualify for the study but may not be able to participate due to other 
reasons such as the timing of enrollment. 
 
WHAT WILL HAPPEN IF YOU JOIN THIS STUDY AND HOW LONG 
WILL IT LAST? 
 
This is a randomized, double-blind, placebo-controlled study. “Randomized” means that the 
group you will be placed in is decided by chance, similar to drawing numbers out of a hat or 
flipping a coin.  “Double-blind” means that neither you nor the study doctor will know which 
treatment group you have been placed in (ie, if you are receiving sarilumab or placebo). This is 
done to make sure the results of the study cannot be influenced by anyone. If there is an urgent 
need, the study doctor can find out quickly which study drug you are receiving.  A placebo is an 
inactive substance, that looks like the medicine, but which contains no medicine. If you agree to 
take part in this study, you will receive either sarilumab or placebo. 
 
Your participation in this study may last up to 60 days or until you are discharged from the 
hospital.  This study consists of: 
 
• A screening visit (1 day)  
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• A baseline visit (1 day), this can occur at the same time as the screening visit, if 
necessary.   
• Monitoring period (58 to 59 days) or until discharged  
• Follow-up telephone call on day 29 (if you are discharged before day 29) and at day 60 
 
HOW BIG IS THE STUDY? 
 
This study will include about 2300 patients at research centers in the United States.  Due to the 
status of the current outbreak of the COVID-19 virus, the study may continue enrolling patients 
unless the study drug is shown to not work or not be safe for patients with COVID-19.  
 
HOW WILL I BE GIVEN THE DRUG? 
 
The study drug or placebo will be given through a vein (intravenous [IV] infusion).  The infusion 
will last for about 1 hour. From here on, sarilumab and placebo will be referred to as the “study 
drug”.   
 
You will be given the study drug on day 1.  If your COVID-19 symptoms do not improve, you 
may be given another dose on day 2.  Then you may also be given the study drug on a weekly 
basis (up to 4-6 doses) until your COVID-19 symptoms improve or you are discharged from the 
hospital. 
 
If you were enrolled into cohort 1, before April 27, 2020, you were randomly assigned to 1 of 3 
possible study treatments (200 mg or 400 mg of sarilumab or placebo, IV, single or multiple 
doses). 
 
If you are enrolled into cohort 1 after April 27, 2020, you will be randomly assigned to 1 of 
2 possible study treatments (400 mg of sarilumab or placebo, IV, single or multiple doses). 
 
• If you were in the 200 mg study treatment group and have not reached the 6-dose 
maximum, your study drug will be discontinued, and you will continue to be monitored 
until you are discharged from the hospital and have your follow-up telephone call(s). 
• If you are on a ventilator and were in the placebo or 400 mg study treatment groups and 
you have not reached your 6-dose maximum, you will continue study treatment during 
the monitoring period as long as you are still on the ventilator. If you are no longer on a 
ventilator, your study treatment will be discontinued (if you have not already reached 
your 6-dose maximum) and you will continue to be monitored until you are discharged 
from the hospital and have your follow-up telephone call(s). 
 
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If you were in the placebo or 400 mg group, based on the severity of your disease when you 
enrolled into the study, the study doctor and sponsor may have you discontinue the study drug.  
You will continue to be monitored until you are discharged from the hospital and have your 
follow-up telephone call(s). 
 
If you are enrolled into cohort 2 or 3, will be assigned to 1 of 2 possible study treatments. 
 
You will be given either:  
• 800 mg of sarilumab, IV, single or multiple dose (up to 4 doses maximum) 
• Placebo, IV, single or multiple dose (up to 4 doses maximum)  
 
The study will no longer enroll and give study drug to patients who are not on ventilators as of 
06 June 2020. This change was made because patients who were not on a ventilator did not 
respond to study treatment, and among these patients, there were more deaths in patients who 
were receiving sarilumab than placebo. While these deaths could be due to COVID-19 and not 
sarilumab, patients not on a ventilator will no longer be enrolled or be given the study treatment.  
If you are not on a ventilator, your study drug will be discontinued, and you will continue to be 
monitored until you are discharged from the hospital and have your follow-up telephone call(s). 
 
A data monitoring committee, that is not part of Regeneron, reviews safety and efficacy data 
from the study.  This committee has recommended, and Regeneron agreed, that study drug can 
continue to be given to patients who are on ventilators.   
 
The study staff will try to use the already established IV catheter line that was given to you for 
fluids to administer the study drug.  There may be a chance that this is not possible, and the study 
staff will have to insert a new IV catheter line for the study drug.  
 
Sarilumab has been approved for subcutaneous (under the skin) use.  This is the first study where 
200 mg, 400 mg and 800 mg IV infusion will be given to human volunteers and the first study in 
which the 400 mg and 800 mg dose levels will be used. 
 
WHAT ELSE DO I HAVE TO DO WHILE PARTICIPATING IN THIS 
STUDY? 
 
Some of the study procedures listed below are also part of your standard-of-care that you will 
receive while in the hospital, these procedures will not be repeated if your nurse had already 
performed them.  The study staff will instead record the results from your chart.  There may be 
times that the study staff may have to perform some of the procedures below if they had not 
already been done.  These procedures will occur at different times during your hospital stay and 
may occur more than once in a single day.  You can talk to the study staff if you have any 
questions about how and when these procedures will occur.   
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Questions/Information Collected About Your Health  
 
The study staff may either ask you or collect the following information from your charts (if 
available): how you feel, current health status, your age, race, ethnicity, medical and surgical 
history, your food intake, smoking and alcohol habits, menopausal history (women only), 
physical activity, sexual habits or behavior, contraception and previous and current medications. 
 
The study staff may collect the results from any tests run on biological samples (blood, urine, 
etc) taken from you, chest X-rays or imaging scans that were performed on you while you are in 
the hospital.  The study staff will also collect information about any procedures done on you in 
relation to the COVID-19 virus. 
 
Follow-up Call 
 
If you are discharged from the hospital before day 29, the study staff will call you for a 
follow-up to check on your health status.  You will receive a 2nd follow-up telephone call on day 
60 to check on your health status again. 
 
Electrocardiogram 
 
An electrocardiogram (ECG) may be done.  An ECG records electrical activity of your heart.  
For ECG recordings, a few sticky patches, called electrodes, will be placed on your chest. 
 
Blood Draws 
 
Study-related blood samples will be taken at different times during your participation in the 
study.  The study staff will work with your doctor and nurse to ensure that, when possible, blood 
samples for this study are being taken at the same time as your standard-of-care blood samples 
are being taken and that samples are not accidently taken twice. See section “What types of 
tests will be done during the study?” for more information on blood samples.    
 
Vital Signs 
 
The study staff will take your vital signs, which will include measuring your blood pressure, 
pulse rate, and breathing rate. 
 
Body Temperature 
 
Your temperature may be measured from but not limited to your mouth, rectal, ear, or forehead.  
 
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Oxygen Level Measurements 
 
Your blood-oxygen level (the amount of oxygen in your blood) will be measured by using a 
small device that will be placed on your index or middle finger.  
 
The study staff will also record the amount of the oxygen that your body is absorbing from the 
devices that are being used to supply you with oxygen. You will not have to do anything for 
these tests to be done.  
 
Physical Exams 
 
A physical exam is a test used to check your overall health.  Your weight will also be taken.  
 
Pregnancy Test 
 
If you are a woman of child bearing potential, a blood or urine pregnancy test will be required at 
screening. 
 
Mouth, Nose and/or Throat Swabs 
 
During the study, a swab of your mouth, nose and/or throat area may be done to test for COVID-
19 virus and potentially for other types of infections.  The study staff will determine the best 
location depending on your health. 
 
WHAT ARE THE RISKS ASSOCIATED WITH THIS STUDY DRUG AND 
STUDY PROCEDURES? 
 
The risks involved in giving sarilumab intravenously (given through a vein) are not fully known.  
There are known and predictable discomforts and common risks or side effects that you might 
experience with the use of the study drug or study procedures, including a decrease in 
neutrophils, a type of white blood cell that helps fight infection. There may be other risks not yet 
known when you take the study drug alone or when it is used with other medications. If 
important information is learned during the study which might affect you or make you change 
your mind about being in the study, the study doctor will tell you. The study doctor is trained to 
take the right measures to reduce risks and limit any discomfort you might feel.  If you need 
more information, please ask your study doctor. 
 
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Risks Involved with the Study Drug 
 
Risk for Infections  
 
Because sarilumab may lead to a significant decrease in neutrophils (a type of white blood cell 
that helps fight infection), there is a chance that you could get a new infection after taking the 
study drug, even for 60 days after taking the drug or possibly longer.  There is also a chance that 
your COVID-19 infection may last longer because of the study drug. See section “What are the 
side effects associated with the study drug” for more information on what types of infections 
have been experienced by patients who have taken sarilumab.  
 
The information on infections with sarilumab is based on patients who have received lower doses 
under the skin every 2 weeks for long periods of time.  This study will give a higher dose of 
sarilumab IV either as a single dose or multiple doses.  You will not be given additional doses of 
the study drug if your neutrophil count is below a certain level.  
 
Unforeseeable Risks 
 
It is possible that there will be other side effects associated with sarilumab which are unknown at 
this time, some of which may be serious or life-threatening.  
 
You should tell your nurse and/or study staff about any new health problems that happen while 
you are in this study and about any new medications you start taking (including vitamins and 
minerals, herbal remedies, over-the-counter drugs, and prescription drugs). 
 
There may be unknown risks or side effects to an unborn baby or nursing child.  You should not 
become pregnant or breast-feed while taking part in this study. 
 
Risks Involved with the Study Procedures 
 
Answer Questions About Your Health 
 
These questions may make you uncomfortable. 
 
Follow-up Call 
 
There are no expected risks from the follow-up call.  
 
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Electrocardiogram 
 
Sometimes it may hurt or produce slight pain when sticky patches placed on your chest are 
removed.  In some people, these electrodes may cause slight irritation or redness of the skin in 
which goes away without any treatment. 
 
Blood Draws 
 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or develop an 
infection with redness and/or irritation of the vein at the site where blood is drawn. Frequent 
blood collection may cause anemia (low red blood cell count), which may create a need for a 
blood transfusion. 
 
Vital Signs 
 
The inflation of the blood pressure cuff may cause discomfort.  
 
Body Temperature 
 
There may be slight discomfort when your temperature is measured in the ear or rectum. There is 
no discomfort expected when taking your temperature from your mouth or forehead.  
 
Oxygen Level Measurements 
 
There are no expected risks or pain expected for taking blood oxygen levels.   
 
Physical Exams 
 
There are no expected risks or pain expected for performing physical exams. 
 
Pregnancy Test 
 
There are no expected risks or pain expected for performing a urine or blood pregnancy test.  
 
Mouth, Nose and/or Throat Swabs 
 
The swabbing of your mouth, nose and/or throat may cause mild temporary pain/discomfort in 
the area swabbed. 
 
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WHAT ARE THE OTHER TREATMENTS AVAILABLE FOR MY 
ILLNESS OR CONDITION? 
 
Currently, there are no approved treatments for COVID-19, but the FDA may allow certain 
medicines to be used during the pandemic for COVID-19. You can choose not to participate in 
this study and receive standard of care medication currently used to try to treat viruses like 
COVID-19.  Or you can volunteer in other COVID-19 clinical trials occurring at this hospital, if 
there are any available.  
 
If you have any questions about alternative treatments, please ask your doctor. You and your 
doctor can decide what is best for you. 
 
WHAT TYPES OF TESTS WILL BE DONE DURING THE STUDY? 
 
Up to 3 tablespoons (approximately 40-45 mL) of blood may be drawn, at certain visits, during 
the study to run blood tests to check your overall health and disease-related tests. 
 
The following will be tested at different times: drug concentration, study related biomarkers, 
including protein and virus in your blood and safety testing (if applicable).  A blood or urine 
pregnancy test may be performed.   
 
Blood samples will also be taken to monitor your safety and for possible infections by your 
doctor.  
 
Additional blood and swabs (mouth, nose and/or throat) for research relating to measuring 
the study drug and how it works in your body as well as information about the amount of virus in 
your body may be collected.  
 
WILL ADDITIONAL SAMPLES BE COLLECTED?  
 
As described in this consent form, biological samples, including blood and mouth/nose/throat 
swabs will be collected as part of this study. Your coded samples will be used by Regeneron 
Parties for the purposes of the study, including exploratory research, to identify new learnings, 
such as: 
 
• How the study drug works in the body; 
• What makes some people respond better to the study drug; 
• Why some people develop side effects; 
• How the study drug or other related medications could affect COVID-19 and related 
viruses or conditions. 
 
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These samples will be stored in a secure storage space, at Regeneron Pharmaceuticals, 777 Old 
Saw Mill River Rd., Tarrytown, NY 10591, USA, for up to 15 years following completion of the 
study for the research purposes described in this consent form, unless you withdraw your consent 
to store your samples. Your samples will only be analyzed by Regeneron Parties. After 15 years, 
your samples will be destroyed. Identifiers might be removed from your identifiable private 
information or identifiable biospecimens and after such removal, the information or 
biospecimens could be used for future research studies or distributed to another investigator for 
future research studies without additional informed consent from you. 
 
If you wish to withdraw your consent to use and store your samples, please notify the study 
doctor in writing. If you withdraw from the study, but do not withdraw your consent to use and 
store your samples, your samples will continue to be used as described in this form. If you 
withdraw your consent to use the sample and you wish to have the samples destroyed, your study 
doctor, Regeneron, and the laboratory responsible for processing the samples will make every 
reasonable effort to ensure your samples are destroyed.  However, it is important that you 
understand that if your sample has already been processed and analyzed, the results and 
information obtained cannot be destroyed and will continue to be available to the Regeneron 
Parties.  
 
You should also know that it is possible that products may someday be developed with the help 
of your specimens and data, and there are no plans to share any profits from such products with 
you, regardless of whether your identifiable information is removed. 
 
WILL THIS STUDY BENEFIT ME? 
 
You may or may not benefit from your participation in the study. If the study drug is effective, 
and you are randomized to receive the study drug, it is possible that you may benefit by reducing 
the amount of time you have symptoms related to your COVID-19 infection.  
 
However, your participation will provide new information on the effects of sarilumab in people 
with COVID-19. As a result, the information from this study might help other people like you in 
the future with COVID-19 or other viruses.  
 
WHAT ARE THE SIDE EFFECTS ASSOCIATED WITH THE STUDY 
DRUG? 
 
Sarilumab has been generally well tolerated by patients with rheumatoid arthritis. However, 
sarilumab has not been studied in patients with the coronavirus infection. There is always a 
chance that you may experience some side effects.  It is important that you tell the study staff 
about these possible side effects. 
 
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Expected side effects, based on the experience from the studies of patients using sarilumab 
include the following: 
 
Infections 
 
Infections, mainly common colds and urinary infections are the most common side effects 
reported in patients participating in sarilumab clinical studies. You can also experience oral 
herpes (cold sores) when using sarilumab. At this time, infections are the most common serious 
side effect reported in patients who have been in sarilumab clinical studies. Treatment with 
sarilumab may increase the risk of a serious infection including tuberculosis (TB), due to the fact 
that your immune system may become weaker and not be able to fight infections caused by 
bacteria, fungi, or viruses. Rarely, the serious infections can be life-threatening (eg, sepsis) and 
may cause death.  A few examples of serious infections experienced by study patients include 
pneumonia, skin infections called cellulitis, and shingles (a painful skin rash caused by the 
chicken pox virus).  A few patients have had severe infections quickly develop after minor skin 
injuries (bruise or cut). 
 
At any time after starting the study, if you have any new infection(s) or symptoms of 
infection(s), or if you injure yourself, have any kind of skin damage or skin wound, sore, or skin 
ulcer, you or your caregiver should immediately notify the study doctor. 
 
Here are some examples of new symptoms you might feel if you have an additional infection for 
which you or your caregiver should immediately notify the study doctor: 
 
• Fever, sweats, chills 
• Muscle aches 
• Feel like you are coming down with the flu or feeling generally ill 
• Feel very tired 
• Warm, red, swollen, or painful skin 
• Diarrhea, vomiting or stomach pain 
• Difficulty breathing, cannot seem to “catch your breath”, pain when you breathe, 
persistent coughing or coughing up blood 
• Thick mucus coming from your lungs 
• Hoarseness, runny or stuffy nose, or sore throat 
• Burning, or pain when you urinate or urinating more often than normal for you 
• Sudden or severe headache 
 
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Here are some examples of the types of skin injuries and skin rashes for which you or your 
caregiver should immediately notify the study doctor: 
 
• Skin cut, scrape, tear, scratch, or an abrasion (for example a “skinned knee”) other than 
as a part of your medical care 
• Skin ulcer(s) or open sores on your body 
• Sores or bumps on your skin filled with pus (collection of yellow-white fluid) 
• Blisters, peeling skin or red skin rash 
• Sores or white patches on your lips, mouth or tongue 
• Bruised, punctured, or torn skin on hands, feet, arms or legs 
 
Allergic Reactions (hypersensitivity reaction) 
 
Allergic reactions (sometimes severe, or in rare cases, fatal) have occurred with other biologic 
products that are similar to sarilumab. There have been a few reports of allergic reactions after 
sarilumab was given.  These reactions were described as mild and moderate allergic reactions 
(for example, hives and swelling in the face), so you may experience skin rash, or rash with red, 
raised, itchy bumps.  In addition, there have also been rare cases of severe skin reactions in 
patients receiving sarilumab. Whether sarilumab caused these severe reactions could not be 
clearly determined.  
 
Laboratory abnormalities 
 
• Low white blood cell count  
• Low neutrophil blood cell count (the neutrophil is a type of white blood cell, that helps 
fight off infection). A decrease in neutrophil count was not associated with the 
occurrences of infections, including severe infections.  
In most cases of patients who experienced a drop in neutrophil counts with subcutaneous 
administration of sarilumab, the neutrophil cell counts increased when dosing was 
interrupted without additional medical problems or complications. However, the duration 
of low neutrophil cell counts following intravenous administration of sarilumab is not 
known and may be longer compared to subcutaneous administration. 
• Elevation in cholesterol, including LDL and HDL and/or elevation of triglyceride. Risk 
of heart problems or stroke may increase due to LDL increase. If this happens, your 
doctor might recommend starting another medication to control your cholesterol. This 
may not occur in patients only receiving a limited number of doses of sarilumab.  
• Elevations in liver function tests (these tests indicate inflammation in the liver). 
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• Low platelet count: a few cases of low platelet counts (without bleeding problems) were 
reported in patients using sarilumab. Risk of bleeding and bruising might increase due to 
low platelet count. Sometimes the low platelet count may be treated with a blood 
transfusion. 
 
You may not receive additional doses of study drug if your neutrophil count is too low or certain 
liver function tests are too high. 
 
For most people, their blood test results will return to normal after stopping sarilumab. In rare 
cases, the abnormal blood tests might be serious and may lead to a hospitalization. 
 
Potential side effects, based on experience with long term use of sarilumab and other biologic 
medicines (which are usually given by injection or directly into the bloodstream) including an 
approved drug which works in the same way as sarilumab, include the following: 
 
• A few cases of diverticulitis, small bulging pouches that form in the digestive tract and 
that can become infected, were reported in patients using sarilumab.  Sometimes these 
infected pouches can cause small holes in the intestines causing a perforation (seen on a 
special type of X-ray called a CT [or CAT] scan).  If you have had severe diverticulitis or 
an intestinal perforation, please report this information to your study doctor so he/she can 
determine if it is still safe for you to participate in the study. 
• People with chronic inflammatory diseases, especially those with very active disease, 
may be more likely to get lymphoma and other types of cancer, such as that observed in 
rheumatoid arthritis patients.  The risk of getting lymphoma or other cancers may 
increase with the use of other types of biological drugs since they affect immune system. 
Sarilumab may also decrease the activity of your immune system.   
 
To date, clinical studies have not suggested an increase in the frequency of cancer in 
patients treated with sarilumab.  
 
Some of the potential side effects seen with long term use of sarilumab, as described above, may 
not be relevant for studies only using a limited number of doses of sarilumab.  
 
It is also possible that there may be other risks that are not known at this time that can occur with 
the use of the study drug, including interactions with other medications. 
 
Side Effects for Intravenous Infusion 
 
The study drug will be given by IV infusion. You may bruise or feel pain or discomfort at the 
infusion site. Also, infusion related reactions (side effects) such as the following can occur 
within 2 hours after finishing the infusion:  
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• Nausea  
• Vomiting  
• Low or high blood pressure  
• Headache  
• Flushing (red cheeks)  
• Swollen lips tongue and uvula (soft hanging palate between the tonsils in the mouth) 
• Bronchospasm (constriction of the airways, with shortness of breath), or other acute 
pulmonary response  
• Angioedema (swelling below the skin or eyelids or throat) 
• Syncope (temporary loss of consciousness caused by a fall in blood pressure)  
• Cardiac arrhythmias (irregular heartbeats)  
• Tachycardia (increased heartbeats) 
• Dizziness 
• Dyspnea (difficulty breathing), chest pain 
• Headache 
• Malaise (general feeling of discomfort, fatigue, or uneasiness) 
• Skin rash  
• Itching or hives  
• Seizure, other neurologic symptoms (confusion, loss of consciousness, paresthesia, 
paralysis) 
 
There is also the potential for infiltration, that is when the study drug leaks out of the vein under 
the skin and causes swelling to the tissue around the IV site.  
 
WHAT HAPPENS IF I GET INJURED WHILE I AM IN THE STUDY?  
 
If you think you have been injured as a result of participating in the study: 
 
1. Promptly seek medical treatment, and  
2. Call the emergency contact number on the first page of this form.  
 
If you have an injury that is directly caused by taking the study drug or any properly performed 
study procedures included in the study (procedures you receive only because of your 
participation in the study) and you have followed the directions of your study doctor, Regeneron 
will provide reimbursement for reasonable and necessary medical costs to treat your injury that 
are not covered by your medical or hospital insurance, or from third party or other programs 
providing such coverage. 
 
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Regeneron will not routinely provide monetary or financial compensation for:  
 
• other injury- or illness-related costs (such as lost wages, disability or discomfort due to an 
injury),  
• medical expenses that are paid for by a third party,  
• medical expenses that happen due to a violation of the study or other misconduct or 
negligence, in each case by any agent or employee of the Institution conducting the study 
(including the study staff), or  
• medical expenses for injury or illness unrelated to the study drug and unrelated to the 
proper performance of any other procedure required by the study or Regeneron’s written 
instructions to the Institution conducting the study, including, without limitation, medical 
expenses associated with a pre-existing medical condition.  
 
No funds have been set aside to provide you with any further monetary or financial 
compensation in case of injury. 
 
By agreeing to participate in this study, you do not waive any of your legal rights.   
 
This research is covered by the Public Readiness and Emergency Preparedness (PREP) Act. The 
PREP Act limits your ability to sue if you are injured by the study drug or study procedures. 
However, you may be able to seek compensation from the Health Resources and Services 
Administration (HRSA) Countermeasure Injury Compensation Program for certain serious 
physical injuries. The declaration is available at: https://www.govinfo.gov/content/pkg/FR-2020-
03-17/pdf/2020-05484.pdf. 
 
For more information, please contact the study doctor or a member of the study staff. 
 
WHAT HAPPENS IF I GET PREGNANT?  
 
It is possible that sarilumab may harm the unborn child. It is unclear what the effect of sarilumab 
is on a baby born from a mother that took sarilumab while she was pregnant.  As of 12 Jan 2020, 
there were a total of 30 patients, including 6 male patients whose partners became pregnant 
during non-COVID studies. Two of the male patients had female partners who became pregnant 
twice.  There were 18 full-term births, 9 miscarriages, 2 elective abortions and 1 pregnancy with 
an unknown outcome. Three of the patients with miscarriages had a prior history of miscarriages. 
 
One patient delivered a baby who was diagnosed with pneumonia when born. The baby received 
treatment and recovered. 
 
It is unknown if sarilumab is present the milk of breast-feeding mothers. It is known that 
monoclonal antibodies are excreted in small amounts in breast milk.   
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For Women 
 
You will still be allowed to participate in this study even if you are pregnant or become pregnant 
during your participation.  But, it is important that you do all that you can to not become 
pregnant and not to breastfeed while participating in this study. Please talk to your study doctor 
for approved methods of birth control that you can use during this study.  
 
WILL I BE PAID TO PARTICIPATE IN THIS STUDY? 
 
You will not be paid for participating in this study.  
 
WILL I HAVE TO SPEND MONEY TO BE IN THIS STUDY? 
 
There will be no cost to you for the study drug, study doctor’s time or certain procedures and 
supplies required by this study.  
 
You are responsible for the cost of your standard medication, in addition to any costs related to 
procedures and supplies not required by the study.  
 
WHY WOULD I BE ASKED TO DISCONTINUE THE STUDY? 
 
The study doctor or Regeneron can remove you from the study without your consent at any time 
for any reason including: 
 
• To improve your medical care,  
• If you experience unusual or serious side effects, 
• If you do not follow the study procedures as instructed,  
• If the study is stopped by Regeneron or a health/regulatory agency such as FDA, or 
• Other reasons not listed here. 
 
The same procedures will be followed as those that would happen if you decided to discontinue 
from the study. 
 
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DATA PROTECTION: YOUR RIGHTS AND CHOICES 
 
WHAT INFORMATION WILL THE STUDY STAFF COLLECT FROM 
OR ABOUT YOU IN CONNECTION WITH THIS STUDY? 
 
As part of this study, the study doctor and study staff (“Researchers”) will collect and review 
information about you that contains your name and other personal information.  In addition, your 
treating physicians and other healthcare providers may disclose information from your medical 
records to the Researchers. The information collected from or about you (“Personal 
Information”) for this study includes: 
 
• Your medical information, including how you feel, medical and surgical history, your 
food intake, smoking and alcohol habits, menopausal history (women only), physical 
activity, sexual habits or behavior, contraception and previous and current medications. 
• Other personally identifying information, including your name and other information 
(such as your age, race or ethnicity, gender and country location). 
• Results of examinations and laboratory tests.  
• Biological samples (from the mouth, nose, and/or throat, blood, or other samples taken as 
part of your standard-of-care).  
 
Access to your records, directly at the study site or remotely may be available to regulatory 
authorities, monitors, auditors, and representatives of the Sponsor at the study site for 
monitoring, auditing, and verification of research procedures and/or study data. 
 
The Sponsor or its representatives may conduct site visits to monitor and ensure that the trial is 
executed according to the study protocol and applicable local laws and regulations.  
 
WHO ELSE WILL BE ABLE TO LOOK AT MY PERSONAL INFORMATION? 
 
The Researchers will use and disclose your Personal Information to the following organizations:  
 
• Regeneron, its collaborators or those developing the study drug; and their affiliates, 
representatives, agents and contractors (the “Regeneron Parties”)  
• The U.S. Food and Drug Administration (FDA), other U.S. government agencies, and 
government authorities in other countries 
• The Institutional Review Board (IRB), a group that looks out for the rights and welfare of 
research participants  
 
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Generally, your permission to use and/or share your Personal Information for the purposes 
described in this form does not have an expiration date, subject to applicable law, unless you 
withdraw your permission in writing to the study doctor at the address listed on page 1 of this 
form.   
 
WHAT PRECAUTIONS WILL BE TAKEN TO PROTECT MY PRIVACY? 
 
Every effort will be taken to maintain your privacy. Your name will not be attached to records or 
samples released for research purposes.  Instead, your records and samples will only be identified 
by a code. Only the study doctor and authorized personnel will be able to connect this code to 
your name.  Your Personal Information will be protected by your study doctor and site in 
accordance with relevant data protection laws.   
 
All data will be stored in locked cabinet files and restricted-access computers. While these 
security measures reduce the risk of your personal information being misused or accessed by 
unauthorized individuals, such risks cannot be eliminated entirely. Although we believe that 
these risks are low, absolute confidentiality cannot be promised. However, all information will 
be collected and shared in accordance with applicable law and data sharing guidelines that the 
Sponsor must follow.  
 
HOW WILL MY PERSONAL INFORMATION AND RESULTS FROM 
THIS STUDY BE USED? 
 
The Researchers and organizations listed above will use and disclose your Personal Information 
in connection with the study to assure quality control, analyze the data, and comply with 
regulatory duties. This includes the submission of the study results, regulatory approvals of the 
study drug, to report adverse events, and government reporting, if applicable.  In addition, 
Regeneron Parties will use the study data to assess the safety and efficacy of the study drug.  
 
Your coded Personal Information will be added to a computerized database.  This database will 
be part of the study results. Data and results from this study will be presented at meetings or 
published in journals.  To fulfill regulatory requirements and industry guidelines, the results from 
this study will also be provided to qualified researchers who request it for legitimate research 
purposes. While your coded information may be shared with these researchers or publications, 
your identity (such as your name, address and email) will not be shared with these researchers 
and will not be in any presentation or publication.  
 
As advancements in medical technology continue, Regeneron Parties may reanalyze the study 
data and the results in future research projects to find new scientific information about the study, 
study drug, COVID-19, or other related diseases.  
 
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Once your Personal Information is disclosed to the Regeneron Parties and to the other 
organizations identified above, it may be subject to further disclosure and no longer protected by 
federal privacy law. 
 
WILL I HAVE ACCESS TO MY RESULTS? 
 
The results produced as part of this study are for research purposes only.  The results are not 
reviewed for medical diagnosis of any disease. Because the results obtained during the course of 
the research have only clinical research value and are not for medical diagnosis, the Sponsor 
does not provide individual results to you. In some circumstances, the Sponsor may provide 
certain results to your study doctor. If, during the course of the study, the study doctor learns 
information related to your health from the study procedures, the study doctor may discuss this 
information and your options with you. 
 
WHAT ARE MY PRIVACY RIGHTS? 
 
Your Right to Access and/or Correct Your Information  
 
You have the right to access, through your study doctor, all of the information collected about 
you in your medical record, and to ask for corrections, according to the rules of the study site. 
You have the right to request information on how the Personal Information reported to the 
Sponsor are being used and with whom the data have been shared. Please note that your right to 
access certain information in your medical records may be suspended during your participation 
in the study. Therefore, if you would like immediate access to your records, you may not be able 
to continue participating in the study. 
 
Your Right to Object/Withdraw 
 
In order to participate in this study, the Sponsor must collect and use your Personal Information. 
Your decision to allow the collection and use of your health information is completely voluntary 
but if you do not allow it, you may not participate in the study. If you change your mind about 
your Personal Information being used, you can voluntarily withdraw from the study at any time. 
If you choose to withdraw your permission, you will not be punished in any way or lose any 
right to access care, treatment, or services outside of the study. 
 
If you withdraw your permission to use your Personal Information, the Personal Information 
collected prior to your withdrawal will still be processed along with other data collected as part 
of the study in order to preserve the integrity of the results and in accordance with regulatory 
requirements. The information collected about you up to the point when you discontinue from  
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the study, or information obtained after you withdraw in connection with a safety issue related to 
the study, will continue to be used, including lab results, clinic notes, and any other information 
collected. However, no new information will be collected unless you specifically consent to that.  
 
Your Right to Request Deletion 
 
If you withdraw from the study, you may also request that the Personal Information already 
collected from you in connection with the study be deleted. However, your right to deletion is 
limited due to regulatory requirements and to preserve scientific integrity, as your Personal 
Information must be managed in specific ways in order for the research to be reliable and 
accurate. The study results and coded data will be kept as long as they are needed for research 
purposes, any regulatory requirements, and the Sponsor’s Data Retention Schedule.  
 
Please be aware that because the Sponsor only maintains coded study data, it generally cannot 
respond directly to individual requests regarding your privacy rights. Therefore, you should 
address any of these requests regarding these rights to the study site using the contact 
information on the first page of this consent form. If you have any questions, concerns, or 
complaints as to how your Personal Information has been handled, you can contact the 
Sponsor’s Data Protection Officer at DataProtection@Regeneron.com.  
 
WILL MY INFORMATION BE ON THE INTERNET? 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.  A 
description will also be available on https://www.clinicaltrialsregister.eu/. Some regulatory 
authorities and ethics committees may also make information available on their websites. 
 
CAN I CHANGE MY MIND ABOUT BEING IN THE STUDY? 
 
Yes. Your participation is voluntary.  You may discontinue being in the study at any time. You 
do not need to give a reason and your medical care (outside of the study) will not be affected by 
your decision.  Refusal to participate or discontinuing participation will not involve penalty or 
loss of benefits to which you are otherwise entitled.  
 
If you decide to discontinue being in the study, you should let the study doctor know before you 
stop. If you have already taken the study drug, you will be asked whether you allow the Sponsor 
to continue to collect information about your health. You may be asked to provide a final blood 
draw sample before you withdraw from the study.  You will be asked to allow the Sponsor to 
contact you for a follow-up call to ensure there have been no changes in your health.  
 
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If you would like to withdraw from the study completely without allowing the Sponsor to 
continue to collect additional information about you, you can do so by telling your study doctor.   
 
WHAT IF SOMETHING IS DEVELOPED FROM THIS RESEARCH? 
 
By participating in this study, you do not acquire any ownership rights in the samples you 
contribute or in any medical or genetic tests, drugs or other commercial products that may be 
developed through this research.  
 
WHO DO I CALL IF I HAVE QUESTIONS?  
 
The people to contact for any questions, concerns, complaints, a research-related injury, or 
problems in the study are listed on the first page of this consent. You may ask questions before 
you sign the consent, at any time during your participation in the study, and after you are 
finished with the study.  
 
This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a group of 
people who perform independent review of research studies. You may talk to them at (800) 562-4789, 
help@wirb.com if:  
 
• You have questions, concerns, or complaints that are not being answered by the research 
team. 
• You are not getting answers from the research team. 
• You cannot reach the research team. 
• You want to talk to someone else about the research. 
• You have questions about your rights as a research subject. 
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Protocol Title: 
An Adaptive Phase 2/3, Randomized, Double-Blind, 
Placebo-Controlled Study Assessing Efficacy and 
Safety of Sarilumab for Hospitalized Patients with 
COVID-19 
Protocol Number: 
Sponsor: 
Research Site: 
6R88-COV-2040 
Regeneron Pharmaceuticals, Inc. 
[Site Name] 
 
PARTICIPANT’S AGREEMENT 
All subjects unable to consent are required to assent, unless the investigator determines that the 
capability of the subject is so limited that the subject cannot reasonably be consulted. 
 
If assent is obtained, have the person obtaining assent document assent on the consent form. 
 
• I have read and understand this Informed Consent Form (ICF).  This study has been 
explained to me in detail and all of my questions have been answered to my satisfaction. I 
have been given enough time to decide whether I want to participate or not. 
• I authorize the collection, use, disclosure and storage of my Personal Information and 
biological samples for the purposes of this study as described in this form. 
• I volunteer to participate in this research study.  
• I have been informed of my privacy rights related to the collection, use and disclosure of 
my Personal Information and consent to such collection, use and disclosure. 
• I am free to withdraw my consent to the collection, use, and disclosure of my Personal 
Information at any time without penalty and without affecting my medical treatment; 
however, I will not be able to continue my participation in the research study after I 
withdraw consent, and data already collected will continue to be included in study 
analyses, in accordance with regulatory requirements.  
• I agree that my GP/personal physician can be informed of my participation in this study. 
• By signing this form, I have not waived any of the legal rights that I otherwise would 
have as a participant in a research study.  I understand that I will receive a signed copy of 
this form for my records. 
 
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A copy of the information sheet and your signed consent form will be given to you to keep. 
 
 
________________________________ 
Name of Participant (printed) 
 
 
________________________________ 
________________ 
Signature of Participant 
Date (DDMMMYYYY) 
 
LEGALLY AUTHORIZED REPRESENTATIVE AND PERSON 
OBTAINING CONSENT SIGNATURES 
 
The Legally Authorized Representative signature should be added if the patient is unable to sign 
for himself or herself. The relationship between the patient and the Legally Authorized 
Representative should be stated. 
 
 
________________________________ 
Name of Legally Authorized  
Representative (if applicable) 
 
 
________________________________ 
___________________ 
Signature of Legally Authorized  
Date (DDMMMYYYY) 
Representative (if applicable) 
 
 
____________________________________________________________________________ 
Relationship of Legally Authorized Representative to Participant (Printed)  
 
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I have fully informed the participant/Legally Authorized Representative about the study: 
 
❑ I have explained the study to the extent compatible with the subject’s capability, and the 
subject has agreed to be in the study. 
OR 
❑ The subject is not able to assent because the capability of the subject is so limited that the 
subject cannot reasonably be consulted. 
 
 
________________________________ 
Name of Study Investigator 
Or Person Obtaining Consent/Assent 
 
 
________________________________ 
___________________ 
Signature of Investigator or  
Date (DDMMMYYYY) 
Person Obtaining Consent/Assent 
 
WITNESS SIGNATURE 
 
❑ Not applicable, witness signature is not needed. 
❑ Applicable – See witness signature and language below.  
 
As an impartial third party, I witnessed the entire consent discussion.  I attest that the 
above-named participant received a verbal and written description of the study.  This individual 
had sufficient time to consider this information, had an opportunity to ask questions, and 
voluntarily agreed to participate in this study. 
 
 
_______________________________ 
________________ 
Name of Witness (printed) 
Date (DDMMMYYYY) 
 
 
_______________________________ 
________________ 
Signature of Witness 
Date (DDMMMYYYY) 
 
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**For Sites in California** 
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
RESEARCH PURPOSES 
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
• Past and present medical records 
• Research records 
• Records about phone calls made as part of this research 
• Records about your study visits. 
 
Who may use and give out information about you? 
The study doctor and the study staff.  [They may also share the research information 
with [enter SMO company name], an agent for the study doctor. delete if the site 
does not have an SMO] 
 
Who might get this information? 
The sponsor of this research.  “Sponsor” means any persons or companies that are: 
• working for or with the sponsor, or  
• owned by the sponsor. 
 
Your information may be given to:  
• The U.S. Food and Drug Administration (FDA), 
• Department of Health and Human Services (DHHS) agencies, 
• Governmental agencies in other countries,  
• The institution where the research is being done, 
• Governmental agencies to whom certain diseases (reportable diseases) must 
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• Institutional Review Board (IRB)  
 
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Why will this information be used and/or given to others? 
• to do the research,  
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If the results of this study are made public, information that identifies you will not 
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What if I decide not to give permission to use and give out my health information? 
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Yes, but only after the research is over.  
 
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This permission will be good until December 31, 2070. 
 
You may withdraw or take away your permission to use and disclose your health 
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If you withdraw your permission, you will not be able to stay in this study. 
 
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There is a risk that your information will be given to others without your 
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Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 64 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
 
 
 
STATISTICAL ANALYSIS PLAN 
FOR PHASE 2 PORTION OF STUDY 
VERSION: FINAL 
 
AN ADAPTIVE PHASE 2/3, RANDOMIZED, DOUBLE-BLIND,  
PLACEBO-CONTROLLED STUDY ASSESSING EFFICACY AND SAFETY OF  
SARILUMAB FOR HOSPITALIZED PATIENTS WITH COVID-19 
 
Compound: 
REGN88 (sarilumab; Kevzara®) 
Protocol Number: 
6R88-COV-2040 
Clinical Phase: 
Phase 2/3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatisticians: 
 
 
Clinical Trial Manager: 
 
Study Medical Directors: 
 
 
Version/Date: 
Original (Version 1.0) / 13 APR 2020 
 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 13 APR 2020 
 
CONFIDENTIAL 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatisticians  
(
 
 
 
See appended electronic signature page 
Study Pharmacokinetics 
 
 
 
See appended electronic signature page 
Study Medical Directors 
 
 
 
See appended electronic signature page 
Head of BDM  
 
 
 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 13 APR 2020 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.4. 
Revision History for SAP Amendments .....................................................................11 
2. 
INVESTIGATION PLAN ..........................................................................................12 
2.1. 
Study Design and Randomization ..............................................................................12 
2.2. 
Sample Size and Power Considerations for Phase 2 ..................................................13 
2.3. 
Study Plan ...................................................................................................................14 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
3.1. 
Intention-to-Treat (ITT) population ............................................................................15 
3.2. 
Modified Intention-to-Treat (mITT) population .........................................................15 
3.3. 
Per Protocol Set (PPS) ................................................................................................15 
3.4. 
Safety (SAF) population .............................................................................................15 
3.5. 
Pharmacokinetics Analysis Sets .................................................................................15 
4. 
ANALYSIS VARIABLES .........................................................................................16 
4.1. 
Demographics and Baseline Characteristics ...............................................................16 
4.2. 
Medical History ..........................................................................................................17 
4.3. 
Prior / Concomitant Medications or Procedures .........................................................18 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................19 
4.5. 
Efficacy Variables ......................................................................................................20 
4.5.1. 
Primary Efficacy Variable – Percent Change from Baseline in C-Reactive 
Protein .........................................................................................................................20 
4.5.2. 
Key Secondary Efficacy Variable – Time-to-improvement (≥2 points) in 
clinical status assessment using 7-point ordinal scale ................................................21 
4.5.3. 
Other Secondary Efficacy Variables ..........................................................................23 
4.5.3.1. 
Fever ...........................................................................................................................24 
4.5.3.2. 
Oxygenation ................................................................................................................25 
4.5.3.3. 
Clinical status using 7-point ordinal scale ..................................................................26 
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4.5.3.4. 
National Early Warning Score 2 (NEWS2) ................................................................26 
4.5.3.5. 
Ventilation outcomes ..................................................................................................27 
4.5.3.6. 
Other respiratory outcomes .........................................................................................28 
4.5.3.7. 
Hospitalization, Intensive Care Unit (ICU) and Mortality .........................................28 
4.6. 
Safety Variables ..........................................................................................................29 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................29 
4.6.2. 
Adverse Events of Special Interest .............................................................................30 
4.6.3. 
Laboratory Safety Variables .......................................................................................31 
4.6.4. 
Vital Signs ..................................................................................................................31 
4.6.5. 
Physical Examination Variables .................................................................................31 
4.7. 
Pharmacokinetic Variables .........................................................................................31 
4.8. 
Pharmacodynamic and Other Biomarker Variables ...................................................32 
5. 
STATISTICAL METHODS .......................................................................................33 
5.1. 
Demographics and Baseline Characteristics ...............................................................33 
5.2. 
Medical History ..........................................................................................................33 
5.3. 
Prior / Concomitant Medications or Procedures .........................................................33 
5.4. 
Rescue/ Prohibited Medications if applicable ............................................................33 
5.5. 
Subject Disposition .....................................................................................................33 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................34 
5.6.1. 
Measurement of Compliance ......................................................................................34 
5.6.2. 
Exposure to Investigational Product ...........................................................................34 
5.7. 
Analyses of Efficacy Variables ..................................................................................35 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................35 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................37 
5.7.3. 
Analysis of Other Secondary Efficacy .......................................................................39 
5.7.4. 
Adjustment for Multiple Comparison .........................................................................39 
5.8. 
Analysis of Safety Data ..............................................................................................40 
5.8.1. 
Adverse Events ...........................................................................................................40 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................41 
5.8.3. 
Clinical Laboratory Measurements.............................................................................41 
5.8.4. 
Analysis of Vital Signs ...............................................................................................42 
5.8.5. 
Physical Exams ...........................................................................................................42 
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Statistical Analysis Plan 
Date: 13 APR 2020 
 
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5.9. 
Analysis of Pharmacokinetics, Pharmacodynamics and Biomarker Data ..................42 
5.9.1. 
Analysis of Drug Concentration Data .........................................................................42 
5.9.2. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................42 
6. 
DATA CONVENTIONS ............................................................................................43 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................43 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................43 
6.3. 
Data Handling Convention for Missing Data .............................................................43 
6.4. 
Visit Windows ............................................................................................................44 
6.5. 
Unscheduled Assessments ..........................................................................................44 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................44 
7. 
INTERIM ANALYSIS ...............................................................................................45 
8. 
SOFTWARE ...............................................................................................................46 
9. 
REFERENCES ...........................................................................................................47 
10. 
APPENDIX.................................................................................................................48 
10.1. 
Schedule of Time and Events .....................................................................................48 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................53 
10.3. 
List of Antipyretics .....................................................................................................61 
10.4. 
Conversion from Oxygen flow rate to estimated FiO2 (fraction inspired 
oxygen) .......................................................................................................................64 
 
LIST OF TABLES 
Table 1: 
The National Early Warning Score 2 (NEWS2) Scoring System ..............................27 
Table 2: 
Grading System for Adverse Events Not Listed in NCI-CTCAE ..............................29 
Table 3: 
Time Window for Summary of Laboratory Parameters .............................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram for Phase 2 and Phase 3 ............................................................13 
 
 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of covariance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRP 
C-reactive protein 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
FiO2 
Fraction inspired oxygen 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IL-6 
Interleukin 6 
ITT 
Intention-to-treat 
IWRS 
Interactive Web Response System 
IV 
Intravenous 
mITT 
Modified intention-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV 
Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NEWS2 
National Early Warning Score2 
OP 
Oropharyngeal 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
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Abbreviation 
Definition 
NP 
Nasopharyngeal 
PCSV 
Potentially Clinically Significant Value 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PPS 
Per Protocol population set 
PT 
Preferred Term 
RA 
Rheumatoid Arthritis 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
SpO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper Limit Normal 
US 
United States (of America) 
VFD 
Ventilator-free days 
WBC 
White blood cell 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to the Phase 2 
database lock of this Phase 2/3 adaptive study. This Phase 2 SAP is intended to be a comprehensive 
and detailed description of the strategy and statistical methods to be used in the analysis of data 
for Phase 2 portion of the 6R88-COV-2040 study based on Protocol Amendment 4 (dated 
07-APR-2020). A separate Phase 3 SAP will be written for the Phase 3 portion of the Phase 2/3 
study. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned analyses. 
These revisions will be based on blinded review of the study and data, and a final plan will be 
issued prior to the Phase 2 data lock and before code breaking. 
1.1. 
Background/Rationale 
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel enveloped RNA 
betacoronavirus that emerged in December 2019 in Wuhan, China. The term COVID-19 is the 
disease caused by SARS-CoV-2 with symptoms that manifest a median of 5 days and up to 14 days 
after infection. Patients with COVID-19 infection are at risk for the development of pneumonia 
and acute respiratory distress syndrome (ARDS), a syndrome of severe impairment of gas 
exchange, which clinically presents with severe hypoxemia. The most frequent clinical 
presentation of severe COVID-19 is pneumonia with symptoms including fever, cough, and 
dyspnea (shortness of breath). 
COVID-19 infection can be associated with a degree of pulmonary cytokine release, with IL-6 
being a major contributor to the development of fever and hypoxemia.  In the current study, 
sarilumab (Kevzara®), an anti-IL-6R monoclonal antibody (mAb), 200 mg intravenous (IV) and 
400 mg IV doses will be evaluated for efficacy and safety in treatment of COVID-19.  Kevzara® 
(sarilumab) is currently approved for treatment in patients with rheumatoid arthritis (RA) at 
200 mg Q2W (subcutaneous [SC]) [with down dosing to 150 mg Q2W (SC) for certain laboratory 
changes]. Sarilumab is highly similar to tocilizumab and there is reported evidence in a recent 
study in 21 patients that IV treatment with 400 mg of tocilizumab (Actemra®), another anti-IL-6R 
mAb, provided a clinically meaningful improvement in clinical symptoms that are thought to be 
mediated by cytokine release in patients with severe or critical COVID-19 infection (Xu, 2020 
[7]). 
Currently, however, there are no specific COVID-19 treatments. SARS-CoV-2 that causes 
COVID-19 results in a similar acute lower respiratory disease caused by SARS-CoV, identified in 
2002, and by the Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV). (Hereafter, 
SARS-CoV2 and COVID-19 are interchangeably used.) Many therapeutic agents have been used 
to treat patients with SARS-CoV and MERS-CoV, including corticosteroids, type 1 IFN agents, 
convalescent plasma, ribavirin, lopinavir/ritonavir, proteases, and agents targeting viral entry 
proteins. However, none have been proven to be efficacious in clinical trials, justifying the use of 
placebo as a comparator for this study. 
This study is an adaptive Phase 2/3, randomized, double-blind, placebo-controlled trial to evaluate 
the efficacy and safety of sarilumab compared with placebo in hospitalized adults with severe or 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 13 APR 2020 
 
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critical COVID-19 (as broadly defined below). The study will be conducted in the United States 
(US) in up to 100 sites.  
Patients were to be randomized in a 2:2:1 allocation ratio to sarilumab 400 mg IV, sarilumab 200 
mg IV, or placebo.  Randomization was to be stratified by: 
 Severity of illness at enrollment 
 Severe disease 
 Critical disease 
 Multi-system organ dysfunction 
 Immunocompromised† 
 Systemic corticosteroids (Yes/No) 
† Immunocompromised patients were permitted to be enrolled in this study after Protocol Amendment #3 (28-MAR-
2020) at the request of the FDA.  For Phase 2 analysis, these patients will be reported as a subset of the Multi-system 
organ dysfunction strata. 
Due to the novel nature of COVID-19, efficacy endpoints are not well established, and the standard 
of care is expected to evolve over time. The adaptive design allows for the assessment of efficacy 
endpoints in Phase 2 which will then be confirmed in the Phase 3 portion of the study, as well as 
evaluate the benefit-risk of 2 doses of sarilumab (200 mg IV or 400 mg IV). This study is therefore 
intended to allow for multiple adaptations, including dropping of a sarilumab dose arm, 
modification of the primary endpoint for Phase 3, and sample size re-estimation for Phase 3. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
Phase 2:  
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the 
control arm in adult patients hospitalized with COVID-19 regardless of severity strata. 
Phase 3:  
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the 
control arm in adult patients hospitalized with severe and critical COVID-19. 
1.2.2. 
Secondary Objectives 
Phase 2 and Phase 3: 
Efficacy 
The secondary efficacy objectives of the study are to: 
1. Evaluate the clinical efficacy of sarilumab compared to the control arm in all disease 
severity levels and by clinical severity 
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2. Evaluate the clinical efficacy of sarilumab compared to the control arm by baseline IL-6 
level 
3. Evaluate changes in the National Early Warning Score 2 (NEWS2) 
4. Evaluate the duration of predefined symptoms and signs (if applicable) 
5. Evaluate the duration of supplemental oxygen dependency (if applicable) 
6. Evaluate the incidence of new mechanical ventilation use during the study 
7. Evaluate the duration of new mechanical ventilation use during the study 
8. Evaluate need for admission into intensive care unit (ICU) 
9. Evaluate duration of hospitalization (days) 
10. Evaluate the 28-day mortality rate 
Phase 2 and Phase 3: 
Safety 
The secondary safety objectives of the study are to evaluate the safety of sarilumab through 
hospitalization (up to Day 29 if patient is still hospitalized) compared to the control arm as assessed 
by incidence of: 
 Serious adverse events (SAEs) 
 Grade 4 neutropenia (ANC < 500/mm3) 
 Grade 4 neutropenia (ANC < 500/mm3) with concurrent severe or life-threatening 
bacterial, invasive fungal, or opportunistic infection  
 Grade ≥2 infusion-related reactions 
 Grade ≥2 hypersensitivity reactions 
 Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥3X 
upper limit of normal (ULN) (for patients with normal baseline) or >3X ULN AND at 
least 2-fold increase from baseline value (for patients with abnormal baseline) 
 Invasive bacterial or fungal infections of clinical significance with confirmed 
diagnosis based on the investigator’s assessment with appropriate diagnostic workups 
and consultations 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
The initial protocol and analysis plan was based on a published case series from China suggesting 
IL-6R blockade in patients with COVID led to rapid reversal of respiratory compromise.  
Subsequent data suggest that these reference data may have been highly selective.  Therefore, in 
the absence of reliable antecedent data, it was decided that the Phase 2 portion of the study should 
focus on describing the differences between treatment with sarilumab on top of standard of care 
versus standard of care alone.  Consistent with this decision, the modification in the SAP compared 
to the protocol is that in the Phase 2 analysis the key secondary endpoint of time-to-improvement 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 13 APR 2020 
 
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(≥2 points) in clinical status assessment using the ordinal scale will be analyzed descriptively rather 
than as formal hypothesis testing (see Section 5.7.2 and Section 5.7.4).  The approach to control 
multiplicity has changed, but overall Type 1 error will still be controlled at 0.05. 
1.2.4. 
Revision History for SAP Amendments 
Not applicable. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This study is an adaptive Phase 2/3, randomized, double-blind, placebo-controlled trial to evaluate 
the efficacy and safety of sarilumab in hospitalized adults with severe or critical COVID-19. The 
study will be conducted in the United States (US) in up to 100 sites. All patients must have 
evidence of SARS-CoV-2 infection pneumonia by radiograph or clinical findings, and respiratory 
compromise as demonstrated by a requirement for oxygen supplementation above their 
background requirements. 
Patients will be randomized in a 2:2:1 allocation ratio to sarilumab 400 mg IV, 
sarilumab 200 mg IV, or placebo, in a stratified manner.  Randomization will be performed 
according to a central randomization scheme using an interactive web response system (IWRS). 
While serum IL-6 and cytokines will be measured at a central laboratory predose on Day 1 and 
periodically after treatment, entering patients will not be stratified based on serum IL-6 levels. 
Randomization will be stratified by: 
 Severity of illness at enrollment 
 Severe disease 
 Critical disease 
 Multi-system organ dysfunction 
 Immunocompromised† 
 Systemic corticosteroids (Yes/No) 
† Immunocompromised patients were permitted to be enrolled in this study after Protocol Amendment #3 (28-MAR-
2020) at the request of the FDA.  For Phase 2 analysis, these patients will be reported as a subset of the Multi-system 
organ dysfunction strata. 
The severity categories are: 
1. Severe disease  
 Requires supplemental oxygen administration by nasal cannula, simple face mask, or 
other similar oxygen delivery device  
2. Critical disease:  
 Requires supplemental oxygen requiring delivered by non-rebreather mask or 
high-flow nasal cannula, OR 
 Use of invasive or non-invasive ventilation, OR 
 Requiring treatment in an intensive care unit.  
3. Multi-system organ dysfunction:  
 Multi-system organ dysfunction: use of vasopressors, extracorporeal life support, or 
renal replacement therapy 
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4. Immunocompromised 
 Immunocompromised patients (or on immunosuppressant treatments) 
The total sample size for Phase 2 will be approximately 460 to include patients with all baseline 
IL-6 levels.  
For the Phase 3 portion of this study, the primary endpoint will be determined after data from the 
Phase 2 portion is analyzed by the unblinded study team.   
Sample size may be re-estimated for Phase 3 based on results from Phase 2 data. 
Figure 1: 
Study Flow Diagram for Phase 2 and Phase 3 
 
2.2. 
Sample Size and Power Considerations for Phase 2 
For the Phase 2 portion of the study, approximately 200 patients (80 in each of the two sarilumab 
dose groups and 40 on placebo) are required in all disease severity strata with high baseline IL-6 
levels to test for superiority of sarilumab versus placebo with respect to percent change from 
baseline CRP levels at Day 4.  This sample size will provide 90% power using a two-sample t-test 
to detect an effect size (ie, difference/SD) of 0.633 at the 0.05 (2-sided) significance level.  The 
effect size of 0.633 assumes that the mean treatment difference in percent change from baseline 
using natural logarithm of CRP levels (sarilumab minus placebo) would be -6.6% with a standard 
deviation of 10.43% (percent change from baseline in sarilumab is estimated to be mean =  45.98% 
and SD=10.43% based on tocilizumab data from China study in COVID-19; See Figure 2 in (Xu, 
2020 [7])).  If the effect in placebo group is assumed to be negligible (~0%) and variability in CRP 
is high, then the power could be much greater than 90% for larger effect sizes (e.g., treatment 
difference =  50% and SD = 30%, effect size = 1.667). 
Additional patients are being included in Phase 2 to allow for adequate estimation and improve 
precision of the treatment effect using the proposed Phase 3 clinical endpoint—time to 
improvement (2 points) in clinical status (7-point ordinal scale)—prior to making adaptations to 
the Phase 3 study design.  The total sample size for Phase 2 is updated to be approximately 460 
patients, to include patients with all baseline IL-6 levels. 
As the Phase 2 data evolve, power calculations will be reassessed, and the Phase 3 endpoints may 
be changed and the sample size may be re-estimated.  Considering the status of the current 
pandemic, the study will continue to enroll regardless of the number of patients until an active 
decision is taken to discontinue the study for efficacy, safety, or futility.   
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2.3. 
Study Plan 
The Study event table is presented in Section 10.1. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference for Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analyses in the Phase 2 portion of this study. 
3.1. 
Intention-to-Treat (ITT) population 
The intention-to-treat (ITT) population includes all randomized patients who received at least one 
dose of the study drug.  Analysis of the ITT population will be done according to the initial 
treatment assigned to the patient (as randomized). The ITT population may be used for sensitivity 
analysis of the efficacy endpoints, as well as for analysis of data including (but not limited to) 
demographics and baseline characteristics. 
3.2. 
Modified Intention-to-Treat (mITT) population 
The modified intention-to-treat (mITT) population includes all randomized patients who received 
at least one dose of the study drug and have high baseline IL-6 levels (>ULN). Analysis of the 
mITT population will be done according to the initial treatment assigned to the patient (as 
randomized). The mITT population will be the primary population for analysis of primary and 
secondary efficacy endpoints, as well as for data including (but not limited to) demographics and 
baseline characteristics. 
3.3. 
Per Protocol Set (PPS) 
The per protocol population set (PPS) includes all ITT patients who did not have any relevant 
major protocol deviations, e.g., patients who are randomized and treated, but do not have 
laboratory-confirmed SARS-CoV-2 infection will be excluded from PPS.  The final determination 
of the exclusion of patients from the PPS will be made prior to the first database lock (for Phase 3 
only).  Analysis of the PPS will be done according to the treatment the patient actually received 
(as treated).  The PPS will be used for sensitivity analysis of the primary efficacy endpoint in 
Phase 3 portion of the study. 
3.4. 
Safety (SAF) population 
The Safety population (SAF) includes all randomized patients who received at least one dose of 
the study drug. Analysis of the Safety population will be done according to the treatment received 
(as treated).  Determination of “as treated” will be based on the actual study drug received on 
Day 1. 
3.5. 
Pharmacokinetics Analysis Sets 
The pharmacokinetics (PK) analysis population includes all patients who received any study drug 
and who had at least 1 non-missing result following the first dose of study drug. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristic variables include the following: 
 Age at screening (years) 
 Age group (18 to <65, 65 to <85,  >=85 years) 
 Sex (Male, Female) 
 Race (Asian, Black/African American, Native Hawaiian/Other Pacific Islander, White 
and Other) 
 Ethnicity (Hispanic or Latino, Not-Hispanic or Latino) 
 Baseline Weight (kg) 
 Baseline Height (cm) 
 Baseline Body mass index (BMI) (kg/m2) calculated from weight and height  
 Severity of illness (per IRT) (severe, critical, multi-system organ dysfunction or 
immunocompromised [recorded on CRFs or IRT, as applicable]) 
 Systemic corticosteroids use (per IRT) 
 SARS-CoV-2 virus result (per CRF) (Positive/Negative) (Note: SARS-CoV-2 
infection is laboratory-confirmed by PCR prior to randomization) 
 Cycle Threshold, if SARS-CoV-2 positive (per CRF)  
Other baseline disease characteristic variables for this study population are as follows.   
Pneumonia status at baseline – (selected from Pneumonia Status at Baseline CRF) 
 History of or current chronic hypercapnic respiratory failure (yes/no) – (selected from 
NEWS2 CRF at baseline or Pneumonia status at baseline CRF, depending on original 
or amended versions of CRFs) 
 Presence of pneumonia based on historical chest X-ray or CT scan (yes/no) 
 Duration of pneumonia prior to baseline (calculated as earliest onset date for symptoms 
of pneumonia to first dose date) 
 Presence of rales/crackles on lung auscultation (yes/no) 
 Presence of documented fever in medical record (yes/no) 
 Highest temperature recorded 24 hours prior to dosing 
 Use of supplemental oxygen by device type (yes/no) 
 Nasal cannula 
 Face mask 
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 Non-rebreather mask 
 High-flow nasal cannula 
 Other (specify) 
 Use of non-invasive ventilation (yes/no) 
 Use of invasive ventilation (mechanical ventilation) (yes/no) 
 Use of vasopressors (yes/no) 
 Use of extracorporeal life support (yes/no) 
 Use of renal replacement therapy (yes/no) 
 Number of patients requiring treatment in intensive care unit (ICU) 
Oxygen administration and Oxygenation at baseline 
 Type of oxygen delivery device  
 Nasal cannula 
 Simple face mask 
 Non-rebreather face mask,  
 High-flow nasal cannula 
 Non-invasive ventilation 
 Invasive mechanical ventilation 
 Extracorporeal life support 
 Other) 
 SpO2 % (peripheral capillary oxygen saturation) (range is 0% to 100%) 
 FiO2 (fraction of inspired oxygen) (range is 0.0 to 1.0) – See Section 4.5.3.2 for 
derivations 
 SpO2 / FiO2 ratio– See Section 4.5.3.2 for derivations 
Hospital or ICU stay 
 Length of hospital stay including ICU prior to randomization (days) 
 Admitted into ICU during hospital stay prior to randomization (yes/no) 
 Length of ICU stay prior to randomization (days) 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to Medical Dictionary for Regulatory Activities (MedDRA®) version 23.0. 
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4.3. 
Prior / Concomitant Medications or Procedures 
Medications/Procedures will be recorded from the day of informed consent until the final study 
assessment (Day 29 or discharge or death). Medications will be coded to the ATC level 2 
(therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), according to WHO 
Drug Dictionary (WHODD) version 202003. Patients will be counted once in all ATC categories 
linked to the medication. 
Prior medications/procedures are: medications taken or procedures performed prior to 
administration of the study drug. 
Concomitant medications/procedures are: medications taken or procedures performed 
following the first dose of study drug through the final study assessment (Day 29 or discharge or 
death).  This includes medications taken that started before the study and are ongoing during the 
study. 
Concomitant medications in a hospitalized population change daily and are difficult to collect in 
the setting of a pandemic with limited resources in some settings. It is therefore difficult to attribute 
to success and failure of therapy and impact on safety. Therefore, only select concomitant 
medications will be captured in this trial. The select list of medications include corticosteroids, 
remdesivir, lopinavir-ritonavir, chloroquine, hydroxychloroquine, interferon beta, and 
convalescent serum. 
Analysis of medications data will be focused on the targeted medications (specified in the protocol) 
that are expected to be reviewed and recorded by sites.  Targeted medications include but are not 
limited to: 
 antipyretics, such as aspirin, acetaminophen, ibuprofen, and other non-steroidal anti 
inflammatory drugs (NSAIDs) 
 warfarin  
 cyclosporine A 
 theophylline 
 digoxin  
 antiepileptics, such as carbamazepine (Carbatrol®, Tegretol®), divalproex 
(Depakote®), phenytoin (Dilantin®), valproic acid (Depakene®);  
 antiarrhythmics, such as disopyramide (Norpace®), procainamide (Procan®, 
Pronestyl®), quinidine (Quinidex®, Quin Release Quin- G®) 
 antivirals, 
such 
as 
remdesivir, 
lopinavir-ritonavir, 
ganciclovir, 
acyclovir, 
valganciclovir 
 chloroquine  
 hydroxychloroquine 
 interferon beta  
 corticosteroids 
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 convalescent serum  
 angiotensin receptor blockers, such as Azilsartan (Edarbi), Candesartan (Atacand), 
Eprosartan (Teveten), Irbesartan (Avapro), Losartan (Cozaar), Olmesartan (Benicar), 
Telmisartan (Micardis), Valsartan (Diovan) 
 angiotensin converting enzyme inhibitors: benazepril (Lotensin), captopril (Capoten), 
enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril 
(Univasc), perindopril (Aceon), quinapril (Accupril) 
4.4. 
Rescue Medication/or Prohibited Medication During Study 
There are no rescue, prohibited or permitted medications in this study, except for those in the 
exclusion criteria of study enrollment.  Patients may continue their normal regimen of medications 
and procedures.  All data collected on medications/procedures (pre-treatment and concomitant) 
will be summarized. 
 
 
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4.5. 
Efficacy Variables 
4.5.1. 
Primary Efficacy Variable – Percent Change from Baseline in C-Reactive 
Protein 
The primary efficacy variable is the percent change from baseline in C-reactive protein (CRP) 
levels at Day 4.   
CRP levels measured by local labs at both Day 1 (baseline) and Day 4 will be used (by default) to 
compute the primary efficacy variable.  If both local lab and central lab data are available at both 
time points, then central lab data will be used. 
In case of missing local lab CRP data, every attempt will be made to send blood samples for testing 
to central labs and the following imputation rules will be applied. 
1. If local lab CRP data is missing at Day 1, then central lab CRP data at both Day 1 and Day 
4 will be used.  If the Day 1 blood sample was not taken or not evaluable, CRP from levels 
from the screening period (at any time prior to Day 1) will be used.   
2. If local lab data is available for Day 1 but missing for Day 4, then missing CRP levels will 
be imputed by local lab CRP data for Day 3 or Day 5 when available, in this order of 
priority.   
3. If local lab CRP data at both Day 1 and post-baseline Days 3/4/5 are missing, then central 
lab data at both Day 1 and Day 4 will be used. 
4. If local lab CRP data at Day 1 and Days 3, 4, 5 are all missing and no samples are available 
for testing at the central lab, then CRP data will be left missing (no imputation). 
Baseline CRP levels will be defined as CRP levels measured at baseline visit (Day 1) based on 
blood sample taken prior to dosing.   
Percent change from baseline in CRP levels at Day 4 will be calculated on both raw scale and 
natural log-transformed data (used to estimate treatment effect based on ANCOVA model; 
Section 5.7.1). 
 Raw scale:  [(CRP at Day 4)] −(Baseline CRP) (Baseline CRP)
⁄
 
 Natural-log scale: {[ln(CRP at Day 4) −ln(Baseline CRP)] ln(Baseline CRP)
⁄
}.   
 
 
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4.5.2. 
Key Secondary Efficacy Variable – Time-to-improvement (≥2 points) in clinical 
status assessment using 7-point ordinal scale 
The key secondary efficacy variable for Phase 2 is time-to-improvement (≥2 points) in clinical 
status assessment from baseline using the 7-point ordinal scale. 
This variable will be used to evaluate the following 2 key secondary efficacy endpoints in 2 
different sets of patients: 
1. Time to improvement (≥2 points) in clinical status assessment from baseline on the 7-point 
ordinal scale in severe or critical patients with high baseline IL-6 levels (> upper limit of 
normal), and  
2. Time to improvement (≥2 points) in clinical status assessment from baseline on the 7-point 
ordinal scale reporting in severe or critical patients with all IL 6 levels. 
The ordinal scale is an assessment of the clinical status of a patient (Peterson, 2017 [4] ). The 7-
point ordinal scale is as follows:  
1. Death;  
2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO);  
3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices;  
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise) 
6. Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care 
7. Not hospitalized 
The clinical status of a patient will be assessed in the morning to consider the worst assessments 
for the previous day (ie, midnight to midnight; 00:00 – 00:00 [24 hour clock]).  If it is the first 
assessment and 24 hours of data are not available, then the clinical status will be recorded  at 
randomization.  Data for clinical status (ordinal scale) is recorded on the Clinical Status 
Assessment Ordinal Scale case report form (CRF). 
Baseline clinical status (prior to dosing on Day 1) in this hospitalized patient population 
(randomized and treated) will take values 2, 3, or 4, i.e., all patients entering the study will require 
either supplemental oxygen or require ventilation (non-invasive, invasive or ECMO), and must be 
hospitalized (as specified in study Inclusion Criteria).  Patients who are randomized but not treated, 
for example who die or are discharged prior to dosing, may have baseline value of 1 or 7, 
respectively.  Randomized but not treated patients are excluded from the analysis.   
Post-baseline clinical status can take values 1 through 7 on ordinal scale and data will be as 
recorded on the ordinal scale case report form (CRF).  However, since the ordinal scale on a given 
study is recorded in the morning and it reflects the patient’s clinical status during the prior 24 hour 
period, derivations for death and hospital discharge on that study day will be done as follows. 
 
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Handling of deaths or discharge on ordinal scale (post-baseline): 
For patients who die, the clinical status ordinal scale value will be retained for the study day as 
recorded, but the clinical status for the next study day will be derived as “1=Death”.  After this 
study day, the observed clinical status ordinal value will be kept missing for derivation of time-to-
improvement variable (described below) and this value will be carried forward until end of study.  
Death date may be obtained from Adverse Events or Study Completion CRFs or phone call at Day 
60 (end of study).   
For example, a patient’s clinical status may be recorded as “2= Hospitalized, requiring invasive 
mechanical ventilation or extracorporeal membrane oxygenation (ECMO)” on the morning of Day 
5, but the patient dies later in the evening of Day 5.  In this case, clinical status (observed) = 2 for 
Day 5, and clinical status (derived) = 1 for Day 6 and carried forward for all subsequent study 
days. 
Similarly, hospital discharge information may be obtained from Hospital & ICU admission & 
discharge CRF.  Earliest available date of hospital discharge will be used and clinical status 
imputed to 7, for the study day after discharge date. After this study day, the observed clinical 
status ordinal value will be kept missing for derivation of time-to-improvement variable (described 
below)  and this value will be carried forward until end of study. If it is learned during follow-up 
that some patients are subsequently readmitted for COVID-related reasons, the data will be 
explored to assess effects of readmission in the analyses. 
Handling of other missing data on ordinal scale (post-baseline): 
For patients who are alive and not discharged (i.e., still hospitalized), missing clinical status 
(ordinal scale) value on a given study Day X will be imputed using data on the type of oxygen 
delivery device used by the patient on the previous day, i.e., Day X-1. Clinical status = 2 (if using 
invasive mechanical ventilation or ECMO), or 3 (if using non-invasive mechanical ventilation or 
high-flow nasal cannula), or 4 (if using nasal cannula, simple face mask, or non-breathter face 
mask) or 5/6 (if not using supplemental oxygen).  Clinical status of 5 or 6 will be assigned through 
medical review of data, or query of site. 
Time-to-improvement (≥2 points) in clinical status assessment from baseline: 
Patients with (post-baseline clinical status – baseline clinical status value) ≥2 will be regarded as 
an improvement (event).  Time to improvement (event) is computed as the (first date of 
improvement – first dose date).  Patients who do not experience improvement of 2 points or more 
on the ordinal scale will be censored at the last observed time point.  Patients who die at any time 
in the study will be censored at Day 60 (end of study – phone call follow-up) in case of final 
database lock for Phase 2 (or censored at date of data cut-off in case of interim locks). 
 
 
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4.5.3. 
Other Secondary Efficacy Variables 
The other secondary efficacy endpoints specified in the protocol are as follows.  Details for 
deriving the variables associated with these endpoints are in Sections 4.5.3.1, 4.5.3.2, 4.5.3.3, 
4.5.3.4, 4.5.3.5, 4.5.3.6, and  4.5.3.7. 
1. Time to resolution of fever for at least 48 hours without antipyretics or until discharge, 
whichever is sooner, in patients with documented fever ≥38°C (oral), ≥38.4°C (rectal or 
tympanic), or ≥37.6°C (temporal or axillary) at Baseline   
(Resolution of fever is defined as postbaseline body temperature <37.2°C (oral), or 
<37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary). 
2. Time to resolution of fever (defined as above) for at least 48 hours without antipyretics or 
until discharge, whichever is sooner, in patients defined as above, by clinical severity. 
3. Time to resolution of fever (defined as above) for at least 48 hours without antipyretics or 
until discharge, whichever is sooner, in patients defined as above, by baseline IL-6 levels. 
4. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to 
the nadir SpO2/FiO2) for at least 48 hours or until discharge, whichever is sooner. 
5. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to 
the nadir SpO2/FiO2) for at least 48 hours, or until discharge, whichever is sooner, by 
clinical severity 
6. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to 
the nadir SpO2/FiO2) for at least 48 hours, or until discharge, whichever is sooner, by 
baseline IL-6 level 
7. Time to resolution of fever (as defined above) and improvement in oxygenation (as defined 
above) 
8. Mean change in the 7-point ordinal scale from baseline to Days 3, 5, 8, 11, 15, and 29 (or 
until discharge) 
9. Percentage of patients in each clinical status category using the 7-point ordinal scale at 
Days 3, 5, 8, 11, 15, and 29  
10. Time to discharge or to a NEWS2 of ≤2 and maintained for 24 hours, whichever occurs 
first 
11. Change from baseline to Days 3, 5, 8, 11, 15, and 29 in NEWS2 
12. Days with fever (≥38°C °C [oral], ≥38.4°C [rectal or tympanic], or ≥37.6°C [temporal or 
axillary])  
13. Proportion of patients alive, off oxygen at Day 29 
14. Days of resting respiratory rate >24 breaths/min (recorded at least once each day)  
15. Days of hypoxemia (SpO2 ≤93% on room air, or requiring supplemental oxygen, or 
mechanical ventilatory support)  
16. Days of supplemental oxygen use  
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17. Time to saturation ≥94% on room air 
18. Ventilator free days in the first 28 days (to Day 29) 
19. Initiation of mechanical ventilation, non-invasive ventilation, or use of high flow nasal 
cannula (for those not requiring these interventions at baseline)  
20. Admission into an ICU (among those not in an ICU at baseline) 
21. Days of hospitalization among survivors  
22. All-cause mortality 
4.5.3.1. 
Fever 
Body temperature data is collected on the following CRFs using various routes, i.e., oral, rectal, 
tympanic, temporal or axillary, or other (e.g., urinal catheter): 
 Pneumonia status at baseline (highest temperature recorded within 24 hours prior to 
dosing) 
 Body temperature (Day 1 – Day 3) 
 For baseline, pre-dose on Day 1 will be used  
 For post-baseline (after dosing on Day 1), temperature recorded in morning, noon, 
evening, bedtime will be used 
 Body temperature (Day 4 onwards) – all post-baseline 
 Body temperature – baseline or post-baseline (highest temperature during the day) 
 National Early Warning Score 2 (NEWS2) 
 Vital signs 
Baseline Body Temperature for a patient is defined as the maximum temperature (using original 
route) at any time prior to dosing obtained from data across all CRFs.  In order to determine the 
maximum, all body temperatures recorded prior to dosing with various routes (oral, 
rectal/tympanic, or temporal/axillary) will be first converted to oral scale: 
 (Rectal or Tympanic) – 0.4 °C = Oral °C 
 (Temporal or Axillary) + 0.4 °C = Oral °C 
Other routes of body temperature (e.g., urinary catheter) will follow same conversion rule as rectal. 
Maximum body temperature using the original route (prior to dosing) that corresponds to the 
maximum oral body temperature (prior to dosing) will be the Baseline Body Temperature. 
Similarly, Post-baseline Body Temperature will be derived as the maximum body temperature 
(keeping the original route) on a given study day. 
Presence of Fever (yes/no) on a given study day is defined as body temperature ≥38°C (oral), 
≥38.4°C (rectal or tympanic), or ≥37.6°C (temporal or axillary). 
Resolution of fever is defined as post-baseline body temperature <37.2°C (oral), or <37.6°C 
(rectal or tympanic) or <36.8°C (temporal or axillary), for at least 48 hours without antipyretics.  
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Antipyretics are defined in Appendix 10.3.  Resolution of fever is defined only in patients with 
presence of fever at Baseline (Day 1) (fever defined as above). 
Time to resolution of fever is defined as [min(earliest date of resolution of fever, hospital 
discharge date) – first dose date]+1, in patients who experience resolution of fever (event).  Patients 
who do not experience resolution of fever will censored at the last observed study day.  Patients 
who die at any time in the study will be censored at Day 60 (end of study), even if fever is resolved. 
4.5.3.2. 
Oxygenation 
All oxygenation-related data will be summarized from the Oxygen Administration and 
Oxygenation CRF. Supplemental oxygen may be administered to patients through an oxygen 
delivery device (e.g., nasal cannula, simple face mask, non-breather face mask, high-flow nasal 
cannula, non-invasive ventilation, invasive mechanical ventilation, extracorporeal life support, 
etc.). 
As applicable, the following supplemental oxygen / FiO2 data will be recorded: 
 Oxygen flow rate in Liters/min (if receiving nasal cannula, simple face mask, non-
rebreather mask)  
 FiO2 (if receiving high flow nasal cannula, non-invasive ventilation, invasive 
mechanical ventilation, or extracorporeal life support) 
For devices that report both Oxygen flow rate and FiO2, only FiO2 data will be used.  For devices 
reporting only oxygen flow rate, this data will be converted to FiO2 as given in Appendix 10.3. 
Resting SpO2 (peripheral capillary oxygen saturation) will also be measured to assess arterial 
oxyhemoglobin saturation (ie., SpO2 is the percentage of hemoglobin containing oxygen compared 
to total amount of hemoglobin in the blood).  SpO2 will be measured simultaneously with the 
recorded supplemental oxygen/FiO2 data. 
The variable SpO2 (peripheral capillary oxygen saturation) will be reported in % units (range: 0% 
to 100%) and FiO2 (fraction of inspired oxygen) will be reported in decimals (range: 0.0 to 1.0).    
Baseline SpO2 / FiO2 ratio will be the last available ratio prior to dosing.  Both SpO2 and FiO2 
values must be nonmissing; missing baseline values will not be imputed. 
Post-baseline SpO2 / FiO2 ratio will be the minimum of all ratios (in case of multiple values) on 
a given study day. 
Change from baseline in SpO2 / FiO2 ratio will be calculated for each study day. 
Improvement in oxygenation is defined as any post-baseline SpO2/FiO2 ratio ≥ nadir + 50, after 
the nadir occurs, where nadir is the lowest SpO2/FiO2 ratio 
Time to improvement in oxygenation is defined as the time from first dose date to the first 
improvement in oxygenation, lasting for at least 48 hours or until discharge, whichever is sooner. 
Patients who do not experience improvement in oxygenation will be censored at the last observed 
time point.  Patients who die will be censored at Day 60 (even if improvement in oxygenation is 
yes before they die). 
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4.5.3.3. 
Clinical status using 7-point ordinal scale 
See definition and derivations in Section 4.5.2. 
Number and percentage of patients in each clinical status category (ordinal scale) will be 
calculated for each study day, based on observed data.  Handling of data for deaths, discharge and 
missing data is given in Section 4.5.2.  Percentages will be calculated based on number of patients 
in a given category on that study day.  
Change from baseline in clinical status (ordinal scale) per patient will be calculated for each 
post-baseline study day as points of change. In this study population, baseline will only take values 
2, 3, 4 (on ordinal scale) and post-basline will take values 1, 2, 3, 4, 5 6, 7.  Change from baseline 
will take values: e.g., -3, ,2, -1, 0, +1, +2, +3, +4, +5 (representing worsening, no change, or 
improvement).  Number and percentage of patients will be calculated for each study day, for the 
change from baseline points, e.g.,  -3, -2, -1, 0, +1, +2, +3, +4 and +5. 
4.5.3.4. 
National Early Warning Score 2 (NEWS2) 
The NEWS2 scoring system is a composite score derived from 7 physiological parameters 
(Williams, 2019 [6] ), (See Table 1):  
1. Respiratory rate (per minute),  
2. SpO2 Scale 1 (%) or SpO2 Scale 2 (%),  
3. Use of air or oxygen (?),  
4. Systolic blood pressure (mm Hg),  
5. Pulse (per minute),  
6. Consciousness, and  
7. Temperature (°C).    
Notes:  Level of consciousness of a patient will be recorded as alert (A), confusion (C), arousable 
to voice (V), pain (P), or unresponsive (U).  SpO2 Scale 2 is used only in patients with history of 
or current Chronic hypercapnic respiratory failure (as recorded on NEWS2 CRF in the original 
CRFs, and on Pneumonia Status at Baseline CRF after Protocol Amendments #1 /#3).  For all 
other patients, SpO2 Scale 1 is used. 
The NEWS2 score is assessed in patients daily in the morning from baseline visit (Day 1) until 
Day 29, discharge or death, whichever is sooner. 
If any component (physiological parameter) is missing, then that value will be imputed using last 
observation carried forward. 
Time to (discharge or to a NEWS2 score of ≤2) and maintained for 24 hours, whichever occurs 
first, will be derived.  Patients who die will be censored at Day 60. 
Note that the Total NEWS2 score for a patient can theoretically range from 0 to 23.  For descriptive 
analysis, NEWS2 score will be regarded as continuous data. 
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Table 1: 
The National Early Warning Score 2 (NEWS2) Scoring System 
 
4.5.3.5. 
Ventilation outcomes 
Ventilator-free days based on Study Day 29 
Ventilator-free days (VFD) depend on both duration of ventilation and mortality through study 
Day 29.  The maximum number of VFD can be 28 days. (Assuming that patient is observed at the 
same time on each study day, there are 28 24-hour periods from Day 1 to Day 29.) VFD will be 
calculated and reported only in patients using invasive mechanical ventilation in Critical COVID-
19 patients at baseline. 
Assisted ventilation is defined as the use of invasive mechanical ventilation or extracorporeal 
membrane oxygenation. For those receiving assisted ventilation, the duration of ventilation is 
defined as [Last date of assisted ventilation in the hospital – max(first date of assisted ventilation, 
first dose date)], if last day is prior to Day 29.  (Note:  Some patients may be randomized while on 
assisted ventilation. Hence maximum of first date of assisted ventilation and first dose date is 
used.) Otherwise, duration of ventilation is (Date of Study Day 29 - first date of assisted 
ventilation).  (Isolated periods of ventilation briefer than 24 hours for surgical procedures and 
ventilation solely for sleep disordered breathing will not count towards duration of ventilation.)  
In patients who never require assisted breathing, duration of ventilation is zero. 
Ventilator-free days are defined as 28 minus duration of ventilation, with following 
considerations. 
 Patients discharged prior to Day 29 (but not to home) on unassisted breathing will be 
assumed to remain on unassisted breathing through Day 29.   
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 For patients who experience multiple episodes of assisted ventilation (e.g. may be on a 
ventilator, then come off the ventilator and be on a ventilator again) ventilator free days 
will be computed between each episode of ventilation and total VFD calculated. 
 Patients who do not survive 29 days will be assigned zero VFD. 
Number and percentage of patients with initiation of mechanical ventilation, non-invasive 
ventilation, or use of high flow nasal cannula (for those not requiring these interventions at 
baseline) will be calculated. 
Ventilator-free days based on Study Days 8, 15, 22 
VFD variable for each patient will also be calculated similarly (as above) based on data up to Study 
Day 8, 15, and 22 (replace Day 29 by respective study day).  Maximum VFD will be 7 days, 14 
days, and 21 days, respectively. 
4.5.3.6. 
Other respiratory outcomes 
The following respiratory outcomes will be summarized descriptively for each treatment group.  
Descriptive statistics will be provided for number of days related outcomes in terms of n, mean, 
sd, median, min and max. 
 Proportion of patients who are alive and off oxygen at Day 29 
 i.e., no supplemental oxygen or mechanical ventilation used, or clinical status is 5, 
6, or 7. 
 Number of days of resting respiratory rate >24 breaths/min (recorded at least once each 
day) (obtained from NEWS2 CRF) 
 Number of days of hypoxemia (SpO2 ≤93% on room air, or requiring supplemental 
oxygen, or mechanical ventilatory support) (obtained from Oxygen administration and 
Oxygenation CRF) 
 Number of days of supplemental oxygen use  
 Time to saturation ≥94% on room air calculated as days until SpO2 ≥ 94% without 
supplemental oxygen or ventilation 
4.5.3.7. 
Hospitalization, Intensive Care Unit (ICU) and Mortality 
Number and percentage of patients admitted into the ICU out of those not in the ICU at 
baseline will be summarized by treatment group.  Among patients who are discharged from the 
hospital alive, number of days of hospitalization will also be summarized by treatment group 
using descriptive statistics. All-cause mortality will be summarized as proportion of patients who 
died.  Time-to-death from first dose date will be analyzed using survival analysis methods.  Death 
(mortality) data will be based on the recorded death date. 
ICU-free days will be calculated using the same logic as Ventilator-free days at study days 8, 15, 
22 and 29 (Section 4.5.3.5). 
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4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Serious adverse events and AESIs will be collected from the time of informed consent signature 
and then at each visit through Day 29 or discharge or death, whichever is sooner. Patients 
discharged prior to Day 29 will have a follow-up phone call on Day 29 to assess vital status, collect 
data on serious adverse event  and history of hospital re-admission. At the Day 60 phone call 
follow-up, data on vital status of the patient (alive or dead) and history of hospital re-admission 
will be collected. All adverse events are to be coded to a “Preferred Term (PT)” and associated 
primary “System Organ Class (SOC)” according to the Medical Dictionary for Regulatory 
Activities (MedDRA version 23.0). 
An Adverse Event is any untoward medical occurrence in a patient administered a study drug 
which may or may not have a causal relationship with the study drug. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol. 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed. 
The severity of AEs will be graded using the NCI-CTCAE v5.  Adverse events not listed in the 
NCI-CTCAE v5 will be graded according to the following scale: 
Table 2: 
Grading System for Adverse Events Not Listed in NCI-CTCAE 
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.   
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
3  
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
ADL**. 
4  
Life–threatening 
Life-threatening consequences; urgent intervention 
indicated. 
5  
Death 
Death related to AE 
* 
Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
Laboratory results, vital signs, or ECG (if feasible) abnormalities will be recorded as AEs if they 
are medically relevant: symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion. 
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The secondary safety variables are (also see Section 4.6.2): 
1. Incidence of serious adverse events 
2. Incidence of Grade 4 neutropenia (absolute neutrophil count (ANC)  < 500/mm3) 
3. Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection 
4. Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection 
in patients with Grade 4 neutropenia (ANC < 500/mm3) 
5. Incidence of hypersensitivity reactions 
6. Incidence of infusion reactions 
7. Incidence of gastrointestinal perforation 
8. White cell count, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, on Days 1, 
3, 5, 8, 11, 15, and 29 (if still hospitalized) 
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) of scientific and 
medical interest specific to this drug program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor will be done.  
In this study, the AESIs are listed below: 
 Grade 4 neutropenia (absolute neutrophil count (ANC) < 500/mm3) :  
 selected from Local Lab-Hematology CRF 
 Grade 4 neutropenia (ANC < 500/mm3) with concurrent severe or life-threatening 
bacterial, invasive fungal, or opportunistic infection :  
 selected from Adverse Event CRF 
 Grade ≥2 infusion related reactions 
 selected from Adverse Events CRF 
 Grade ≥2 hypersensitivity reactions 
 selected from Adverse Events CRF 
 Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥ 3xupper 
limit of normal (ULN) (for patients with normal baseline) or >3X ULN AND at least 2 
fold increase from baseline value (for patients with abnormal baseline) 
 selected from Local Lab-Chemistry CRFs 
 Invasive bacterial or fungal infections of clinical significance with confirmed diagnosis 
based on the investigator's assessment with appropriate diagnostic workups and 
consultations 
 selected from Adverse Event CRF 
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4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of blood chemistry (including C-Reactive Protein, liver 
function tests, creatinine and other), hematology, urinalysis, infection testing, SARS-Cov-2 RT-
PCR, serum sIL-6R, and other (as specified in the protocol). 
Clinical laboratory values will be converted to standard international (SI) units and grouped by 
function in summary tables. Conventional unit may be provided. Functions are defined as follows: 
 Liver function including ALT, AST, alkaline phosphatase, total bilirubin, 
 Renal function including creatinine, uric acid, 
 Electrolytes including sodium, potassium, 
 C-Reactive Protein (CRP), 
 Creatine Phosphokinase (CPK) 
 Metabolic parameters including total proteins, albumin, 
 White blood cells (WBCs) including WBCs count and differential count (neutrophils, 
lymphocytes, eosinophils, basophils, monocytes), 
 Red blood cells (RBCs) and platelets including red blood cells count, hemoglobin, 
hematocrit and platelets count, 
 Other 
4.6.4. 
Vital Signs 
Vital signs, including blood pressure, pulse, and respiration, are recorded at multiple time points 
according to Schedule of Time and Events table (See Section 10.1).  Temperature is also recorded 
at multiple time points (See Section 4.5.3.1). 
4.6.5. 
Physical Examination Variables 
A targeted physical examination including lung auscultation will be performed at time point 
according to Schedule of Time and Events table (See Section 10.1). Care will betaken by the 
investigator to examine and assess any abnormalities that may be present, as indicated by the 
patient’s medical history.  
During screening period, if any existing clinically significant abnormalities are present, these will 
be recorded in the Medical History CRF. Post-screening period, if any new clinically significant 
abnormalities are present (per investigator discretion), the relevant event will be recorded in the 
Adverse Event CRF, if applicable 
4.7. 
Pharmacokinetic Variables 
The PK variable is the concentration of sarilumab and sIL-6R in serum at each time point specified 
in the Schedule of Time and Events table (See Section 10.1) . 
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4.8. 
Pharmacodynamic and Other Biomarker Variables  
Exploratory endpoint variables include measurement of SARS-CoV-2 in OP or NP swabs over 
time using RT-PCR. Qualitative (positive or negative) or relative quantitation of viral copies may 
be evaluated. Pharmacodynamic variables may include the time to reach a negative OP or NP RT 
PCR result. 
Additional biomarker testing may include, but not be limited to, evaluation of inflammatory 
cytokines in serum, and ANC.  
Pharmacodynamic variables may include the time to nadir (or peak), descriptive statistics of 
absolute value, absolute change from baseline, percent change from baseline by nominal time 
(visit), and area under the curve (AUC) of mean and median change from baseline for IL-6 and 
ANC. 
These results may be reported outside the clinical study report (CSR). 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation (sd), minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics variables given in Section 4.1 will be summarized 
descriptively by treatment group, and all groups combined.  These will be analyzed for both mITT 
and ITT populations. 
5.2. 
Medical History 
Medical history will be summarized by SOC and PT and by treatment group and all groups 
combined in the ITT population. 
5.3. 
Prior / Concomitant Medications or Procedures 
Prior or concomitant medications/procedures will be summarized by treatment groups.  Focus of 
the results will be on the list of targeted medications (Section 4.3) in the ITT population.   
5.4. 
Rescue/ Prohibited Medications if applicable 
Not applicable.  See Section 4.3. 
5.5. 
Subject Disposition 
The following summaries will be provided for both mITT and ITT populations. 
 The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
 The total number of randomized patients:  received a randomization number 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation.   
(Note: Until Protocol Amendment #3 was effective, patients were given only a single 
dose.  After Protocol Amendment #4, repeat dosing is permitted after 24 hours of 
dosing and weekly under protocol-defined criteria.  Discontinuation from study 
treatment refers to either study treatment interruption (if single dose) or study drug 
discontinuation (if multiple doses).) 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
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(Note:  Applicable only on data after Protocol Amendment #4 is in effect, as described 
above.) 
 The ITT population and mITT population (defined in Sections 3.1 and 3.2) 
 The Safety population (defined in Section 3.4) 
5.6. 
Extent of Study Treatment Exposure and Compliance 
Until Protocol Amendment #3 was effective, treated patients were given a single dose of study 
drug (sarilumab 400 mg IV, sarilumab 200 mg IV, or placebo IV).  After Protocol Amendment #4, 
repeat dosing of study drug is permitted after 24 hours if no clinical response is observed and 
repeat weekly dosing is permitted for patients requiring supplemental oxygen (under protocol-
defined criteria).   
5.6.1. 
Measurement of Compliance 
Treatment compliance in a given patient is defined as the number of fully completed infusions of 
study drug divided by number of doses administered (applicable, both, to patients receiving only 
single dose or multiple doses since Protocol Amendment #4).  Treatment compliance will be 
summarized by treatment group using descriptive statistics based on the Safety population. 
5.6.2. 
Exposure to Investigational Product 
Exposure to study drug will be examined for each patient as recorded on the Study Drug 
Administration-IV CRF. The following variables will be analyzed by treatment group: 
 Duration of intravenous infusion 
 Location of drug administration 
 Total volume of drug administered (units: mL) 
 Number of patients with total planned dose administered (yes/no) 
 If no, reason for not administration of total planned dose (equipment failure, 
adverse event, other) 
 Number of patients with infusion interruptions 
 Number of patients receiving 1, 2, 3, etc. doses 
 Number of patients receving drug by time, e.g., Day 1, Day 2, and weekly thereafter 
(Days 8, 15, 22) 
 
 
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5.7. 
Analyses of Efficacy Variables 
For the Phase 2 portion of the study, the hypothesis to be tested is the superiority of sarilumab 400 
mg IV versus placebo with respect to the primary endpoint of percent change from baseline in 
CRP levels at Day 4 (Section 4.5.1). 
The statistical hypotheses (null H0 vs. alternative H1) for the primary endpoint are: 
𝐻0: 𝜇1 = 𝜇2     versus    𝐻1: 𝜇1 ≠𝜇2 
where μ1 and μ2 are mean percent changes from baseline in CRP-levels at Day 4 (based on natural 
logarithm scale) in the two treatment groups.  
The statistical hypotheses (null H0 vs. alternative H1) for the Phase 2 key secondary efficacy 
endpoint of time-to-improvement (≥ 2 points) in clinical status from baseline using the 7-point 
ordinal scale (Section 4.5.2 ), and other secondary endpoints of time-to-resolution of fever and 
time-to-improvement in oxygenation (Section 4.5.2 ) are stated below. 
𝐻0: 𝑆1(𝑡) = 𝑆2(𝑡) for all time 𝑡     versus    𝐻1: 𝑆1(𝑡) ≠𝑆2(𝑡) for some time 𝑡  
where S1 (t) and S2 (t) are the survival probability functions of the above endpoints. 
5.7.1. 
Analysis of Primary Efficacy Variable 
The primary efficacy analysis (for Phase 2) will be a pairwise comparison between sarilumab 400 
mg IV and placebo with respect to the primary endpoint of percent change from baseline in CRP 
levels (natural logarithm scale) at Day 4 (Section 4.5.1) in COVID-19 patients with high baseline 
IL-6 levels in all disease severity strata (mITT; all disease severity strata).  
CRP levels measured by local labs at both Day 1 (baseline) and Day 4 will be used (by default) to 
compute the primary efficacy variable. Handling of missing CRP data is described in Section 4.5.1.  
Hypothesis test of superiority of sarilumab versus placebo will be based on an ANCOVA model 
with change from baseline in CRP levels at Day 4 (CRP levels on log-scale) as dependent variable; 
baseline CRP (log-scale) as covariate and treatment group, severity of illness and systemic 
corticosteroid use as fixed effects. 
ANCOVA model is stated as below: 
[ln(CRP at Day 4) −ln(Baseline CRP)] =  𝛽∗ln(Baseline CRP) + 𝛼𝑖 +𝛽𝑗 + 𝛿𝑘  
where [ln(CRP at Day 4) −ln(Baseline CRP)] is the dependent variable, ln(Baseline CRP) is the 
covariate with β as the regression coefficient, and 𝛼𝑖 , 𝛽𝑗, 𝛿𝑘  represent the fixed effects for 
treatment group (i=1,2), disease severity strata (j=1,2,3), and systemic corticosteroid use (k=1,2), 
respectively.  If the sample size in the cells for systemic corticosteroids use (strata variable) are 
approximately 10 or below, then this variable will be dropped from the model. 
Adjusted treatment mean estimates with standard errors, the adjusted estimate of treatment mean 
difference with standard error, and a 95 % confidence interval for the treatment mean difference 
will be estimated from the model.  
Treatment effect will be estimated using the adjusted treatment means (Least Squares means) from 
the ANCOVA model as follows:  
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 LS-means estimate for each treatment group= [ln(CRP at Day 4) −ln(Baseline CRP)]
̂
, 
i.e., ln(CRP at Day 4 Baseline CRP
⁄
)
̂
 
 Percent change from baseline in CRP (on raw scale) will be estimated by back 
transformation of the log-scale, i.e., anti-log of LS-means estimate minus 1 
exp[ln(CRP at Day 4 Baseline CRP
⁄
)]
̂
−1 
 Treatment difference based on the LS-means difference (as described above) and 
corresponding 95% confidence intervals will be reported 
P-values for the treatment effect from this model will be compared to the 0.05 (two-sided) level of 
significance. 
To determine the success of the Phase 2 portion of the trial, first the data in patients with high 
baseline IL-6 will be analyzed (mITT; all disease severity strata).  If the treatment difference is 
statistically significant, similar analysis will be done between sarilumab 400 mg IV and placebo 
on the data for the full Phase 2 ITT population, ie., without regard to baseline IL-6 levels (ITT; all 
disease severity strata). 
Sensitivity analyses:  
Missing data derivation rules described in Section 4.5.1 will be followed. Although efforts will be 
made to obtain data from sites (hospitals) for baseline CRP and at Day 4 during routine local lab 
testing, or through central labs using collected blood samples, certain CRP data may still be 
missing in case of some patients given the serious nature of the COVID-19 pandemic and the 
intense workload on the hospital health care system. 
Sensitivity analysis #1 
Only patients with baseline CRP data will be used in the sensitivity analysis (and those with 
missing baseline will be excluded).  If there are any post-baseline missing data (i.e., any post-
baseline through Day 5 are missing), they will be imputed assuming data are missing at random as 
follows. 
 Missing post-baseline CRP data will be imputed using a regression method with 
adjustment for disease severity strata, treatment group, and baseline CRP. 
 Multiple imputation method will be used to create 50 complete datasets under  
monotone missing data pattern assumption using PROC MI step in SAS (with seed 
number 6882040). 
 Each imputed dataset will be analyzed using ANCOVA model as described above. 
 Results from the 50 analyses will then be combined using PROC MIANALYZE step 
in SAS to provide the statistical inferences (treatment effect estimates, confidence 
intervals and p-values) 
Sensitivity analysis #2 
Sensitivity analysis will also be conducted similar to #1, using normalized CRP data, i.e., 
value/ULN to account for multiple local labs. 
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Sensitivity analysis #3 
Descriptive analysis will be presented for Percent change from baseline for CRP based on both 
raw-scale and log-scale based on all available data. 
Supportive analyses: 
Comparison between sarilumab 200 mg IV and placebo will also be performed descriptively. 
If the sarilumab 400 mg treatment arm is dropped for safety reasons, then sarilumab 200 mg will 
be formally compared for efficacy against placebo.  Due to the pandemic nature of the COVID-19 
disease with public health significance, it also possible that both sarilumab dose arms may be found 
to be efficacious and no multiplicity adjustment is planned in that case. 
Pooled analysis (combining sarilumab 200 mg IV and 400 mg IV treatment groups) versus placebo 
will be also conducted using the same statistical methods as primary efficacy analysis. 
Subgroup analyses: 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment effects 
by the following variables: 
 Severity of illness strata at enrollment (severe, critical, multi-system organ dysfunction, 
immunocompromised) 
 Systemic corticosteroids use (yes/no), provided cell size is larger than approximately 
10 
 Median duration of pneumonia at baseline 
 Baseline IL-6 category (eg., ≥ or < median, tertiles, etc.) 
5.7.2. 
Analysis of Secondary Efficacy Variables 
The secondary efficacy analysis (for Phase 2) will be a pairwise comparison between sarilumab 
400 mg IV and placebo for the key secondary endpoint of time-to-improvement (≥2 points) in 
clinical status assessment from baseline using the 7-point ordinal scale (Section 4.5.2 ) in  
1. COVID-19 patients with high baseline IL-6 within the severe and critical strata (mITT; 
severe and critical strata), and 
2. COVID-19 patients with all baseline IL-6 levels within the severe and critical strata (ITT; 
severe and critical strata). 
For descriptive purpose, hypothesis test of superiority of sarilumab versus placebo will be done 
using the stratified log-rank test with severity of illness and systemic corticosteroid use as 
stratification factors.  (Systemic corticosteroid use strata variable may be dropped from the model 
if the cell size is approximately 10 or lower, as stated in Section 5.7.1).  
Estimation of treatment effect will be provided as difference in median times-to-improvement (2 
points) in clinical status (placebo – sarilumab) using Kaplan-Meier survival method as well as 
hazard ratio using Cox proportional hazards model along with two-sided confidence intervals. 
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In case of non-proportional hazards, stratified weighted log-rank test may be conducted using the 
Fleming-Harrington family of parameters for early, middle or late differences. 
P-values and 95% confidence levels will be reported, for descriptive purpose on the Phase 2 data. 
Supportive analysis: 
The clinical status assessment is reported using the 7-point ordinal scale (k=1,…7; 1=Death, 7=Not 
hospitalized; see Section 4.5.2).  
This ordinal data will also be analyzed using the proportional odds model stated as below: 
logit(𝜃ℎ𝑖𝑘) = 𝛼𝑘+ 𝒙𝒉𝒊
′ 𝜷,   
for stratum level ℎ ; treatment group 𝑖= 1,2; and ordinal scale category 𝑘= 2, ⋯,7. 
Here: 
The dependent variable, logit(𝜃ℎ𝑖𝑘) = log[𝜃ℎ𝑖𝑘(1 −𝜃ℎ𝑖𝑘)
⁄
], is the log odds of at least as favorable 
outcome(s) (as k or greater) over less favorable outcome(s) than k, 
𝜃ℎ𝑖𝑘 is the cumulative probability of at least as favorable outcome as k, 
(1 −𝜃ℎ𝑖𝑘) is the cumulative probability of outcomes less favorable than k 
𝛼𝑘 is the intercept for kth level in ordinal scale, 
𝒙ℎ𝑖 is the regression variable for disease severity strata and treatment group, and 
𝜷 is the regression coefficient which is assumed to be constant for all k levels in ordinal scale 
due to the proportional odds assumption. 
Analysis time for clinical status based on ordinal data will include all data available up to the data 
lock point.  Analysis population will be mITT in patients in the severe and critical strata, as well 
as ITT in the severe and critical strata. 
Treatment effect will be estimated in terms of odds ratio (OR) for sarilumab 400 mg IV over 
placebo based on this model, along with 95% confidence interval for the OR.  P-values for this 
OR will be reported for descriptive purpose.  Similar analysis will be conducted for sarilumab 200 
mg IV versus placebo. 
Subgroup analyses: 
Descriptive analyses will also be performed on the key secondary endpoint to summarize the 
treatment effects within the severity of illness subgroups (severe, critical, multi-system organ 
dysfunction, immunocompromised) by the following variables: 
 Demographics (e.g., Age, gender, race) 
 Comorbidities (e.g., hypertension, diabetes, obesity) 
 Median duration of pneumonia at baseline 
 Baseline IL-6 category (eg., ≥ or < median, tertiles, etc.) 
 
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5.7.3. 
Analysis of Other Secondary Efficacy 
Other secondary efficacy variables listed in Section 4.5.2  will be analyzed as follows.  
1. Differences in time-to-event endpoints by treatment (eg., all-cause mortality, time to 
resolution of fever, improvement in oxygentation, and other time-to-event endpoints) will 
be summarized with Kaplan-Meier estimates and 95% confidence intervals. 
2. Changes from baseline in ordinal scale at all study days will be summarized by number 
and percentage of patients over time (eg., patients who have a 1-, 2-, 3-, 4- or 5-point 
improvement or no change (0) or 1-, 2-, 3-, 4-point worsening; see Section 4.5.3.3). 
3. Total NEWS2 score and changes from baseline NEWS2 score at all study days will be 
summarized with descriptive statistics as continuous variables 
4. Duration of event (eg., duration of mechanical ventilation, ventilator free days, ICU-free 
days, days of supplemental oxygen use etc.) will be summarized with descriptive statistics 
(n, mean, sd, median, quartiles, min, max) across all disease severity strata as well as by 
severity. 
5. Incidence data (eg., patients alive and off oxygen use) will be summarized as proportions 
with 95% confidence intervals. 
6. Continuous endpoints and their changes from baseline will be summarized through 
descriptive statistics including mean, standard deviation, median and quartiles. 
7. Categorical data (eg., 28-day mortality or ordinal scale by day) will be summarized 
according to proportions. 
Win ratio method (Pocock et al., 2012 [5]) on a hierarchical composite of the selected efficacy 
endpoints (e.g., 28-day mortality, ventilator-free days, and improvement (≥ 2 points) in clinical 
status based on ordinal scale) as an exploratory analysis may also be conducted. 
5.7.4. 
Adjustment for Multiple Comparison 
For the Phase 2 portion of the study, hypothesis test will be conducted for the Phase 2 primary 
endpoint of percent change from baseline in CRP levels at Day 4 in patients across all disease 
severity strata in mITT population (i.e., high baseline IL-6).  If there is substantial overlap between 
mITT, e.g., ≥ 95%, then ITT will be the primary population.  Otherwise, ITT population will be 
tested sequentially.   
The key secondary endpoint of time-to-improvement (≥2 points) in clinical status assessment will 
only be descriptively analyzed.  P-values will be reported for descriptive purpose.   
Overall Type 1 error will be controlled at 0.05 level (2-sided) in Phase 2. 
 
 
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5.8. 
Analysis of Safety Data 
The analysis of safety data will be performed on the SAF, as defined in Section 3.4. 
The safety analysis will be based on the reported SAEs and AESIs and other safety information 
(clinical laboratory evaluations and vital signs).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Section 10.2. 
The summary of safety results will be presented for each treatment group. 
5.8.1. 
Adverse Events  
The verbatim text, the PT, and the primary SOC will be listed in subject listings. Summaries that 
include frequencies and proportions of patients reporting AEs will include the PTs and the SOCs. 
Period of observation: The observation period will be the on-treatment period defined as the day 
from first dose of study drug (Day 1) to study Day 29. (Patients who are discharged prior to Day 
29 will receive a follow-up phone call to collect data on SAEs (if any), survival and history of 
hospital re-admission.) 
Treatment-emergent AEs (TEAEs) are defined as those AEs that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the on-treatment period.  In this study, 
only SAEs and AESIs are collected.  As such TEAEs will reflect this data. 
For details on handling missing data and partial dates, see Section 6. 
Summaries of AE incidence in each treatment group will include: 
 Overview of TEAEs, summarizing number of events, summarizing number and 
percentage of patients within the specified category 
 Total number of TEAEs, SAEs, AESIs, serious AESIs 
 Patients with any TEAEs, any SAEs, any AESIs, serious AESIs 
 Patients with any TEAEs leading to study drug interruption or study 
discontinuation, leading to death 
 TEAEs by system organ class (SOC) and preferred terms (PT) 
 All TEAEs 
 TEAEs by relationship to treatment (related, not related) 
 TEAEs by CTC grade (according to the grading scale outlined in Section 4.6.1), 
presented by SOC and PT 
 TEAEs leading to study drug interruption or study discontinuation 
 TEAEs leading to death 
 AESIs by PT 
 SAEs by SOC and PT 
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 Deaths 
Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients from the safety population in each treatment group. 
Primary SOCs will be sorted according to decreasing order of frequency. Within each primary 
SOC, PTs will be sorted by decreasing frequency of investigational product. 
A second type of table with counts of each PT in decreasing order of frequency will also be 
provided. 
5.8.2. 
Analysis of Adverse Events of Special Interest 
Summaries of AESIs (given in Section 4.6.2) will include the following and presented by PT in 
each treatment group: 
1. Incidence of Grade 4 neutropenia (ANC < 500/mm3) 
2. Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic infection 
(presented in listings and summarized through patient narratives) 
3. Incidence of Grade 4 neutropenia (ANC < 500/mm3) with concurrent severe or life-
threatening bacterial, invasive fungal, or opportunistic infection 
4. Incidence of Grade ≥2 hypersensitivity reactions, Grade ≥ 2 infusion reactions, 
gastrointestinal perforation 
5. White cell count, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, on all study 
days (available data) 
6. Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥ 3xupper 
limit of normal (ULN) (for patients with normal baseline) or >3X ULN AND at least 2 fold 
increase from baseline value (for patients with abnormal baseline) 
7. Incidence of any invasive bacterial or fungal infections 
5.8.3. 
Clinical Laboratory Measurements  
A treatment-emergent Potential Clinically Significant abnormal value (PCSV) is a laboratory value 
that was normal at Screening and Baseline but abnormal after treatment with study drug, or a 
laboratory value that was abnormal at Baseline and exacerbates after treatment with study drug.  
“Exacerbations” will be identified by the Medical Monitor using clinical judgment.  See 
Appendix 10.2 for the criteria of PCSV values.  Treatment-Emergent Potentially clinically 
significant values (PCSVs) will be summarized by treatment group. 
Baseline clinical laboratory analytes and change from Baseline in clinical laboratory analytes to 
each scheduled assessment time will be summarized with descriptive statistics. Summary statistics 
will include the number of patients, mean, median, standard deviation, quartiles, minimum, and 
maximum.   
Listings will be provided with flags indicating out of laboratory range values. 
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5.8.4. 
Analysis of Vital Signs 
Vital signs (including temperature, blood pressure, pulse, and respiration) will be summarized by 
Baseline and change from Baseline to each scheduled assessment time with descriptive statistics.  
The graphs of mean (or median) value of some vital sign parameter vs. visit will also be plotted. 
5.8.5. 
Physical Exams 
As physical examination is limited in this study, only the targeted examination of lung auscultation 
will be provided in patient listing. 
5.9. 
Analysis of Pharmacokinetics, Pharmacodynamics and Biomarker 
Data  
5.9.1. 
Analysis of Drug Concentration Data 
The concentrations of sarilumab and sIL-6R over time and selected PK parameters, as appropriate, 
will be summarized using descriptive statistics. 
No formal statistical hypothesis testing will be performed. 
5.9.2. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The concentrations of exploratory PD/Biomarkers over time will be summarized using descriptive 
statistics. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Definitions of baseline for efficacy variables are defined in Section 4.5 . 
For safety variables, baseline will be the latest available valid measurement taken prior to the 
administration of study drug.  
6.2. 
Data Handling Convention for Efficacy Variables  
6.3. 
Data Handling Convention for Missing Data 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Sections 4.5.1, 4.5.2, 4.5.3, 5.7.1, 5.7.2 and 5.7.3. 
For other continuous variables not mentioned in above sections, missing clinical efficacy data will 
be imputed using last observation carried forward (LOCF) as these are hospitalized patients and 
missing data is assumed to be missing at random.  
For categorical variables, patients with missing data will be included in calculations of 
percentages.  Number of patients with missing data will be presented. 
Handling of Medications with missing/partial dates 
To determine whether a medication is prior or concomitant medication, the missing medication 
start date is estimated as early as possible up to first dose date, and the missing medication end 
date is estimated as late as possible up to Day 29. If the medication start date is missing, the onset 
day will not be imputed in medication listings. 
Handling of Adverse events Severity and Relatedness 
If the intensity of a SAE and AESI is missing, it will be classified as “severe” in the frequency 
tables by intensity of SAE and AESIs. If the assessment of relationship of the investigational 
product is missing, it will be classified as related to the investigational product. 
Date of injections 
Date of injection is the non-missing administration date filled in the Study Drug Administration-
IV CRF. If the first dose of study drug administration date is missing (even after site is queried), 
then the dosing date is will be imputed with the randomization date.  If any subsequent study drug 
administration date is missing, the date of dispensation of study drug from IRT will be used. 
 
 
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6.4. 
Visit Windows 
Following windows will be used for summarizing laboratory parameters.  However, for the 
primary efficacy analysis of CRP, no windows will be applied (See Section 5.7.1). 
Table 3: 
Time Window for Summary of Laboratory Parameters 
Visit label 
Target Day 
Hematology, Chemistry 
Baseline 
1 
≤1 
Day 4 
4 
2-5 
Day 7 
7 
6-10 
Day 15 
15 
11-17 
Day 21 
21 
18-24 
Day 29 
29 
≥25 
6.5. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries except for the endpoint determination.  If more than one laboratory value is 
available for a given visit, the first observation will be used in summaries and all observations will 
be presented in listings. 
6.6. 
Pooling of Centers for Statistical Analyses 
Additional analyses on primary and key secondary efficacy endpoints may be performed by sites 
and pooling sites enrolling less than 5 patients. 
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7. 
INTERIM ANALYSIS 
To maximize safety, approximately the first 12 patients who are randomized and receive study 
drug will be monitored for safety (assuming a total of ~10 patients are dosed with sarilumab 200 
mg IV or 400 mg IV).  Safety data on these 12 patients will be reviewed by an IDMC after the last 
of these patients dosed reaches Day 7.  Data on the first ~12, ~25, and ~50 patients (regardless of 
severity of illness) who reach at least Day 7 will be reviewed by the independent data monitoring 
committee (IDMC) and Regeneron senior physicians to determine if a treatment arm should be 
discontinued for safety reasons.  Selected treatment groups in the Phase 2 portion may be continued 
forward in the remainder of the study.  In addition to these specific assessment times, the IDMC 
will actively monitor interim data to make recommendations about early study closure or changes 
to study arms throughout the course of the study. 
A first-step analysis of the data will be conducted for the Phase 2 portion of the study once ~460 
patients are randomized and treated for 14 days, to allow for study design adaptation of Phase 3. 
Decisions on sample size re-estimation, if needed, for Phase 3 and choice of primary endpoint for 
Phase 3 will be based on the unblined data from Phase 2.   
Dropping of a treatment arm in Phase 3 may not be feasible or needed for this single-dose study 
due to the rapid enrollment given the dire COVID-19 pandemic situation.  However, this 
adaptation decision may be based on the unblinded Phase 2 data or based on recommendations 
from the Independent Data Monitoring Committee (IDMC). 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4. 
 
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9. 
REFERENCES 
1. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and  content of 
clinical study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
2. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
4. Peterson RL, Vock DM, Powers JH, Emery S, Cruz EF, Hunsberger S, et al. Analysis of 
an ordinal endpoint for use in evaluating treatments for severe influenza requiring 
hospitalization. Clin Trials 2017; 14(3):264-76. 
5. Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of 
composite endpoints in clinical trials based on clinical priorities.  European Heart Journal 
2012; 33: 176-182. 
6. Williams B. The National Early Warning Score 2 (NEWS2) in patients with hypercapnic 
respiratory failure. Clin Med (Lond) 2019; 19(1):94-5. 
7. Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y et al. "Effective treatment of severe 
COVID-19 patients with Tocilizumab." ChinaXiv preprint (2020). https://www.ser.es/wp-
content/uploads/2020/03/TCZ-and-COVID-19.pdf  
 
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10. 
APPENDIX 
10.1. 
Schedule of Time and Events  
Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 or 
discharge3,4 
60 
Window  
 
 
±6 hours 
 
 
 
±7 days 
±7 days 
Screening/Baseline: 
 
 
 
 
 
 
    
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Demographics and Medical History1 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
   
 
 
 
 
Study Drug Administration 
 
X 
X5 
 
 
X6 
 
 
 
 
 
If no clinical 
response 
 
 
Repeat weekly for 
patients requiring 
any supplemental O2 
 
 
Assessments: 
Oxygen administration (FiO2) and 
Oxygenation (SpO2)7 
X 
X 
2 times a day  
 
Clinical Status Assessment (7-point ordinal 
scale)8 
 
X 
Daily until discharge 
 
NEWS2 Score 
 
 
 
 
Air or oxygen 
 
X 
Daily in the morning until discharge 
 
Respiratory rate  
 
X  
Daily in the morning until discharge 
 
BP 
 
X 
Daily in the morning until discharge 
 
Pulse 
 
X 
Daily in the morning until discharge 
 
Consciousness 
 
X 
Daily in the morning until discharge 
 
Body temperature before antipyretics or 
4 hours after antipyretics9 
 
X 
Daily in the morning until discharge 
 
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Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 or 
discharge3,4 
60 
Window  
 
 
±6 hours 
 
 
 
±7 days 
±7 days 
Imaging, microbiology results, and arterial 
blood gas results (as available)10 
 
 
If available in the medical record 
 
Limited physical examination (lung 
auscultation only) 
X 
 
 
 
Electrocardiogram (ECG), if feasible11 
X 
 
 
 
Record Targeted Medications12 
 
 
Daily until discharge 
 
Adverse Events13 
X 
 
                                                X 
Pregnancy Test (WOCBP)14 
X 
 
 
 
Follow-up Phone Call 
 
 
 
 
 
 
X 
X 
Laboratory Testing: 
C-Reactive Protein (mandatory) 
X 
X 
 
X 
X  
 
 
 
 
 
 
Add CRP to all routine labs and obtain at the same time  
Record all results available in medical chart 
 
Hematology15 
X 
 
Record all results available in medical chart1 
Must be collected within 48 hours prior to redosing 
 
Blood chemistry (including LFTs and 
creatinine)16 
X 
 
Record all results available in medical chart1 
Must be collected within 48 hours prior to redosing 
 
Blood cultures for bacteria and fungi 
(mandatory)17 
 
 
 
 
X 
X (Day 15) 
 
 
PK/Biomarkers/Research (defer to footnotes for sampling requirements): 
 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 or 
discharge3,4 
60 
Serum for PK/Sarilumab Concentration18 
 
X1 
X5,18 
X 
X 
X 
X16 
 
Serum sIL-6R plus research18 
 
X1 
 
X 
X 
X 
X 
 
Serum cytokines including IL-6 and biomarker 
testing1,18 
 
X1 
 
X 
X 
X 
X 
 
Blood for PCR SARS-CoV-219 
X 
X 
 
X 
 
 
X 
 
Oropharyngeal or nasopharyngeal swab for 
SARS-COV-2 detection and sequencing19,20 
X 
X 
 
X 
 
 
X 
 
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Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 or 
discharge3,4 
60 
Window  
 
 
±6 hours 
 
 
 
±7 days 
±7 days 
Blood for research plasma19 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
1. Screening and baseline may occur on the same day. Assessments that are noted for both visits should only be assessed once. Medical 
history should include collecting onset of pneumonia symptoms.  Body temperature, SpO2, and FiO2 must be collected at 
randomization.  All samples should be collected before study drug administration at baseline visit except post-infusion PK and sIL-
6R samples. 
2. Patients will have an end of study (EOS) assessment to collect data on survival and history of hospital re-admission.  This assessment 
may be performed by phone. 
3. Patients discharged prior to Day 29 will have a follow-up phone call on Day 29 to collect data on survival and history of hospital re-
admission. 
4. Patients discharged prior to Day 29 should have a sample collected for on or before day of discharge.  If day of discharge is not Day 
29 and coincides with another visit, the Day 29 assessments should be performed. 
5. Patients can be re-dosed at 24 hours (±6 hours) if the patient: 
a. Remains febrile OR 
b. Fails to improve gas exchange (eg, as measured by ventilator settings or O2 requirements) OR 
c. Is hemodynamically unstable OR 
d. Exhibits other objective evidence of clinical worsening (eg, mental status change, etc.) 
After informed consent is obtained, patients enrolled prior to Amendment 4 are permitted to receive a second dose prior to 
commencing weekly dosing.  The second dose should not be administered within 18 hours of the first dose. 
6. Study drug should not be administered if the ANC is less than 500/mm3 or ALT is >5x ULN within 48 hours of redosing. Weekly 
dosing begins as early as Day 8 then weekly thereafter. If a patient received a 2nd dose other than Day 2, adjust subsequent weekly 
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doses accordingly.  Study drug should be held if there is a high degree of suspicion of active bacterial or fungal infection.  A 
maximum of 6 doses can be administered. 
7. Oxygen administration and oxygenation: refer to Section 9.2.2.3 of the protocol for details. SpO2 must be measured after 5 minutes 
of rest (sitting or supine) and must be measured simultaneously with oxygen administration and ventilation data. Record oxygen 
flow rate (L/min) for patients receiving nasal cannula, simple face mask, or non-rebreather mask. Record FiO2 for patients receiving 
high flow nasal cannula, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation.  
8. Clinical Status Assessment using the 7-point ordinal scale: refer to Section 9.2.2.4 of the protocol for details. The Ordinal Scale 
should be assessed in the morning to consider the worst assessments for the previous day (ie, midnight to midnight; 00:00 – 00:00 
[24-hour clock]).  If it is the first assessment and 24 hours of data are not available, report status at randomization. 
9. Temperature may be measured using the following methods: oral, rectal, tympanic, or temporal according to local hospital protocols 
and according to the manufacturer’s instructions for use of the device. Body temperature should be measured using the same method 
each time. Temperature should be measured predose after at least 5 minutes of rest (supine or sitting).  
10. If available in the medical record, chest CT images will be collected as part of a separate effort related to this study for predictive 
exploratory analysis and may be provided in a separate study report. 
11. ECG only if feasible.  Historical ECG from current hospital admission is acceptable. 
12. Targeted medications: refer to Section 9.2.3.4 of the protocol for details.  
13. Adverse events: Only SAEs and AESIs will be recorded in eCRF. 
14. Pregnancy testing to be performed in women of childbearing potential (WOCBP) only. Serum or urine pregnancy test are both 
acceptable. 
15. Hematology: refer to Section 9.2.3.5 of the protocol for details. CBC is required prior to randomization (standard of care labs may 
be used). After Day 1, CBC will not be performed as a study procedure. When CBC is performed as part of the patient’s clinical 
care, the results will be entered in eCRF. 
16. Blood Chemistry: refer to Section 9.2.3.5 of the protocol for details. LFTs and creatinine are required prior to randomization 
(standard of care labs may be used). After Day 1, LFTs and creatinine will not be performed as a study procedure. When chemistries 
are performed as part of the patient’s clinical care, the results will be entered in eCRF. 
17. If patient is discharged before Day 15, obtain blood culture for bacteria and fungi prior to discharge. 
18. Sample collection for serum: 
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 Samples collected on dosing days are mandatory:  
 One predose (as close to initiation of treatment as reasonable) and  
 One within 60 minutes after the end-of-infusion (EOI).  The EOI sample or flush should be collected from the arm, 
contralateral to that used for IV infusion, if possible.  If not medically feasible, the sample can be drawn from the same 
arm 
 Day 4 samples are mandatory (if PPE and appropriate lab facilities are available). 
 The Day 1 predose sample and Day 29 or Early Termination PK sample may be used for ADA analysis. 
Day 1/baseline samples are mandatory.  
19. Swab and tests will be for exploratory analysis only not for inclusion or diagnosis 
 
 
 
 
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10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) 
 
Parameter 
PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required; multiple levels are optional 
for phase 2/3 studies. If it is desirable to get the distribution 
across the different  PCSV levels, additional shift table on 
≤3, >3 to ≤5,  > 5 to  ≤10, >10 to ≤20, and > 20 category 
for baseline vs. post baseline may be provided  
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple levels are optional 
for phase 2/3 studies. If it is desirable to get the distribution 
across the different  PCSV levels, additional shift table on 
≤3, >3 to ≤5,  > 5 to ≤10, >10 to ≤20, and > 20 category for 
baseline vs. post baseline may be provided 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
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Parameter 
PCSV 
Comments 
Total Bilirubin* 
>1.5 and ≤ 2 ULN and baseline ≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
* At least one level is required, multiple levels are optional 
for phase 2/3 studies. If it is desirable to get the distribution 
of  significant level, additional shift table on  ≤1.5, >1.5 to 
≤2.0 and > 2.0 category for baseline vs. post baseline may 
be provided 
Conjugated 
Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN, and baseline Total 
Bilirubin ≤ 35% or TBILI ≤1.5 ULN 
Conjugated bilirubin determined on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN, and baseline ALT ≤ 3 ULN or 
TBILI ≤ 2ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, multiple levels are optional 
for phase 2/3 studies. If it is desirable to get the distribution 
of  significant level, additional shift table on ≤3, >3 to ≤10, 
and > 10 category for baseline vs. post baseline may be 
provided 
Creatinine 
≥150 μmol/L (Adults) or ≥ULN (if ULN≥150 μmol/L)  and 
baseline < 150 μmol/L or <ULN (if ULN≥150 μmol/L)   
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
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Parameter 
PCSV 
Comments 
Creatinine 
Clearance 
(Cockcroft's 
formula) 
<15 ml/min and baseline ≥15 ml/min (end stage renal 
impairment) 
≥15 -<30 ml/min and baseline ≥30 ml/min  (severe renal 
impairment) 
≥30 - < 60 ml/min and baseline  ≥60 ml/min  (moderate renal 
impairment) 
≥60 - < 90 ml/min and baseline  ≥90 ml/min  (mild renal 
impairment) 
Use is optional. 
FDA draft guidance 2010 
Four independent criteria, will provide additional shift table 
if needed 
 
Uric Acid 
Hyperuricemia: 
 
Hypouricemia: 
 
>408 μmol/L or >ULN (if ULN≥408 μmol/L)  and baseline ≤408 
μmol/L or ≤ULN (if ULN≥408 μmol/L)   
<120 μmol/L or <LLN (if LLN≤120 μmol/L)  and baseline ≥ 120 
μmol/L or ≥LLN (if LLN≤120 μmol/L)   
Harrison- Principles of Internal Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L or ≥ULN (if ULN≥17 mmol/L)  and baseline <17 
mmol/L  or <ULN (if ULN≥17 mmol/L)   
Two independent criteria 
Chloride 
                
Hypochloremia: 
 
               
Hyperchloremia: 
 
<80 mmol/L or <LLN (if LLN≤80 mmol/L)  and baseline ≥ 80 
mmol/L  or ≥LLN (if LLN≤80 mmol/L)   
>115 mmol/L or >ULN (if ULN≥115 mmol/L)  and baseline ≤ 
115 mmol/L  or ≤ULN (if ULN≥115 mmol/L)   
Two independent criteria  
Sodium 
                  
Hyponatremia: 
 
                 
Hypernatremia: 
 
≤129 mmol/L  or ≤LLN (if LLN≤129 mmol/L) and baseline > 
129 mmol/L  or >LLN (if LLN≤129 mmol/L)   
≥160 mmol/L  or ≥ULN (if ULN≥160 mmol/L )  and baseline 
<160 mmol/L  or <ULN (if ULN≥160 mmol/L )   
Two independent criteria 
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Parameter 
PCSV 
Comments 
Potassium 
                  
Hypokalemia 
 
                  
Hyperkalemia 
 
<3 mmol/L or  <LLN (if LLN≤3 mmol/L)  and baseline ≥ 3 
mmol/L or  ≥LLN (if LLN≤3 mmol/L)   
≥5.5 mmol/L or ≥ULN (if ULN≥5.5 mmol/L)  and baseline <5.5 
mmol/L or <ULN (if ULN≥5.5 mmol/L) 
FDA Feb 2005. 
Two independent criteria 
Total Cholesterol ≥7.74 mmol/L or ≥ULN (if ULN≥7.74 mmol/L)  and baseline  < 
7.74 mmol/L or <ULN (if ULN≥7.74 mmol/L) 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L or ≥ULN (if ULN≥4.6 mmol/L)  and baseline < 4.6 
mmol/L or <ULN (if ULN≥4.6 mmol/L) 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN  and baseline < 3 ULN  
 
Amylasemia 
≥3 ULN and baseline < 3 ULN  
 
Glucose 
                
Hypoglycaemia 
 
               
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN and baseline >3.9 mmol/L or ≥ LLN  
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) and baseline < 11.1 
mmol/L (unfasted); <7 mmol/L (fasted)  
 
ADA Jan 2008. 
HbA1c 
>8%  and baseline  ≤ 8%  
 
Albumin 
≤25 g/L or ≤LLN (if LLN≤25 g/L) and baseline >25 g/L or >LLN 
(if LLN≤25 g/L)   
 
CRP  
>2 ULN or >10 mg/L (if ULN not provided) and 
baseline  ≤2 ULN or ≤10 mg/L (if ULN not provided)  
 FDA Sept 2005. 
Hematology 
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Parameter 
PCSV 
Comments 
WBC 
<3.0 Giga/L or <LLN (if LLN≤3.0 Giga/L)  and baseline  ≥3.0 
Giga/L or ≥LLN (if LLN≤3.0 Giga/L) (Non-Black);  
<2.0 Giga/L or <LLN (if LLN≤2.0 Giga/L)  and baseline ≥2.0 
Giga/L or ≥LLN (if LLN≤2.0 Giga/L) (Black)* 
 
≥16.0 Giga/L or ≥ULN (if ULN≥16.0 Giga/L)  and baseline  < 16 
Giga/L or <ULN (if ULN≥16.0 Giga/L) 
Increase in WBC: not relevant. 
*The default criteria. Summary by race (black and Non-
black) are optional. 
 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L or >ULN (if ULN≥4.0 Giga/L)  and baseline ≤ 4.0 
Giga/L or ≤ULN (if ULN≥4.0 Giga/L) 
 
Neutrophils 
<1.5 Giga/L or <LLN (if LLN≤1.5 Giga/L)  for Non-Black or 
<1.0 Giga/L  or <LLN (if LLN≤1.0 Giga/L)  for Black and 
baseline  ≥1.5 Giga/L  or ≥LLN (if LLN≤1.5 Giga/L) for Non-
Black or ≥1.0 Giga/L or ≥LLN (if LLN≤1.0 Giga/L)  for Black* 
 
<1.5 Giga/L or <LLN (if LLN≤1.5 Giga/L)  and baseline ≥1.5 
Giga/L  or ≥LLN (if LLN≤1.5 Giga/L) (Non-Black);  
<1.0 Giga/L or <LLN (if LLN≤1.0 Giga/L)  and baseline ≥1.0 
Giga/L or ≥LLN (if LLN≤1.0 Giga/L)  (Black) 
 
<500 Giga/L regardless of baseline value or racce 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
*The default criteria. By race (black and Non-black) are 
optional. 
Monocytes 
>0.7 Giga/L or >ULN (if ULN≥0.7 Giga/L)  and baseline ≤ 0.7 
Giga/L or ≤ULN (if ULN≥0.7 Giga/L)   
 
Basophils 
>0.1 Giga/L or >ULN (if ULN≥0.1 Giga/L)  and baseline ≤ 0.1 
Giga/L or ≤ULN (if ULN≥0.1 Giga/L)   
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) and  baseline ≤0.5 
Giga/L or ≤ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of Internal Medicine 17th Ed., 2008. 
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Parameter 
PCSV 
Comments 
Hemoglobin 
≤115 g/L or ≤LLN (if LLN≤115 g/L)  for male or ≤95 g/L or 
≤LLN (if LLN≤95 g/L)  for female and baseline  > 115 g/L  or 
>LLN (if LLN≤115 g/L)  for male or > 95 g/L or >LLN (if 
LLN≤95 g/L)  for Female* 
 
≤115 g/L or ≤LLN (if LLN≤115 g/L)  and baseline  > 115 g/L or 
>LLN (if LLN≤115 g/L)  for male; 
 ≤95 g/L or ≤LLN (if LLN≤95 g/L)   and baseline > 95 g/L or 
>LLN (if LLN≤95 g/L)  for Female. 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L)  for male or ≥165 g/L or 
≥ULN (if ULN≥165 g/L)  for female and baseline  <185 g/L  or 
<ULN (if ULN≥185 g/L)  for male or  <165 g/L or <ULN (if 
ULN≥165 g/L)  for Female* 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L)  and baseline <185 g/L  or 
<ULN (if ULN≥185 g/L)  for Male; 
 ≥165 g/L or ≥ULN (if ULN≥165 g/L)  and baseline < 165 g/L  or 
<ULN (if ULN≥165 g/L) for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
*The default criteria. By gender (male and female) are 
optional. 
 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other categories for 
decrease from baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 g/L). 
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Parameter 
PCSV 
Comments 
Hematocrit 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v)  for Male or ≤0.32 v/v or 
≤LLN (if LLN≤0.32 v/v)  for Female and baseline > 0.37 v/v or 
>LLN (if LLN≤0.37 v/v)  for Male or > 0.32 v/v   or >LLN (if 
LLN≤0.32 v/v)  for Female* 
 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v)  and baseline > 0.37 v/v   
or >LLN (if LLN≤0.37 v/v)  for Male ; ≤0.32 v/v or ≤LLN (if 
LLN≤0.32 v/v)  and baseline > 0.32 v/v   or >LLN (if 
LLN≤0.32v/v)  for Female 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v)  for Male or ≥0.5 v/v or 
≥ULN (if ULN≥0.5 v/v)  for Female and baseline < 0.55 v/v or 
<ULN (if ULN≥0.55 v/v)  for Male < 0.5 v/v  or <ULN (if 
ULN≥0.5 v/v)  for Female* 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v)  and baseline < 0.55 v/v  or 
<ULN (if ULN≥0.55 v/v)  for Male ; ≥0.5 v/v or ≥ULN (if 
ULN≥0.5 v/v)  and baseline < 0.5 v/v  or <ULN (if ULN≥0.5 v/v) 
for Female 
Two Criteria are independent 
 
*The default criteria. By gender (male and female) are 
optional. 
RBC 
≥6 Tera/L or ≥ULN (if ULN≥6 Tera/L)  and baseline < 6 Tera/L 
or <ULN (if ULN≥6 Tera/L) 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Platelets 
<100 Giga/L or <LLN (if LLN≤100 Giga/L)  and baseline ≥100 
Giga/L or ≥LLN (if LLN≤100 Giga/L) 
≥700 Giga/L or ≥ULN (if ULN≥700 Giga/L)  and baseline < 700 
Giga/L  or <ULN (if ULN≥700 Giga/L)   
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
Two independent criteria 
 
Urinalysis 
 
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Parameter 
PCSV 
Comments 
pH 
≤4.6 or ≤LLN (if LLN≤4.6)  and baseline > 4.6 or >LLN (if 
LLN≤4.6)   
≥8 or ≥ULN (if ULN≥8)  and baseline < 8 or <ULN (if ULN≥8)   
Two independent criteria 
Vital signs 
HR 
<45 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions except STANDING 
 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions except STANDING 
 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions except STANDING 
Weight 
 5% increase from baseline 
5% decrease from baseline 
FDA Feb 2007  
 
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10.3. 
List of Antipyretics 
To search antipyretics in the datasets, ATC codes ‘M01A’ and ‘N02B’ and below standardized 
medication names, as well as ‘PARACETAMOL’ and ‘acetaminophen’ may be used. 
STANDARDIZED MEDICATION NAME: 
ACECLOFENAC 
ACEMETACIN 
ACETYLSALICYLATE LYSINE 
ACETYLSALICYLIC ACID 
ALOE VERA;METHYL SALICYLATE 
AMTOLMETIN GUACIL 
BENZYDAMINE 
BENZYDAMINE HYDROCHLORIDE 
BENZYDAMINE HYDROCHLORIDE;CHLORHEXIDINE GLUCONATE 
CAFFEINE;CODEINE PHOSPHATE;METAMIZOLE 
SODIUM;NAPROXEN;PHENOBARBITAL 
CAFFEINE;DROTAVERINE 
HYDROCHLORIDE;NAPROXEN;PARACETAMOL;PHENIRAMINE MALEATE 
CELECOXIB 
CHLORPHENAMINE MALEATE;IBUPROFEN;PSEUDOEPHEDRINE HYDROCHLORIDE 
CHLORZOXAZONE;DICLOFENAC SODIUM;PARACETAMOL 
CHOLINE SALICYLATE 
CODEINE PHOSPHATE HEMIHYDRATE;PARACETAMOL 
CODEINE PHOSPHATE;DICLOFENAC SODIUM 
CODEINE PHOSPHATE;IBUPROFEN 
CODEINE PHOSPHATE;IBUPROFEN;PARACETAMOL 
CODEINE;IBUPROFEN;PARACETAMOL 
CYANOCOBALAMIN;DICLOFENAC SODIUM;PYRIDOXINE 
HYDROCHLORIDE;THIAMINE HYDROCHLORIDE 
CYCLOBENZAPRINE HYDROCHLORIDE;LIDOCAINE;PIROXICAM 
DEXAMETHASONE;PHENYLBUTAZONE 
DEXIBUPROFEN 
DEXKETOPROFEN 
DEXKETOPROFEN TROMETAMOL 
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DIACEREIN 
DICLOFENAC 
DICLOFENAC DIETHYLAMINE 
DICLOFENAC POTASSIUM 
DICLOFENAC POTASSIUM;PARACETAMOL;SERRAPEPTASE 
DICLOFENAC SODIUM 
DICLOFENAC SODIUM;HEPARIN SODIUM 
DICLOFENAC SODIUM;LIDOCAINE HYDROCHLORIDE 
DICLOFENAC SODIUM;LINUM USITATISSIMUM;MENTHOL;METHYL 
SALICYLATE;THIOCOLCHICOSIDE 
DICLOFENAC SODIUM;MISOPROSTOL 
DICLOFENAC SODIUM;OMEPRAZOLE 
DICLOFENAC SODIUM;PARACETAMOL 
DICLOFENAC;MISOPROSTOL 
DICYCLOVERINE;PARACETAMOL 
DIFLUNISAL 
DIMETHYL SULFOXIDE 
DIPHENHYDRAMINE HYDROCHLORIDE;NAPROXEN SODIUM 
DIPHENHYDRAMINE;IBUPROFEN 
ESOMEPRAZOLE MAGNESIUM;NAPROXEN 
ETODOLAC 
ETOFENAMATE 
ETORICOXIB 
FAMOTIDINE;IBUPROFEN 
FENOPROFEN 
FENOPROFEN CALCIUM 
FLURBIPROFEN 
HYDROCODONE;IBUPROFEN 
IBUPROFEN 
IBUPROFEN;LEVOMENTHOL 
IBUPROFEN;METHOCARBAMOL 
IBUPROFEN;PARACETAMOL 
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IBUPROFEN;PSEUDOEPHEDRINE 
IBUPROFEN;PSEUDOEPHEDRINE HYDROCHLORIDE 
INDOMETACIN 
KETOPROFEN 
KETOROLAC 
KETOROLAC TROMETHAMINE 
LORNOXICAM 
MEFENAMIC ACID 
MELOXICAM 
METHYL SALICYLATE 
NABUMETONE 
NAPROXEN 
NAPROXEN SODIUM 
NAPROXEN SODIUM;PSEUDOEPHEDRINE HYDROCHLORIDE 
NEPAFENAC 
NIFLUMIC ACID 
NIMESULIDE 
OTHER ANTIINFLAMMATORY AND ANTIRHEUMATIC AGENTS, NON-STEROIDS 
OXAPROZIN 
PARECOXIB 
PARECOXIB SODIUM 
PHENYLBUTAZONE 
PIROXICAM 
PIROXICAM BETADEX 
SALICYLATE SODIUM 
SALICYLIC ACID 
SALSALATE 
SALSALATE 
SULINDAC 
TENOXICAM 
VIMOVO 
 
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10.4. 
Conversion from Oxygen flow rate to estimated FiO2 (fraction 
inspired oxygen) 
 
Method  
(Oxygen delivery device) 
Oxygen flow rate 
O2 flow (liters/min) 
Fraction of Inspired Oxygen 
[FiO2] (%) 
Nasal cannula  
1 
24 
 
2 
28 
 
3 
32 
 
4 
36 
 
5 
40 
 
6 
44 
 
>=7 
Impute as (O2*4)+20.  Max is 
100 
Nasopharyngeal catheter 
4 
40 
 
5 
50 
 
6 
60 
 
>=7 
Impute as O2*10. Max is 100 
Face mask 
5 
40 
 
6 
50 
 
7 
55 (impute) 
 
8 
60 
 
9 
65 (impute) 
 
>=10 
70 (impute) 
Face mask with reservoir 
(also called non-breather face 
mask) 
<6 
60 (impute) 
6 
60 
 
7 
70 
 
8 
80 
 
9 
90 
 
10 
95 
 
>=10 
95 (impute) 
OTHER 
Any value 
Keep as recorded or NULL 
(no imputation) 
Note: If FiO2 data is entered in the CRF for above devices, ignore value and derive as above. If 
no supplemental oxygen is used, then derive FiO2 as 21%. For Other devices, data query may 
be done. Nasopharyngeal catheter is not a pre-specified option on the CRF page.   
 
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Clinical Development and Regulatory Affairs 
 
 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 69 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
FOR PHASE 3 PORTION OF THE STUDY 
VERSION: FINAL 
 
AN ADAPTIVE PHASE 2/3, RANDOMIZED, DOUBLE-BLIND,  
PLACEBO-CONTROLLED STUDY ASSESSING EFFICACY AND SAFETY OF 
SARILUMAB FOR HOSPITALIZED PATIENTS WITH COVID-19 
 
Compound: 
REGN88 (sarilumab, Kevzara®) 
Protocol Number: 
6R88-COV-2040 
Clinical Phase:  
Phase 2/3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatisticians: 
 
 
 
 
Clinical Trial Manager: 
 
Study Medical Directors: 
 
 
Version/Date: 
Original (Version 1.0) / 16 MAY 2020 
 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatisticians 
 
 
 
See appended electronic signature page 
Study Pharmacokinetics 
 
 
 
See appended electronic signature page 
Study Medical Directors 
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives for Phase 3 ......................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................12 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................13 
1.2.4. 
Revision History for SAP Amendments .....................................................................13 
2. 
INVESTIGATION PLAN ..........................................................................................14 
2.1. 
Study Design and Randomization ..............................................................................14 
2.2. 
Sample Size and Power Considerations .....................................................................16 
2.3. 
Study Plan ...................................................................................................................18 
3. 
ANALYSIS POPULATIONS ....................................................................................19 
3.1. 
Intention-to-Treat (ITT) Population ...........................................................................19 
3.2. 
Per Protocol Set (PPS) ................................................................................................19 
3.3. 
Safety Population (SAF) .............................................................................................19 
3.4. 
Exploratory ITT population (EITT) ............................................................................19 
3.5. 
Exploratory Safety Population (ESAF) ......................................................................20 
3.6. 
Pharmacokinetics Analysis Set ...................................................................................20 
4. 
ANALYSIS VARIABLES .........................................................................................21 
4.1. 
Demographic and Baseline Characteristics ................................................................21 
4.2. 
Medical History ..........................................................................................................23 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................23 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................24 
4.5. 
Efficacy Variables ......................................................................................................24 
4.5.1. 
Primary Efficacy Variable ..........................................................................................24 
4.5.2. 
Key Secondary Efficacy Variables .............................................................................26 
4.5.2.1. 
At least 1-point improvement in clinical status – Phase 3 Cohort 1 Critical 
Stratum only ................................................................................................................27 
4.5.2.2. 
Recovery from COVID-19 – Phase 3 Cohort 1, Cohort 2 and Cohort 3 ....................27 
4.5.2.3. 
Mortality (Survival Status) .........................................................................................28 
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4.5.3. 
Other Secondary Efficacy Variables ..........................................................................29 
4.5.3.1. 
Mechanical ventilation or ECMO related outcomes ..................................................30 
4.5.3.2. 
At least x-point improvement in clinical status on ordinal scale related 
outcomes .....................................................................................................................31 
4.5.3.3. 
Discharged and Alive .................................................................................................31 
4.5.3.4. 
Time-to-recovery ........................................................................................................31 
4.5.3.5. 
Time-to-death (all-cause mortality) ............................................................................31 
4.5.3.6. 
Ventilator-free days ....................................................................................................31 
4.5.3.7. 
Days of Hospitalization ..............................................................................................32 
4.6. 
Safety Variables ..........................................................................................................33 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................33 
4.6.2. 
Adverse Events of Special Interest .............................................................................34 
4.6.3. 
Laboratory Safety Variables .......................................................................................35 
4.6.4. 
Vital Signs ..................................................................................................................35 
4.6.5. 
Physical Examination Variables .................................................................................35 
4.7. 
Pharmacokinetic Variables .........................................................................................36 
4.8. 
Pharmacodynamic and Other Biomarker Variables ...................................................36 
5. 
STATISTICAL METHODS .......................................................................................37 
5.1. 
Demographics and Baseline Characteristics ...............................................................37 
5.2. 
Medical History ..........................................................................................................37 
5.3. 
Prior/concomitant Illnesses and Medications .............................................................38 
5.4. 
Rescue/ Prohibited Medications if applicable ............................................................38 
5.5. 
Subject Disposition .....................................................................................................38 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................39 
5.6.1. 
Measurement of Compliance ......................................................................................39 
5.6.2. 
Exposure to Investigational Product ...........................................................................39 
5.7. 
Analyses of Efficacy Variables ..................................................................................40 
5.7.1. 
Analysis of Primary Efficacy Variables .....................................................................40 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................41 
5.7.3. 
Analysis of Other Secondary Efficacy .......................................................................42 
5.7.4. 
Adjustment for Multiple Comparison .........................................................................42 
5.8. 
Analysis of Safety Data ..............................................................................................44 
5.8.1. 
Adverse Events ...........................................................................................................44 
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5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................45 
5.8.3. 
Clinical Laboratory Measurements.............................................................................46 
5.8.4. 
Analysis of Vital Signs ...............................................................................................46 
5.8.5. 
Physical Exams ...........................................................................................................46 
5.9. 
Analysis of Pharmacokinetics, Pharmacodynamics and Biomarker data ...................46 
5.9.1. 
Analysis of Drug Concentration Data .........................................................................46 
5.9.2. 
Analysis of Pharmacodynamic and Exploratory Biomarker data ...............................47 
6. 
DATA CONVENTIONS ............................................................................................48 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................48 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................48 
6.3. 
Data Handling Convention for Missing Data .............................................................48 
6.4. 
Visit Windows ............................................................................................................48 
6.5. 
Unscheduled Assessments ..........................................................................................49 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................49 
7. 
INTERIM ANALYSIS ...............................................................................................50 
8. 
SOFTWARE ...............................................................................................................51 
9. 
REFERENCES ...........................................................................................................52 
10. 
APPENDIX.................................................................................................................53 
10.1. 
Schedule of Events .....................................................................................................53 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................58 
10.3. 
Criteria for Relevant Major Protocol Deviations ........................................................66 
10.4. 
Program codes (SAS or R codes) ...............................................................................68 
10.4.1. 
SAS code for primary efficacy variables ....................................................................68 
10.4.2. 
R code for alpha spending at interim analysis ............................................................69 
 
LIST OF TABLES 
Table 1: 
Summary of Phase 3 Adaptations ...............................................................................15 
Table 2: 
Phase 3 – Other Secondary Efficacy Endpoints .........................................................29 
Table 3: 
Grading System for Adverse Events Not Listed in NCI-CTCAE ..............................33 
Table 4: 
Testing Strategy for Control of Multiplicity in Phase 3 Cohorts 1, 2 and 3 
(Overall Type 1 Error in each cohort will be 0.05 [2-sided]) .....................................43 
Table 5: 
Time Window for Summary of Laboratory Parameters .............................................49 
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Table 6: 
Protocol Deviations List .............................................................................................66 
 
LIST OF FIGURES 
Figure 1: 
Phase 3 Study Design – Cohorts 1, 2 and 3 ................................................................16 
Figure 2: 
Study Flow Diagram for Phase 2 and Phase 3 ............................................................18 
Figure 3: 
Sample Output for a Group Sequential Design with Interim Analysis ......................69 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of covariance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRP 
C-reactive protein 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
FiO2 
Fraction inspired oxygen 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IL-6 
Interleukin 6 
IRT 
Interactive Response Technology 
ITT 
Intention-to-treat 
IWRS 
Interactive Web Response System (web system of IRT) 
IV 
Intravenous 
mAb 
Monoclonal Antibody 
mITT 
Modified intention-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV 
Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) 
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Abbreviation 
Definition 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
OP 
Oropharyngeal 
NP 
Nasopharyngeal 
PA5 
Protocol Amendment #6 incorporating Phase 3 adaptations 
PCSV 
Potentially Clinically Significant Value 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PPS 
Per Protocol population set 
PT 
Preferred Term 
RA 
Rheumatoid Arthritis 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
SpO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper Limit Normal 
US 
United States (of America) 
VFD 
Ventilator-free days 
WBC 
White blood cell 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the integrity of the study results by 
pre-specifying the statistical approaches for the analysis of study data prior to the Phase 3 
database lock of the Phase 2/3 adaptive study 6R88-COV-2040 of sarilumab (Kevzara®) in 
patients with COVID-19.  This Phase 3 SAP is intended to be a comprehensive and detailed 
description of the strategy and statistical methods to be used in the analysis of data for the Phase 
3 portion of the study based on Protocol Amendment 6 (PA6) (dated 16-MAY-2020). 
The SAP for the Phase 2 portion of the study (called Phase 2 SAP) was finalized on 
13-APR-2020 prior to the first interim database lock for Phase 2 on 15-APR-2020.  The last 
patient in Phase 2 was randomized and dosed on 31-MAR-2020.  Phase 2 included ~460 patients 
randomized (2:2:1) to sarilumab 400 mg IV, sarilumab 200 mg IV or placebo in all COVID-19 
severity strata: severe, critical, and multi-organ system dysfunction (MSOD) (including 
immunocompromised).    
Beginning on 01-APR-2020 patients began enrolling into the Phase 3 portion of the study into 
the same treatment arms and disease severity strata as Phase 2 until 27-APR-2020 when changes 
were made based on recommendations from the Independent Data Monitoring Committee.  
These changes and additional adaptations were incorporated into Protocol Amendment 6 
(16-May-2020).  
The Phase 2 and Phase 3 portions of this study will be analyzed separately. 
The main focus of this Phase 3 SAP is analysis of the following sets of patients described as 
cohorts, which were comprised of subjects of differing severity, randomized to differing 
treatment regimens: 
1. Cohort 1:  Consists of all Phase 3 patients randomized to sarilumab 400 mg IV, sarilumab 
200 mg IV or placebo across disease severity strata (severe, critical, multi-system organ 
dysfunction or immunocompromised).  Within this Cohort, the primary focus of this SAP 
is on the efficacy and safety data on patients in the critical stratum randomized to 
sarilumab 400 mg or placebo.  For patients in the critical stratum randomized to 
sarilumab 200mg, only safety data will be analyzed.  
2. Cohort 2:  Cohort of hospitalized COVID-19 patients to be randomized to sarilumab 800 
mg or placebo who are receiving mechanical ventilation at baseline. 
3. Cohort 3:  Cohort of hospitalized COVID-19 patients to be randomized to sarilumab 800 
mg or placebo who are receiving high-intensity oxygen therapy without mechanical 
ventilation at baseline.   
Analyses of patients previously enrolled in Phase 3Cohort 1 randomized to sarilumab 400 mg 
IV, sarilumab 200 mg IV or placebo will be done for each disease severity stratum of severe, 
MSOD, or immunocompromised, for exploratory purpose only. These exploratory analyses will 
be designed similarly as the main analyses described in this SAP.  Exploratory analyses will be 
summarized in one or more clinical study reports.  
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1.1. 
Background/Rationale 
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel enveloped RNA 
betacoronavirus that emerged in December 2019 in Wuhan, China. The term COVID-19 is the 
disease caused by SARS-CoV-2 with symptoms that manifest a median of 5 days and up to 
14 days after infection. In March 2020, the World Health Organization officially declared 
COVID-19 a pandemic.  (Hereafter, SARS-CoV2 and COVID-19 are interchangeably used.)  
The most frequent clinical presentation of severe COVID-19 is pneumonia with symptoms 
including fever, cough, and dyspnea (shortness of breath). Acute viral pneumonia is a major 
cause of morbidity in patients with COVID-19 and patients can be at risk of developing acute 
respiratory distress syndrome (ARDS), a syndrome of severe impairment of gas exchange.  
Clinically, ARDS presents with severe hypoxemia (abnormally low levels of oxygen in the 
blood). 
A key driver of this deterioration is an overactive inflammatory response in the lungs 
(Mehta, 2020 [10]). Seriously ill patients infected by SAR-CoV-2 were found to have elevated 
circulatory inflammatory mediators such as C-reactive protein (CRP), IL-1B, IL-1RA, IL-7, IL-
8, IL-9, IFNγ, IFN-γ-inducible protein (IP10), monocyte chemoattractant protein (MCP1), tumor 
necrosis factor (TNFα) (Huang, 2020 [5]), resembling the cytokine storm observed in similar 
lower respiratory disease caused by infections due to SARS-CoV, identified in 2002, and by the 
Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) (Zhang, 2020 [14]). 
COVID-19 has been associated with pulmonary release of cytokines such as interleukin-6 (IL-6) 
which has been shown to be a major contributor to the development of fever and hypoxemia. 
One hypothesis is that IL-6 is a modifiable driver of progression of COVID-19 pneumonia.  
Therefore, a potential therapeutic approach would be to attenuate the overactive inflammatory 
immune response in the lungs through blockade of the IL-6 receptor.  In the current study, 
sarilumab (Kevzara®), an anti-IL-6 receptor (anti-IL-6R) monoclonal antibody (mAb), is being 
evaluated for efficacy and safety in treatment of patients with COVID-19 at the doses of 200 mg 
intravenous (IV), 400 mg IV and 800 mg IV. Kevzara® (sarilumab) has been previously 
approved for the treatment of rheumatoid arthritis (RA) at 200 mg Q2W (subcutaneous [SC]) 
[with down dosing to 150 mg Q2W (SC) for certain laboratory changes]. Sarilumab is highly 
similar to tocilizumab (Actemra®), another anti-IL-6R mAb, and there is reported evidence from 
a preliminary uncontrolled study in China in 21 patients that IV treatment with 400 mg of 
tocilizumab  provided a clinically meaningful improvement in clinical symptoms that are thought 
to be mediated by cytokine release in patients with severe or critical COVID-19 infection 
(Xu, 2020 [12]). 
At the time of the start of this study, there were no specific COVID-19 treatments. Hospitalized 
patients were managed clinically through supportive therapy including supplemental oxygen 
therapy, empiric treatments and intensive care as required. Many therapeutic agents have been 
used to treat patients with SARS-CoV and MERS-CoV, including corticosteroids, type 1 
interferon (IFN) agents, convalescent plasma, ribavirin, lopinavir/ritonavir, proteases, and agents 
targeting viral entry proteins. However, none have been proven to be efficacious in clinical trials 
at the time of the initiation of this study, justifying the use of placebo as a comparator for this 
study. 
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This study 6R88-COV-2040 is designed as a randomized well-controlled Phase 2/3 clinical trial 
in hospitalized patients across multiple disease severity stages of COVID-19. Due to the novel 
nature of COVID-19, efficacy endpoints are not well established. The Phase 2/3 adaptive design 
of the study allows for identification of early signs of clinical efficacy in the Phase 2 data (e.g., 
reduction in C-Reactive Protein, estimates of effects on clinical status), which will allow 
adaptation of the Phase 3 study design including: 1) selection of clinical outcome endpoints in 
Phase 3 (e.g., well defined endpoints based on clinical status assessment of patients),  
2) confirming the Phase 3 population, 3) evaluate further doses of sarilumab and 4) sample size 
adjustment for Phase 3. 
In the Phase 2 portion of the study, patients were randomized in a 2:2:1 allocation ratio to 
sarilumab 400 mg IV, sarilumab 200 mg IV, or placebo in 3 disease severity strata: severe, 
critical and multi-system organ dysfunction (MSOD).  The Phase 3 portion of the study 
seamlessly enrolled patients similarly as in Phase 2 until a Phase 2 interim analysis was 
reviewed, which informed adaptations to the Phase 3 design.   
Following review of the Phase 2 interim data, and based on IDMC recommendations, enrollment 
in Phase 3 continued in only the 400 mg sarilumab dose and placebo arms and only in the critical 
stratum.  Adaptations to the study design also included division of Phase 3 into 3 cohorts as 
previously described in Section 1.  Enrollment will continue in Cohort 1 until approximately 170 
patients randomized to 400 mg or placebo in the critical stratum who were on mechanical 
ventilation at baseline have been treated.  Cohort 2 which consists of patients who are on 
mechanical ventilation at baseline and Cohort 3 which consists of patients not on mechanical 
ventilation but on high intensity oxygen therapy at baseline, will not begin enrollment until after 
Cohort 1 enrollment has completed.  The new Cohorts 2 and 3 will be randomized 1:1 to 
sarilumab 800 mg or placebo.  Further details of the Phase 2/3 adaptive study design are 
described in Section 2.1. 
1.2. 
Study Objectives for Phase 3 
1.2.1. 
Primary Objectives 
Phase 3 Cohort 1:  
 
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the 
control arm in adult patients hospitalized with critical COVID-19 on mechanical ventilation at 
baseline.  
Phase 3 Cohort 2:  
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the 
control arm in adult patients hospitalized with COVID-19 receiving mechanical ventilation at 
baseline. 
Phase 3 Cohort 3:  
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the 
control arm in adult patients hospitalized with COVID-19 receiving high-intensity oxygen 
therapy* without mechanical ventilation at baseline. 
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* High intensity oxygen therapy is defined as the use of non-rebreather mask with an oxygen flow rate of 
at least 10 L/min; use of a high flow device with at least 50% FiO2, or use of non-invasive ventilation 
(eg, BiPAP™) or continuous positive airway pressure (CPAP) to treat hypoxemia. 
1.2.2. 
Secondary Objectives 
Phase 3 Efficacy 
The secondary efficacy objectives of the study are to: 
Phase 3 Cohort 1: 
• Determine whether sarilumab improves respiratory outcomes in patients with critical 
COVID-19 
• Determine whether sarilumab reduces mortality in patients with critical COVID-19 
• Determine whether sarilumab shortens hospitalization in patients with critical 
COVID-19 
Phase 3 Cohort 2: 
• Determine whether sarilumab improves respiratory outcomes in patients with 
COVID-19 receiving mechanical ventilation 
• Determine whether sarilumab reduces mortality in patients with COVID-19 receiving 
mechanical ventilation 
• Determine whether sarilumab shortens hospitalization in patients with COVID-19 
receiving mechanical ventilation 
Phase 3 Cohort 3: 
• Determine whether sarilumab improves respiratory outcomes in patients with 
COVID-19 receiving high intensity oxygen therapy without mechanical ventilation 
• Determine whether sarilumab reduces mortality in patients with COVID-19 receiving 
high intensity oxygen therapy without mechanical ventilation 
• Determine whether sarilumab shortens hospitalization in patients with COVID-19 
receiving high intensity oxygen therapy without mechanical ventilation 
Phase 3 Safety 
Safety 
The secondary safety objectives of the study are to evaluate the safety of sarilumab through 
hospitalization (up to Day 29 if patient is still hospitalized) compared to the control arm as 
assessed by incidence of: 
• Serious adverse events (SAEs) 
• Grade 4 neutropenia (absolute neutrophil count [ANC]<500/mm3) 
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• Grade 4 neutropenia (ANC<500/mm3) with concurrent severe or life-threatening 
bacterial, invasive fungal, or opportunistic infection  
• Grade ≥2 infusion related reactions 
• Grade ≥2 hypersensitivity reactions 
• Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥3X 
upper limit of normal (ULN) (for patients with normal baseline) or >3X ULN AND at 
least 2 fold increase from baseline value (for patients with abnormal baseline) 
• Invasive bacterial or fungal infections of clinical significance with confirmed 
diagnosis based on the investigator’s assessment with appropriate diagnostic workups 
and consultations 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
Not applicable. 
1.2.4. 
Revision History for SAP Amendments 
Not applicable. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This study is an adaptive Phase 2/3, randomized, double-blind, placebo-controlled trial to 
evaluate the efficacy and safety of sarilumab compared with placebo in hospitalized adults with 
severe or critical COVID-19 (as broadly defined below).  
At the time of the original Phase 3 SAP, the study is ongoing and being conducted in the United 
States (US) in up to 150 sites. Enrollment in the study began on 17 Mar 2020.   
Phase 2 Study Design 
In the Phase 2 portion of the study, a total of approximately 460 patients were randomized in a 
2:2:1 allocation ratio to sarilumab 400 mg IV, sarilumab 200 mg IV, or placebo in a stratified 
manner up to 26 Apr 2020.  A Phase 2 interim analysis was conducted on 27 Apr 2020 whereby 
upon recommendation of the Independent Data Monitoring Committee (IDMC), adaptations 
were made to the Phase 3 portion of the study (described below). 
In Phase 2 randomization was stratified by 
• Severity of illness at enrollment 
− Severe disease 
− Critical disease 
− Multi-system organ dysfunction 
− Immunocompromised† 
• Systemic corticosteroids (Yes/No) 
† Immunocompromised patients were permitted to be enrolled in this study after Protocol Amendment #3 (28-
MAR-2020) at the request of the FDA.  For Phase 2 analysis, these patients will be reported as a subset of the Multi-
system organ dysfunction strata. 
The severity categories are: 
1. Severe disease  
• Requires supplemental oxygen administration by nasal cannula, simple face mask, or 
other similar oxygen delivery device  
2. Critical disease  
• Requires supplemental oxygen requiring delivered by non-rebreather mask or 
high-flow nasal cannula, OR 
• Use of invasive or non-invasive ventilation, OR 
• Requiring treatment in an intensive care unit.  
3. Multi-system organ dysfunction  
• Multi-system organ dysfunction: use of vasopressors, extracorporeal life support, or 
renal replacement therapy 
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4. Immunocompromised 
• Immunocompromised patients (or on immunosuppressant treatments) 
Phase 3 Study Design 
For Phase 3 Cohort 1, randomization was similarly stratified as in Phase 2, by disease severity at 
enrollment (severe, critical, MSOD, immunocompromised) and use of systemic corticosteroids 
(yes/no) 
As part of the Phase 3 adaptation plan, the following adaptations were made to the Phase 3 study 
design (see Table 1). Refer to Protocol Section 3.2.2 for the interim Phase 2 results and rationale 
for study design adaptation. 
Table 1: 
Summary of Phase 3 Adaptations 
Study Component 
Adaptation 
Phase 3 endpoint 
At least 1-point improvement from baseline in clinical status on the 
7-point ordinal scale 
(For example, a 1-point improvement from baseline in clinical 
status for a patient in Cohort 1 in critical stratum who is on 
mechanical ventilation at baseline, will imply that the patient is now 
off mechanical ventilation.  This kind of a treatment effect measure 
by a 1-point improvement on the ordinal scale is considered 
clinically important.) 
Phase 3 primary analysis 
population 
• Cohort 1: Critical patients receiving mechanical ventilation at 
baseline 
• Cohort 2: Patients on mechanical ventilation at baseline  
• Cohort 3: Patients on high intensity oxygen therapy without 
mechanical ventilation at baseline* 
Dose regimens 
• Cohort 1: Primary comparison will be between sarilumab 400 
mg and placebo 
• Cohort 2: Sarilumab 800 mg and placebo 
• Cohort 3: Sarilumab 800 mg and placebo 
Sample size for the Primary 
Analysis Population in Cohort 1 
~170 
Sample Size for Cohort 2 
225 
Sample Size for Cohort 3 
225 
* High intensity oxygen therapy is defined as the use of non-rebreather mask with an oxygen flow rate of at least 
10 L/min; use of a high flow device with at least 50% FiO2, or use of non-invasive ventilation (eg, BiPAP™) or 
CPAP to treat hypoxemia. 
Phase 3 Cohort 1 
Until 26 Apr 2020, the Phase 3 portion of the study randomized patients in a stratified manner 
similar to the Phase 2 study design described above.  As of 27 Apr 2020 (as per recommendation 
of the IDMC), patients in Phase 3 Cohort 1 were randomized to sarilumab 400 mg or placebo 
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only in the critical stratum in a 2:1 manner.  Based on the IDMC recommendation, patients in the 
severe and MSOD strata were no longer enrolled nor received study drug. 
Enrollment into Cohort 1 will end approximately 22 days after the 170th patient in the critical 
stratum on mechanical ventilation at baseline who were randomized to receive either sarilumab 
400 mg or placebo is enrolled.   
Phase 3 Cohort 2 and Cohort 3 
Cohort 2 and Cohort 3 will enroll in parallel when Cohort 1 enrollment is completed.  In Cohorts 
2 and 3, patients will be randomized 1:1 to receive sarilumab 800 mg IV or placebo stratified by: 
• Use of a non-IL6/6R therapy administered under an Emergency Use Authorization 
(EUA) at randomization (yes/no) 
• Use of systemic corticosteroids at randomization (yes/no) 
 
Figure 1: 
Phase 3 Study Design – Cohorts 1, 2 and 3 
 
 
2.2. 
Sample Size and Power Considerations 
For the Phase 2 portion of the study, a total of approximately 460 patients were randomized 
(2:2:1) to sarilumab 400 mg IV, sarilumab 200 mg IV or placebo. This sample size was 
estimated to provide at least 90% power to detect a treatment effect in the Phase 2 endpoint of 
reduction in CRP levels as well as allow adequate estimation and improve precision for selection 
of Phase 3 efficacy endpoints. 
The data lock point for the first interim analysis of the Phase 2 portion of the study was set at 
15 days after the last of the approximately 460 patients in Phase 2 had been randomized.  These 
data were used to determine the adaptations and analysis plan for the Phase 3 portion of this 
adaptive Phase 2/3 study.  Based on the Phase 2 interim results, the sample size for Cohort 1 of 
Phase 3 was recalculated using the chosen Phase 3 endpoint of the proportion of patients with at 
least 1 point improvement in clinical status on the ordinal scale at Day 22 in patients in the 
critical stratum who were on mechanical ventilation at baseline. 
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In Phase 3 Cohort 1, the hypothesis will be tested only in patients in the critical stratum, first in 
the subset of patients on mechanical ventilation without ECMO at baseline as an enrichment 
strategy and then in the overall critical stratum (ITT).  In the Phase 2 portion of the study, in a 
subgroup analysis of the critical stratum based on being on a mechanical ventilator at baseline, in 
the mechanical ventilator group, approximately 17% of patients treated with placebo (ie, 
standard of care) and 57% of patients treated with sarilumab 400 mg (on top of standard of care) 
achieved at least 1-point improvement by Day 22.   
Cohort 1:  
With a 2:1 randomization ratio (sarilumab 400 mg IV: placebo), an effect size the same as that 
observed in Phase 2, and 170 patients in the critical stratum on mechanical ventilation, then the  
comparison between sarilumab 400 mg (n~113) and placebo (n~57) would have >99% power. 
Assuming the rate on placebo is 17% and the rate on sarilumab 400 mg is 37% (ie, a difference 
in proportions is one-half that observed in Phase 2), then the sample size of 170 would provide 
approximately 80% power to detect this reduced difference.  These calculations assume α=0.045, 
allowing for an interim analysis at the 0.005 level.  Therefore, this study plans to enroll 
approximately 450 critical patients in order to have approximately 170 patients within the critical 
stratum who are on mechanical ventilation and randomized to 400 mg or placebo.   
Note that the total number of patients enrolled in Phase 3 Cohort 1 is larger than that to account 
for the patients who had been randomized to the severe stratum, MSOD stratum, or to the 200 
mg dose group before the IDMC decision to discontinue further enrollment into those strata and 
dose groups.   
Cohort 2:  
With a 1:1 randomization ratio (sarilumab 800 mg IV: placebo), an effect size the same as that 
observed in Phase 2 for 400 mg, and approximately 225 patients total, then the comparison 
between sarilumab 800 mg and placebo (n=~112 for each group) would have >99% power to 
detect the difference observed in Phase 2, and would have 92% power if the effect were half of 
that observed in Phase 2 (ie, 20% difference).  These calculations assume α=0.045 (2-sided), 
allowing for an interim analysis at the 0.005 level.  A sample size re-estimation may occur after 
Phase 3 Cohort 1 results are determined.   
Cohort 3:  
A sample size of 225 subjects randomized 1:1 (sarilumab 800 mg IV:placebo) would have 92% 
power to detect a difference in proportions of 20%.  These calculations assume α=0.045 (2-
sided), allowing for an interim analysis at the 0.005 level.  A sample size re-estimation may 
occur after Phase 3 Cohort 1 results are determined.   
 
 
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2.3. 
Study Plan 
Study flow for both Phases 2 and 3 is shown in Figure 2. 
 
Figure 2: 
Study Flow Diagram for Phase 2 and Phase 3 
 
Patients will be assessed daily while hospitalized and undergo a series of efficacy, safety, and 
laboratory assessments while in the hospital. Discharged patients will be contacted by telephone 
on Day 29 to assess status and occurrence of re-admission to a hospital.  All patients will have an 
end of study (EOS) assessment at Day 60 to collect data on survival status and history of hospital 
re-admission, and this assessment may be done by phone. 
The Study event table is presented in Section 10. 
Study patients, the principal investigators, and study site personnel continue to remain and will 
remain blinded to all randomization assignments throughout the Phase 3 portion of study that is 
covering: 1) Cohort 1 Critical stratum randomized to sarilumab 400 mg or placebo, and 2) 
Cohorts 2 and 3 randomized to sarilumab 800 mg or placebo.  Similarly, for this portion of the 
Phase 3 study, the Regeneron Medical/Study Director, Study Monitor, study team directly 
involved with the conduct of the study and any other Regeneron and contract research 
organization (CRO) personnel who are in regular contact with the study site will remain blinded 
to patient randomization assignments. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998 [4]), the following population of analysis will 
be used for all statistical analysis: 
3.1. 
Intention-to-Treat (ITT) Population 
The intention-to-treat (ITT) population includes all randomized patients who received at least 
one dose of the study drug.  Analysis of the ITT population will be done according to the initial 
treatment assigned to the patient (as randomized).  
ITT population will be the primary analysis population for the Phase 3 Cohort 1, Cohort 2 and 
Cohort 3 and each cohort will be analyzed separately. For Phase 3 Cohort 1, the specific primary 
population will be the subset of patients in the critical stratum who are on mechanical ventilation 
without ECMO at baseline and randomized to sarilumab 400 mg or placebo.  In addition, for 
Cohort 1, the ITT population of patients in the critical stratum will be analyzed for some of the 
key secondary efficacy outcomes.  Demographics, baseline characteristics, and patient 
disposition will be summarized in the ITT population. 
3.2. 
Per Protocol Set (PPS) 
The per protocol population set (PPS) includes all ITT patients who do not have any relevant 
major protocol deviations, ie, patients with relevant major protocol deviations will be excluded 
from PPS. A relevant major protocol deviation is one that may affect the interpretation of study 
efficacy results. The final determination of the definition of the PPS will be made prior to the 
first database lock. Criteria for relevant major protocol deviations are given in Appendix 10.3. 
Analysis of the PPS will be done according to the treatment the patient actually received (as 
treated). Determination of “as treated” will be based on the actual study drug received on Day 1. 
The PPS will be used only in Phase 3 Cohort 1, Cohort 2 and Cohort 3 for sensitivity analysis of 
the primary efficacy endpoints. 
3.3. 
Safety Population (SAF) 
The Safety population (SAF) includes all randomized patients who received at least one dose of 
the study drug. Analysis of the Safety population will be done according to the treatment 
received (as treated). Determination of “as treated” will be based on the actual study drug 
received on Day 1. The SAF will be used for analysis of all safety data, treatment exposure, 
medical history and medications use in the Phase 3 Cohort 1 Critical stratum of patients 
randomized to sarilumab 400 mg IV, sarilumab 200 mg IV, or placebo, and in Phase 3 Cohort 2 
and Cohort 3 of patients randomized to sarilumab 800 mg IV or placebo. 
3.4. 
Exploratory ITT population (EITT) 
An Exploratory ITT Population will also be defined similarly as the ITT to perform efficacy 
analyses in the Phase 3 Cohort 1 population of patients in the strata that were discontinued after 
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Phase 2 interim data press release, namely, severe, MSOD and immunocompromised patients in 
all 3 treatment groups (sarilumab 400 mg, sarilumab 200 mg or placebo).  Analyses will be done 
separately for each stratum. 
3.5. 
Exploratory Safety Population (ESAF)  
An Exploratory Safety Population will also be defined similarly as the SAF to perform safety 
analyses in the Phase 3 Cohort 1 population of patients in the strata that were discontinued after 
Phase 2 interim data press release, namely, severe, MSOD, and immunocompromised patients in 
all 3 treatment groups (sarilumab 400 mg, sarilumab 200 mg, or placebo). Analyses will be done 
separately for each stratum. 
3.6. 
Pharmacokinetics Analysis Set 
The pharmacokinetics (PK) analysis population includes all patients who received any study 
drug and who had at least 1 non-missing result following the first dose of study drug. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristic variables include the following: 
• Age at screening (years) 
• Age group (years) (18-24, 25-34, 35-44, 45-54, 55-64, 65-74, 75-84, >=85)  
(lower and upper limits of ranges are inclusive) 
• Sex (Male, Female) 
• Race (American Indian or Alaska Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic or Latino, Not-Hispanic or Latino) 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) (kg/m2) calculated from weight and height 
• BMI category (≤30 kg/m2, BMI >30 kg/m2 [defined as obese]) 
• Systemic corticosteroids use (per Interactive Response Technolgy (IRT)) 
• SARS-CoV-2 virus result (per CRF) (Positive/Negative) (Note: SARS-CoV-2 
infection is laboratory-confirmed by PCR prior to randomization) 
• Cycle Threshold, if SARS-CoV-2 positive (per CRF, as available)  
• Baseline IL-6 (pg/mL) 
• Baseline CRP (mg/L) 
• Baseline absolute neutrophil counts 
• Baseline Neutrophils-Lymphocyte Ratio (NLR) 
• Non-IL6/6R therapy under and EUA at randomization (for Cohorts 2 and 3 only) 
Other baseline disease characteristic variables for this study population are as follows.   
Pneumonia status at baseline – (selected from Pneumonia Status at Baseline CRF) 
• History of or current chronic hypercapnic respiratory failure (yes/no) – (selected from 
NEWS2 CRF at baseline or Pneumonia status at baseline CRF, depending on original 
or amended versions of CRFs) 
• Presence of pneumonia based on historical chest X-ray or CT scan (yes/no) 
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• Duration of illness prior to baseline (calculated as earliest onset date for symptoms of 
pneumonia to first dose date. If date of earliest onset of pneumonia is missing, then 
date is not imputed) 
• Presence of rales/crackles on lung auscultation (yes/no) 
• Presence of documented fever in medical record (yes/no) 
• Highest temperature recorded 24 hours prior to dosing  
(All temperature is converted to Oral temperature.  Rectal/Tympanic minus 0.4 deg C 
= Oral deg C, or Axillary/Temporal plus 0.4 deg C = Oral deg C) 
• Baseline oxygen device type used (in case multiple devices are recorded at baseline, 
the “worst” device type will be selected) 
− Nasal cannula 
− Face mask 
− Non-rebreather mask 
− High-flow nasal cannula 
− Non-invasive ventilation 
− Invasive ventilation (mechanical ventilation) 
− Extracorporeal life support (eg, ECMO) 
• Use of vasopressors (yes/no) 
• Use of renal replacement therapy (yes/no) 
• Requires treatment in intensive care unit (ICU) (yes/no) 
Oxygen administration and Oxygenation at baseline 
• SpO2 % (peripheral capillary oxygen saturation) (range is 0% to 100%) 
• FiO2 (fraction of inspired oxygen) (range is 0.0 to 1.0) – Refer to Phase 2 SAP for 
derivations 
• SpO2 / FiO2 ratio– Refer to Phase 2 SAP for derivations 
Hospital or ICU stay 
• Length of hospital stay including ICU prior to randomization (days) 
• Admitted into ICU during hospital stay prior to randomization (yes/no) 
• Length of ICU stay prior to randomization (days) 
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4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to Medical Dictionary for Regulatory Activities (MedDRA®) 
version 23.0. 
4.3. 
Pre-Treatment / Concomitant Medication 
Medications/Procedures will be recorded from the day of informed consent until the final study 
assessment (Day 29 or discharge or death). Medications will be coded to the ATC level 2 
(therapeutic main group) and ATC level 4 (chemical/therapeutic subgroup), according to WHO 
Drug Dictionary (WHODD) version 202003. Patients will be counted once in all ATC categories 
linked to the medication. 
Prior medications/procedures are: medications taken or procedures performed prior to 
administration of the study drug. 
Concomitant medications/procedures are: medications taken or procedures performed 
following the first dose of study drug through the final study assessment (Day 29 or discharge or 
death).  This includes medications taken that started before the study and are ongoing during the 
study. 
Concomitant medications in a hospitalized population change daily and are difficult to collect in 
the setting of a pandemic with limited resources in some settings. It is therefore difficult to 
attribute to success and failure of therapy and impact on safety. Therefore, only select 
concomitant medications will be captured in this trial. The select list of medications include 
corticosteroids, remdesivir, lopinavir-ritonavir, chloroquine, hydroxychloroquine, interferon 
beta, and convalescent serum. 
Analysis of medications data will be focused on the targeted medications (specified in the 
protocol) that are expected to be reviewed and recorded by sites.  Targeted medications include 
but are not limited to: 
• antipyretics, such as aspirin, acetaminophen, ibuprofen, and other non-steroidal anti 
inflammatory drugs (NSAIDs) 
• warfarin  
• cyclosporine A 
• theophylline 
• digoxin  
• antiepileptics, such as carbamazepine (Carbatrol®, Tegretol®), divalproex 
(Depakote®), phenytoin (Dilantin®), valproic acid (Depakene®);  
• antiarrhythmics, such as disopyramide (Norpace®), procainamide (Procan®, 
Pronestyl®), quinidine (Quinidex®, Quin Release Quin- G®) 
• antivirals, antibacterials, and antifungals 
• anti-parasitics (chloroquine or hydroxychloroquine) 
• interferon beta  
• corticosteroids 
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• convalescent serum  
• angiotensin receptor blockers, such as Azilsartan (Edarbi), Candesartan (Atacand), 
Eprosartan (Teveten), Irbesartan (Avapro), Losartan (Cozaar), Olmesartan (Benicar), 
Telmisartan (Micardis), Valsartan (Diovan) 
• angiotensin converting enzyme inhibitors: benazepril (Lotensin), captopril (Capoten), 
enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril 
(Univasc), perindopril (Aceon), quinapril (Accupril) 
4.4. 
Rescue Medication/or Prohibited Medication During Study 
There are no rescue, prohibited or permitted medications in this study, except for those in the 
exclusion criteria of study enrollment. Patients may continue their normal regimen of 
medications and procedures. All data collected on medications/procedures (pre-treatment and 
concomitant) will be summarized. 
4.5. 
Efficacy Variables 
In this section, details on the derivation of efficacy variables are provided.  Distinction is made 
between the term “efficacy variable” and “efficacy endpoint”. 
Whether an efficacy variable is used as a primary efficacy endpoint, key secondary endpoint, or 
other secondary efficacy endpoint will depend on the population of interest for the variable. 
4.5.1. 
Primary Efficacy Variable 
The primary efficacy variable is the proportion of patients with at least 1-point improvement 
in clinical status from baseline to Day 22 using the 7-point ordinal scale. 
The ordinal scale is an assessment of the clinical status of a patient (Peterson, 2017 [11]). The 7-
point ordinal scale is as follows:  
1. Death;  
2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO);  
3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices;  
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise) 
6. Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical 
care 
7. Not hospitalized 
The clinical status of a patient will be assessed in the morning to consider the worst assessments 
for the previous day (ie, midnight to midnight; 00:00 – 00:00 [24 hour clock]).  If it is the first 
assessment and 24 hours of data are not available, then the clinical status will be recorded  at 
randomization.  Data for clinical status (ordinal scale) is recorded on the Clinical Status 
Assessment Ordinal Scale case report form (CRF). 
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Baseline clinical status (prior to dosing on Day 1) in the Phase 3 Cohort 1 patient population 
(randomized and treated) will take values 2, 3, or 4, based on their respiratory status on the 
baseline pneumonia treatment page, using the value 2 for patients on mechanical ventilation or 
ECMO, 3 for patients on high-flow nasal canula, or non-mechanical ventilation (BiPaP) and 4 
for patients on other less intensive oxygen therapy.  Patients who are randomized but not treated, 
for example who die or are discharged prior to dosing, are excluded from the analysis.   
Post-baseline clinical status on a Study Day can take values 1 through 7 on ordinal scale and 
data will be as recorded on the ordinal scale case report form (CRF).  However, since the ordinal 
scale on a given study is recorded in the morning and it reflects the patient’s clinical status 
during the prior 24 hour period, the value will be attributed to the prior study day.  Derivations 
for death and hospital discharge will be done as described below.  Handling of other missing 
post-baseline values is also mentioned below.  After these methods of data handling, any remain 
missing data will be left missing and not imputed. 
Change from baseline on the ordinal scale <in clinical status> on Study Day is defined as 
post-baseline clinical status on Study Day minus baseline clinical status 
Handling of deaths on ordinal scale (post-baseline): 
For patients who are recorded on Day X as having died on the 7-point scale, the clinical status 
ordinal scale value will be retained for the study day X-1 and the clinical status for Study Day X 
will be derived as “1=Death”.  After this, the clinical status ordinal value will be carried forward 
until Day 29 (for key secondary efficacy endpoint [see Section 4.5.2.3]) and until end of study 
(Day 60) (for other endpoints as specified).  Death date may be obtained from Adverse Events or 
Study Completion CRFs or phone call at Day 60 (end of study).   
For example, a patient’s clinical status may be recorded as “2= Hospitalized, requiring invasive 
mechanical ventilation or extracorporeal membrane oxygenation (ECMO)” on the morning of 
Day 5, but the patient dies later in the evening of Day 5.  In this case, clinical status (observed) = 
2 for Day 4, and clinical status (derived) = 1 for Day 5 and carried forward for all subsequent 
study days through Day 20 or Day 60 (as described above). 
Handling of discharge on ordinal scale (post-baseline): 
Similarly, hospital discharge information may be obtained from Hospital & ICU Admission & 
Discharge CRF.  Earliest available date of hospital discharge (Day X) will be used.  Clinical 
status as recorded on the day of discharge (Day X) will be retained as recorded and clinical status 
for the study day after discharge date (e.g., Day X+1) will be derived as “7=Not hospitalized”. 
After this study day (X+1), the clinical status ordinal value will be carried forward until end of 
study. If it is learned during follow-up that some patients are subsequently readmitted for 
COVID-related reasons, the data will be explored to assess effects of readmission in the 
analyses. 
Handling of other missing data on ordinal scale (post-baseline): 
For patients who are alive and not discharged (i.e., still hospitalized), missing clinical status 
(ordinal scale) value on a given study Day X will be imputed using data on the type of oxygen 
delivery device used by the patient on the previous day, i.e., Day X-1. Clinical status = 2 (if 
using invasive mechanical ventilation or ECMO), or 3 (if using non-invasive mechanical 
ventilation, or high-flow nasal cannula), or 4 (if using non-rebreather mask, nasal cannula or 
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simple face mask) or 5/6 (if not using supplemental oxygen).  Clinical status of 5 or 6 will be 
imputed as the worst value of “5= Hospitalized, not requiring supplemental oxygen – requiring 
ongoing medical care (COVID-19 related or otherwise)”. 
Phase 3 Cohort 1: 
For each treatment group (sarilumab 400 mg or placebo) in Phase 3 Cohort 1, the primary 
efficacy endpoint will be calculated as: 
Number of patients for whom change from baseline on the ordinal scale is ≥+1 at Day 22
Number of patients in the treatment group in Phase 3 Cohort 1 critical stratum 
who were receiving mechanical ventilation at baseline
 
Phase 3 Cohort 2: 
For each treatment group (sarilumab 800 mg or placebo) in Cohort 2, the primary efficacy 
endpoint will be calculated as:  
Number of patients for whom change from baseline on the ordinal scale is ≥+1 at Day 22
Number of patients in the treatment group in Phase 3 Cohort 2 
(i.e., who received mechanical ventilation at baseline)
 
Phase 3 Cohort 3: 
For each treatment group (sarilumab 800 mg or placebo) in Cohort 3, the primary efficacy 
endpoint will be calculated as: 
Number of patients for whom change from baseline on the ordinal scale is ≥+1 at Day 22
Number of patients in the treatment group in Phase 3 Cohort 3 
(i.e., who were not on mechanical ventilation but received high intensity oxygen therapy* at baseline)
 
*High intensity oxygen therapy will be per IRT stratum (as defined in the protocol). 
 
Note that the numerator and denominator for primary efficacy endpoint could be different 
depending on the analysis population, i.e., ITT for primary analysis or PPS for sensitivity 
analysis (See Section 3). 
4.5.2. 
Key Secondary Efficacy Variables 
The key secondary efficacy variables for the Phase 3 portion of the study are as follows.   
1. Proportion of patients with at least 1-point improvement in clinical status from baseline 
to Day 22 (Cohort 1 only) 
2. Proportion of patients who recover (discharged, or alive without supplemental oxygen 
use or at pre-COVID oxygen use) by Day 22 
3. Proportion of patients who die through Day 29. 
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However, the key secondary endpoints will be assessed differently depending on the Phase 3 
Cohorts.  Derivations for variable 1 are in Section 4.5.1 and for variables 2 and 3 are in 
Section 4.5.2.2 and Section 4.5.2.3. 
4.5.2.1. 
At least 1-point improvement in clinical status – Phase 3 Cohort 1 Critical 
Stratum only 
For each treatment group (sarilumab 400 mg or placebo), the key secondary efficacy endpoint in 
Phase 3 Cohort 1 only, will be calculated as: 
• Number of patients for whom change from baseline on the ordinal scale is ≥+1 at Day 22 
divided by number of patients in the treatment group in Phase 3 Cohort 1 Critical stratum 
(ITT) 
This endpoint will be analyzed in the ITT population.  Derivation of variables for this endpoint 
are given in Section 4.5.1. 
4.5.2.2. 
Recovery from COVID-19 – Phase 3 Cohort 1, Cohort 2 and Cohort 3 
Baseline Oxygen use is defined as the oxygen delivery device given to the hospitalized patient 
prior to being dosed and is obtained from the CRF for Pneumonia Status at Baseline.  Oxygen 
delivery devices may be (in increasing order of complexity): 1) nasal cannula, 2) face mask, 3) 
non-rebreather mask, 4) high-flow nasal cannula, 5) non-invasive ventilation (eg, BiPAP), 6) 
invasive ventilation (mechanical ventilation), or 7) extracorporeal life support (eg, extracorporeal 
membrane oxygenation [ECMO]).  Other types of devices used in this study will be classified 
into categories 1 through 6 and finalized prior to the first database lock.  In case multiple devices 
are recorded at baseline, then the oxygen device in the highest category will be used.  In case of 
missing data on oxygen devices on the CRF for Pneumonia Status at Baseline, the CRF for 
Oxygen Administration and Oxygenation at Baseline will be used to impute this data. 
Post-baseline Oxygen use on a Study Day is defined as the oxygen delivery device used on 
Study Day as recorded on the Oxygen Administration and Oxygenation CRF on that Study Day.  
If oxygen delivery device is blank or site records that no supplemental oxygen was used, then 
post-baseline oxygen use will be derived as “None”. 
A patient is considered recovered if they are either discharged from the hospital, or are alive in 
the hospital without supplemental oxygen use or at pre-COVID oxygen use. 
Patients who recover at Study Day are defined as those who are:  
1. discharged, or  
(Subject discharged from hospital before Day 29 is marked as Yes, or Hospital discharge 
date is non-missing on the Hospital & ICU Admission & Discharge CRF) 
2. alive without supplemental oxygen use, or  
(The question “Was any supplemental Oxygen or mechanical ventilation used?” is 
marked as “No” on the Oxygen Administration and Oxygenation CRF), or 
3. at pre-COVID oxygen use. 
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(Post-baseline oxygen use at Study Day is the same as or better than the baseline oxygen 
use category.)  
Phase 3 Cohort 1: 
For each treatment group (sarilumab 400 mg or placebo) in Phase 3 Cohort 1, the key secondary 
efficacy endpoint will be calculated as: 
• Number of patients who recovered divided by number of patients in the treatment group 
in Phase 3 Cohort 1 Critical stratum receiving mechanical ventilation without ECMO at 
baseline 
Phase 3 Cohort 2 and Cohort 3: 
For each treatment group (sarilumab 800 mg or placebo) in Phase 3 Cohort 2 and Cohort 3, the 
key secondary efficacy endpoints will be calculated as: 
• Number of patients who recovered divided by number of patients in the treatment group 
in Phase 3 Cohort 2 receiving mechanical ventilation at baseline 
• Number of patients who recovered divided by number of patients in the treatment group 
in Phase 3 Cohort 3 on high-intensity oxygen therapy without mechanical ventilation at 
baseline 
4.5.2.3. 
Mortality (Survival Status) 
A patient’s survival status at Study Day X is derived as “Died” if there is death data on that study 
day on any of these CRFs – Study Completion, Adverse Events, Phone Call, or Subject Eligibility 
(in case of screen failures or randomized not treated).  In case of missing data on these CRFs, the 
Clinical Status Assessment Ordinal Scale CRF data may be used to check death status.  
However, this CRF could have a lag of upto 24 hours and if clinical status ordinal scale is 
recorded as 1= “Death” on Day X, then death date will be assigned to the previous Day X-1. 
Otherwise, the patient’s survival status is “Alive” on that Study Day.  If a patient dies, survival 
status of death will be carried forward after the study day that patient dies. 
Phase 3 Cohort 1: 
For each treatment group (sarilumab 400 mg or placebo) in Phase 3 Cohort 1, the key secondary 
efficacy endpoint will be calculated as: 
• Number of patients who died through Day 29 divided by number of patients in the 
treatment group in Phase 3 Cohort 1 Critical stratum receiving mechanical ventilation 
without ECMO at baseline. 
• Number of patients who died through Day 29 divided by number of patients in the 
treatment 
group 
in 
Phase 
3 
Cohort 
1 
ALL 
Critical 
stratum 
(ITT). 
 
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Phase 3 Cohort 2 and Cohort 3: 
 
For each treatment group (sarilumab 800 mg or placebo) in Phase 3 Cohort 2 and Cohort 3, the 
key secondary efficacy endpoints will be calculated as: 
• Number of patients who died through Day 29 divided by number of patients in the 
treatment group in Phase 3 Cohort 2 receiving mechanical ventilation at baseline 
• Number of patients who died through Day 29 divided by number of patients in the 
treatment group in Phase 3 Cohort 3 on high-intensity oxygen therapy without 
mechanical ventilation at baseline 
4.5.3. 
Other Secondary Efficacy Variables 
Additional secondary efficacy variables and populations of interest specified in the protocol are 
shown in Table 2.   
Table 2: 
Phase 3 – Other Secondary Efficacy Endpoints 
Efficacy Variable 
Populations of Interest 
 
Cohort 1:  
sarilumab 400 mg or placebo 
Cohort 2:  
sarilumab 
800 mg or 
placebo 
(receiving 
mechanical 
ventilation at 
baseline) 
 
Cohort 3:  
sarilumab 
800 mg or 
placebo 
(receiving high-
intensity oxygen 
therapy without 
mechanical 
ventilation at 
baseline) 
Critical  
ITT 
Critical 
receiving 
mechanical 
ventilation 
at baseline 
Critical not 
receiving 
mechanical 
ventilation at 
baseline1 
Proportion of patients 
alive not requiring 
invasive mechanical 
ventilation or ECMO at 
Day 22 
Secondary 
(Same as 
Primary) 
Descriptive 
(Same as 
Primary) 
Secondary 
Proportion of patients 
receiving invasive 
mechanical ventilation or 
ECMO at Day 22 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
Proportion of patients 
with a 2-point 
improvement in clinical 
status on the 7-point 
ordinal scale from 
baseline to Day 22 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
Time to at least 1-point 
improvement in clinical 
status assessment from 
baseline on the 7-point 
ordinal scale 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
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Efficacy Variable 
Populations of Interest 
 
Cohort 1:  
sarilumab 400 mg or placebo 
Cohort 2:  
sarilumab 
800 mg or 
placebo 
(receiving 
mechanical 
ventilation at 
baseline) 
 
Cohort 3:  
sarilumab 
800 mg or 
placebo 
(receiving high-
intensity oxygen 
therapy without 
mechanical 
ventilation at 
baseline) 
Critical  
ITT 
Critical 
receiving 
mechanical 
ventilation 
at baseline 
Critical not 
receiving 
mechanical 
ventilation at 
baseline1 
Time to at least 2-point 
improvement in clinical 
status assessment from 
baseline on the 7-point 
ordinal scale 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
Proportion of patients 
discharged and alive at 
Day 22 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
Time to recovery 
(discharged, or alive 
without supplemental 
oxygen use or at pre-
COVID oxygen use) 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
Time to death (all-cause 
mortality) 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
Number of ventilator free 
days between baseline 
and Day 8, 15, 22, and 29 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
Number of days of 
hospitalization among 
survivors up to Day 8, 15, 
22, and 29 
Secondary 
Secondary 
Descriptive 
Secondary 
Secondary 
1 The main approach in Cohort 1 to the analysis of patients “Critical not receiving mechanical ventilation at 
baseline” will be through an analysis of a subset of the overall ITT population to assess if an effect observed in the 
ITT population is observed both in the subset of patients on mechanical ventilation and not on mechanical 
ventilation at baseline. 
4.5.3.1. 
Mechanical ventilation or ECMO related outcomes 
Patients are considered to be receiving invasive mechanical ventilation or ECMO, if their post-
baseline oxygen use (see Section 4.5.2.2) is invasive (mechanical) ventilation or extracorporeal 
life support.  Otherwise, patients are considered as not requiring invasive mechanical ventilation 
or ECMO. 
Proportion of patients alive not requiring mechanical ventilation or ECMO at Day 22, is 
calculated as number of patients who are (alive and not on mechanical ventilation or ECMO) at 
Day 22 divided by the population of interest. 
Proportion of patients receiving mechanical ventilation or ECMO at Day 22 is calculated as 
number of patients who are receiving mechanical ventilation or ECMO at Day 22 divided by the 
population of interest. 
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4.5.3.2. 
At least x-point improvement in clinical status on ordinal scale related outcomes 
Proportion of patients with a 2-point improvement in clinical status on the 7-point ordinal 
scale from baseline to Day 22 is calculated as number of patients for whom change from baseline 
on the ordinal scale is ≥+2 at Day 22 divided by population of interest. 
Time to at least 1 (2)-point improvement (event) in clinical status on the 7-point ordinal scale 
is defined as the first date of change from baseline in clinical status ≥+1(+2) minus first dose 
date. Patients who do not experience improvement of 1 (2) point(s) or more on the ordinal scale 
will be censored at the last observed time point.  Patients who die at any time in the study will be 
censored at Day 60 (end of study – phone call follow-up) in case of final database lock (In case 
of an interim data lock, censoring will occur on the study day of the longest follow-up of an alive 
patient at the time of data cut-off, e.g., if the longest follow-up of an alive patient at the data cut-
off date of interim lock is Day 15, then patients who died will be censored at Day 15.) 
4.5.3.3. 
Discharged and Alive 
Proportion of patients who are discharged and alive at Day 22 is the number of patients who 
are alive and have a discharge date (or marked as discharged from hospital before Day 29 in case 
date is missing) on the Hospital & ICU Admission & Discharge CRF divided by the population 
of interest. 
4.5.3.4. 
Time-to-recovery 
Time to recovery (event) is computed as the first date a patient has recovered (as defined in 
Section 4.5.2.2) minus the first dose date + 1.  Patients who do not recover will be censored at 
the last observed time point.  Patients who die at any time in the study will be censored at Day 60 
(end of study – phone call follow-up) in case of final database lock (In case of an interim data 
lock, censoring will occur on the study day of the longest follow-up of an alive patient at the 
time of data cut-off, e.g., if the longest follow-up of an alive patient at the data cut-off date of 
interim lock is Day 15, then patients who died will be censored at Day 15.) 
4.5.3.5. 
Time-to-death (all-cause mortality) 
Time to death (all-cause mortality) (event) will be computed as the date of death (death for any 
cause) minus the first dose date +1.  Patients who are alive will be censored at the last observed 
timepoint.  Survival status is derived from the CRFs as described in Section 4.5.2.3.  If the date 
of death is missing (even after data query to the study site) but patient is marked as died, then 
death date will be imputed as Study Day 1. 
4.5.3.6. 
Ventilator-free days 
Assisted ventilation is defined as the use of invasive mechanical ventilation or extracorporeal life 
support (eg, extracorporeal membrane oxygenation [ECMO]).  Duration of ventilation and 
ventilator-free days variables are defined in this section. 
Ventilator-free days based on Study Day 29 
For those receiving assisted ventilation at baseline see derivations below: 
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• The duration of ventilation is defined as [Last date of assisted ventilation in the 
hospital – max(first date of assisted ventilation, first dose date)], if last day is prior to 
Day 29.  (Note:  Some patients may be randomized while on assisted ventilation. 
Hence maximum of first date of assisted ventilation and first dose date is used.) 
Otherwise, duration of ventilation is (Date of Study Day 29 - first date of assisted 
ventilation). 
For those not receiving assisted ventilation at baseline see derivations below: 
• In patients who never require assisted ventilation, duration of ventilation is zero. 
• In patients who initiated assisted ventilation during the study, duration of ventilation 
is defined as (stop date of assisted ventilation minus start date of assisted ventilation).  
If a patient has been on and off ventilation then it will be the summation of all days 
on ventilation.  If the assisted ventilation is ongoing and there is no stop date, then use 
the last observed date on assisted ventilation. 
Ventilator-free days (VFD) depend on both duration of ventilation and mortality through study 
Day 29.  The maximum number of VFD can be 28 days. (Assuming that patient is observed at 
the same time on each study day, there are 28 24-hour periods from Day 1 to Day 29.)  
VFD will be calculated and reported in patients using assisted ventilation (or not) at baseline.  
VFD may also be analyzed in these 2 groups after excluding patients using ECMO at baseline. 
Ventilator-free days are defined as 28 minus duration of ventilation, with following 
considerations. 
• Patients who do not survive 29 days will be assigned zero VFD. 
• Patients discharged and alive prior to Day 29 on unassisted breathing will be assumed 
to remain on unassisted breathing through Day 29.   
• For patients who experience multiple episodes of assisted ventilation (e.g. may be on 
a ventilator, then come off the ventilator and be on a ventilator again) ventilator free 
days will be computed between each episode of ventilation and total VFD calculated. 
Ventilator-free days based on Study Days 8, 15, 22 
VFD variable for each patient will also be calculated similarly (as above) based on data up to 
Study Day 8, 15, and 22 (replace Day 29 in the above derivation rules by respective study day).  
Maximum VFD will be 7 days, 14 days, and 21 days, respectively. 
4.5.3.7. 
Days of Hospitalization 
Length of hospitalization after randomization will be calculated as date of the last observed 
study day in the hospital minus first dose date +1.  If a patient dies, then date of last observed 
study day will be death date.  If a patient is discharged, then date of last observed study day will 
be the date of discharge. 
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4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Serious adverse events and AESIs will be collected from the time of informed consent signature 
and then at each visit through Day 29 or discharge or death, whichever is sooner. Patients 
discharged prior to Day 29 will have a follow-up phone call on Day 29 to assess vital status, 
collect data on serious adverse event  and history of hospital re-admission. At the Day 60 phone 
call follow-up, data on vital status of the patient (alive or dead) and history of hospital re-
admission will be collected. All adverse events are to be coded to a “Preferred Term (PT)” and 
associated primary “System Organ Class (SOC)” according to the Medical Dictionary for 
Regulatory Activities (MedDRA version 23.0). 
An Adverse Event is any untoward medical occurrence in a patient administered a study drug 
which may or may not have a causal relationship with the study drug. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol. 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 
hours after the infusion is completed. 
The severity of AEs will be graded using the NCI-CTCAE v5.  Adverse events not listed in the 
NCI-CTCAE v5 will be graded according to the following scale: 
Table 3: 
Grading System for Adverse Events Not Listed in NCI-CTCAE 
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.   
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
3  
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care 
ADL**. 
4  
Life–threatening 
Life-threatening consequences; urgent intervention 
indicated. 
5  
Death 
Death related to AE 
* 
Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
Laboratory results, vital signs, or ECG (if feasible) abnormalities will be recorded as AEs if they 
are medically relevant: symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion. 
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The secondary safety variables are (also see Section 4.6.2): 
1. Proportion of patients with serious adverse events 
2. Proportion of patients with Grade 4 neutropenia (absolute neutrophil count 
(ANC) < 500/mm3) 
3. Proportion of patients with severe or life-threatening bacterial, invasive fungal, or 
opportunistic infection 
4. Proportion of patients with severe or life-threatening bacterial, invasive fungal, or 
opportunistic infection in patients with Grade 4 neutropenia (ANC < 500/mm3) 
5. Proportion of patients with hypersensitivity reactions 
6. Proportion of patients with infusion reactions 
7. Proportion of patients with gastrointestinal perforation 
8. White cell count, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, on Days 1, 
3, 5, 8, 11, 15, and 29 (if still hospitalized) 
 
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) of scientific and 
medical interest specific to this drug program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor will be done.  
In this study, the AESIs are listed below: 
• Grade 4 neutropenia (absolute neutrophil count (ANC) < 500/mm3) :  
− selected from Local Lab-Hematology CRF 
• Grade 4 neutropenia (ANC < 500/mm3) with concurrent severe or life-threatening 
bacterial, invasive fungal, or opportunistic infection :  
− selected from Adverse Event CRF 
• Grade ≥2 infusion related reactions 
− selected from Adverse Events CRF 
• Grade ≥2 hypersensitivity reactions 
− selected from Adverse Events CRF 
• Increase 
in 
alanine 
transaminase 
(ALT) 
or 
aspartate 
aminotransferase 
(AST) ≥ 3 X upper limit of normal (ULN) (for patients with normal baseline) or 
> 3 X ULN AND at least 2 fold increase from baseline value (for patients with 
abnormal baseline) 
− selected from Local Lab-Chemistry CRFs 
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• Invasive bacterial or fungal infections of clinical significance with confirmed 
diagnosis based on the investigator's assessment with appropriate diagnostic workups 
and consultations 
− selected from Adverse Event CRF 
4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of blood chemistry (including C-Reactive Protein, liver 
function tests, creatinine and other), hematology, urinalysis, infection testing, SARS-Cov-2 RT-
PCR, and other (as specified in the protocol). 
Clinical laboratory values will be converted to standard international (SI) units and grouped by 
function in summary tables. Conventional unit may be provided. Functions are defined as 
follows: 
• Liver function including ALT, AST, alkaline phosphatase, total bilirubin, 
• Renal function including creatinine, uric acid, 
• Electrolytes including sodium, potassium, 
• C-Reactive Protein (CRP), 
• Creatine Phosphokinase (CPK) 
• Metabolic parameters including total proteins, albumin, 
• White blood cells (WBCs) including WBCs count and differential count (neutrophils, 
lymphocytes, eosinophils, basophils, monocytes), 
• Red blood cells (RBCs) and platelets including red blood cells count, hemoglobin, 
hematocrit and platelets count, 
• Other 
4.6.4. 
Vital Signs 
Vital signs, including temperature, blood pressure, pulse, and respiration, are recorded at 
multiple time points according to Schedule of Time and Events table (See Section 10.1). 
4.6.5. 
Physical Examination Variables 
A targeted physical examination including lung auscultation will be performed at time point 
according to Schedule of Time and Events table (See Section 10.1). Care will betaken by the 
investigator to examine and assess any abnormalities that may be present, as indicated by the 
patient’s medical history.  
During screening period, if any existing clinically significant abnormalities are present, these 
will be recorded in the Medical History CRF. Post-screening period, if any new clinically 
significant abnormalities are present (per investigator discretion), the relevant event will be 
recorded in the Adverse Event CRF, if applicable. 
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4.7. 
Pharmacokinetic Variables 
The PK variables are the concentration of sarilumab and concentration of sIL-6R in serum at 
each time point specified in the Schedule of Time and Events table (See Section 10.1).  
4.8. 
Pharmacodynamic and Other Biomarker Variables  
Exploratory endpoint variables include measurement of SARS-CoV-2 in OP or NP swabs over 
time using RT-PCR. Qualitative (positive or negative) or relative quantitation of viral copies may 
be evaluated. Pharmacodynamic variables may include the time to reach a negative OP or NP RT 
PCR result. 
Additional biomarker testing may include, but not be limited to, evaluation of inflammatory 
cytokines in serum, and ANC.  
Pharmacodynamic variables include the ANC, and the concentration of IL-6 in serum at each 
time point. 
These results may be reported outside the clinical study report (CSR). 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, quartiles, minimum, and 
maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Separate analyses will be conducted for Phase 3 Cohort 1, Cohort 2, and Cohort 3. The main 
focus of the Phase 3 analysis will be on patients in  
1. Cohort 1† Critical stratum randomized to sarilumab 400 mg IV or placebo treatment 
groups,  
2. Cohort 2 randomized to sarilumab 800 mg IV or placebo treatment groups receiving 
mechanical ventilation at baseline, and  
3. Cohort 3 randomized to sarilumab 800 mg IV or placebo treatment groups receiving 
high-intensity oxygen therapy without mechanical ventilation at baseline. 
† Note that Cohort 1 consists of all Phase 3 patients randomized to sarilumab 400 mg IV, sarilumab 
200 mg IV or placebo across disease severity strata.  Within this Cohort, the primary focus of this SAP is 
on the efficacy and safety data on patients in the critical stratum randomized to sarilumab 400 mg or 
placebo.  For patients in the critical stratum randomized to sarilumab 200 mg, only safety data will be 
analyzed. 
 
Efficacy analyses of previously enrolled Phase 3 Cohort 1 patients randomized to sarilumab 
200 mg versus placebo in all disease severity strata will be done for exploratory purpose only. 
Efficacy and safety analyses of previously enrolled Phase 3 Cohort 1 patients randomized to 
sarilumab 400 mg IV versus placebo for the disease severity strata of severe, MSOD, or 
immunocompromised, will also be done for exploratory purpose only.  These exploratory 
analyses will be designed similarly as the main analyses described in this SAP. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics variables given in Section 4.1 will be summarized 
descriptively by treatment group, and all groups combined.  These will be analyzed for the ITT 
population and the subset population of interest within ITT as specified by the primary efficacy 
endpoints. 
5.2. 
Medical History 
Medical history will be summarized by SOC and PT and by treatment group and all groups 
combined in the ITT population and the subset population of interest within ITT as specified by 
the primary efficacy endpoints. 
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5.3. 
Prior/concomitant Illnesses and Medications  
Prior or concomitant medications/procedures will be summarized by treatment groups.  Focus of 
the results will be on the list of targeted medications (Section 4.3) in the ITT population. 
5.4. 
Rescue/ Prohibited Medications if applicable 
Not applicable.  See Section 4.4. 
5.5. 
Subject Disposition 
The following summaries will be provided for all screened patients. 
Total number of  
• Screened patients:  met the inclusion criteria regarding the target indication and 
signed the ICF 
• Randomized patients:  received a randomization number per IRT 
• Patients treated but not randomized 
• Patients randomized and not treated 
• Screen failures 
• Reasons for screen failure 
The following summaries will also be provided for the ITT population (see Section 3.1 for 
definition). 
• The total number of randomized patients 
• The total number of patients who completed the study 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation.   
(Note: Until Protocol Amendment #3 was effective, patients were given only a single 
dose.  After Protocol Amendment #4, repeat dosing is permitted after 24 hours of 
dosing and weekly under protocol-defined criteria.  Discontinuation from study 
treatment refers to either study treatment interruption (if single dose) or study drug 
discontinuation (if multiple doses).) 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
(Note:  Applicable only on data after Protocol Amendment #4 is in effect, as 
described above.) 
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In addition, the number of patients in each treatment group and combined groups will be 
summarized for the analysis sets of ITT population and Per Protocol Set defined in Section 3.1 
and Section 3.2, Safety population defined in Section 3.3, and Pharmacokinetics Analysis Set 
defined in Section 3.6. This analysis will be done in ITT. 
5.6. 
Extent of Study Treatment Exposure and Compliance 
Prior to Protocol Amendment #4 treated patients were given a single dose of study drug 
(sarilumab 400 mg IV, sarilumab 200 mg IV, or placebo IV).  After Protocol Amendment #4, 
repeat dosing of study drug was permitted after 24 hours (Day 2) if no clinical response is 
observed and additional (repeat) weekly dosing is permitted (under protocol-defined criteria).  In 
Cohort 1, a maximum of 6 doses of study drug in total are permitted during the study.  In 
Cohort  2, a maximum of 4 doses of study are permitted during the study with no dose after Day 
21. 
5.6.1. 
Measurement of Compliance 
Treatment compliance in a given patient is defined as the number of fully completed infusions of 
study drug divided by number of doses administered (applicable, both, to patients receiving only 
single dose or multiple doses since Protocol Amendment #4).  Treatment compliance will be 
summarized by treatment group using descriptive statistics based on the Safety population. 
5.6.2. 
Exposure to Investigational Product 
Exposure to study drug will be examined for each patient as recorded on the Study Drug 
Administration-IV and Study Drug Administration-IV (Re-Dose) CRFs.  
The following variables will be descriptively summarized (and/or) provided in patient listings by 
treatment group: 
• Number of patients who received single dose 
• Number of patients who received multiple doses 
• Number of patients receiving 1, 2, 3, 4, 5, or 6 doses (up to maximum if maximum is 
higher than 6, even though 6 is maximum specified in protocol) 
• Duration of intravenous infusion (mins) (infusion end time – infusion start time) on 
the days of dosing 
• Location of administration on the days of dosing 
• Total volume of drug administered (units: mL) on the days of dosing 
• Number of patients with infusion interruptions on days of dosing 
• Number of patients receving study drug over time, e.g., on Day 1, Day 2, and weekly 
thereafter (Days 8, 15, 22, 29).  Cohort 1 can receive maximum of 6 doses.  Cohort 2 
can receive maximum of 4 doses with no dosing after Day 21. 
In addition, duration on study (days) will also be descriptively summarized by treatment group. 
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5.7. 
Analyses of Efficacy Variables 
Post adaptations to the Phase 3 study design, the main focus of the efficacy analyses will be 
3 separate pairwise comparisons, namely in:  
1. Cohort 1 critical patients with mechanical ventilation without ECMO at baseline 
comparing sarilumab 400 mg IV versus placebo, 
2. Cohort 
2 
patients 
with 
mechanical 
ventilation 
at 
baseline 
comparing 
sarilumab 800 mg IV versus placebo, and  
3. Cohort 3 patients without mechanical ventilation but on high-intensity oxygen therapy at 
baseline comparing sarilumab 800 mg IV versus placebo. 
5.7.1. 
Analysis of Primary Efficacy Variables 
The primary efficacy analysis for each comparison will be using the efficacy variable of 
proportion of patients with at least 1 point improvement in clinical status from baseline to Day 
22 using the 7-point ordinal scale (defined in Section 4.5.1).  The primary analysis population 
will be ITT (defined in Section 3.1). 
Hypothesis tests of superiority of sarilumab (400 mg or 800 mg dose) versus placebo will be 
done using the stratified Cochran-Mantel-Haenszel (CMH) test for two proportions.  For Cohort 
1, the stratification factor will be use of steroids at baseline (yes/no). For Cohort 2 and Cohort 3, 
the stratification factors will be use of non-IL6/6R therapy under an EUA at randomization 
(yes/no) and use of steroids at baseline (yes/no).   
Estimation of the treatment effect will be provided as differences in proportions and confidence 
intervals calculated using thestrata-adjusted confidence intervals from CMH method (Zhang, 
2016 [13]).  Stratification factors are as mentioned above. 
For each cohort, p-values and confidence intervals will be reported with overall Type 1 error 
controlled at 0.05 (2-sided) (see Section 7). 
Sensitivity analysis:  
Sensitivity analysis will be conducted on the primary efficacy variable using the population of 
PPS (defined in Section 3.2) 
Supportive analyses: 
The analysis of the secondary efficacy variable of time to at least 1 point improvement in clinical 
status from baseline on the 7-point ordinal scale will be used as supportive analysis.  Kaplan-
Meier estimates on proportion of patients with at least 1 point improvement at Day 22 in each 
treatment group will be reported for descriptive purpose. Comparisons between groups will be 
made using Restricted Mean Survival Time (RMST) computed at Day 22 (Kim, 2017 [9]). Two-
sided confidence intervals and p-values for specified significance level can be computed for 
differences in RMST based on asymptotic normal distribution. 
Subgroup analyses: 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects by the following variables: 
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• Age (<median vs. ≥median) (years) 
• Sex (Male vs. Female) 
• Race (e.g., White vs. Asian vs. Other) 
• Baseline comorbidities (Hypertension, Diabetes, Obesity) 
• Steroid use (yes/no) 
• Duration of illness (<median vs. ≥median) (days) 
• Length of hospital stay include ICU prior to randomization (1-2, 3-4, >=5 days) 
(days) 
• Length of hospital stay including ICU prior to randomization (<median vs. ≥median) 
(days) 
• Length of ICU stay prior to randomization (1-2, 3-4, >=5 days) (days) 
• Length of ICU stay prior to randomization (<median vs. ≥median) (days) 
• Baseline IL-6 level (<230 pg/mL vs. ≥230 pg/mL; other cutpoints eg, 70 and 140 
pg/mL will also be analyzed) 
• Baseline CRP tertiles 
• Baseline neutrophil-to-lymphocyte ratio tertiles 
• Use of other COVID-19 therapies 
5.7.2. 
Analysis of Secondary Efficacy Variables 
The statistical methods used for the primary and sensitivity analysis (ITT and PPS) of key 
secondary efficacy variables will be same as the methods described for the primary efficacy 
variable.  
These key secondary endpoints for the Phase 3 portion of the study will be tested sequentially in 
a hierarchical manner, while preserving the overall significance level at 0.05 (2-sided). 
Cohort 1 
1. Proportion of patients with at least 1-point improvement in clinical status assessment 
from baseline to Day 22 in patients with critical COVID-19  
2. Proportion of patients who recover (discharged, or alive without supplemental oxygen 
use or at pre-COVID oxygen use) by Day 22 in patients with critical COVID-19 
receiving mechanical ventilation without ECMO at baseline 
3. Proportion of patients who die through Day 29 in patients with critical COVID-19 
receiving mechanical ventilation without ECMO at baseline 
4. Proportion of patients who die through Day 29 in patients with critical COVID-19 
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Cohort 2 
1. Proportion of patients who recover (discharged, or alive without supplemental oxygen 
use or at pre-COVID oxygen use) by Day 22 in patients with COVID-19 receiving 
mechanical ventilation at baseline 
2. Proportion of patients who die through Day 29 in patients with COVID-19 receiving 
mechanical ventilation at baseline 
Cohort 3 
1. Proportion of patients who recover (discharged, or alive without supplemental oxygen 
use or at pre-COVID oxygen use) by Day 22 in patients receiving high-intensity oxygen 
therapy without mechanical ventilation at baseline 
2. Proportion of patients who die through Day 29 in patients high-intensity oxygen therapy 
without mechanical ventilation at baseline 
5.7.3. 
Analysis of Other Secondary Efficacy 
Other secondary efficacy variables listed in Section 4.5.3 will be analyzed as follows depending 
on the variable: 
1. Categorical data will be summarized as proportions by Study Day in each treatment 
group.  For the specific time points (e.g., Day 22) in the secondary endpoint, p-values and 
95% confidence intervals will be reported for descriptive purpose using stratified CMH 
test and strata-adjusted CMH method, respectively (as mentioned for the primary 
endpoints). 
2. Differences in time-to-event endpoints by treatment (eg, time to a one category 
improvement in ordinal scale, and other time-to-event endpoints) will be summarized 
with Kaplan-Meier estimates and nominal 95% confidence intervals on medians will be 
reported. P-values and confidence intervals for hazard ratios comparing treatment groups 
will also be reported using Cox proportional hazards model with stratification factors 
mentioned earlier.  Cumulative incidence rates will be plotted with comparisons between 
groups descriptively tested using log-rank test. 
3. Duration of event (eg, ventilator-free days, days of hospitalization) will be summarized  
through descriptive statistics including mean, median, and median days with quartiles. P-
values using two-sample t-test and 95% confidence intervals using normal approximation 
will also be reported for descriptive purpose. 
4. Change in ordinal scale at specific time points will be summarized by proportions (eg, 
proportion who have a 1-, 2-, 3-, 4-, or 5-point improvement or 1-, 2-, or 3-point 
worsening). 
5.7.4. 
Adjustment for Multiple Comparison 
Primary analyses in Cohort 1, Cohort 2 and Cohort 3 will be conducted separately.  Overall type 
1 error will be controlled within each cohort at 0.05 (2-sided) level. 
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Multiplicity adjustment will be made for interim looks (Section 7) and significance level will be 
adjusted for final analysis of primary endpoint to control overall type I error.  Based on the alpha 
spending rules for interim analysis, the final significance level for primary endpoint will be 
0.0493 (2-sided) . 
Multiplicity will be controlled for testing the specified primary ane key secondary endpoints 
using a hierarchical testing order as shown in Table 4. 
Table 4: 
Testing Strategy for Control of Multiplicity in Phase 3 Cohorts 1, 2 and 3 
(Overall Type 1 Error in each cohort will be 0.05 [2-sided]) 
Order 
Timing of 
Analysis 
Type of 
Endpoint 
Endpoint 
Population 
Example 
Nominal 
Significance 
level, α 
Cohort 1 
1 
Final 
Primary 
Proportion of patients with a 
1- point improvement in 
clinical status from baseline 
to Day 22 
Critical COVID-19 
patients receiving 
mechanical ventilation at 
baseline 
0.049† 
2 
Final 
Key 
Secondary 
Proportion of patients with a 
1- point improvement in 
clinical status assessment 
from baseline to Day 22  
All Critical stratum 
COVID-19 patients 
(including ventilated or 
ECMO or not ventilated 
at baseline) 
0.049† 
3 
Final 
Key 
Secondary 
Proportion of patients who 
recover (discharged, or alive 
without supplemental oxygen 
use) by Day 22 
Critical COVID-19 
patients receiving 
mechanical ventilation at 
baseline 
0.049† 
4 
Final 
Key 
Secondary 
All-cause mortality at Day 29 
Critical COVID-19 
patients receiving 
mechanical ventilation at 
baseline 
0.049† 
5 
Final 
Key 
Secondary 
All-cause mortality at Day 29 
All Critical stratum 
COVID-19 patients 
(including ventilated or 
ECMO or not ventilated 
at baseline) 
0.049† 
Cohort 2 
1 
Final 
Primary 
Proportion of patients with a 
1- point improvement in 
clinical status from baseline 
to Day 22 
COVID-19 patients 
receiving mechanical 
ventilation at baseline 
0.049‡ 
2 
Final 
Key 
Secondary 
Proportion of patients who 
recover (discharged, or alive 
without supplemental oxygen 
use) by Day 22 
COVID-19 patients 
receiving mechanical 
ventilation at baseline 
0.049‡ 
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Order 
Timing of 
Analysis 
Type of 
Endpoint 
Endpoint 
Population 
Example 
Nominal 
Significance 
level, α 
3 
Final 
Key 
Secondary 
All-cause mortality at Day 29 
COVID-19 patients 
receiving mechanical 
ventilation at baseline 
0.049‡ 
Cohort 3 
1 
Final 
Primary 
Proportion of patients with a 
1- point improvement in 
clinical status from baseline 
to Day 22 
COVID-19 patients not 
receiving mechanical 
ventilation but using 
high intensity oxygen 
therapy at baseline 
0.049‡ 
2 
Final 
Key 
Secondary 
Proportion of patients who 
recover (discharged, or alive 
without supplemental oxygen 
use) by Day 22 
COVID-19 patients not 
receiving mechanical 
ventilation but using 
high intensity oxygen 
therapy at baseline 
0.049‡ 
3 
Final 
Key 
Secondary 
All-cause mortality at 
Day  29 
COVID-19 patients not 
receiving mechanical 
ventilation but using 
high intensity oxygen 
therapy at baseline 
0.049‡ 
† If the interim analysis results for primary endpoint are statistically significant, then the Sponsor may decide to 
stop the cohort earlier and the alpha used at interim will be reallocated to test the key secondary endpoints at the 
full α=0.05 (2-sided).  If the interim analysis on the primary endpoint is not significant, then the Sponsor will 
continue the follow-up of the cohort and any results on the secondary endpoints at interim will be exploratory.  
The Sponsor may present nominal p-values for key secondary endpoints at the interim without formal testing at 
interim. 
‡ Interim analyses are planned for Cohort 2 and 3.  In case of interim analyses, similar alpha spending and alpha 
re-allocation rules will be used for Cohorts 2 and 3. 
5.8. 
Analysis of Safety Data 
The analysis of safety data will be performed on the SAF, as defined in Section 3.3. 
The safety analysis will be based on the reported SAEs and AESIs and other safety information 
(clinical laboratory evaluations and vital signs).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Appendix 10.2 . 
The summary of safety results will be presented for each treatment group. 
5.8.1. 
Adverse Events  
The verbatim text, the PT, and the primary SOC will be listed in subject listings. Summaries that 
include frequencies and proportions of patients reporting AEs will include the PTs and the SOCs. 
Period of observation: The observation period will be the on-treatment period defined as the 
day from first dose of study drug (Day 1) to study Day 29. (Patients who are discharged prior to 
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Day 29 will receive a follow-up phone call to collect data on SAEs (if any), survival and history 
of hospital re-admission.) 
Treatment-emergent AEs (TEAEs) are defined as those AEs that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the on-treatment period.  In this 
study, only SAEs and AESIs are collected.  As such TEAEs will reflect this data. 
For details on handling missing data and partial dates, see Section 6. 
Summaries of AE incidence in each treatment group will include: 
• Overview of TEAEs, summarizing number of events, summarizing number and 
percentage of patients within the specified category 
− Total number of TEAEs, SAEs, AESIs, serious AESIs 
− Patients with any TEAEs, any SAEs, any AESIs, serious AESIs 
− Patients with any TEAEs leading to study drug interruption or study 
discontinuation, leading to death 
• TEAEs by system organ class (SOC) and preferred terms (PT) 
− All TEAEs 
− TEAEs by relationship to treatment (related, not related) 
− TEAEs by CTC grade (according to the grading scale outlined in Section 4.6.1), 
presented by SOC and PT 
− TEAEs leading to study drug interruption or study discontinuation 
− TEAEs leading to death 
• AESIs by PT 
• SAEs by SOC and PT 
• Deaths 
Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients from the safety population in each treatment 
group. 
Primary SOCs will be sorted according to decreasing order of frequency in the combined 
treatment groups. Within each primary SOC, PTs will be sorted by decreasing frequency of 
investigational product. 
A second type of table with counts of each PT in decreasing order of frequency will also be 
provided. 
5.8.2. 
Analysis of Adverse Events of Special Interest 
Summaries of AESIs (given in Section 4.6.2) will include the following and presented by PT in 
each treatment group: 
1. Incidence of Grade 4 neutropenia (ANC < 500/mm3) 
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2. Incidence of severe or life-threatening bacterial, invasive fungal, or opportunistic 
infection (presented in listings and summarized through patient narratives) 
3. Incidence of Grade 4 neutropenia (ANC < 500/mm3) with concurrent severe or life-
threatening bacterial, invasive fungal, or opportunistic infection 
4. Incidence of Grade ≥2 hypersensitivity reactions, Grade ≥ 2 infusion reactions, 
gastrointestinal perforation 
5. White cell count, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, on all 
study days (available data) 
6. Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥ 3xupper 
limit of normal (ULN) (for patients with normal baseline) or >3X ULN AND at least 2 
fold increase from baseline value (for patients with abnormal baseline) 
7. Incidence of any invasive bacterial or fungal infections 
5.8.3. 
Clinical Laboratory Measurements  
A treatment-emergent Potential Clinically Significant abnormal value (PCSV) is a laboratory 
value that was normal at Screening and Baseline but abnormal after treatment with study drug, or 
a laboratory value that was abnormal at Baseline and exacerbates after treatment with study drug. 
“Exacerbations” will be identified by the Medical Monitor using clinical judgment. Treatment-
Emergent Potentially clinically significant values (PCSVs) will be summarized by treatment 
group. Additionally, shift table for PCSV may be displayed. See Appendix Section 10.2 for the 
criteria of PCSV values. 
Baseline clinical laboratory analytes and change from Baseline in clinical laboratory analytes to 
each scheduled assessment time will be summarized with descriptive statistics. Summary 
statistics will include the number of patients, mean, median, standard deviation, quartiles, 
minimum, and maximum.   
Listings will be provided with flags indicating out of laboratory range values. 
5.8.4. 
Analysis of Vital Signs 
Vital signs (including temperature, blood pressure, pulse, and respiration) will be summarized by 
Baseline and change from Baseline to each scheduled assessment time with descriptive statistics. 
5.8.5. 
Physical Exams 
As physical examination is limited in this study, only the targeted examination of lung 
auscultation will be provided in patient listing. 
5.9. 
Analysis of Pharmacokinetics, Pharmacodynamics and Biomarker 
data 
5.9.1. 
Analysis of Drug Concentration Data 
The concentrations of sarilumab and sIL-6R over time and selected PK parameters, as 
appropriate, will be summarized using descriptive statistics. 
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No formal statistical hypothesis testing will be performed. 
5.9.2. 
Analysis of Pharmacodynamic and Exploratory Biomarker data 
The concentrations of exploratory PD/Biomarkers over time will be summarized using 
descriptive statistics. 
Pharmacodynamic analysis may include a summary of the time to nadir (or peak) ANC, 
descriptive statistics of absolute value, absolute change from baseline, percent change from 
baseline by nominal time (visit), and area under the curve (AUC) concentration of mean and 
median change from baseline for IL-6 and ANC in serum at each time point. No formal 
statistical hypothesis testing will be performed. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Definitions of baseline for efficacy variables are defined in Section 4.5. 
For safety variables, baseline will be the latest available valid measurement taken prior to the 
administration of study drug. 
6.2. 
Data Handling Convention for Efficacy Variables  
6.3. 
Data Handling Convention for Missing Data 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 4.5.1, Section 4.5.2 and Section 4.5.3. 
For other continuous variables not mentioned in above sections, missing clinical efficacy data 
will be imputed using last observation carried forward (LOCF) as these are hospitalized patients 
and missing data is assumed to be missing at random.  
For categorical variables, patients with missing data will be included in calculations of 
percentages.  Number of patients with missing data will be presented. 
Handling of Medications with missing/partial dates 
To determine whether a medication is prior or concomitant medication, the missing medication 
start date is estimated as early as possible up to first dose date, and the missing medication end 
date is estimated as late as possible up to Day 29. If the medication start date is missing, the 
onset day will not be imputed in medication listings. 
Handling of Adverse events Severity and Relatedness 
If the intensity of a SAE and AESI is missing, it will be classified as “severe” in the frequency 
tables by intensity of SAE and AESIs. If the assessment of relationship of the investigational 
product is missing, it will be classified as related to the investigational product. 
Date of infusions 
Date of infusion is the non-missing administration date filled in the Study Drug Administration-
IV CRF. If the first dose of study drug administration date is missing (even after site is queried), 
then the dosing date is will be imputed with the randomization date.  If any subsequent study 
drug administration date is missing, the date of dispensation of study drug from IRT will be used. 
6.4. 
Visit Windows 
Following windows will be used for summarizing laboratory parameters. 
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Table 5: 
Time Window for Summary of Laboratory Parameters 
Visit label 
Target Day 
Hematology, Chemistry 
Baseline 
1 
≤1 
Day 4 
4 
2-5 
Day 7 
7 
6-10 
Day 15 
15 
11-17 
Day 21 
21 
18-24 
Day 29 
29 
≥25 
6.5. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
Extra assessments (e.g., laboratory data or vital signs associated with non-protocol clinical visits 
or obtained in the course of investigating or managing adverse events) will be included in 
listings, but not summaries except for the endpoint determination.  If more than one laboratory 
value is available for a given visit, the first observation will be used in summaries and all 
observations will be presented in listings. 
6.6. 
Pooling of Centers for Statistical Analyses 
Additional analyses on primary and key secondary efficacy endpoints may be performed by sites 
and pooling sites enrolling less than 5 patients as exploratory analyses. 
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7. 
INTERIM ANALYSIS 
Because of the unmet medical need for effective medicines in this global COVID-19 pandemic 
situation, interim analyses are planned for efficacy in the Phase 3 portion of the study.  The 
timing of the first interim analysis will be determined once approximately 110 patients in the 
Phase 3 Cohort 1 critical stratum requiring mechanical ventilation at baseline and randomized to 
400 mg or placebo are enrolled, with a data lock point 22 days later.  Interim analysis for this 
data lock will be conducted in all critical Phase 3 patients who were enrolled until the first dose 
date of the last 110th patient in Cohort 1 critical stratum randomized to sarilumab 400 mg or 
placebo who was on a ventilator at baseline.  
In the Phase 3 Cohort 1, the primary efficacy endpoint will be tested at interim analysis at the 
0.005 (2-sided) significance level. This will correspond to 65% information fraction at the first 
interim look (ie, 110 patients out of 170 at final). Under the Hwang-Shih-DeCani alpha spending 
function (Hwang, 1990 [6], Anderson, 2020 [1]), if the interim analysis is not significant, then 
the significance level for testing the final analysis of primary endpoint will be 0.049 (2-sided).  
The overall Type 1 error with this alpha spending function is preserved at 0.05 (2-sided).  (See 
Appendix 10.4.2). 
Should the interim analysis be positive, the alpha from the interim analysis will be reallocated 
and added to the alpha for the planned key secondary endpoints which will allow them to be 
tested at a significance level of 0.05.   
Similar interim analyses at approximately 50% to 70% information fraction are planned for the 
Phase 3 Cohort 2 and Cohort 3 (one interim look per cohort). 
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8. 
SOFTWARE 
Statistical analyses will be done using SAS Version 9.4.  Some analyses may also be done using 
the R language. 
 
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9. 
REFERENCES 
1. Anderson 
KM. 
Package 
“gsDesign” 
version 
3.1.1, 
May 
7, 
2020.  
Available at: http://cran.r-project.org/web/packages/gsDesign/gsDesign.pdf . Accessed: May 
13, 2020. 
2. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and  content of clinical 
study reports (E3). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
3. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
4. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
5. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z. 
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The 
lancet. 2020 Feb 15;395(10223):497-506. 
6. Hwang IK, Shih WJ, and DeCani JS. Group sequential designs using a family of type 1 error 
probability spending functions. Statistics in Medicine, 9:1439–1445, 1990. 
7. Farrington CP, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk.  
Statistics in Medicine 1990; 9(12): 1447-54. 
8. Garner W. Constructing Confidence Intervals for the Differences of Binomial Proportions in 
SAS®. Gilead Sciences. https://www.lexjansen.com/wuss/2016/127_Final_Paper_PDF.pdf. 
9. Kim DH, Uno H, Wei LJ. Restricted mean survival time as a measure to interpret clinical 
trial results. JAMA cardiology. 2017 Nov 1;2(11):1179-80. 
10. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ.  COVID-19: 
Consider cytokine storm syndromes and immunosuppression. Lancet 2020. Vol 395 (10229), 
p1033-1034. 
11. Peterson RL, Vock DM, Powers JH, Emery S, Cruz EF, Hunsberger S, et al. Analysis of an 
ordinal endpoint for use in evaluating treatments for severe influenza requiring 
hospitalization. Clin Trials 2017; 14(3):264-76. 
12. Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y et al. "Effective treatment of severe 
COVID-19 patients with Tocilizumab." ChinaXiv preprint (2020). https://www.ser.es/wp-
content/uploads/2020/03/TCZ-and-COVID-19.pdf 
13. Zhang Huiping. Proportion difference and confidence interval based on Cochran-Mantel-
Haenszel method in stratified multi-center clinical trial. PharmSUG China 2016 – Paper 25. 
https://www.lexjansen.com/pharmasug-cn/2016/PS/PharmaSUG-China-2016-PS07.pdf  
14. Zhang W, Zhao Y, Zhang F, et al., The use of anti-inflammatory drugs in the treatment of 
people with severe coronavirus disease 2019 (COVID-19): The experience of clinical 
immunologists 
from 
China, 
Clinical 
Immunology 
(2020), 
https://doi.org/10.1016/j.clim.2020.108393.  
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10. 
APPENDIX 
10.1. 
Schedule of Events 
Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 and 
discharge3,4 
60 
Window  
 
 
 
 
 
 
±7 days 
±7 days 
Screening/Baseline: 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History1 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Treatment: 
Study Drug Administration 
 
X 
X5 
 
 
X5 
 
 
 
 
 
If no clinical 
response 
 
 
Repeat weekly for 
patients requiring 
supplemental O2 
 
 
Assessments: 
Oxygen administration (FiO2) and Oxygenation 
(SpO2)6 
X 
X 
Phase 2 & Phase 3 Cohort 1 - 2 times a day 
Phase 3 Cohorts 2 and 3 - At least once per day and any time clinical 
status changes (eg, endotracheal intubation/extubation or requires change 
in oxygen delivery device) 
 
Clinical Status Assessment (7-point ordinal 
scale)7 
 
X 
Daily until discharge 
 
NEWS2 Score 
 
 
 
 
Air or oxygen 
 
X 
Daily in the morning until discharge 
 
Respiratory rate  
 
X  
Daily in the morning until discharge 
 
BP 
 
X 
Daily in the morning until discharge 
 
Pulse 
 
X 
Daily in the morning until discharge 
 
Consciousness 
 
X 
Daily in the morning until discharge 
 
Body temperature before antipyretics or 
4 hours after antipyretics8 
 
X 
Daily in the morning until discharge 
 
Imaging, microbiology results, and arterial 
 
 
If available in the medical record 
 
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Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 and 
discharge3,4 
60 
Window  
 
 
 
 
 
 
±7 days 
±7 days 
blood gas results (as available)9 
Limited physical examination (lung 
auscultation only) 
X 
 
 
 
Electrocardiogram (ECG), if feasible10 
X 
 
 
 
Record Targeted Medications11 
X 
 
Daily until discharge 
 
Adverse Events12 
X 
 
X 
Pregnancy Test (WOCBP)13 
X 
 
 
 
Follow-up Phone Call 
 
 
 
 
 
 
X 
X 
Laboratory Testing: 
C-Reactive Protein (mandatory) 
X 
X 
 
X 
X  
 
 
 
 
 
 
Order CRP with all routine labs and obtain at the same time  
Record all results when available in medical chart 
 
Hematology14 
X 
 
Must be collected within 48 hours prior to redosing  
Record all results when available in medical chart 
 
Blood chemistry (including LFTs and 
creatinine)15 
X 
 
Must be collected within 48 hours prior to redosing  
Record all results when available in medical chart 
 
Ferritin, LDH, d-dimer 
 
X 
(mandatory) 
When available 
 
Blood cultures for bacteria and fungi16  
 
 
 
 
X 
X 
Weekly culture based 
on ANC16 
 
 
PK/Biomarkers/Research (defer to footnotes for sampling requirements): 
 
-1 or 1 
1 
2 
4 
7 
8 to 23 
(Only collect on day 
of dosing) 
29 or 
discharge3,4 
60 
Serum for PK/Sarilumab Concentration17 
 
X 
X 
X 
X 
X 
X 
 
Serum sIL-6R plus research17 
 
X 
 
X 
X 
X 
X 
 
Serum cytokines including IL-6 and biomarker 
testing17 
 
X 
 
X 
X 
X 
X 
 
Blood for PCR SARS-CoV-217,18 
X 
X 
 
X 
 
 
X 
 
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Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 and 
discharge3,4 
60 
Window  
 
 
 
 
 
 
±7 days 
±7 days 
Oropharyngeal or nasopharyngeal swab for 
SARS-COV-2 detection and sequencing17,18 
X 
X 
 
X 
 
 
X 
 
Blood for research plasma17 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Footnotes for the Schedule of Events Table 
1. 
Screening and baseline may occur on the same day. Assessments that are noted for both visits should only be assessed once. 
Medical history should include collecting onset of pneumonia symptoms.  Body temperature, SpO2, and FiO2 must be collected 
at randomization.   
2. 
Patients will have an end of study (EOS) assessment to collect data on survival and history of hospital re-admission.  This 
assessment may be performed by phone. 
3. 
Patients discharged prior to Day 29 will have a follow-up phone call on Day 29 to collect data on survival and history of hospital 
re-admission and do not need to be recalled to the hospital for a visit. 
4. 
Patients discharged prior to Day 29 should have a sample collected.  If day of discharge is not Day 29 and coincides with another 
visit, the Day 29 assessments should be performed. 
5. 
Patients will be re-dosed according to Section 6.1 of the protocol.  
6. 
Oxygen administration and oxygenation: refer to Section 9.2.2.3 of the protocol for details. SpO2 must be measured after 5 
minutes of rest (sitting or supine) and must be measured simultaneously with oxygen administration and ventilation data. Record 
oxygen flow rate (L/min) for patients receiving nasal cannula, simple face mask, or non-rebreather mask. Record FiO2 for 
patients receiving high flow nasal cannula, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane 
oxygenation.  
7. 
Clinical Status Assessment using the 7-point ordinal scale: refer to Section 9.2.2.4 of the protocol for details.  
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8. 
Temperature may be measured using the following methods: oral, rectal, tympanic, or temporal according to local hospital 
protocols and according to the manufacturer’s instructions for use of the device. Body temperature should be measured using the 
same method each time. Temperature should be measured predose after at least 5 minutes of rest (supine or sitting).  
9. 
If available in the medical record, chest CT images will be collected as part of a separate effort related to this study for predictive 
exploratory analysis and may be provided in a separate study report. 
10. ECG only if feasible.  Historical ECG from current hospital admission is acceptable. 
11. Targeted medications: refer to Section 9.2.3.4 of the protocol for details.  
12. Adverse events: Only SAEs and AESIs will be recorded in eCRF. 
13. Pregnancy testing to be performed in women of childbearing potential (WOCBP) only. Serum or urine pregnancy test are both 
acceptable. 
14. Hematology: refer to Section 9.2.3.5 of the protocol for details. CBC is required prior to randomization (standard of care labs 
may be used). After Day 1, CBC will not be performed as a study procedure. When CBC is performed as part of the patient’s 
clinical care, the results will be entered in eCRF. 
15. Blood Chemistry: refer to Section 9.2.3.5 of the protocol for details. LFTs and creatinine are required prior to randomization 
(standard of care labs may be used). After Day 1, LFTs and creatinine will not be performed as a study procedure. When 
chemistries are performed as part of the patient’s clinical care, the results will be entered in eCRF. 
16.  Surveillance blood cultures for bacteria and fungi should be performed weekly for patients who have had a sustained ANC 
<1000/µL for >48 hours post-randomization. 
17. All samples should be collected before study drug administration except post-infusion PK and sIL-6R samples: 
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• 
PK and sIL-6R samples collected on dosing days for the initial dose and for the FIRST repeat dose are mandatory.  
Samples for subsequent doses are requested if sufficient PPE are available:  
⎯ 
One predose (as close to initiation of treatment as reasonable) and  
⎯ 
One within 60 minutes after the end-of-infusion (EOI).  The EOI sample or flush should be collected from the arm, 
contralateral to that used for IV infusion, if possible.  If not medically feasible, the sample can be drawn from the same 
arm.  If the sample cannot be obtained within 60 minutes of the end of infusion, the time from end of infusion should be 
provided in the CRF  
⎯ 
Day 4 samples are mandatory (if PPE and appropriate lab facilities are available). 
• 
The Day 1 predose sample and Day 29 or Early Termination PK sample may be used for ADA analysis. 
18. Swab and tests will be for exploratory analysis only not for inclusion or diagnosis. 
 
 
. 
 
 
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10.2. 
Criteria for Potentially Clinically Significant Values (PCSV)  
 
Parameter 
PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be 
expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Each category is calculated 
independently. 
* At least one level is required; 
multiple levels are optional for 
phase 2/3 studies. If it is 
desirable to get the distribution 
across the different  PCSV 
levels, additional shift table on 
≤3, >3 to ≤5,  > 5 to  ≤10, >10 
to ≤20, and > 20 category for 
baseline vs. post baseline may 
be provided  
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be 
expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
Each category is calculated 
independently. 
* At least one level is required, 
multiple levels are optional for 
phase 2/3 studies. If it is 
desirable to get the distribution 
across the different  PCSV 
levels, additional shift table on 
≤3, >3 to ≤5,  > 5 to ≤10, >10 to 
≤20, and > 20 category for 
baseline vs. post baseline may 
be provided 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be 
expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
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Parameter 
PCSV 
Comments 
Total Bilirubin* >1.5 and ≤ 2 ULN and baseline ≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not 
in µmol/L or mg/L. Categories 
are cumulative. 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
* At least one level is required, 
multiple levels are optional for 
phase 2/3 studies. If it is 
desirable to get the distribution 
of  significant level, additional 
shift table on  ≤1.5, >1.5 to ≤2.0 
and > 2.0 category for baseline 
vs. post baseline may be 
provided 
Conjugated 
Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN, and 
baseline Total Bilirubin ≤ 35% or TBILI ≤1.5 ULN 
Conjugated bilirubin 
determined on a case-by-case 
basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN, and baseline ALT ≤ 3 
ULN or TBILI ≤ 2ULN 
Concept paper on DILI – FDA 
draft Guidance Oct 2007. 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, 
multiple levels are optional for 
phase 2/3 studies. If it is 
desirable to get the distribution 
of  significant level, additional 
shift table on ≤3, >3 to ≤10, and 
> 10 category for baseline vs. 
post baseline may be provided 
Creatinine 
≥150 μmol/L (Adults) or ≥ULN (if ULN≥150 μmol/L)  
and baseline < 150 μmol/L or <ULN (if ULN≥150 
μmol/L)   
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
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Parameter 
PCSV 
Comments 
Creatinine 
Clearance 
(Cockcroft's 
formula) 
<15 ml/min and baseline ≥15 ml/min (end stage renal 
impairment) 
≥15 -<30 ml/min and baseline ≥30 ml/min  (severe 
renal impairment) 
≥30 - < 60 ml/min and baseline  ≥60 ml/min  (moderate 
renal impairment) 
≥60 - < 90 ml/min and baseline  ≥90 ml/min  (mild 
renal impairment) 
Use is optional. 
FDA draft guidance 2010 
Four independent criteria, will 
provide additional shift table if 
needed 
 
Uric Acid 
 
Hyperuricemia: 
 
Hypouricemia: 
 
 
>408 μmol/L or >ULN (if ULN≥408 μmol/L)  and 
baseline ≤408 μmol/L or ≤ULN (if ULN≥408 μmol/L)   
<120 μmol/L or <LLN (if LLN≤120 μmol/L)  and 
baseline ≥ 120 μmol/L or ≥LLN (if LLN≤120 μmol/L)   
Harrison- Principles of Internal 
Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L or ≥ULN (if ULN≥17 mmol/L)  and 
baseline <17 mmol/L  or <ULN (if ULN≥17 mmol/L)   
Two independent criteria 
Chloride 
                
Hypochloremia: 
 
               
Hyperchloremia: 
 
 
<80 mmol/L or <LLN (if LLN≤80 mmol/L)  and 
baseline ≥ 80 mmol/L  or ≥LLN (if LLN≤80 mmol/L)   
 
>115 mmol/L or >ULN (if ULN≥115 mmol/L)  and 
baseline ≤ 115 mmol/L  or ≤ULN (if ULN≥115 
mmol/L)   
Two independent criteria  
Sodium 
                  
Hyponatremia: 
 
                 
Hypernatremia: 
 
 
≤129 mmol/L  or ≤LLN (if LLN≤129 mmol/L) and 
baseline > 129 mmol/L  or >LLN (if LLN≤129 
mmol/L)   
≥160 mmol/L  or ≥ULN (if ULN≥160 mmol/L )  and 
baseline <160 mmol/L  or <ULN (if ULN≥160 mmol/L 
)   
Two independent criteria 
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Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 61 of 69 
 
Parameter 
PCSV 
Comments 
Potassium 
                  
Hypokalemia 
 
                  
Hyperkalemia 
 
 
<3 mmol/L or  <LLN (if LLN≤3 mmol/L)  and baseline 
≥ 3 mmol/L or  ≥LLN (if LLN≤3 mmol/L)   
 
≥5.5 mmol/L or ≥ULN (if ULN≥5.5 mmol/L)  and 
baseline <5.5 mmol/L or <ULN (if ULN≥5.5 mmol/L) 
FDA Feb 2005. 
Two independent criteria 
Total 
Cholesterol 
≥7.74 mmol/L or ≥ULN (if ULN≥7.74 mmol/L)  and 
baseline  < 7.74 mmol/L or <ULN (if ULN≥7.74 
mmol/L) 
Threshold for therapeutic 
intervention. 
Triglycerides 
≥4.6 mmol/L or ≥ULN (if ULN≥4.6 mmol/L)  and 
baseline < 4.6 mmol/L or <ULN (if ULN≥4.6 mmol/L) 
Threshold for therapeutic 
intervention. 
Lipasemia 
≥3 ULN  and baseline < 3 ULN  
 
Amylasemia 
≥3 ULN and baseline < 3 ULN  
 
Glucose 
                
Hypoglycaemia 
 
               
Hyperglycaemia 
 
 
≤3.9 mmol/L and <LLN and baseline >3.9 mmol/L or ≥ 
LLN  
 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) and 
baseline < 11.1 mmol/L (unfasted); <7 mmol/L (fasted) 
ADA Jan 2008. 
HbA1c 
>8%  and baseline  ≤ 8%  
 
Albumin 
≤25 g/L or ≤LLN (if LLN≤25 g/L) and baseline >25 
g/L or >LLN (if LLN≤25 g/L)   
 
CRP  
>2 ULN or >10 mg/L (if ULN not provided) and 
baseline  ≤2 ULN or ≤10 mg/L (if ULN not provided)  
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L or <LLN (if LLN≤3.0 Giga/L)  and 
baseline  ≥3.0 Giga/L or ≥LLN (if LLN≤3.0 Giga/L) 
(Non-Black);  
<2.0 Giga/L or <LLN (if LLN≤2.0 Giga/L)  and 
baseline ≥2.0 Giga/L or ≥LLN (if LLN≤2.0 Giga/L) 
(Black)* 
 
≥16.0 Giga/L or ≥ULN (if ULN≥16.0 Giga/L)  and 
baseline  < 16 Giga/L or <ULN (if ULN≥16.0 Giga/L) 
Increase in WBC: not relevant. 
*The default criteria. Summary 
by race (black and Non-black) 
are optional. 
 
To be interpreted only if no 
differential count available. 
                                        VV-RIM-00110347-1.0 Approved - 16 May 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 62 of 69 
 
Parameter 
PCSV 
Comments 
Lymphocytes 
>4.0 Giga/L or >ULN (if ULN≥4.0 Giga/L)  and 
baseline ≤ 4.0 Giga/L or ≤ULN (if ULN≥4.0 Giga/L) 
 
Neutrophils 
<1.5 Giga/L or <LLN (if LLN≤1.5 Giga/L)  for Non-
Black or <1.0 Giga/L  or <LLN (if LLN≤1.0 Giga/L)  
for Black and baseline  ≥1.5 Giga/L  or ≥LLN (if 
LLN≤1.5 Giga/L) for Non-Black or ≥1.0 Giga/L or 
≥LLN (if LLN≤1.0 Giga/L)  for Black* 
 
<1.5 Giga/L or <LLN (if LLN≤1.5 Giga/L)  and 
baseline ≥1.5 Giga/L  or ≥LLN (if LLN≤1.5 Giga/L) 
(Non-Black);  
<1.0 Giga/L or <LLN (if LLN≤1.0 Giga/L)  and 
baseline ≥1.0 Giga/L or ≥LLN (if LLN≤1.0 Giga/L)  
(Black) 
 
<500 Giga/L regardless of baseline value or racce 
International Consensus 
meeting on drug-induced blood 
cytopenias, 1991. 
*The default criteria. By race 
(black and Non-black) are 
optional. 
Monocytes 
>0.7 Giga/L or >ULN (if ULN≥0.7 Giga/L)  and 
baseline ≤ 0.7 Giga/L or ≤ULN (if ULN≥0.7 Giga/L)   
 
Basophils 
>0.1 Giga/L or >ULN (if ULN≥0.1 Giga/L)  and 
baseline ≤ 0.1 Giga/L or ≤ULN (if ULN≥0.1 Giga/L)   
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) and  
baseline ≤0.5 Giga/L or ≤ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of Internal 
Medicine 17th Ed., 2008. 
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Regeneron Pharmaceuticals, Inc. 
Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 63 of 69 
 
Parameter 
PCSV 
Comments 
Hemoglobin 
≤115 g/L or ≤LLN (if LLN≤115 g/L)  for male or ≤95 
g/L or ≤LLN (if LLN≤95 g/L)  for female and baseline  
> 115 g/L  or >LLN (if LLN≤115 g/L)  for male or > 
95 g/L or >LLN (if LLN≤95 g/L)  for Female* 
 
≤115 g/L or ≤LLN (if LLN≤115 g/L)  and baseline  > 
115 g/L or >LLN (if LLN≤115 g/L)  for male; 
 ≤95 g/L or ≤LLN (if LLN≤95 g/L)   and baseline > 95 
g/L or >LLN (if LLN≤95 g/L)  for Female. 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L)  for male or ≥165 
g/L or ≥ULN (if ULN≥165 g/L)  for female and 
baseline  <185 g/L  or <ULN (if ULN≥185 g/L)  for 
male or  <165 g/L or <ULN (if ULN≥165 g/L)  for 
Female* 
 
≥185 g/L or ≥ULN (if ULN≥185 g/L)  and baseline 
<185 g/L  or <ULN (if ULN≥185 g/L)  for Male; 
 ≥165 g/L or ≥ULN (if ULN≥165 g/L)  and baseline < 
165 g/L  or <ULN (if ULN≥165 g/L) for Female 
 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
*The default criteria. By gender 
(male and female) are optional. 
 
Criteria based upon decrease 
from baseline are more relevant 
than based on absolute value. 
Other categories for decrease 
from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
                                        VV-RIM-00110347-1.0 Approved - 16 May 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 64 of 69 
 
Parameter 
PCSV 
Comments 
Hematocrit 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v)  for Male or 
≤0.32 v/v or ≤LLN (if LLN≤0.32 v/v)  for Female and 
baseline > 0.37 v/v or >LLN (if LLN≤0.37 v/v)  for 
Male or > 0.32 v/v   or >LLN (if LLN≤0.32 v/v)  for 
Female* 
 
≤0.37 v/v or ≤LLN (if LLN≤0.37 v/v)  and baseline > 
0.37 v/v   or >LLN (if LLN≤0.37 v/v)  for Male ; ≤0.32 
v/v or ≤LLN (if LLN≤0.32 v/v)  and baseline > 0.32 
v/v   or >LLN (if LLN≤0.32v/v)  for Female 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v)  for Male or 
≥0.5 v/v or ≥ULN (if ULN≥0.5 v/v)  for Female and 
baseline < 0.55 v/v or <ULN (if ULN≥0.55 v/v)  for 
Male < 0.5 v/v  or <ULN (if ULN≥0.5 v/v)  for 
Female* 
 
≥0.55 v/v or ≥ULN (if ULN≥0.55 v/v)  and baseline < 
0.55 v/v  or <ULN (if ULN≥0.55 v/v)  for Male ; ≥0.5 
v/v or ≥ULN (if ULN≥0.5 v/v)  and baseline < 0.5 v/v  
or <ULN (if ULN≥0.5 v/v)  for Female 
Two Criteria are independent 
 
*The default criteria. By gender 
(male and female) are optional. 
RBC 
≥6 Tera/L or ≥ULN (if ULN≥6 Tera/L)  and baseline < 
6 Tera/L or <ULN (if ULN≥6 Tera/L) 
Unless specifically required for 
particular drug development, 
the analysis is redundant with 
that of Hb. 
Platelets 
<100 Giga/L or <LLN (if LLN≤100 Giga/L)  and 
baseline ≥100 Giga/L or ≥LLN (if LLN≤100 Giga/L) 
≥700 Giga/L or ≥ULN (if ULN≥700 Giga/L)  and 
baseline < 700 Giga/L  or <ULN (if ULN≥700 Giga/L)  
International Consensus 
meeting on drug-induced blood 
cytopenias, 1991. 
Two independent criteria 
Urinalysis 
 
pH 
≤4.6 or ≤LLN (if LLN≤4.6)  and baseline > 4.6 or 
>LLN (if LLN≤4.6)   
≥8 or ≥ULN (if ULN≥8)  and baseline < 8 or <ULN (if 
ULN≥8)   
Two independent criteria 
Vital signs 
HR 
<45 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions 
except STANDING 
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 65 of 69 
 
Parameter 
PCSV 
Comments 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions 
except STANDING 
 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions 
except STANDING 
Weight 
 5% increase from baseline 
5% decrease from baseline 
FDA Feb 2007  
 
 
 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 66 of 69 
 
10.3. 
Criteria for Relevant Major Protocol Deviations 
The relevant major protocol deviations leading to exclusion of patients from the Per Protocol Set 
(PPS) are listed below. 
Table 6: 
Protocol Deviations List 
Category 
Description of Protocol Deviation 
Protocol 
Deviation 
Identification 
(PDID) 
Entered study even though entry criteria was 
not satisfied 
Incl1: Patient was not >=18 years of age at time of 
enrollment but was randomized 
1.01 
Entered study even though entry criteria was 
not satisfied  
Incl2a: Patient did not have evidence of pneumonia by chest 
radiograph, chest computed tomography or chest 
auscultation (rales, crackles), requires supplemental oxygen 
and/or ventilation 
1.02 
Entered study even though entry criteria was 
not satisfied  
Incl2b: Patient did not meet at least one of the criterion of 
Severe disease, Critical disease, Multi-organ dysfunction, or 
Immunocompromised category at Baseline Visit 
1.03 
Entered study even though entry criteria was 
not satisfied  
Incl3. Patient did not have laboratory confirmed SARS-
CoV-2 infection as determined by PCR, result from any 
specimen (or other commercial or public health assay) 
within 2 weeks prior to randomization 
1.04 
Entered study even though entry criteria was 
not satisfied  
Incl4. Patient did not comply with clinic visits and study -
related procedures 
1.05 
Entered study even though entry criteria was 
not satisfied  
Incl5. Patient or legally acceptable representative did not 
provide informed consent 
1.06 
Entered study even though entry criteria was 
not satisfied 
Excl1. Patient, in the opinion of the investigator, not 
expected to survive for >= 48 hours from screening but was 
randomized 
1.07 
Entered study even though entry criteria was 
not satisfied 
Excl2a. Absolute neutrophil count (ANC) less than 
2000mm3 
1.08 
Entered study even though entry criteria was 
not satisfied 
Excl2b. AST or ALT great than 5 x ULN 
1.09 
Entered study even though entry criteria was 
not satisfied 
Excl2c. Platelets <50,000 per mm3 
1.10 
Entered study even though entry criteria was 
not satisfied 
Excl3. Treatment with anti-IL 6, anti IL 6R antagonists, or 
with a Janus kinase inhibitors (JAKi) in the past 30 days or 
plans to receive during the study period 
1.11 
Entered study even though entry criteria was 
not satisfied 
Excl4. Current treatment with the simultaneous 
combination of leflunomide and methotrexate 
1.14 
Entered study even though entry criteria was 
not satisfied 
Excl5a. Known active tuberculosis or a history of 
incompletely treated tuberculosis 
1.17 
Entered study even though entry criteria was 
not satisfied 
Excl5b. Suspected or known extrapulmonary tuberculosis  
1.18 
Entered study even though entry criteria was 
not satisfied 
Excl6. Patients with suspected or known active systemic 
bacterial or fungal infections 
1.19 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 67 of 69 
 
Category 
Description of Protocol Deviation 
Protocol 
Deviation 
Identification 
(PDID) 
Entered study even though entry criteria was 
not satisfied 
Excl8. Participation in any clinical research study within 3 
months and < 5 half-lives of investigational product prior to 
the Screening Visit 
1.21 
Entered study even though entry criteria was 
not satisfied 
Excl9. Any physical exam findings and/or history of any 
illness that, might confound the results of the study or pose 
risk to the patient by participating the study 
1.22 
Entered study even though entry criteria was 
not satisfied 
Excl10. Known systemic hypersensitivity to sarilumab or 
the excipients of the drug product 
1.23 
Subject developed withdrawal criteria but 
were not withdrawn 
Patient experienced AEs listed in protocol section 8.3.1.2 
that  warrants permanent termination of the IV study drug 
infusions, but continued to receive study drug 
2.01 
Received wrong treatment or incorrect dose 
Subject was given study drug but was not randomized 
4.01 
Received wrong treatment or incorrect dose 
Subject received incorrect treatment (e.g., wrong kit given, 
kit dispensed without IWRS transaction)  
4.02 
Received wrong treatment or incorrect dose 
Subject received incorrect dose administration or 
unacceptable IP (expired or temperature excursion deemed 
unacceptable) 
4.03 
Other Treatment compliance 
Staff inappropriately unblinded to treatment assignment 
5.01 
Other Treatment compliance 
Treatment assignment inappropriately unblinded 
5.02 
Randomization Error 
Stratification error - not stratified by severity of illness at 
enrollment or systemic corticosteroids for COVID-19 
6.01 
Visit not performed  
Baseline Visit not performed 
7.02 
Inadequate Informed Consent administration 
Patient or legally acceptable representative did not sign an 
ICF and study procedures initiated (never signed ICF or 
signed after procedure) 
11.01 
Inadequate Informed Consent administration 
Patient or legally acceptable representative did not sign an 
amended ICF and study procedures initiated  
11.02 
Inadequate Informed Consent administration 
Patient confidentiality not maintained  
11.03 
Inadequate Informed Consent administration 
Study Procedures performed after patient withdrew full 
consent 
11.04 
 
 
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 68 of 69 
 
10.4. 
Program codes (SAS or R codes) 
10.4.1. 
SAS code for primary efficacy variables 
The following code is written in the SAS programming language for the statistical analysis of 
proportions comparing two groups.  Statistical method for testing the two proportions is the 
stratified Cochran-Mantel-Haenszel test with SAS code shown below.  
For calculating the confidence intervals for differences in two proportion using the strata-
adjusted CMH method, refer to the SAS code in Zhang, 2016 [13]. 
 
data sampledata; 
  input strata trtgrp $ outcome $ count @@; 
  datalines; 
1 placebo 1Yes 18 1 placebo 2No 26 
2 placebo 1Yes 12 2 placebo 2No 13 
1 drug1   1Yes 40 1 drug1   2No 54 
2 drug1   1Yes 26 2 drug1   2No 26 
1 drug2   1Yes 51 1 drug2   2No 37 
2 drug2   1Yes 35 2 drug2   2No 25 
; 
run; 
 
/* Analysis using "strata" as stratification factor */ 
proc freq data=sampledata(where=(trtgrp in ('placebo','drug2'))); 
  weight count; 
  tables strata*trtgrp*outcome / cmh nopercent nocol; 
run; 
 
 
 
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Protocol: 6R88-COV-2040 
Statistical Analysis Plan 
Date: 16 MAY 2020 
 
CONFIDENTIAL 
Page 69 of 69 
 
10.4.2. 
R code for alpha spending at interim analysis 
The following code is written in the R programming language and uses the R package gsDesign 
[1] which is used to design group sequential clinical trials. 
install.packages("gsDesign") 
library(gsDesign) 
 
#Assume 2 looks: 1 Interim Look and 1 Final Look 
#Data will be available for 110 patients at Interim Analysis, out 
of 170 at Final Analysis 
#Information fraction for binomial endpoint is 65% (=110/170). 
 
#Fix nominal alpha=0.005 at interim 
x.Phase3.IA.option1 <- gsDesign(k=2, test.type=4, alpha=0.025, 
beta=0.1, timing=c(110/170,1), sfupar=-6.5) 
x.Phase3.IA.option1 
The output of the above R code is shown in Figure 3.  As displayed in the output, the nominal 
significance level at 1st interim look will be α=2*0.0025=0.005 (2-sided) (ie, corresponds to 
critical boundary for efficacy (upper bound), Z = 2.8070).  At the final look, the significance 
level will be α = 2*0.0245 = 0.049 (2-sided) (ie, corresponds to critical Z=±1.9660 for a 2-sided 
test). 
 
Figure 3: 
Sample Output for a Group Sequential Design with Interim Analysis 
 
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Prot_001.pdf: 
IND Number: 148185 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
AN ADAPTIVE PHASE 2/3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY ASSESSING EFFICACY AND 
SAFETY OF SARILUMAB FOR HOSPITALIZED PATIENTS WITH 
COVID-19 
Compound: 
REGN88 (sarilumab; Kevzara®) 
Clinical Phase: 
2/3 
Protocol Number: 
6R88-COV-2040 
Protocol Version: 
6R88-COV-2040 Amendment 7 
Amendment 7 Date of Issue: 
See appended electronic signature page 
Amendment 6 Date of Issue: 
16 May 2020 
Amendment 5 Date of Issue: 
09 May 2020 – not implemented 
Amendment 4 Date of Issue: 
06 Apr 2020 
Amendment 3 Date of Issue: 
28 Mar 2020 
Amendment 2 Date of Issue: 
Withdrawn and not implemented 
Amendment 1 Date of Issue: 
19 Mar 2020 
Original Date of Issue: 
15 Mar 2020 
Medical/Study Director: 
 
Senior Director, Early Clinical Development 
and Experimental Sciences 
 
Medical Director Clinical Sciences 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This document contains confidential information that is the property of Regeneron 
Pharmaceuticals, Inc., and must not be disclosed to anyone other than designees of Regeneron for the conduct 
of the study, the recipient clinical Investigator(s) and their designees and members of the Institutional Review 
Board. This information must not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Regeneron Pharmaceuticals, Inc. 
                                        VV-RIM-00114290-1.0 Approved - 11 Jun 2020 GMT-5:00


Clinical Study Protocol 
6R88-COV-2040 Amendment 7 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 
CONFIDENTIAL 
AMENDMENT HISTORY  
Amendment 7 
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale  
Sections Changed 
Based on feedback from the IDMC which noted 
safety concerns, the following changes have been 
made to the protocol: 
• In Phase 3 Cohort 1, only patients 
receiving mechanical ventilation will be 
re-dosed.  
• In Phase 3 Cohort 2, patients will only 
receive study drug while receiving 
mechanical ventilation. 
• In Phase 3 Cohort 3, no additional patients 
will be enrolled and patients on study will 
not be re-dosed. 
All patients will continue to be monitored and 
complete all assessments per protocol.   
Clinical 
Study 
Protocol 
Synopsis: 
Objectives, Study Design, Treatments, 
Endpoints, Statistical Plan 
Section 1 Introduction  
Section 2.1 Primary Objective 
Section 2.2 Secondary Objectives 
Section 3.1 Hypotheses 
Section 3.2.2 Rationale for Study Design 
Adaptation 
Section 3.3 Risk-Benefit for REGN88 
(sarilumab, Kevzara®) 
Section 3.2.4 
Rationale 
for 
Phase 
3 
Cohorts 2 and 3 Dose Selection 
Section 4.1.1 Primary Endpoints 
Table 4 Phase 3 Efficacy Endpoints 
Section 6.1 Study Description and Duration 
Figure 1 Study Flow Diagram for Phase 2 
and Phase 3 
Section 6.2 Planned Timing of Analysis 
Section 7.1 Number of Patients Planned 
Section 7.2.1 Inclusion Criteria #2 
Section 7.2.2 Exclusion Criteria 
Section 8.1 Investigational Treatment 
Section 8.2.1 Dose Modification  
Section 8.4 Method of Treatment 
Assignment 
Table 5 Schedule of Events 
Section 9.2.2.4 Clinical Status Assessment 
(7-Point Ordinal Scale) 
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Clinical Study Protocol 
6R88-COV-2040 Amendment 7 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 3 
CONFIDENTIAL 
Section 9.2.3.5 Laboratory Testing 
Section 11 
Statistical 
Plan 
(including 
subsections) 
Table 8 Testing Strategy for Control of 
Multiplicity in Phase 3 Cohorts 1 and 2 
(Overall Type 1 Error in Each Cohort is 0.05 
[2-sided]) 
                                        VV-RIM-00114290-1.0 Approved - 11 Jun 2020 GMT-5:00


Clinical Study Protocol 
6R88-COV-2040 Amendment 7 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 4 
CONFIDENTIAL 
Amendment 6 
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale  
Sections Changed 
As part of the Phase 3 adaptation and to explore 
whether a higher dose could provide further 
clinical benefit in patients with COVID-19, 
2 additional independently powered cohorts were 
added to evaluate sarilumab 800 mg versus 
placebo in patients on mechanical ventilation at 
baseline (Cohort 2) and in patients not on 
mechanical ventilation but on high-intensity 
oxygen therapy without mechanical ventilation at 
baseline (Cohort 3).   Each Cohort will be analyzed 
separately and efficacy endpoints within each 
Cohort will be tested using a hierarchical testing 
order. 
Clinical 
Study 
Protocol 
Synopsis: 
Objectives, Study Design, Treatments, 
Endpoints, Statistical Plan 
Section 1 Introduction 
Section 2.1 Primary Objective 
Section 3.1 Hypotheses 
Section 3.2.2 Rationale for Study Design 
Adaptation 
Table 3 Summary of Phase 3 Adaptations 
Section 3.2.4 Rationale for Phase 3 Cohorts 
2 and 3 Dose Selection 
Section 4.1.1 Primary Endpoints 
Table 4 Phase 3 Efficacy Endpoints 
Section 6.1 Study Description and Duration 
Figure 1 Study Flow Diagram for Phase 2 
and Phase 3 
Section 6.2 Planned Timing of Analysis 
Section 7.1 Number of Patients Planned 
Section 7.2.1 Inclusion Criteria, #2 
Section 8.1 Investigational Treatment 
Section 8.4 
Method 
of 
Treatment 
Assignment 
Table 5 Schedule of Events 
Section 9.2.2.4 Clinical Status Assessment 
(7-Point Ordinal Scale) 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample Size 
Section 11.3.1 Efficacy Analysis Set 
Section 11.4.3.1 Primary Efficacy Analysis 
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Clinical Study Protocol 
6R88-COV-2040 Amendment 7 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 5 
CONFIDENTIAL 
Section 11.4.3.2 
Secondary 
Efficacy 
Analysis 
Section 11.4.4 Control of Multiplicity 
Table 8 Testing Strategy for Control of 
Multiplicity in Phase 3 Cohorts 1 and 2 
(Overall Type 1 Error is 0.05 [2-sided] in 
Cohort 1, and each stratum of Cohort 2) 
Section 11.5.1 Interim Analysis in Phase 3 
To expedite reporting of key efficacy results, 
changed the key secondary efficacy endpoint of 
Day 60 all-cause mortality to Day 29 all-cause 
mortality. 
Clinical Study Protocol Synopsis: Key 
Secondary Endpoints 
Table 4 Phase 3 Efficacy Endpoints 
Section 4.1.3 Exploratory Endpoints 
Section 11.4.3.2 
Secondary 
Efficacy 
Analysis 
Table 8 Testing Strategy for Control of 
Multiplicity in Phase 3 Cohorts 1 and 2 
(Overall Type 1 Error is 0.05 [2-sided] in 
Cohort 1, and each stratum of Cohort 2) 
Surveillance blood cultures for bacteria and fungi 
should be performed weekly only for patients with 
sustained ANC <1000/µL for >48 hours post-
randomization.  Previously, surveillance blood 
cultures were mandatory at Days 7 and 15 
regardless of ANC. 
Table 5 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of 
Events Table, 16 
Section 9.2.3.5 Laboratory Testing 
Editorial changes made for consistency and clarity 
based on site feedback, and correction of 
typographical errors 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 
Section 11.3.2 Safety Analysis Set 
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Amendment 5 
The following table outlines the changes made to the protocol and the affected sections. 
Change and Rationale  
Sections Changed 
Based on feedback from the IDMC, patients will 
no longer receive sarilumab 200 mg or be eligible 
for repeat dosing of 200 mg, and patients in the 
severe and MSOD strata will no longer receive 
sarilumab 400 mg or placebo.   
Patients will continue to be monitored and 
complete all assessments per protocol.  No new 
safety findings were noted. 
Section 2.1 Primary Objective 
Section 3.2.1 Rationale for Study Design 
Section 3.3 Risk-Benefit for REGN88 
(sarilumab, Kevzara®) 
Section 8.2.1 Dose Modification 
Updated Phase 3 endpoints, sample size, and 
statistical plan based on interim Phase 2 data. 
Section 2.3 Exploratory Objectives 
Section 3.1 Hypotheses 
Section 3.2.4 Rationale for Phase 3 Dose 
Selection 
Section 4.1.1 Primary Endpoints 
Section 4.1.2 Secondary Endpoints 
Section 4.1.2.1 Phase 2 Secondary 
Endpoints 
Section 4.1.2.2 Phase 3 Secondary 
Endpoints 
Table 4 Phase 3 Efficacy Endpoints 
Section 4.1.2.3 Safety Endpoints 
Section 4.1.3 Exploratory Endpoints 
Section 6.2 Planned Timing of Analysis 
Section 7.1 Number of Patients Planned 
Section 11 Statistical Plan 
Section 11.2 Justification of Sample Size 
Section 11.4.5.1 Adverse Events 
Section 11.4.5.3 Treatment Exposure 
Section 11.4.5.4 Treatment Compliance 
Cohort 1 of Phase 3, patients randomized to 
receive sarilumab 400 mg, sarilumab 200 mg, or 
placebo, 
will 
complete 
enrollment 
after 
Section 1 Introduction 
Section 2.1 Primary Objective 
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approximately 170 patients on a ventilator at 
baseline have been randomized in the critical 
stratum.  Cohort 2 of Phase 3, in which patients are 
randomized to receive sarilumab 800 mg or 
placebo, will start enrolling patients upon the 
completion of enrollment in Cohort 1. 
As part of Phase 3 adaptation and to explore 
whether a higher dose could provide further 
clinical benefit in patients with COVID-19, an 
additional cohort (Cohort 2) in 2 strata of patients 
only was added, to evaluate sarilumab 800 mg 
versus placebo in patients on mechanical 
ventilation at baseline and in patients not on 
mechanical ventilation but on high-intensity 
oxygen therapy. 
Section 2.2 Secondary Objectives 
Section 3.1 Hypotheses 
Section 3.2.2 Rationale for Study Design 
Adaptation 
Table 1 Interim Phase 2 Results 
 
 
 
 
 
 
 
 
Table 3 Summary of Phase 3 Adaptations 
Section 3.2.4 Rationale for Phase 3 Cohort 
2 Dose Selection 
Section 4.1.1 Primary Endpoints 
Table 4 Phase 3 Efficacy Endpoints 
Section 6.1 Study Description and Duration 
Section 7.2.1 Inclusion Criteria, #2 
Section 7.2.2 Exclusion Criteria, #11, #12, 
#13, #14 
Section 8.1 Investigational Treatment 
Section 8.4 
Method 
of 
Treatment 
Assignment 
Table 5 Schedule of Events 
Section 11 Statistical Plan 
Section 11.1 Statistical Hypothesis 
Section 11.3.1 Efficacy Analysis Sets 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.3.2 
Secondary 
Efficacy 
Analysis 
Section 11.4.4 Control of Multiplicity 
Table 8 Testing Strategy for Control of 
Multiplicity in Phase 3 Cohorts 1 and 2 
(Overall Type 1 Error is 0.05 [2-Sided] in 
each Cohort) 
Section 11.5.1 Interim Analysis in Phase 3 
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Removed the surveillance blood cultures as there 
is no clinically relevant findings based on the 
Phase 2 database, and this relieves site burden. 
Section 9.1 Schedule of Events 
Section 9.2.3.5 Laboratory Testing 
Editorial changes made for consistency and clarity 
based on site feedback, and correction of 
typographical errors 
Table 5 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of 
Events Table, 1, 3, 5, 6, 7, 16, 17 
Section 9.2.2.4 Clinical Status Assessment 
(7-Point Ordinal Scale) 
Section 9.2.3.5 Laboratory Testing 
Section 10.1.3 
Events 
that 
Require 
Expedited Reporting to Sponsor 
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Amendment 4 
The following table outlines the changes made to the protocol and the affected sections. 
Change and Rationale 
Sections Changed 
Repeat dosing is permitted after 24 hours of dosing 
if no clinical response is observed.  Additionally, 
repeat weekly dosing is permitted for patients 
requiring supplemental O2. 
This change is justified by a favorable safety 
profile to date and the potential of increased 
clearance of the drug in the setting of inflammation 
associated with COVID pneumonia may lead to 
lower than effective exposure.   
Clinical Study Protocol Synopsis: Study 
Design, Treatments  
Section 1 Introduction  
Section 3.2.3 Rationale for Dose Selection 
Section 6.1 Study Description and Duration 
Section 8.1 Investigational Treatment 
Section 8.2.1 Dose Modification 
Section 8.2.2 Study Drug Discontinuation 
Section 9.1 Schedule of Events 
Section 1.1.1 Footnotes for the Schedule of 
Events Table 
Section 11.4.5.4 Treatment Compliance 
Additional patients are being included in Phase 2 
to allow for adequate estimation of the treatment 
effect of the potential Phase 3 clinical endpoint. 
Clinical Study Protocol Synopsis: Sample 
Size, Statistical Plan 
Section 7.1 Number of Patients Planned 
Section 11.2 Justification of Sample Size 
The Sponsor may close enrollment into one or 
more severity categories at any time to ensure 
adequate numbers of patients are enrolled into 
other categories or for other reasons related to 
safety, futility, or new external information. 
Section 6.1 Study Description and Duration 
Removing exclusion for immunocompromised 
patients as the study stratifies for these patients 
Section 7.2.2 Exclusion Criteria 
Updated drug supply of sarilumab to include 
distribution of vials to sites 
Section 8.7.1 Packaging, Labeling, Storage 
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Change and Rationale 
Sections Changed 
Statistical model for primary efficacy analysis was 
changed to reflect the correct dependent variable in 
ANCOVA model 
Clinical Study Protocol Synopsis: Statistical 
Plan  
Section 11.4.3.1 Primary Efficacy Analysis 
Editorial changes made for consistency and clarity 
based on site feedback, and correction of 
typographical errors 
Section 6.1.1.1 Individual Patient Stopping 
Rules 
Section 7.2.1 Inclusion Criteria  
Section 9.2.3.4 Targeted Medication 
Review  
Section 8.5 Blinding  
Section 8.8 Concomitant Medications 
Section 9.1 Schedule of Events 
Section 9.2.3.5 Laboratory Testing 
Section 10.1.2 Reporting Procedure 
Section 11.4.5.1 Adverse Events 
 
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Amendment 3 
The following table outlines the changes made to the protocol and the affected sections. 
Change and Rationale 
Sections Changed 
Changed the primary endpoint in Phase 2 to 
"percent reduction in C-reactive protein (CRP) 
from baseline to Day 4 in patients with baseline 
IL-6 levels > ULN".  Reduced N of patients for 
Phase 2 to a total of approximately 200 patients 
with high IL-6 levels at baseline. 
Clinical Study Protocol Synopsis: Primary 
Endpoint, Secondary Endpoint, Statistical 
Plan 
Section 3.1 Hypotheses 
Section 4.1.1 Primary Endpoint 
Section 4.1.2 Secondary Endpoints 
Section 4.1.3 Exploratory Endpoints 
Section 5.2 Efficacy Variables 
Section 5.5 Pharmacodynamic and Other 
Biomarker Variables 
Section 6.2 Planned Timing of Analysis 
Section 8.5 Blinding 
Section 9.2.3.5 Laboratory Testing 
Section 11.1 Statistical Hypothesis 
Section 11.4.3.1 Primary Efficacy Analysis 
Removed the requirement for documented fever at 
randomization so patients with pneumonia who are 
screened and do not have a fever are still eligible 
for enrollment. 
Section 7.2.1 Inclusion Criteria 
Removed exclusion criteria which previously 
prohibited 
patients 
who 
received 
immunosuppressive therapies from participating in 
this study. These patients are now included at 
request of FDA as this could provide useful 
information on the benefit/risk for this more 
vulnerable population. 
Patients 
who 
are 
receiving 
simultaneous 
leflunomide and methotrexate are still excluded 
due to concerns about hepatotoxicity related to this 
drug combination.  
Section 7.2.1 Inclusion Criteria  
Section 7.2.2 Exclusion Criteria 
Section 8.4 Method of Treatment 
Assignment 
Updated for consistency with IDMC charter 
Section 6.1.1.2 Study Level Stopping Rules 
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Change and Rationale 
Sections Changed 
Limitations in clinical site research staff made it 
challenging to have separate study personnel to not 
have access to clinical laboratory data. 
Section 8.5 Blinding 
• Updated to reflect hospital procedures and 
restrictive infection control measures to 
minimize staff contact with infected patients.   
• Added collection (from patients’ charts) of 
temperatures from patient admission to 
randomization 
Section 9.2.2.2 Body Temperature 
The Schedule of Events table was updated based 
on revised primary endpoint of percent change in 
baseline in CRP for the Phase 2 portion of the 
study.  It was also updated based on site feedback 
regarding the inability to collect research samples 
due to lack of personal protective equipment 
(PPE). 
Duplicative 
assessments 
were 
also 
removed. 
Clinical 
Study 
Protocol 
Synopsis: 
Procedures and Assessments 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 
Added temporal measurement for assessment of 
fever.  Redefined fever thresholds for resolution of 
fever endpoint. 
Clinical Study Protocol Synopsis:  Primary 
Endpoint, Secondary Endpoint, Statistical 
Plan 
Section 4.1.1 Primary Endpoint 
Section 4.1.2 Secondary Endpoints 
Section 9.2.2.2 Body Temperature 
Editorial changes made for consistency and clarity 
based on site feedback  
Section 6.1 Study Description and 
Duration 
Section 7.2.2 Exclusion Criteria 
Section 8.3.1 Acute Intravenous Infusion 
Reactions 
Section 8.4 Method of Treatment 
Assignment  
Section 9.2.2.3 Oxygen Administration and 
Oxygenation  
Section 9.2.2.4 Clinical Status Assessment 
(7-Point Ordinal Scale) 
Section 9.2.2.5 NEWS2 Scoring System  
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Change and Rationale 
Sections Changed 
Section 9.2.3.1 Vital Signs 
Section 9.2.3.3 Electrocardiogram 
Section 11 Statistical Plan 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample Size 
Section 11.4.3 Efficacy Analysis 
Section 11.4.3.1 Primary Efficacy Analysis 
 
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Amendment 2 – withdrawn and not implemented 
Amendment 1 
The following table outlines the changes made to the protocol and the affected sections. 
Change and Rationale 
Sections Changed 
Aligned safety objectives and endpoints with 
adverse events of special interest (AESI) in 
response to Health Authority feedback 
Clinical Study Protocol Synopsis: Study 
Design 
Section 2.2 Secondary Objectives 
Section 4.1.2 Secondary Endpoints 
Aligned exploratory objectives with Section 9.2.5 
in response to Health Authority feedback 
Section 2.3 Exploratory Objectives 
Section 4.1.3 Exploratory Endpoints 
Updated from a 6-point scale to a 7-point scale in 
response to Health Authority feedback such that no 
ordinal categories are collapsed after or during data 
analysis. 
Clinical Study Protocol Synopsis: Primary 
Endpoint, Statistical Plan 
Section 4.1.1 Primary Endpoint 
Section 4.1.2 Secondary Endpoints 
Section 5.2 Efficacy Variables 
Section 9.2.2.3 Clinical Data Collection 
Section 11.4.3.1 Primary Efficacy Analysis 
Clarified that data reviews will include data, 
including deaths, for all enrolled study participants, 
in response to Health Authority feedback 
Section 3.2.1 Rationale for Study Design 
Section 6.2 Planned Timing of Analysis 
Included the safety findings of severe neutropenia 
with sarilumab at the 2 mg/kg IV dose in Study 
6R88-RA-0703 in response to Health Authority 
feedback 
Section 3.2.2 Rationale for Dose Selection 
Section 4.1.2 Secondary Endpoints 
Revised the known potential benefits of sarilumab 
to include a benefit based on data from China and 
the use of IL-6R antagonists for CAR-T 
cell-induced cytokine release syndrome (CRS), in 
response to Health Authority feedback 
Section 3.3 Risk-Benefit for REGN88 
(sarilumab, Kevzara®) 
Nasopharyngeal swab added as an acceptable 
method to collect virus based on emerging 
guidelines for SarsCOV-2 testing. 
Section 4.1.3 Exploratory Endpoints 
Table 1 Schedule of Events 
Section 9.2.3.5 Laboratory Testing 
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Change and Rationale 
Sections Changed 
A specific definition of chronic hypercapnic 
respiratory failure has been added in response to 
Health Authority feedback 
Section 5.1 Demographics and Baseline 
Characteristics 
Updated inclusion criteria to accept a positive PCR 
result within 2 weeks of randomization, a range 
typically associated with the disease, to not exclude 
critical patients as a result of testing delays.  In 
addition, patients develop the severe/critical 
complications of COVID-19 on average during 2nd 
week after symptom onset (and PCR testing 
typically done at that time) and because this is the 
target population for the study, PCR tests conducted 
up to 2 weeks from enrollment will be accepted. A 
sample will be collected at baseline and analyzed to 
confirm infection but will not be used to determine 
study inclusion.   
Section 7.2.1 Inclusion Criteria (#3) 
Patients with a known systemic hypersensitivity to 
sarilumab or the excipients of the drug product are 
excluded from the study, per the protocol template. 
Section 7.2.2 Exclusion Criteria, #11 
The exclusion of patients with a past history of, or 
current, autoimmune or inflammatory systemic or 
localized disease(s) other than rheumatoid arthritis 
was removed as inclusion of these patients does not 
impact safety or efficacy assessments of these 
patients in this study population.   
Section 7.2.2 Exclusion Criteria, #6 
Clarified that patients withdrawn from therapy 
should continue to be assessed for major outcomes 
in response to Health Authority feedback 
Section 7.3 Premature Withdrawal from the 
Study 
Section 9.1.2 Early Termination from the 
Study 
Body temperature will be collected as clinically 
indicated throughout the study in response to 
Health Authority feedback 
Section 9.1 Schedule of Events 
Added Day 1 predose sarilumab concentration 
collection for ADA analysis  
Section 9.1.1 Footnotes for the Schedule of 
Events Table, Footnote 16  
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Change and Rationale 
Sections Changed 
Removed serum sIL-6R sample on Day 1 at 
randomization to reduce site burden 
Section 9.1.1 Footnotes for the Schedule of 
Events Table, Footnote 18 
Clarified that any new infection that occurs on 
study, regardless of organism will be captured, in 
response to Health Authority feedback  
Section 9.2.3.5 Laboratory Testing 
Change made in response to Health Authority 
feedback regarding multiplicity and statistical 
hypothesis. 
Section 11.1 Statistical Hypothesis  
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.4 Control of Multiplicity 
Editorial changes made for consistency, clarity, and 
correction of typographical errors 
Clinical 
Study 
Protocol 
Synopsis: 
Procedures and Assessments, Objectives, 
Secondary 
Endpoints, 
Population, 
Statistical Plan 
Section 4.1.2 Secondary Endpoints 
Section 7.2 Study Population 
Section 7.2.2 Exclusion Criteria (#1, #5, #9, 
and #10) 
Section 8.1 Investigational Treatment  
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of 
Events Table, Footnote 1  
Section 9.2.3.4 Target Medication Review 
Section 9.2.3.5 Laboratory Testing 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count  
ANCOVA 
Analysis of covariance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CDC 
Center for Disease Control 
COVID-19 
Coronavirus Disease 2019 
CMH 
Cochran-Mantel-Haenszel test 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
EDC 
Electronic data capture 
EUA 
Emergency Use Authorization 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDL 
High-density lipoprotein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
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Abbreviation 
Definition 
IL-6 
Interleukin 6 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
mITT 
Modified intention-to-treat 
MSOD 
Multiple System Organ Dysfunction 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NEWS2 
National Early Warning Score2 
OP 
Oropharyngeal 
NP 
Nasopharyngeal 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PPS 
Per Protocol population set 
RA 
Rheumatoid arthritis  
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
sJIA 
Systemic juvenile idiopathic arthritis  
SOC 
System organ class 
SpO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood cell 
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Abbreviation 
Definition 
WHO 
World Health Organization 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................26 
1. 
INTRODUCTION ......................................................................................................36 
2. 
STUDY OBJECTIVES ..............................................................................................41 
2.1. 
Primary Objective .......................................................................................................41 
2.2. 
Secondary Objectives .................................................................................................41 
2.3. 
Exploratory Objectives ...............................................................................................42 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................44 
3.1. 
Hypotheses ..................................................................................................................44 
3.2. 
Rationale .....................................................................................................................44 
3.2.1. 
Rationale for Study Design .........................................................................................44 
3.2.2. 
Rationale for Study Design Adaptation ......................................................................45 
3.2.3. 
Rationale for Phase 2 and Phase 3 Cohort 1 Dose Selection ......................................47 
3.2.4. 
Rationale for Phase 3 Cohorts 2 and 3 Dose Selection ..............................................50 
3.3. 
Risk-Benefit for REGN88 (sarilumab, Kevzara®).....................................................51 
4. 
ENDPOINTS ..............................................................................................................54 
4.1. 
Primary and Secondary Endpoints..............................................................................54 
4.1.1. 
Primary Endpoints ......................................................................................................54 
4.1.2. 
Secondary Endpoints ..................................................................................................54 
4.1.2.1. 
Phase 2 Secondary Endpoints: ....................................................................................55 
4.1.2.2. 
Phase 3 Secondary Endpoints .....................................................................................56 
4.1.2.3. 
Safety Endpoints .........................................................................................................58 
4.1.3. 
Exploratory Endpoints ................................................................................................58 
5. 
STUDY VARIABLES................................................................................................60 
5.1. 
Demographic and Baseline Characteristics ................................................................60 
5.2. 
Efficacy Variables ......................................................................................................60 
5.3. 
Safety Variables ..........................................................................................................60 
5.4. 
Pharmacokinetic Variables .........................................................................................60 
5.5. 
Pharmacodynamic and Other Biomarker Variables ...................................................60 
6. 
STUDY DESIGN .......................................................................................................61 
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6.1. 
Study Description and Duration .................................................................................61 
6.1.1. 
Study Stopping Rules .................................................................................................65 
6.1.1.1. 
Individual Patient Stopping Rules ..............................................................................65 
6.1.1.2. 
Study Level Stopping Rules .......................................................................................65 
6.1.2. 
End of Study Definition ..............................................................................................66 
6.2. 
Planned Timing of Analysis .......................................................................................66 
6.3. 
Study Committees .......................................................................................................66 
6.3.1. 
Independent Data Monitoring Committee ..................................................................66 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............67 
7.1. 
Number of Patients Planned .......................................................................................67 
7.2. 
Study Population .........................................................................................................67 
7.2.1. 
Inclusion Criteria ........................................................................................................67 
7.2.2. 
Exclusion Criteria .......................................................................................................68 
7.3. 
Premature Withdrawal from the Study .......................................................................69 
7.4. 
Replacement of Patients .............................................................................................70 
8. 
STUDY TREATMENTS............................................................................................71 
8.1. 
Investigational Treatment ...........................................................................................71 
8.2. 
Dose Modification and Study Treatment Discontinuation Rules ...............................71 
8.2.1. 
Dose Modification ......................................................................................................71 
8.2.2. 
Study Drug Discontinuation .......................................................................................71 
8.3. 
Management of Acute Reactions ................................................................................71 
8.3.1. 
Acute Intravenous Infusion Reactions ........................................................................71 
8.3.1.1. 
Interruption of the Intravenous Infusion .....................................................................72 
8.3.1.2. 
Termination of the Intravenous Infusion ....................................................................72 
8.4. 
Method of Treatment Assignment ..............................................................................73 
8.5. 
Blinding ......................................................................................................................73 
8.6. 
Emergency Unblinding ...............................................................................................74 
8.7. 
Treatment Logistics and Accountability .....................................................................74 
8.7.1. 
Packaging, Labeling, and Storage ..............................................................................74 
8.7.2. 
Supply and Disposition of Treatments .......................................................................74 
8.7.3. 
Treatment Accountability ...........................................................................................75 
8.7.4. 
Treatment Compliance ................................................................................................75 
8.8. 
Concomitant Medications ...........................................................................................75 
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8.8.1. 
Prohibited and Permitted Medications ........................................................................76 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................77 
9.1. 
Schedule of Events .....................................................................................................77 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................81 
9.1.2. 
Early Termination from the Study ..............................................................................83 
9.2. 
Study Procedures ........................................................................................................83 
9.2.1. 
Procedures Performed Only at the Screening/Baseline ..............................................83 
9.2.2. 
Efficacy Procedures ....................................................................................................83 
9.2.2.1. 
C-Reactive Protein ......................................................................................................83 
9.2.2.2. 
Body Temperature ......................................................................................................83 
9.2.2.3. 
Oxygen Administration and Oxygenation ..................................................................83 
9.2.2.4. 
Clinical Status Assessment (7-Point Ordinal Scale) ...................................................84 
9.2.2.5. 
NEWS2 Scoring System .............................................................................................84 
9.2.3. 
Safety Procedures .......................................................................................................86 
9.2.3.1. 
Vital Signs ..................................................................................................................86 
9.2.3.2. 
Limited Physical Examination ....................................................................................86 
9.2.3.3. 
Electrocardiogram .......................................................................................................86 
9.2.3.4. 
Targeted Medication Review ......................................................................................86 
9.2.3.5. 
Laboratory Testing ......................................................................................................87 
9.2.4. 
Drug Concentration and Measurements .....................................................................88 
9.2.5. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................89 
 
 
10. 
SAFETY EVALUATION AND REPORTING .........................................................90 
10.1. 
Recording and Reporting Adverse Events ..................................................................90 
10.1.1. 
General Guidelines .....................................................................................................90 
10.1.2. 
Reporting Procedure ...................................................................................................91 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................91 
10.2. 
Definitions ..................................................................................................................92 
10.2.1. 
Adverse Event .............................................................................................................92 
10.2.2. 
Serious Adverse Event ................................................................................................92 
10.2.3. 
Adverse Events of Special Interest .............................................................................92 
10.2.4. 
Infusion Reactions ......................................................................................................93 
10.2.5. 
Severity .......................................................................................................................93 
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10.2.6. 
Causality .....................................................................................................................93 
10.3. 
Safety Monitoring .......................................................................................................94 
10.4. 
Notifying Health Authorities, Institutional Review Board, and Investigators ...........95 
11. 
STATISTICAL PLAN................................................................................................96 
11.1. 
Statistical Hypothesis ..................................................................................................96 
11.2. 
Justification of Sample Size........................................................................................98 
11.3. 
Analysis Sets ...............................................................................................................99 
11.3.1. 
Efficacy Analysis Sets ................................................................................................99 
11.3.2. 
Safety Analysis Set ...................................................................................................100 
11.3.3. 
Pharmacokinetic Analysis Sets .................................................................................100 
11.4. 
Statistical Methods ....................................................................................................100 
11.4.1. 
Patient Disposition ....................................................................................................100 
11.4.2. 
Demography and Baseline Characteristics ...............................................................101 
11.4.3. 
Efficacy Analyses .....................................................................................................101 
11.4.3.1. 
Primary Efficacy Analysis ........................................................................................101 
11.4.3.2. 
Secondary Efficacy Analysis ....................................................................................102 
11.4.4. 
Control of Multiplicity ..............................................................................................104 
11.4.5. 
Safety Analysis .........................................................................................................106 
11.4.5.1. 
Adverse Events .........................................................................................................106 
11.4.5.2. 
Other Safety ..............................................................................................................107 
11.4.5.3. 
Treatment Exposure ..................................................................................................107 
11.4.5.4. 
Treatment Compliance ..............................................................................................107 
11.4.6. 
Pharmacokinetics ......................................................................................................107 
11.4.6.1. 
Analysis of Drug Concentration Data .......................................................................107 
11.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ............................107 
11.5. 
Timing of Analysis ...................................................................................................107 
11.5.1. 
Interim Analysis in Phase 3 ......................................................................................108 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .......108 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................109 
12.1. 
Data Management and Electronic Systems ..............................................................109 
12.1.1. 
Data Management .....................................................................................................109 
12.1.2. 
Electronic Systems ....................................................................................................109 
12.2. 
Study Monitoring ......................................................................................................109 
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12.2.1. 
Monitoring of Study Sites .........................................................................................109 
12.2.2. 
Source Document Requirements ..............................................................................110 
12.2.3. 
Case Report Form Requirements ..............................................................................110 
12.3. 
Audits and Inspections ..............................................................................................110 
12.4. 
Study Documentation ...............................................................................................111 
12.4.1. 
Certification of Accuracy of Data .............................................................................111 
12.4.2. 
Retention of Records ................................................................................................111 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................112 
13.1. 
Good Clinical Practice Statement .............................................................................112 
13.2. 
Informed Consent .....................................................................................................112 
13.3. 
Patients Confidentiality and Data Protection ............................................................112 
13.4. 
Institutional Review Board .......................................................................................113 
13.5. 
Clinical Study Data Transparency ............................................................................113 
14. 
PROTOCOL AMENDMENTS ................................................................................114 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................115 
15.1. 
Premature Termination of the Study .........................................................................115 
15.2. 
Close-out of a Site ....................................................................................................115 
16. 
CONFIDENTIALITY ..............................................................................................115 
17. 
FINANCING AND INSURANCE ...........................................................................115 
18. 
PUBLICATION POLICY ........................................................................................115 
19. 
REFERENCES .........................................................................................................116 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................119 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................120 
 
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LIST OF TABLES 
Table 1: 
Interim Phase 2 Results ..............................................................................................45 
 
 
 
Table 3: 
Summary of Phase 3 Adaptations ...............................................................................46 
Table 4: 
Phase 3 Efficacy Endpoints ........................................................................................57 
Table 5: 
Schedule of Events .....................................................................................................78 
Table 6: 
The NEWS2 Scoring System ......................................................................................85 
Table 7: 
Grading System for Adverse Events Not Listed in NCI-CTCAE ..............................93 
Table 8: 
Testing Strategy for Control of Multiplicity in Phase 3 Cohorts 1 and 2 
(Overall Type 1 Error in Each Cohort is 0.05 [2-sided]) ..........................................105 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram for Phase 2 and Phase 3 ............................................................64 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-Controlled 
Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients 
with COVID-19 
Site Locations 
 
Principal Investigator 
United States 
A PI will be identified for this study.  
Objectives 
Primary Objective 
Phase 2:  
The primary objective of the study is to evaluate the clinical efficacy of 
sarilumab relative to the control arm in adult patients hospitalized with 
COVID-19 regardless of severity strata. 
Phase 3:  
Cohort 1 
The primary objective of the study is to evaluate the clinical efficacy of 
sarilumab 400 mg relative to the control arm in adult patients hospitalized 
with critical COVID-19 receiving mechanical ventilation at baseline. 
Cohort 2 
The primary objective of the study is to evaluate the clinical efficacy of 
sarilumab 800 mg relative to the control arm in adult patients hospitalized 
with COVID-19 receiving mechanical ventilation at baseline 
Secondary Objectives 
Phase 2: 
The secondary efficacy objectives for the Phase 2 portion of the study are to: 
1. Evaluate the clinical efficacy of sarilumab compared to the control 
arm in all disease severity levels and by clinical severity 
2. Evaluate the clinical efficacy of sarilumab compared to the control 
arm by baseline IL-6 level 
3. Evaluate changes in the National Early Warning Score 2 (NEWS2) 
4. Evaluate the duration of predefined symptoms and signs 
(if applicable) 
5. Evaluate the duration of supplemental oxygen dependency 
(if applicable) 
6. Evaluate the incidence of new mechanical ventilation use during the 
study 
7. Evaluate the duration of new mechanical ventilation use during the 
study 
8. Evaluate need for admission into intensive care unit (ICU) 
9. Evaluate duration of hospitalization (days) 
10. Evaluate the 28-day mortality rate 
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Phase 3 
The secondary efficacy objectives for the Phase 3 portion of the study are 
to: 
Phase 3 Cohort 1:  
• 
Determine whether sarilumab improves respiratory outcomes in 
patients with critical COVID-19 
• 
Determine whether sarilumab reduces mortality in patients with 
critical COVID-19 
• 
Determine whether sarilumab shortens hospitalization in patients 
with critical COVID-19 
Phase 3 Cohort 2:  
• 
Determine whether sarilumab improves respiratory outcomes in 
patients with COVID-19 receiving mechanical ventilation 
• 
Determine whether sarilumab reduces mortality in patients with 
COVID-19 receiving mechanical ventilation 
• 
Determine whether sarilumab shortens hospitalization in patients 
with COVID-19 receiving mechanical ventilation 
 
 
Safety (Phase 2 and 3) 
The secondary safety objectives of the study are to evaluate the safety of 
sarilumab through hospitalization (up to Day 29 if patient is still hospitalized) 
compared to the control arm as assessed by incidence of: 
• 
Serious adverse events (SAEs) 
• 
Grade 4 neutropenia (ANC<500/mm3) 
• 
Grade 4 neutropenia (ANC<500/mm3) with concurrent severe or 
life-threatening bacterial, invasive fungal, or opportunistic infection 
• 
Grade ≥2 infusion-related reactions 
• 
Grade ≥2 hypersensitivity reactions 
• 
Increase 
in 
alanine 
transaminase 
(ALT) 
or 
aspartate 
aminotransferase (AST) ≥3X ULN (for patients with normal 
baseline) or >3X ULN AND at least 2-fold increase from baseline 
value (for patients with abnormal baseline) 
• 
Invasive bacterial or fungal infections of clinical significance with 
confirmed diagnosis based on the investigator’s assessment with 
appropriate diagnostic workups and consultations 
Study Design 
This study is an adaptive Phase 2/3, randomized, double-blind, 
placebo-controlled trial to evaluate the efficacy and safety of sarilumab in 
hospitalized adults with COVID-19.  The study will be conducted in the 
United States (US) in up to 150 sites.  As part of the Phase 3 adaptation plan, 
the Phase 3 portion of the study will include 3 cohorts. In Phase 2 and in 
Cohort 1 of the Phase 3 portion of the study, patients will be randomized in 
a 2:2:1 allocation ratio to sarilumab 400 mg IV, sarilumab 200 mg IV, or 
placebo in a stratified manner up to 26 Apr 2020.  As of 27 Apr 2020 (as per 
recommendation of the IDMC), patients will be randomized to sarilumab 
400 mg or placebo only in the critical stratum in a 2:1 manner.  Enrollment 
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into Cohort 1 closed when approximately 170 patients in the critical stratum 
receiving mechanical ventilation at baseline who were randomized to receive 
either sarilumab 400 mg or placebo were enrolled.  In Cohort 2, patients 
receiving mechanical ventilation at baseline will be randomized 1:1 to 
receive sarilumab 800 mg IV or placebo.  In the Phase 3 portion of the study, 
Cohorts 2 and 3 began enrolling patients in parallel when Cohort 1 
enrollment completed.  Following safety concerns raised by the Independent 
Data Monitoring Committee (IDMC), the Sponsor determined that the 
benefit/risk assessment was not favorable in patients who were not receiving 
mechanical ventilation. Based on this assessment, as of 06 Jun 2020, patients 
in Cohort 3 will no longer receive study drug. In addition, new patients will 
no longer be enrolled into Cohort 3. 
All patients will continue to be monitored and complete all assessments per 
protocol.    
Patients receiving mechanical ventilation will receive a single dose of study 
drug on Day 1.  In Phase 3 Cohorts 1 and 2, patients will be re-dosed on 
Day  2 if the patient is receiving mechanical ventilation and meets 1 of the 
following criteria: 
1. Remains febrile OR 
2. Fails to improve gas exchange (eg, as measured by ventilator settings 
or O2 requirements) OR 
3. Is hemodynamically unstable OR 
4. Exhibits other objective evidence of clinical worsening (eg, mental 
status change, etc) 
Additional doses will be administered weekly only for patients receiving 
mechanical ventilation at the time of re-dosing and whose ANC is >500/mm3 
and ALT is ≤5x ULN. For Cohort 1, a maximum of 6 doses of study drug in 
total can be administered during the study. For Cohort 2, a maximum of 
4 doses of study drug can be administered during the study.  There is no 
dosing after Day 21 in Cohort 2.  Throughout the study, study drug should 
be withheld if there is a high degree of suspicion of active bacterial or fungal 
infection.  Patients who receive a prohibited medication will not be eligible 
for re-dosing.  
Study Duration 
An individual patient will complete the study approximately 60 days from 
screening to follow-up on Day 60 ±7 days.  Patients will not be required to 
return to the hospital once discharged.   
End of Study Definition 
The end of study is defined as the date the last patient completes the last study 
assessment (in the hospital or via a follow-up phone call if the patient was 
discharged from the hospital before Day 60), withdraws from the study, or is 
lost to follow-up (ie, the study patient can no longer be contacted by the 
investigator).  
Population 
 
 
Target Population: 
Hospitalized adult (≥18 years old) male and female patients with COVID-19. 
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Sample Size: 
Total sample size for Phase 2 is expected to be approximately 460 to include 
patients with all baseline IL-6 levels.  Based on results from Phase 2 data, 
sample size for Phase 3 was re-calculated.  For Cohort 1 of the Phase 3 
portion of this study, the total sample size will be approximately 
1,400 patients.  Enrollment into Cohort 1 closed when approximately 
170 patients in the critical stratum receiving mechanical ventilation at 
baseline who were randomized to receive either sarilumab 400 mg or placebo 
were enrolled.  The total sample sizes for Cohort 2 will be approximately 
225 patients. The planned sample size for Cohort 3 was 225 patients, 
however, enrollment ended on 06 Jun 2020 at which time 9 patients enrolled.  
Cohorts 2 and 3 enrolled in parallel when Cohort 1 enrollment completed.   
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
REGN88 (sarilumab; Kevzara®) or placebo 
200 mg IV or 400 mg IV at single or multiple doses (Phase 2 and Phase 3 
Cohort 1) 
800 mg IV at single or multiple doses (Phase 3 Cohorts 2 and 3) 
Endpoints 
Note that for the primary and secondary endpoints, patients will not be 
required to return to the hospital once discharged.  A follow-up phone call 
will occur on Days 29 and/or 60, depending on when the patient is 
discharged.  All patients will be contacted for an end of study (EOS) 
follow-up at Day 60. 
 
Primary: 
Phase 2: 
The primary endpoint is the percent change from baseline in C-reactive 
protein (CRP) levels at Day 4 in patients with serum IL-6 levels greater than 
the upper limit of normal. 
Phase 3 Cohort 1: 
Proportion of patients with at least a 1-point improvement in clinical status 
from baseline to Day 22 using the 7-point ordinal scale in patients with 
critical COVID-19 receiving mechanical ventilation at baseline 
Phase 3 Cohort 2: 
Proportion of patients with at least a 1-point improvement in clinical status 
from baseline to Day 22 using the 7-point ordinal scale in patients with 
COVID-19 receiving mechanical ventilation at baseline   
Separate analyses of Cohorts 1 and 2 are planned. 
 
Secondary: 
The 7-point ordinal scale will be assessed as a secondary endpoint in Phase 2 
and will be used for both Primary and Secondary endpoints in Phase 3.  The 
ordinal scale is an assessment of the clinical status.  The scale is as follows:  
• 
Death;  
• 
Hospitalized, requiring invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO);  
• 
Hospitalized, requiring non-invasive ventilation or high flow 
oxygen devices;  
• 
Hospitalized, requiring supplemental oxygen; 
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• 
Hospitalized, not requiring supplemental oxygen – requiring 
ongoing medical care (COVID-19 related or otherwise) 
• 
Hospitalized, not requiring supplemental oxygen – no longer 
requires ongoing medical care 
• 
Not hospitalized 
Phase 2: 
Key Secondary Efficacy Endpoint 
1. Time to improvement (2 points) in clinical status assessment from 
baseline on the 7-point ordinal scale in severe or critical patients 
with serum IL-6 level greater than the upper limit of normal 
2. Time to improvement (2 points) in clinical status assessment from 
baseline on the 7-point ordinal scale reporting in severe or critical 
patients with all IL-6 levels 
Other Secondary Endpoints: 
Efficacy 
1. Time to resolution of fever for at least 48 hours without 
antipyretics or until discharge, whichever is sooner, in patients 
with documented fever ≥38°C (oral), ≥38.4°C (rectal or tympanic), 
or ≥37.6°C (temporal or axillary) at Baseline   
(Resolution of fever is defined as postbaseline body temperature 
<37.2°C (oral), or <37.6°C (rectal or tympanic) or <36.8°C 
(temporal or axillary). 
2. Time to resolution of fever (defined as above) for at least 48 hours 
without antipyretics or until discharge, whichever is sooner, in 
patients defined as above, by clinical severity 
3. Time to resolution of fever (defined as above) for at least 48 hours 
without antipyretics or until discharge, whichever is sooner, in 
patients defined as above, by baseline IL-6 levels 
4. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 
or greater compared to the nadir SpO2/FiO2) for at least 48 hours 
or until discharge, whichever is sooner 
5. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 
or greater compared to the nadir SpO2/FiO2) for at least 48 hours 
or until discharge, whichever is sooner, by clinical severity 
6. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 
or greater compared to the nadir SpO2/FiO2) for at least 48 hours 
or until discharge, whichever is sooner, by baseline IL-6 level 
7. Time to resolution of fever (as defined above) and improvement in 
oxygenation (as defined above) 
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8. Mean change in the 7-point ordinal scale from baseline to Days 3, 
5, 8, 11, 15, and 29 (or until discharge) 
9. Percentage of patients in each clinical status category using the 
7-point ordinal scale at Days 3, 5, 8, 11, 15, and 29 
10. Time to discharge or to a NEWS2 of ≤2 and maintained for 
24 hours, whichever occurs first 
11. Change from baseline to Days 3, 5, 8, 11, 15, and 29 in NEWS2 
12. Days with fever (≥38°C °C [oral], ≥38.4°C [rectal or tympanic], or 
≥37.6°C [temporal or axillary])  
13. Proportion of patients alive, off oxygen at Day 29 
14. Days of resting respiratory rate >24 breaths/min (recorded at least 
once each day)  
15. Days of hypoxemia (SpO2 ≤93% on room air, or requiring 
supplemental oxygen, or mechanical ventilatory support)  
16. Days of supplemental oxygen use  
17. Time to saturation ≥94% on room air 
18. Ventilator free days in the first 28 days (to Day 29) 
19. Initiation of mechanical ventilation, non-invasive ventilation, or 
use of high flow nasal cannula (for those not requiring these 
interventions at baseline)  
20. Admission into an ICU (among those not in an ICU at baseline) 
21. Days of hospitalization among survivors  
22. All-cause mortality 
Phase 3: 
Key Secondary Efficacy Endpoints 
Cohort 1 
1. Proportion of patients with at least 1-point improvement in clinical 
status assessment from baseline to Day 22 in patients with critical 
COVID-19  
2. Proportion of patients who recover (discharged, or alive without 
supplemental oxygen use or at pre-COVID oxygen use) by Day 22 
in patients with critical COVID-19 receiving mechanical 
ventilation at baseline 
3. Proportion of patients who die through Day 29 in patients with 
critical COVID-19 receiving mechanical ventilation at baseline 
4. Proportion of patients who die through Day 29 in patients with 
critical COVID-19  
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Cohort 2  
1. Proportion of patients who recover (discharged, or alive without 
supplemental oxygen use or at pre-COVID oxygen use) by Day 22 
in patients with COVID-19 receiving mechanical ventilation at 
baseline 
2. Proportion of patients who die through Day 29 in patients with 
COVID-19 receiving mechanical ventilation at baseline 
Other Phase 3 Secondary Endpoints: 
Cohort 1 
1. Proportion of patients who recover (discharged, alive without 
supplemental oxygen use, or at pre-COVID oxygen use) by Day 22 
in the critical ITT population 
2. Proportion of patients who die through Day 29 in the critical ITT 
population 
3. Proportion of patients alive not receiving mechanical ventilation or 
ECMO at Day 22 in the critical ITT population and in patients 
receiving mechanical ventilation at baseline 
4. Proportion of patients with a 2-point improvement in clinical status 
on the 7-point ordinal scale from baseline to Day 22 in the critical 
ITT population and in patients receiving mechanical ventilation at 
baseline 
5. Time to at least 1-point improvement in clinical status assessment 
from baseline on the 7-point ordinal scale in the critical ITT 
population and in patients receiving mechanical ventilation at 
baseline 
6. Time to at least a 2-point improvement in clinical status assessment 
from baseline on the 7-point ordinal scale in the critical ITT 
population and in patients receiving mechanical ventilation at 
baseline 
7. Proportion of patients receiving mechanical ventilation or ECMO at 
Day 22 in the critical ITT population and in patients receiving 
mechanical ventilation at baseline 
8. Proportion of patients discharged and alive at Day 22 in the critical 
ITT population and in patients receiving mechanical ventilation at 
baseline 
9. Time to recovery (discharged, or alive without supplemental 
oxygen use or at pre-COVID oxygen use) in the critical ITT 
population and in patients receiving mechanical ventilation at 
baseline 
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10. Time to death (all-cause mortality) in the critical ITT population 
and in patients receiving mechanical ventilation at baseline 
11. Number of ventilator free days between baseline and Day 8, 15, 22, 
and 29 in the critical ITT population and in patients receiving 
mechanical ventilation at baseline 
12. Number of days of hospitalization among survivors up to Day 8, 15, 
22, and 29 in the critical ITT population and in patients receiving 
mechanical ventilation at baseline  
Cohort 2   
1. Proportion of patients alive not receiving mechanical ventilation or 
ECMO at Day 22  
2. Proportion of patients with a 2-point improvement in clinical status 
on the 7-point ordinal scale from baseline to Day 22  
3. Time to at a least 1-point improvement in clinical status assessment 
from baseline on the 7-point ordinal scale 
4. Time to at least 2-point improvement in clinical status assessment 
from baseline on the 7-point ordinal scale   
5. Proportion of patients receiving mechanical ventilation or ECMO at 
Day 22  
6. Proportion of patients discharged and alive at Day 22  
7. Time to recovery (discharged, or alive without supplemental 
oxygen use or at pre-COVID oxygen use)  
8. Proportion of patients who die through Day 60 
9. Time to death (all-cause mortality)  
10. Number of ventilator free days between baseline and Day 8, 15, 22, 
and 29  
11. Number of days of hospitalization among survivors up to Day 8, 15, 
22, and 29  
Safety 
The secondary safety endpoints for Phase 2 and 3 are: 
1. Incidence of serious adverse events 
2. Incidence of Grade 4 neutropenia (ANC <500/mm3) 
3. The incidence of severe or life-threatening bacterial, invasive 
fungal, or opportunistic infection 
4. The incidence of severe or life-threatening bacterial, invasive 
fungal, or opportunistic infection in patients with Grade 4 
neutropenia (ANC<500/mm3) 
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5. Proportion of patients with hypersensitivity reactions 
6. Proportion of patients with infusion reactions 
7. Proportion of patients with gastrointestinal perforation 
8. White cell count, hemoglobin, platelets, creatinine, total bilirubin, 
ALT, AST, on Days 1, 4, 5, 8, 11, 15 and 29 (if still hospitalized) 
Procedures and Assessments 
Efficacy procedures and assessments include serum CRP measurement, body 
temperature, oxygen administration (FiO2) and oxygenation (SpO2) clinical 
data assessment, National Early Warning Score2 (NEWS2), and 
biospecimens for biomarker analysis and virology. 
Safety procedures and assessments include laboratory testing, vital signs, 
limited physical examination, and targeted medication review. 
Statistical Plan 
For the Phase 2 portion of the study, a total of approximately 460 patients 
were planned to be randomized (2:2:1) to sarilumab 400 mg IV, sarilumab 
200 mg IV or placebo. This sample size was estimated to provide at least 
90% power to detect a treatment effect in the Phase 2 endpoint of reduction 
in CRP levels as well as allow adequate estimation and improve precision for 
selection of Phase 3 efficacy endpoints. 
The study analysis plan for Phase 2 is based on the analysis of 2 populations; 
modified intention-to-treat (mITT) population defined as randomized and 
treated patients with high baseline IL-6 levels (>ULN) and intention-to-treat 
(ITT) population defined as all randomized and treated patients.  For Phase 3 
portion of the study the primary analysis population for efficacy will be the 
ITT population, unless otherwise specified. Supportive analyses in Phase 3 
may also be performed using the per protocol set (PPS) population. 
For the Phase 2 portion of the study, the primary efficacy analysis will be a 
pairwise comparison between sarilumab 400 mg IV and placebo with respect 
to percent change from baseline in CRP levels at Day 4, in patients with 
COVID-19 disease. Missing values of CRP levels at Day 4 will be imputed 
by Day 3 or Day 5 levels when available, in this order of priority.  Hypothesis 
test of superiority of sarilumab versus placebo will be done using an analysis 
of covariance (ANCOVA) model with treatment group, severity of illness 
and systemic corticosteroid use as fixed effects, and baseline log(CRP) as a 
covariate.  Treatment effect will be reported as difference in mean percent 
change from baseline in CRP levels at Day 4.  P-values will be compared to 
0.05 (2-sided) level of significance and 95% confidence levels reported. 
The data lock point for the first interim analysis of the Phase 2 portion of the 
study was set at 15 days after the last of the approximately 460 patients in 
Phase 2 had been randomized.  These data were used to determine the 
adaptations and analysis plan for the Phase 3 portion of this adaptive 
Phase 2/3 study.  Based on the Phase 2 interim results, the sample size for 
Phase 3 was recalculated using the chosen Phase 3 endpoint of the proportion 
of patients with at least 1-point improvement in clinical status on the ordinal 
scale in patients in the critical stratum who were on mechanical ventilation.  
In the Phase 3 Cohort 1, approximately 450 patients in critical stratum are 
planned to be enrolled in order to have approximately 170 critical patients 
who are on mechanical and randomized to receive either sarilumab 400 mg 
or placebo (sarilumab 400 mg n=113 and placebo n=57).  This sample size 
would provide >99% power to detect a treatment difference of 40% in 
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sarilumab 400 mg compared to placebo (difference assumed to be similar to 
that observed in Phase 2).   
Additional adaptations were made to Phase 3 to enroll 2 new cohorts in Phase 
3 randomized 1:1 to sarilumab 800 mg or placebo.  Cohort 2 will enroll 
patients being treated with using mechanical ventilation.  In Cohort 2, a total 
of 225 patients will be enrolled.  This sample size is estimated to provide at 
least 92% (>99%) power in patients receiving ventilation at baseline to detect 
a treatment difference of 20% (40%) between sarilumab 800 mg and placebo 
in Cohort 2.    Sample size re-estimation may occur after Phase 3 Cohort 1 
results are determined. 
The primary hypotheses are to test the superiority of sarilumab 400 mg IV to 
placebo in Cohort 1 critical patients with mechanical ventilation at baseline 
and to test the superiority of sarilumab 800 mg IV to placebo in Cohort 2, 
with respect to the final primary endpoint of proportion of patients with at 
least 1-point improvement in clinical status on the ordinal scale at Day 22.  
Interim analysis for the Cohort 1 primary analysis populations will be based 
on analysis of all patients enrolled up to the date when approximately 
110 patients have been enrolled on mechanical ventilation at baseline who 
are randomized to 400 mg or placebo, with a data lock point 22 days later.  
The interim analyses will provide for hypothesis testing for the primary 
endpoint at α=0.005 (2-sided) and the final analysis with data after 
approximately 170 patients in Cohort 1 on mechanical ventilation at baseline 
reach Day 22 will be tested at α=0.049 (2-sided).  Similar interim analyses 
are planned for Cohort 2 .  Primary endpoint for each comparison will be 
proportion of patients with a 1-point improvement in clinical status from 
baseline to Day 22 using the 7-point ordinal scale.  Hypothesis tests of 
superiority of sarilumab (400 or 800 mg dose) versus placebo will be done 
using the stratified Cochran-Mantel-Haenszel (CMH) test for differences in 
2 proportions using stratification factors at randomization.  Estimation of the 
treatment effect will be provided as differences in proportions and confidence 
intervals calculated using the strata-adjusted CMH method.  
Key secondary endpoints will be analyzed similarly as the primary endpoint 
and testing of key secondary endpoints will be done in a hierarchical order 
while preserving the overall Type 1 error rate at 0.05 (2-sided) level. 
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1. 
INTRODUCTION 
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel enveloped RNA 
betacoronavirus that emerged in December 2019 in Wuhan, China. The term COVID-19 is the 
disease caused by SARS-CoV-2 with symptoms that manifest a median of 5 days and up to 14 days 
after infection. The most frequent clinical presentation of severe COVID-19 is pneumonia with 
symptoms including fever, cough, and dyspnea. Although fever and cough are the most common 
presenting symptoms of COVID-19, not all patients with pneumonia present with fever (43%) on 
admission to the hospital, although the majority will develop fever later in their hospital course. In 
a report from the Chinese Center for Disease Control and Prevention that included 
44,500 confirmed infections, the majority of infections (80%) are mild (with no or mild 
pneumonia), 14% were severe (defined as dyspnea, hypoxia or >50% lung involvement on 
imaging) and 5% were critical (respiratory failure, shock, or multiorgan failure) (Wu, 2020). 
Approximately 20% to 30% of hospitalized patients with COVID-19 and pneumonia have required 
intensive care for respiratory support (Chen, 2020)(Huang, 2020). In patients with COVID-19, the 
most common laboratory abnormalities in the peripheral white blood cell counts include 
lymphopenia (63%), leukocytosis (24-30%) and leukopenia (9-25%). Procalcitonin serum levels 
are generally not elevated in COVID-19 and were <0.5 in 95% of patients in one study. However, 
COVID-19 is associated with increases in C-reactive protein (CRP) and CRP levels appears to 
track disease severity and outcome. In one study of 150 patients with COVID-19 in China, patients 
who died had a significantly higher serum level of CRP (126.6 vs 34.1 mg/L). The overall case 
fatality rates can range from 1.0% to 3% with the majority of fatal cases occurring in critically ill 
patients with advanced age or underlying medical conditions (Guan, 2020)(Young, 2020).  
Patients with COVID-19 infection are at risk for the development of pneumonia and the acute 
respiratory distress syndrome (ARDS). Acute respiratory distress syndrome is a clinical syndrome 
of severe impairment of gas exchange due to widespread alveolar epithelial cell and pulmonary 
capillary endothelial injury resulting from a variety of etiologies, including respiratory viral 
infections. Clinically, ARDS presents with severe hypoxemia (PaO2/FiO2 ratio <300 mm Hg) 
evolving over days to a week in combination with bilateral pulmonary infiltrates on chest X-ray 
(or other lung imaging) not entirely attributable to elevated pulmonary venous pressure (ie, heart 
failure or fluid overload). ARDS carries a high mortality rate, ranging from 27% for “mild” ARDS 
to 45% for severe ARDS (defined as a PaO2/FiO2 ratio <100 mm Hg). ARDS is a common 
complication of severe viral pneumonia, including pneumonia due to highly pathogenic 
coronaviruses. In one report of 1,099 patients hospitalized with COVID-19, ARDS was reported 
to occur in 15.6% of patients with severe pneumonia. In a smaller case series of 138 hospitalized 
patients, ARDS occurred in 19.6% of patients and in 61.1% of patients admitted to an intensive 
care unit (ICU).  
There are currently no specific treatments for COVID-19. Clinical management of hospitalized 
patients with COVID-19 includes supportive therapy: supplemental oxygen therapy to target SpO2, 
empiric antimicrobials, empiric neuraminidase inhibitor for treatment of influenza when there is 
local circulation and intensive care as required. The routine use of systemic corticosteroids is not 
recommended by the World Health Organization (WHO) for the treatment of COVID-19 
pneumonia or ARDS, although, in practice, corticosteroids are reported to be used in patients with 
severe COVID-19 (WHO, 2020a). The median duration of hospitalization for mild cases is 12 to 
14 days and approximately 3 to 6 weeks for patients with more severe disease (WHO, 2020b). The 
decision to discharge patients from a hospital or to discontinue transmission-based precautions is 
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made on a case-by-case basis but the Center for Disease Control (CDC) recommends waiting until 
there is resolution of fever without use of antipyretic medication, improvements in illness signs 
and symptoms and negative results of COVID-19 PCR from 2 consecutive sets of nasopharyngeal 
and throat swab specimens collected >24 hours apart (Centers for Disease Control and Prevention 
(CDC), 2020).  Among patients who have died, the time from onset of symptoms to death ranges 
from 2 to 8 weeks. 
Data on progression of disease in hospitalized patients are available from a limited number of 
hospitalized cases. In one report describing 1,099 COVID-19 patients in China, approximately 5% 
were admitted to the ICU, 2.3% underwent invasive mechanical ventilation and 1.4% died. Among 
patients with severe disease on admission (defined as pneumonia, hypoxemia and tachypnea), 19% 
were admitted to the ICU, 38.7% underwent invasive or non-invasive mechanical ventilation, and 
8.1% died (Guan, 2020). 
Triggers for severe illness with SARS-CoV-2 are not completely understood. The initial 
inflammatory responses to an infection are rapid and non-specific and regulated by inflammatory 
mediators including cytokines such as interleukin-6 (IL-6). IL-6 is a chief mediator in the early 
response to infection including fever (Gabay, 1999). However, IL-6 has been implicated in many 
pathogenic inflammatory states including the cytokine storm following infection with avian 
influenza A H5N1, SARS and MERS-CoV infection (de Jong, 2006) (Huang, 2005) (Zhang, 
2004). Although the consequences of IL-6 production has been associated with both pro-
inflammatory and anti-inflammatory effects, in the setting of infections, IL-6 is an important 
mediator of fever induction (Evans, 2015). The pyrogenic role of IL-6 was delineated in patients 
receiving T cell based-immunotherapy (specifically, chimeric antigen receptor-expressing T cells 
or a CD19/CD3-bispecific antibody) where treatment with the IL-6 receptor antagonist, 
tocilizumab, quickly reversed the high fevers and other symptoms that developed as part of a 
cytokine release syndrome (CRS) over several days (Teachey, 2013). 
While the majority of patients with COVID-19 have mild infection despite having pneumonia, 
approximately 20% of patients develop severe disease. Of note, like MERS-COV, in patients with 
severe COVID-19, the onset of dyspnea, fever and progressive hypoxia can occur late, often during 
the second week after onset of symptoms suggesting a late pro-inflammatory process associated 
with the deterioration. For example, in one report, while only 43% of patients had fever on hospital 
admission, 88% of patients developed fever during hospitalization (Guan, 2020). In another report, 
dyspnea occurred 8 days (IQR: 5 to 13 days) after onset of symptoms, and ARDS occurred 9 days 
after onset of symptoms (IQR: 8 to 14 days). The delayed pro-inflammatory clinical presentation 
of COVID-19 is similar to what has been shown in primary lung epithelial cells infected with 
MERS-CoV where induction of IL-6 and IL-1b occurs late (30 hours after infection) (Lau, 2013) 
(Margulis, 2015). Interestingly, MERS-CoV patients who had severe infection, defined as need 
for oxygen supplementation, had higher IL-6 levels (median 54 pg/mL; range 5 to 228) compared 
to mild cases (median 3 pg/mL; range 0-44), especially during the 2nd and 3rd week after symptom 
onset, indicating a delayed pro-inflammatory process associated with severe MERS-CoV infection 
(Margulis, 2015).  
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Currently, few data exist on serum IL-6 levels in COVID-19 patients, but a median of 27 ng/L has 
been reported, and in severely ill patients can range widely (4.58-1182.9 ng/L) (Huang, 2020). In 
addition, at this time it is not clear how well serum IL-6 levels functions as a prognostic factor for 
progression of COVID-19. One report from Wuhan, China describe 69 patients with severe 
COVID-19 (defined as having 1 of the following: shortness of breath, respiratory rate >30/min, 
O2sat <93% resting, PaO2/FiO2 ratio <300 mm Hg) and 11 patients with non-severe COVID-19. 
Baseline serum IL-6 level was increased in the severe COVID-19 cases compared to the 
non-severe cases (median 35 pg/mL versus <5 pg/mL), as was the (CRP) levels (Liu, 2020).  
One hypothesis is that IL-6 is a modifiable driver of progression of disease with COVID-19 among 
patients with severe COVID-19. A potential therapeutic approach for patients with severe 
COVID-19 pneumonia therefore would be to temporarily attenuate the localized pulmonary 
“cytokine storm” in severe patients through blockade of the IL-6 receptor (IL-6R).  
Kevzara® (sarilumab) is a human IgG1 monoclonal antibody that binds specifically to both soluble 
and membrane-bound IL-6Rs (sIL-6Rα and mIL-6Rα) and has been shown to inhibit 
IL-6-mediated signaling through these receptors. Sarilumab is formulated for subcutaneous (SC) 
injection at doses of 150 and 200 mg Q2W and was approved for the treatment of rheumatoid 
arthritis (RA) in the US on 22 May 2017, EU on 23 Jun 2017, and Japan on 27 Sep 2017. Sarilumab 
is not currently approved for use in CRS.  
Actemra® (tocilizumab) is a humanized monoclonal antibody against the IL-6R and was approved 
for use in CRS associated with CAR-T cell therapies at a dose of 8 or 12 mg/kg, depending on 
weight, administered intravenously (IV) alone or in combination with corticosteroids. Symptoms 
of CRS can include high fevers, hypotension, respiratory and renal insufficiency, cytopenias and 
coagulopathy, although milder cases of CRS can present with only high fevers and myalgias. 
Several aspects of the CRS mirror those of severe COVID-19, including fever, respiratory 
insufficiency, and elevated markers of systemic inflammation, such as CRP. The experience with 
tocilizumab treated patients with CAR-T cell induced CRS reveals rapid defervescence and 
hemodynamic stability (Maude, 2014).  The pharmacokinetics (PK) of tocilizumab in these 
patients suggests relatively rapid decline in concentrations following a single 8 mg/kg IV dose.  
An analysis performed by the FDA shows that Cmax is about 40% lower in patients with CRS.  The 
analysis indicates a linear clearance of 0.50 L/day and volume of distribution in central 
compartment of 1.8 L, suggesting half-life of 3 to 4 days in serum.  The linear clearance appears 
faster in patients with CRS than in pediatric patients with systemic juvenile idiopathic arthritis 
(sJIA) or in adults with RA. 
There are currently no known published reports of IL-6R antagonist for infectious sepsis or 
pneumonia. Because IL-6 contributes to host defense against bacterial and viral pathogens, there 
is concern that the IL-6R inhibitor drug class, including sarilumab and tocilizumab) may 
exacerbate infections thus delaying recovery from sepsis. Patients chronically treated with 
sarilumab are at increased risk for developing serious and opportunistic infections. Most developed 
infections occur while taking other immunosuppressants with sarilumab. Reported infections 
include active tuberculosis, invasive fungal infections, bacterial and viral infections. While 
decreases in absolute neutrophil count is seen in patients treated with sarilumab, they are not 
reported to be associated with increased incidence of infection or serious infections 
(Fleischmann, 2017). A clinical study of neutrophil trafficking suggested that this decrease is due 
to redistribution into the marginating pool, rather than a net decrease in the neutrophil population 
(Lok, 2017). Other laboratory abnormalities seen with chronic administration of IL-6R antagonists 
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include thrombocytopenia, elevated liver enzymes and lipid abnormalities. Reports of an increased 
risk of gastrointestinal perforation has been reported in patients with concurrent diverticulitis, 
concomitant use of NSAIDS or corticosteroids. Finally, hypersensitivity reactions have been 
reported with SC administration of IL-6R antagonists.  
During the current COVID-19 outbreak, tocilizumab has been used in 21 patients with severe 
COVID-19 infection and described in a retrospective study (Wu, 2020). Patients were treated 
between February 5, 2020 and February14, 2020 if they had severe COVID-19 defined as having 
1 or more of the following criteria: 1) respiratory rate >30 breaths/min; 2) SpO2 <93% on room 
air; 3) PaO2/FiO2 <300 mmHg or had critical COVID-19 defined as respiratory failure requiring 
mechanical ventilation, shock, organ failure or had an ICU admission. Among 21 patients 
17 (81%) were severe and 4 (19%) were critical. Eighteen patients received a single dose of 
tocilizumab and 3 patients received a second dose of tocilizumab 12 hours after the first because 
of ongoing fever. All patients had fever prior to treatment, baseline mean CRP was 75±66.80 and 
mean IL-6 level was 132±278 pg/mL. One day after treatment with tocilizumab all patients had 
normal body temperature. Before treatment, 20 of 21 patients required oxygen therapy through 
high-flow nasal cannula (n=9), nasal cannula (7), mask oxygenation (1), noninvasive ventilation 
(1) and invasive ventilation (2). After tocilizumab 15 (75%) lowered oxygen intake after treatment 
and by Day 3 all patients had SpO2 >94%, including 1 patient who was breathing without 
supplemental oxygen. As of March 5, 2020, a larger clinical trial is ongoing in 14 hospitals in 
Wuhan, China and 272 patients with severe COVID-19 have been treated.   
Conducting well-controlled, randomized clinical trials in the setting of an outbreak has previously 
been found to be feasible and essential to identify safe and efficacious therapeutics for emerging 
infections like Ebola Virus Disease (Mulangu, 2019). In addition, during a pandemic, drug 
shortages and resource limitations can hinder the outbreak response, therefore, obtaining 
high-quality data on multiple therapeutics, even in the same class of drug, against an emerging 
infection is critical. Sarilumab acts by blocking IL-6R and may constitute a novel therapeutic 
strategy for severe COVID-19 to control the uncontrolled inflammatory response. If found to be 
safe and effective as monotherapy, sarilumab could be used in conjunction with future COVID-19-
specific antivirals therapeutics.  Risk of worsening or new infections associated with chronic use 
of IL-6R blockers could be mitigated using a single dose that only leads to short-term (<4 weeks) 
exposure to sarilumab and close monitoring and early treatment of worsening or new infections 
that may occur during the recovery period from COVID-19.  
Study 6R88-COV-2040 
This study protocol describes a multi-center, randomized, placebo-controlled trial of sarilumab for 
the treatment of severe COVID-19 to assess efficacy in reducing time to alleviation of COVID-19 
predefined symptoms and safety in administering an IL-6R blocker during an acute viral 
pneumonia.  The study is an adaptive Phase 2/3 study. In the Phase 2 portion of the study and in 
Cohort 1 of the Phase 3 portion, patients were randomized to receive sarilumab 400 mg, sarilumab 
200 mg, or placebo. In the Phase 3 portion of the study, Cohorts 2 and 3 enrolled patients in parallel 
when Cohort 1 enrollment completed.  In Cohort 2, patients receiving mechanical ventilation will 
be randomized to receive sarilumab 800 mg or placebo.  In Cohort 3, patients receiving 
high-intensity oxygen therapy without mechanical ventilation were randomized to receive 
sarilumab 800 mg or placebo. .  Following safety concerns raised by the Independent Data 
Monitoring Committee (IDMC), the Sponsor determined that the benefit/risk assessment was not 
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favorable in patients who were not receiving mechanical ventilation. Based on this assessment, as 
of 06 Jun 2020, patients in Cohort 3 will no longer receive study drug. In addition, new patients 
will no longer be enrolled into Cohort 3.  All patients will continue to be monitored and complete 
all assessments per protocol. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
Phase 2:  
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the 
control arm in adult patients hospitalized with COVID-19 regardless of disease severity strata.  
Phase 3 Cohort 1:  
The primary objective of the study is to evaluate the clinical efficacy of sarilumab 400 mg relative 
to the control arm in adult patients hospitalized with critical COVID-19 receiving mechanical 
ventilation at baseline  
Phase 3 Cohort 2:  
The primary objective of the study is to evaluate the clinical efficacy of sarilumab 800 mg 
relative to the control arm in adult patients hospitalized with COVID-19 receiving mechanical 
ventilation at baseline  
 
2.2. 
Secondary Objectives 
Phase 2: 
The secondary efficacy objectives of the study are to: 
1. Evaluate the clinical efficacy of sarilumab compared to the control arm in all disease 
severity levels and by clinical severity 
2. Evaluate the clinical efficacy of sarilumab compared to the control arm by baseline IL-6 
level 
3. Evaluate changes in the National Early Warning Score 2 (NEWS2) 
4. Evaluate the duration of predefined symptoms and signs (if applicable) 
5. Evaluate the duration of supplemental oxygen dependency (if applicable) 
6. Evaluate the incidence of new mechanical ventilation use during the study 
7. Evaluate the duration of new mechanical ventilation use during the study 
8. Evaluate need for admission into intensive care unit (ICU) 
9. Evaluate duration of hospitalization (days) 
10. Evaluate the 28-day mortality rate 
Phase 3 
The secondary efficacy objectives of the study are to: 
Phase 3 Cohort 1:  
• Determine whether sarilumab improves respiratory outcomes in patients with critical 
COVID-19 
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• Determine whether sarilumab reduces mortality in patients with critical COVID-19 
• Determine whether sarilumab shortens hospitalization in patients with critical COVID-
19 
Phase 3 Cohort 2:  
• Determine whether sarilumab improves respiratory outcomes in patients with COVID-
19 receiving mechanical ventilation 
• Determine whether sarilumab reduces mortality in patients with COVID-19 receiving 
mechanical ventilation 
• Determine whether sarilumab shortens hospitalization in patients with COVID-19 
receiving mechanical ventilation 
 
Phase 2 and Phase 3: 
Safety 
The secondary safety objectives of the study are to evaluate the safety of sarilumab through 
hospitalization (up to Day 29 if patient is still hospitalized) compared to the control arm as assessed 
by incidence of: 
• Serious adverse events (SAEs) 
• Grade 4 neutropenia (absolute neutrophil count [ANC]<500/mm3) 
• Grade 4 neutropenia (ANC<500/mm3) with concurrent severe or life-threatening 
bacterial, invasive fungal, or opportunistic infection  
• Grade ≥2 infusion-related reactions 
• Grade ≥2 hypersensitivity reactions 
• Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥3X 
upper limit of normal (ULN) (for patients with normal baseline) or >3X ULN AND at 
least 2-fold increase from baseline value (for patients with abnormal baseline) 
• Invasive bacterial or fungal infections of clinical significance with confirmed diagnosis 
based on the investigator’s assessment with appropriate diagnostic workups and 
consultations 
2.3. 
Exploratory Objectives 
Phase 2 and Phase 3: 
The exploratory objectives of the study are to: 
1. Evaluate the virologic changes in the treatment arms compared to the control arm as 
assessed by: 
• Percent of patients with SARS-COV-2 detectable in oropharyngeal (OP) or 
nasopharyngeal (NP) sample  
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• Quantitative SARS-CoV-2 virus in the OP or NP sample   
• Development of SARS-CoV-2 variants in OP or NP sample  
• Quantitative SARS-CoV-2 virus in blood  
2. To evaluate the cytokine profile and additional biomarkers that may be associated with 
efficacy and safety associated with sarilumab treatment and anti-viral immunity 
3. Evaluate the incidence of new or worsening laboratory-confirmed serious secondary 
infections in the treatment arms as compared to the control arm 
4. To characterize the concentrations of sarilumab and sIL-6R in serum over time 
Phase 3  
1. To characterize the efficacy of sarilumab in severe, MSOD, and immunocompromised 
patients using the same primary and secondary efficacy endpoints as in the critical 
patients (Cohort 1 only) 
2. To examine the efficacy of sarilumab in patients by serum IL-6 level, CRP level, and 
neutrophil-to-lymphocyte ratio 
3. To determine whether sarilumab improves vital signs (measured by the NEWS2) 
Patients will not be recalled after discharge for any missing exploratory assessments.  
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Phase 2: Treatment of patients hospitalized with COVID-19 with sarilumab will result in a greater 
reduction in serum CRP compared to the control. 
Phase 3 Cohort 1: Treatment of patients hospitalized with COVID-19 in the critical stratum on 
mechanical ventilation at baseline with sarilumab 400 mg will result in a greater proportion of 
patients who improve their clinical status at Day 22 compared to placebo. 
Phase 3 Cohort 2: In patients hospitalized with COVID-19 who are on mechanical ventilation, 
treatment with sarilumab 800 mg will result in a greater proportion of patients who improve their 
clinical status at Day 22 as compared to placebo. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
Currently, there are no specific COVID-19 treatments. SARS-CoV-2, the betacoronavirus that 
causes COVID-19, results in a similar acute lower respiratory disease caused by SARS-CoV that 
was identified in 2002 and the Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV). 
Many therapeutic agents have been used to treat patients with SARS-CoV and MERS-CoV, 
including corticosteroids, type 1 IFN agents, convalescent plasma, ribavirin, lopinavir/ritonovir, 
proteases, and agents targeting viral entry proteins. However, none have been shown to be 
efficacious in clinical trials. Therefore, the comparator proposed in this study will be placebo.  
Randomization is essential for establishing efficacy of sarilumab compared to placebo. Collection 
of clinical, virologic, and cytokine data using a standardized timeline will provide valuable 
information on the clinical course of severe COVID-19 and the impact of sarilumab on clinical 
recovery from COVID-19. 
The study utilizes an adaptive Phase 2/3 design that intends to maximize efficiency of identifying 
early signs of clinical efficacy and to avoid the use of ineffective therapeutics in critically ill 
patients with COVID-19.  Due to the novel nature of the COVID-19 pandemic, efficacy endpoints 
are not well established, and the standard of care is expected to evolve over time. The adaptive 
design allows for the assessment of efficacy endpoints in Phase 2 which are then seamlessly 
confirmed in the Phase 3 portion of the study, as well as evaluating the benefit-risk of multiple 
doses of sarilumab. This study is therefore intended to allow for multiple adaptations, including 
dropping of a sarilumab dose arm, modification of the primary endpoints for Phase 3, and sample 
size re-estimation for Phase 3.  
The study will begin enrollment of all patients, as planned. To maximize safety, the Independent 
Data Monitoring Committee (IDMC) will perform 3 interim data reviews after approximately 12, 
25, and 50 patients have been dosed and have had at least 7 days of follow-up to determine if a 
treatment arm should be discontinued for safety reasons. These data reviews will include all data, 
including deaths, from all enrolled study participants.  Unblinded Regeneron senior physicians 
who are not directly involved with the study will review data from these 3 interim data reviews 
independently of the IDMC. The IDMC will also meet regularly throughout the course of the study 
to review safety data and make recommendations on study conduct. 
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3.2.2. 
Rationale for Study Design Adaptation 
Adaptations of the Phase 3 portion of the study are based on interim Phase 2 results of this study 
(Table 1 and Table 2). Sarilumab 400 and 200 mg IV reduced serum CRP by 79% and 77%, 
respectively, compared to 21% in the placebo arm in the modified intention-to-treat (mITT) 
population (primary endpoint). Sarilumab did not appear to improve clinical outcomes in patients 
with severe disease.  In patients with critical disease, there were trends toward a benefit of 
sarilumab 400 mg compared to placebo in the proportion of patients who died or did not require 
mechanical ventilation, had clinical improvement according to the 7-point ordinal scale, did not 
require supplemental oxygen, and were discharged (Table 1). Additional analyses did not suggest 
a benefit in patients in the MSOD group. Based on the IDMC recommendation, as of 27 Apr 2020, 
the severe and MSOD groups will no longer enroll or receive study drug.  The IDMC also 
recommended that the sarilumab 200 mg arm be discontinued due to lack of benefit.  
Table 1: 
Interim Phase 2 Results 
Placebo 
Sarilumab 
200 mg 
Sarilumab 
400 mg 
PRIMARY ENDPOINT (REDUCTION IN C-REACTIVE PROTEIN) 
(n=77) 
(n=136) 
(n=145) 
% change from baseline in CRP 
(Patients with high baseline IL-6, where data 
were available) 
-21% 
-77% 
-79% 
EXPLORATORY CLINICAL ENDPOINTS IN THE "CRITICAL" GROUP 
(n=44) 
(n=94) 
(n=88) 
Died or "On a ventilator" 
24 (55%) 
43 (46%) 
28 (32%) 
Died 
12 (27%) 
34 (36%) 
20 (23%) 
On a ventilator 
12 (27%) 
9 (10%) 
8 (9%) 
2-point clinical improvement on a 7-point scale1 
18 (41%) 
48 (51%) 
52 (59%) 
Off supplemental oxygen 
18 (41%) 
40 (43%) 
51 (58%) 
Discharged 
18 (41%) 
37 (39%) 
47 (53%) 
1 See Section 4.1.2.1 for details of the of the 7-point ordinal scale. 
Note: This table is based on the 22 Apr 2020 snapshot 
 
 
 
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Based on these findings, the following adaptations were made to the Phase 3 portion of this study 
implemented in Amendment 6, however, as of 06 Jun 2020, Cohort 3 will no longer enroll patients 
(Table 3). 
Table 3: 
Summary of Phase 3 Adaptations 
Study Component 
Adaptation 
Rationale 
Phase 3 endpoint 
At least a1-point improvement from baseline in 
clinical status on the 7-point ordinal scale 
Phase 2 results 
Phase 3 primary analysis 
population 
• Cohort 1: Critical patients receiving mechanical 
ventilation at baseline 
• Cohort 2: Patients on mechanical ventilation at 
baseline  
• Cohort 3: Patients on high-intensity oxygen 
therapy without mechanical ventilation at 
baseline* 
Phase 2 results 
Dose regimens 
• Cohort 1: Primary comparison will be between 
sarilumab 400 mg and placebo 
• Cohort 2: Sarilumab 800 mg and placebo 
• Cohort 3: Sarilumab 800 mg and placebo 
Section 3.2.4 
Sample size for the Primary 
Analysis Population in Cohort 1 
~170 
Section 11.2  
Sample Size for Cohort 2 
225  
Section 11.2  
Sample Size for Cohort 3 
225 
Section 11.2  
*High-intensity oxygen therapy is defined as the use of non-rebreather mask with an oxygen flow rate of at least 
10 L/min; use of a high flow device with at least 50% FiO2, or use of non-invasive ventilation (eg, BiPAP™) or 
CPAP to treat hypoxemia 
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3.2.3. 
Rationale for Phase 2 and Phase 3 Cohort 1 Dose Selection 
COVID-19 infection can be associated with a degree of pulmonary cytokine release and IL-6 has 
been shown to be a major contributor to the development of fever and hypoxemia.  In the current 
study, both 200 and 400-mg doses of sarilumab (Kevzara®), an anti-IL-6R mAb, are to be 
administered by a 1-hour IV infusion. Sarilumab is currently approved for treatment in patients 
with RA at 200 mg Q2W (SC) [with down dosing to 150 mg Q2W (SC) for certain laboratory 
changes]. Sarilumab is analogous to tocilizumab and there is reported evidence that IV treatment 
with 400 mg of tocilizumab (Actemra®), an anti-IL-6R monoclonal antibody (mAb), provides a 
clinically meaningful improvement in clinical symptoms that are thought to be mediated by 
cytokine release in patients with severe or critical COVID-19 infection.  
There is limited experience in the use of sarilumab by IV infusion and no experience at the doses 
being studied in this protocol. Sarilumab was initially administered IV in a single dose, dose 
escalation, 
safety, pharmacodynamic (PD), and PK study of patients 
with 
RA 
(Study TDU10808/6R88-RA-0703), which was terminated prior to completion due to the 
occurrence of Grade 4 neutropenia (neutrophil count: 400 per mm3) in 1 of 2 patients in the 
2 mg/kg cohort and the intention to develop the drug for SC dosing in RA patients. Thus, following 
this first-in-human study, the SC route of administration was used in all subsequent studies.  The 
appropriateness for the use of sarilumab by the IV route in this setting is supported by the high 
degree of similarity between sarilumab and tocilizumab regarding the clinically observed PK, PD 
(to include safety and PD endpoints), many of which were assessed in randomized trials. These 
similarities extend to other clinically observed pharmacology properties, in vitro properties, as 
well as the physiochemical properties.   
The PK/PD strategy in dose selection for a mAb directed against IL-6R, whether it be tocilizumab 
or sarilumab, is to maintain local and systemic saturation of the target-mediated pathway over an 
identified duration and thereby ensuring saturation or near-saturation of target binding. 
Given the high binding affinity and binding specificity of both tocilizumab and sarilumab, once 
systemic concentrations of the mAb are sufficient to saturate the target-mediated pathway the 
pharmacological response in terms of safety, PD, or efficacy associated with further increases in 
concentration is only increased with respect to the duration of action and, possibly, greater 
penetration into difficult to reach tissues.  
The PK, PD, and safety of sarilumab and tocilizumab were compared in a number of randomized 
trials. In a single-dose, open-label randomized trial the PK and PD were assessed in patients with 
RA randomized 1:1:1:1 to either 150 mg or 200 mg (SC) of sarilumab, or 4 mg/kg or 8 mg/kg (IV) 
of tocilizumab (Study 1309). Also, in a single dose PK/PD study, 150 mg of sarilumab (SC) was 
compared to 162 mg of tocilizumab (SC) in Japanese patients with RA randomized 1:1 (Study 
PDY1419) (Huang, 2020). In the multiple-dose double-blind study ASCERTAIN (NCT01768572) 
the safety and tolerability of sarilumab and tocilizumab were compared in approximately 
200 patients with RA randomized 1:1:2 to receive 150 mg Q2W or 200 mg Q2W of sarilumab 
(SC) or 4 mg/kg Q4W of tocilizumab (IV) for 24 weeks (Emery, 2019).  
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In the single-dose PK/PD studies, consistent with saturation of the target mediated pathway for 
sarilumab and tocilizumab, all dose levels regardless of the route of administration demonstrated 
similar maximal effect in suppression in CRP and ANC lowering.  Notably, higher dose levels and 
the associated higher concentrations, beyond that need to achieve saturation, resulted in a longer 
duration of the maximal PD response, but did not result in a deeper response.  Consistent with the 
longer duration of saturation following IV administration of tocilizumab, but consistent with the 
similar PK/PD relationship for sarilumab and tocilizumab, sIL-6R increased in a dose and 
concentration related manner. Subcutaneous single doses of sarilumab (150 mg) or tocilizumab 
(162 mg) resulted in similar concentration time profiles and yielded nearly identical PD response 
in CRP and ANC, as well as changes in sIL-6R and IL-6 over time.  In the ASCERTAIN study, 
similar PD effects were observed with ANC lowering. Additionally, no clinically meaningful 
differences in treatment-emergent adverse events were observed between sarilumab and 
tocilizumab. Laboratory changes with sarilumab were within the same range as those with 
tocilizumab (Emery, 2019). 
Consistency in PD effects between tocilizumab and sarilumab are also seen in cross-study 
comparison of the radiographic studies performed with the 2 products.  According to their labeling, 
the 162 mg Q2W dose of tocilizumab reduced radiographic progression based on the modified 
total Sharpe score (mTSS) by 50% at 24 weeks; the 150 mg Q2W dose of sarilumab reduced 
radiographic progression based on the modified total Sharpe score (mTSS) by 68% at 52 weeks.   
The best biomarker for PD effect of IL-6R inhibition is decrease in ANC; ANC decreases and 
remains depressed during the period of receptor blockade and increases after systemic levels of 
drug fall below those necessary to saturate.  Recent publications suggests this lowering in ANC 
may be a result of neutrophil margination and not a result of clearance of the neutrophils, while 
the neutrophils maintain their functionality (Lok, 2017). Thus, while a time-dependent increased 
incidence of infection, including serious infection, due to IL-6 receptor blockade has been noted, 
this was not related to the decreases in ANC observed with sarilumab (Kevzara [package insert], 
2017).  It has also been reported that the level of a patient’s inflammatory state may result in 
increased clearance of anti-IL-6R mAb (Le, 2018). Accordingly, patients with CRS may need 
higher doses of anti-IL-6R antagonist than patients with active RA. Consistent with this, the PD 
effect of sarilumab as measured by reduction in ANC in RA patients with active inflammation was 
less pronounced and shorter than in otherwise controlled RA patients.  The need to ensure 
saturation systemically and locally in tissue, together with a shorter time to Cmax support the use 
of IV administration over that of SC and support the study of higher doses of sarilumab than 
approved for the treatment of RA in conditions of cytokine release resulting from COVID-19 
infection.  
Data from the dose ranging portion of Study EFC11072 (MOBILITY Part A) illustrates the 
relationship between trough concentrations of sarilumab obtained from 100 mg Q2W, 
150 mg Q2W, 200 mg Q2W, and 150 mg QW administration and ANC). These results 
demonstrate a plateau of ANC decline despite a greater than 2.5-fold increase in trough 
concentrations with weekly administration. (100 mg QW vs 150 mg QW). This PD effect of IL-6R 
inhibition on neutrophil suppression is clearly on the plateau of the dose-response curve indicating 
that higher exposures would not be predicted to yield a further increase in ANC suppression. 
Furthermore, this expected PD effect on ANC number has not been correlated to an increased risk 
of infection for either the sarilumab or tocilizumab, nor does it interfere with the phagocytosis, 
rate of apoptosis, oxidative burst, or other known neutrophil capacity (Lok, 2017). Therefore, the 
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margination effect of IL-6R inhibition has no known clinical relevance for patients without active 
bacterial infection. 
To date there is a plethora of experience with high doses of tocilizumab; notably it is also approved 
at dose up to 8 mg/kg IV and has been used in clinical practice at these levels for over a decade in 
the treatment of RA and more recently higher IV doses of tocilizumab have been used in cytokine 
release syndrome associated with chimeric antigen receptor T-cell (CART) therapy. Regeneron 
developed sarilumab for subcutaneous administration and performed a head-to-head study 
comparing the 150 and 200 mg SC doses of sarilumab with IV tocilizumab at 4 and 8 mg/kg IV 
(6R88-RA-1309). As expected, the serum concentrations of tocilizumab are substantially higher 
than those of sarilumab. Yet, despite the higher concentrations of tocilizumab, the magnitude of 
the PD effects as measured by reduction in ANC and CRP are the same at early timepoints 
(ie, when drug concentrations of both drugs are at or above those needed to achieve saturation). 
The only difference between these supra-saturating concentrations of tocilizumab and the lower 
concentrations of sarilumab is in duration of peak PD effect. It can also be observed with the loss 
of saturating concentrations there is a temporally rapid decline in these PD effects. These data 
provide strong evidence that higher doses and higher serum concentrations of either of these 
anti-IL-6R antibodies beyond those required for saturation do not provide any greater PD effect 
nor any greater safety concern and these higher doses only serve to extend the duration of the PD 
effects.  
Based on available data, on a per mg basis, tocilizumab and sarilumab behave comparably in vivo 
with respect to potency, PK, PD, efficacy, and safety. Thus, the safety of sarilumab at doses as 
high as 400 mg IV can be extrapolated from the experience with similar and even higher doses of 
tocilizumab. Nonetheless, this needs to be verified with actual clinical data.  In order to test both 
lower and higher doses of sarilumab to treat severe COVID-19 pneumonia, 2 doses will be studied: 
200 mg IV and 400 mg IV.  In the setting of a pandemic where drug supply may become limiting, 
identifying the minimum dose necessary could increase the supply. 
Tocilizumab has been approved for use in patients with CRS as a consequence of CAR-T therapy.  
During the FDA review of the sBLA for this indication, a comparison of the observed Cmax in these 
patients with those for patients with sJIA, indicated that Cmax in patients with CRS was 40% lower 
than for patients with sJIA.  Pharmacokinetic (PK) modeling was performed by FDA, where 
clearance (CL) was estimated to be 0.50 L/day (RSE = 10.8%) and central volume of distribution 
(VC) was estimated to be 1.8 L (RSE = 11.2%) in patients with CRS.  These estimates are higher 
than CL of 0.17 L/day and VC of 0.94 L in similar aged patients with sJIA.  This analysis indicates 
that the half-life of the decline in tocilizumab concentrations following IV doses of 8 mg/kg in the 
patients with CRS (>30kg) is 3 to 4 days. 
Assuming a similar PK profile for sarilumab in COVID patients to the tocilizumab data in patients 
with CRS, a repeat dose of sarilumab at 24 hours should produce approximately the same Cmax as 
originally predicted based on the PK in active RA patients.  Moreover, assuming the same 
clearance for sarilumab as observed for tocilizumab, sarilumab levels could fall by 75% within 
1 week, which may lead to levels which do not completely block signaling through the IL-6R.  
Given the similarities in the PK characteristics of sarilumab and tocilizumab, these data suggest 
that the proposed dosing interval for sarilumab is appropriate. 
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3.2.4. 
Rationale for Phase 3 Cohorts 2 and 3 Dose Selection 
As discussed above, preliminary, open-label data from the use of tocilizumab, initially at a 400 mg 
IV dose (Xu, 2020) supported assessment of IL-6R inhibition in patients with severe or critical 
COVID-19 patients.  Subsequent studies with tocilizumab, however, are being conducted at a 
higher dose: 8 mg/kg up to 800 mg initial dose, with repeat dosing allowed based on clinical 
criteria.  In these studies, benefit has been described in COVID-19 both in ventilated patients and 
in patients not on a ventilator. 
Initial results of the open-label, randomized, controlled Phase 2 study, CORIMUNO-TOCI support 
the administration of an 8 mg/kg IV dose of tocilizumab. In this study, 129 patients hospitalized 
for COVID-19 moderate or severe pneumonia and not requiring intensive care upon admission 
were randomized to standard of care + tocilizumab (8 mg/kg up to a 800 mg maximal dose on 
Day 1 and if no response, with no decrease of oxygen requirement, a second administration at 
Day 3; n=65) or to SOC alone (n=64). Data showed that a significantly lower proportion of patients 
reached ventilation or death at Day 14 in the tocilizumab + SOC arm vs. SOC alone, however, 
details have not been disclosed (APHP, 2020). 
In an interim analysis of the Phase 2 portion of 6R88-COV-2040, based on the prespecified 
analysis of the combined severe and critical strata, there was no evidence of treatment effect with 
either the 200- or 400-mg dose.  In other prespecified analyses, trends in the number of patients in 
the critical stratum who achieved a 2-point improvement in clinical status on the 7-point ordinal 
scale suggested that a single 400 mg dose achieved greater treatment benefit than a single 200-mg 
dose.  
 
 
 
These results with sarilumab are not what had been anticipated.  Either the results of the previous 
uncontrolled or small controlled studies with tocilizumab were misleading OR there is a systematic 
difference in study design between the tocilizumab and sarilumab studies, the most prominent 
difference being dose.  The maximum dose of sarilumab in the Phase 2 and Phase 3 Cohort 1 
portion of the current study was 400 mg with repeat dosing allowed based on clinical criteria.  With 
obesity being a risk factor for severe or critical COVID-19, it is not surprising that the mean 
baseline weight in the 6R88-COV-2040 study, conducted in the US, is ~91 kg.  Thus, patients are 
being dosed at approximately 4.4 mg/kg, significantly less than the dose of tocilizumab in recent 
studies.  And, while sarilumab treatment in the current study readily lowered CRP levels, there has 
been almost no effect on neutrophil counts, another established pharmacodynamic marker of IL-6R 
inhibition.  Indeed, only 2 patients in the Phase 2 portion of the study had Grade 4 neutropenia. 
IL-6 concentration data are consistent with the notion that higher doses of sarilumab are required 
in COVID-19 than were being administered.  Mean baseline IL-6 levels across all treatment arm 
and disease severity in the Phase 2 portion of the current study was 356 pg/mL and in the critical 
strata was 373 pg/mL which far exceeds the IL-6 levels observed in the RA studies.  For example, 
in Study 6R88-RA-1309, which evaluated single dose administration of sarilumab SC (150 and 
200 mg) and tocilizumab IV (4 mg/kg and 8 mg/kg) in RA patients, the mean baseline IL-6 levels 
ranged from ~7 to 22 pg/mL. 
Taken together, the relatively modest efficacy signal, the absence of trends in the safety data to 
suggest harm, and the pharmacodynamic data all suggest that effective blockade of IL-6R in 
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COVID-19 patients may require a higher dose of sarilumab than has been studied.  In the absence 
of a safety signal to suggest otherwise, the dose was increased to sarilumab 800 mg to maximize 
IL-6R inhibition and determine treatment effects in Phase 3 Cohorts 2 and 3.  Therefore, in 
Cohorts 2 and 3 of Phase 3, an 800-mg dose of sarilumab, with the allowance for repeat dosing 
based on clinical criteria will be studied to determine if this higher dose results in more robust 
clinical benefit than has been seen.  Risk mitigation strategies, already in place for the protocol 
were followed including both expedited reporting of adverse events of special interest (AESIs; 
including Grade 4 neutropenia with or without concurrent invasive infections), and active 
engagement with the IDMC to provide adequate assurance for patient safety.  
This increase in dose was supported by the PK data.  In an interim analysis of the preliminary 
Phase 2 data, following IV administration of a single sarilumab dose, mean (SD) Cmax was 
49.2 (±16.8) mg/L (n=146) for the 200-mg dose and 105 (±46.6) mg/L (n=140) for the 400-mg 
dose. Based on the central volume for a typical monoclonal antibody the observed Cmax values are 
25% to 30% lower than expected.  The subsequent decline in concentrations suggests an initial 
half-life of sarilumab in serum of about 3 days, indicating that repeat dosing on a weekly interval 
was not expected to lead to significant accumulation, even at the 800-mg dose.  These observations 
appear to be consistent with the findings for tocilizumab in patients with CRS as a consequence of 
CAR-T therapy described in Section 3.2.3. 
The 
anticipated 
mean sarilumab Cmax following 
a 
single 
800-mg 
dose, 
based 
on 
the preliminary interim PK analysis as well as that expected for a typical monoclonal antibody, is 
about 200 to 250 mg/L. The proposed dosing regimen is supported by the safety and efficacy data 
observed at 400 mg in patients with COVID-19 and the toxicology data described in Investigator 
Brochure, where the average Ctrough at the NOAEL in the monkey following IV dosing ranged from 
504 mg/L (40 mg/kg/week in a 5-week study) to 1780 mg/L (50 mg/kg/week in a 26-week study). 
3.3. 
Risk-Benefit for REGN88 (sarilumab, Kevzara®) 
Sarilumab is currently approved at 200 mg Q2W (SC) for the treatment of RA in multiple 
countries. The risks and adverse reactions are described in the approved prescribing information 
for sarilumab.  
There are currently no known published reports of IL-6R antagonists for infectious sepsis or 
pneumonia. Because IL-6 contributes to host defense against bacterial and viral pathogens, there 
is a concern that IL-6 inhibition may exacerbate infections thus delaying recovery from sepsis. 
Patients chronically treated with sarilumab are at increased risk for developing serious and 
opportunistic infections. Most developed infections while taking other immunosuppressants or 
disease modifying anti-rheumatic arthritis (DMARDs) with sarilumab. Opportunistic infections, 
including de novo cases of tuberculosis, disseminated candidiasis and pneumocystis have been 
infrequently reported with sarilumab. The most frequently reported opportunistic infections were 
cases of non-disseminated herpes zoster with an incidence similar in sarilumab+DMARD and 
placebo+DMARD groups. Other serious infections (eg, histoplasmosis, cryptococcus, aspergillus) 
have not been reported in sarilumab clinical studies but have been reported in patients receiving 
other immunosuppressive agents. In this study, patients are only receiving corticosteroids if 
indicated for an acute medical indication, and close monitoring in the hospital or ICU setting to 
diagnose and treat infections. The risk to subjects is thus minimized.  
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While decreases in ANC is seen in patients treated with sarilumab, they are reported not to be 
associated with increased incidence of infection or serious infections in patients with RA 
(Fleischmann, 2017). A clinical study of neutrophil trafficking suggested that this decrease is due 
to an redistribution into the marginating pool, rather than a net decrease in the neutrophil 
population (Lok, 2017).  
Treatment with sarilumab in clinical studies has also been associated with a higher incidence of 
transaminase elevations. These elevations were transient and did not result in any clinically evident 
hepatic injury in clinical studies. Liver function test monitoring will be performed during the study. 
In addition, gastrointestinal perforation has been reported in clinical studies, including in patients 
receiving corticosteroids. Patients will be closely monitoring in the hospital or ICU setting with 
daily clinically indicated evaluations by health care professionals in detect this event if it occurs. 
In the Phase 2 safety population of Study 6R88-COV-2040 (n=457), sarilumab at doses of 200 mg 
and 400 mg IV were not associated with new safety findings. Transaminase levels were higher in 
sarilumab patients compared to placebo.  Grade 4 neutropenia was rare and clinically significant 
bacterial and fungal infections were similar in sarilumab-treated groups as compared to placebo. 
Serious adverse events were generally representative of the underlying patient population. 
Additional information on possible risks and adverse drug reactions is provided in the IB.  
Sarilumab may or may not improve clinical outcomes of a subject with COVID-19 who is enrolled 
in this trial. During the current COVID-19 outbreak, tocilizumab (another IL-6R antagonist) has 
been used in 21 patients with severe COVID-19 infection and described in a retrospective study 
(Wu, 2020). Data from these patients suggest blockade of the IL-6R may lead to a clinically 
meaningful improvement in symptoms that are thought to be mediated by cytokine release.  
Additionally, tocilizumab is approved for use in CRS associated with CAR-T cell therapies (8 or 
12 mg/kg, based on weight). Several aspects of the CRS mirror those of severe COVID-19, 
including fever, respiratory insufficiency, and elevated markers of systemic inflammation, such as 
CRP.  
In critical patients in the Phase 2 portion of the study, sarilumab 400 mg IV was associated with a 
numerically lower proportion of patients who had died or required mechanical ventilation at 
Day 21 compared to placebo (32% in sarilumab 400 mg vs. 55% in placebo). There were also 
numerical differences favoring sarilumab 400 mg IV compared to placebo in the proportion of 
patients who experienced clinical improvement and who were discharged by Day 21 (Table 1). 
Among patients receiving mechanical ventilation at baseline, sarilumab 400 mg was associated 
with a greater proportion of patients who were alive without mechanical ventilation (57% in 
sarilumab 400 mg vs. 17% in placebo) and a greater proportion of patients who recovered (47% in 
sarilumab 400 mg vs. 17% in placebo) compared to placebo. 
 
 
 
Based on review of the Phase 2 data, the IDMC recommended, and the Sponsor agreed, that the 
benefit/risk assessment supported continued enrollment of only critical COVID-19 patients in 
Phase 3. These changes were implemented in Protocol Amendment 6. 
Based on review of the Phase 3 Cohort 1 data, the IDMC noted a safety concern which led them 
to recommend no further enrollment or dosing of patients who were not on mechanical ventilation 
at baseline.  The Sponsor’s review of the data in patients not on mechanical ventilation at baseline 
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showed no benefit among those treated with sarilumab compared to placebo, and there were more 
deaths among the sarilumab-treated patients.  The imbalances in mortality observed in this subset 
of Phase 3 Cohort 1 had not been observed in the smaller Phase 2 400 mg critical patient dataset.   
Although there had been a small trend in favor of sarilumab 400 mg in the Phase 2 data, no 
meaningful trends either for efficacy or harm are seen in the combined Phase 2/Phase 3 Cohort 1 
data in this subset of patients with critical COVID-19 not on mechanical ventilation.  Considering 
all these data, while it cannot be concluded that there is harm associated with sarilumab treatment 
in critical COVID-19 patients who were not receiving mechanical ventilation at randomization, 
there is also no evidence for benefit.  Thus, the Sponsor agreed with the IDMC that the benefit/risk 
assessment is not favorable and continued dosing of sarilumab in this study is not warranted in 
patients with critical COVID-19 who are not receiving mechanical ventilation.  Enrollment will 
continue in Phase 3 Cohort 2 as the IDMC did not note any safety concerns that precludes 
enrollment into this cohort.  Changes to the Phase 3 planned enrollment are implemented with this 
protocol amendment.   
 
A risk-benefit statement with respect to the overall development program is provided in the IB. 
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4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
Note that for the primary and secondary endpoints, patients will not be required to return to the 
hospital once discharged.  A follow-up phone call will occur on Days 29 and/or 60, depending on 
when the patient is discharged.  All patients will be contacted for an end of study (EOS) follow-up 
at Day 60. 
4.1.1. 
Primary Endpoints 
Phase 2:  
Percent change from baseline in CRP levels at Day 4 in patients with serum IL-6 level greater than 
the upper limit of normal. 
Phase 3 Cohort 1: 
Proportion of patients with at least a 1-point improvement in clinical status from baseline to Day 22 
using the 7-point ordinal scale in patients with critical COVID-19 receiving mechanical ventilation 
at baseline  
Phase 3 Cohort 2: 
Proportion of patients with at least 1-point improvement in clinical status from baseline to Day 22 
using the 7-point ordinal scale in patients with COVID-19 receiving mechanical ventilation at 
baseline  
Separate analyses of Cohorts 1 and 2 are planned. 
4.1.2. 
Secondary Endpoints 
The 7-point ordinal scale will be assessed as a secondary endpoint in Phase 2 and will be used for 
both Primary and Secondary endpoints in Phase 3. The ordinal scale is an assessment of the clinical 
status.  The scale is as follows:  
• Death;  
• Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO);  
• Hospitalized, requiring non-invasive ventilation or high flow oxygen devices;  
• Hospitalized, requiring supplemental oxygen; 
• Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise) 
• Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical 
care 
• Not hospitalized 
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4.1.2.1. 
Phase 2 Secondary Endpoints: 
Efficacy 
Phase 2 Key Secondary Endpoints 
1. Time to improvement (2 points) in clinical status assessment from baseline on the 7-point 
ordinal scale in severe or critical patients with serum IL-6 levels greater than the upper 
limit of normal 
2. Time to improvement (2 points) in clinical status assessment from baseline on the 7-point 
ordinal scale reporting in severe or critical patients with all IL-6 levels 
Other Phase 2 Secondary Endpoints: 
1. Time to resolution of fever for at least 48 hours without antipyretics or until discharge, 
whichever is sooner, in patients with documented fever ≥38°C (oral), ≥38.4°C (rectal or 
tympanic), or ≥37.6°C (temporal or axillary) at Baseline 
(Resolution of fever is defined as postbaseline body temperature <37.2°C (oral), or 
<37.6°C (rectal or tympanic) or <36.8°C (temporal or axillary). 
2. Time to resolution of fever (defined as above) for at least 48 hours without antipyretics or 
until discharge, whichever is sooner, in patients defined as above, by clinical severity. 
3. Time to resolution of fever (defined as above) for at least 48 hours without antipyretics or 
until discharge, whichever is sooner, in patients defined as above, by baseline IL-6 levels. 
4. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to 
the nadir SpO2/FiO2) for at least 48 hours or until discharge, whichever is sooner. 
5. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to 
the nadir SpO2/FiO2) for at least 48 hours, or until discharge, whichever is sooner, by 
clinical severity 
6. Time to improvement in oxygenation (increase in SpO2/FiO2 of 50 or greater compared to 
the nadir SpO2/FiO2) for at least 48 hours, or until discharge, whichever is sooner, by 
baseline IL-6 level 
7. Time to resolution of fever (as defined above) and improvement in oxygenation (as defined 
above) 
8. Mean change in the 7-point ordinal scale from baseline to Days 3, 5, 8, 11, 15, and 29 (or 
until discharge) 
9. Percentage of patients in each clinical status category using the 7-point ordinal scale at 
Days 3, 5, 8, 11, 15, and 29  
10. Time to discharge or to a NEWS2 of ≤2 and maintained for 24 hours, whichever occurs 
first 
11. Change from baseline to Days 3, 5, 8, 11, 15, and 29 in NEWS2 
12. Days with fever (≥38°C °C [oral], ≥38.4°C [rectal or tympanic], or ≥37.6°C [temporal or 
axillary])  
13. Proportion of patients alive, off oxygen at Day 29 
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14. Days of resting respiratory rate >24 breaths/min (recorded at least once each day)  
15. Days of hypoxemia (SpO2 ≤93% on room air, or requiring supplemental oxygen, or 
mechanical ventilatory support)  
16. Days of supplemental oxygen use  
17. Time to saturation ≥94% on room air 
18. Ventilator free days in the first 28 days (to Day 29) 
19. Initiation of mechanical ventilation, non-invasive ventilation, or use of high flow nasal 
cannula (for those not requiring these interventions at baseline)  
20. Admission into an ICU (among those not in an ICU at baseline) 
21. Days of hospitalization among survivors  
22. All-cause mortality 
4.1.2.2. 
Phase 3 Secondary Endpoints 
The Phase 3 secondary endpoints for Cohorts 1 and 2 are outlined in Table 4.
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Table 4: 
Phase 3 Efficacy Endpoints 
 
Cohort 1: sarilumab 400 mg vs. placebo 
Cohort 2: sarilumab 
800 mg  
vs. placebo 
(receiving mechanical 
ventilation at baseline) 
Critical ITT 
Critical receiving 
mechanical 
ventilation at baseline 
Critical not receiving 
mechanical ventilation 
at baseline1 
 
Proportion of patients with at least 1-point improvement in clinical status 
from baseline to Day 22 using the 7-point ordinal scale  
Key Secondary 
Primary 
Descriptive 
Primary 
Proportion of patients who recover (discharged, or alive without 
supplemental oxygen use or at pre-COVID oxygen use) by Day 22 
Secondary 
Key Secondary 
Descriptive 
Key Secondary 
Proportion of patients who die through Day 29 
Key Secondary 
Key Secondary 
Descriptive 
Key Secondary 
Proportion of patients alive not receiving mechanical ventilation or 
ECMO at Day 22 
Secondary 
Secondary 
Descriptive 
Secondary 
Proportion of patients with a 2-point improvement in clinical status on the 
7-point ordinal scale from baseline to Day 22 
Secondary 
Secondary 
Descriptive 
Secondary 
Time to at least 1-point improvement in clinical status assessment from 
baseline on the 7-point ordinal scale 
Secondary 
Secondary 
Descriptive 
Secondary 
Time to at least 2-point improvement in clinical status assessment from 
baseline on the 7-point ordinal scale 
Secondary 
Secondary 
Descriptive 
Secondary 
Proportion of patients receiving mechanical ventilation or ECMO at 
Day 22 
Secondary 
Secondary 
Descriptive 
Secondary 
Proportion of patients discharged and alive at Day 22 
Secondary 
Secondary 
Descriptive 
Secondary 
Time to recovery (discharged, or alive without supplemental oxygen use 
or at pre-COVID oxygen use) 
Secondary 
Secondary 
Descriptive 
Secondary 
Proportion of patients who die through Day 60 
Secondary 
Secondary 
Descriptive 
Secondary 
Time to death (all-cause mortality) 
Secondary 
Secondary 
Descriptive 
Secondary 
Number of ventilator free days between baseline and Day 8, 15, 22, and 
29 
Secondary 
Secondary 
Descriptive 
Secondary 
Number of days of hospitalization among survivors up to Day 8, 15, 22, 
and 29 
Secondary 
Secondary 
Descriptive 
Secondary 
1 The main approach in Cohort 1 to the analysis of patients “Critical not receiving mechanical ventilation at baseline” will be through an analysis of a subset of 
the overall ITT population to assess if an effect observed in the ITT population is observed both in the subset of patients on mechanical ventilation and not on 
mechanical ventilation at baseline. 
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4.1.2.3. 
Safety Endpoints  
The secondary safety endpoints for Phase 2 and 3 are: 
1. Proportion of patients with serious adverse events 
2. Proportion of patients with Grade 4 neutropenia (ANC <500/mm3) 
3. Proportion of patients with severe or life-threatening bacterial, invasive fungal, or 
opportunistic infection 
4. Proportion of patients with severe or life-threatening bacterial, invasive fungal, or 
opportunistic infection in patients with Grade 4 neutropenia (ANC <500/mm3) 
5. Proportion of patients with hypersensitivity reactions  
6. Proportion of patients with infusion reactions  
7. Proportion of patients with gastrointestinal perforation 
8. White cell count, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST, on Days 1, 
3, 5, 8, 11, 15, and 29 (if still hospitalized) 
4.1.3. 
Exploratory Endpoints 
Phase 2 and 3:  
The exploratory endpoints are: 
1. Qualitative and quantitative PCR for SARS-CoV-2 in OP/NP swab on Days 1, 4, and 29 
2. Time to 2 consecutive negative OP/NP swab PCR results for SARS-CoV-2 
3. Qualitative and quantitative PCR for SARS-CoV-2 in blood on Days 1, 4, and 29 
4. Change from baseline in circulating cytokines on Days 4, 7, and 29 
5. Change from baseline in serum CRP levels 
6. Concentrations of sarilumab and sIL-6R in serum 
Phase 3 only: 
1. Efficacy endpoints specified in Table 4 will be used to characterize the efficacy of 
sarilumab 200 mg in all disease severity strata (Cohort 1 only) 
2. Efficacy endpoints specified in Table 4 will be used to characterize the efficacy of 
sarilumab 400 mg in severe, MSOD, and immunocompromised patients (Cohort 1 only) 
3. Subgroup analysis of proportion of patients with at least 1-point improvement in clinical 
status from baseline to Day 22 in patients with a baseline IL-6 level >230 pg/mL and 
<230 pg/mL, by CRP tertile, and by neutrophil-to-lymphocyte ratio tertile 
4. Subgroup analysis of proportion of patients alive and not receiving ventilation at Day 21 
in patients with COVID-19 with baseline IL-6 ≥230 pg/mL compared to those with IL-6 
<230 pg/mL  
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5. Subgroup analysis of proportion of patients who recover (discharged, or alive without 
supplemental oxygen use or at pre-COVID oxygen use) by Day 22 in patients with a 
baseline IL-6 level >230 pg/mL and <230 pg/mL, by CRP tertile, and by 
neutrophil-to-lymphocyte ratio tertile  
6. Subgroup analysis of proportion of patients who die through Day 29 in patients with a 
baseline IL-6 level >230 pg/mL and <230 pg/mL, by CRP tertile, and by 
neutrophil-to-lymphocyte ratio tertile 
7. Subgroup analysis of proportion of patients who die through Day 60 in patients with a 
baseline IL-6 level >230 pg/mL and <230 pg/mL, by CRP tertile, and by 
neutrophil-to-lymphocyte ratio tertile 
8. Subgroup analysis of proportion of patients alive not receiving mechanical ventilation or 
ECMO at Day 22 in patients with a baseline IL-6 level >230 pg/mL and <230 pg/mL, by 
CRP tertile, and by neutrophil-to-lymphocyte ratio tertile 
9. Subgroup analysis of proportion of patients with a 2-point improvement in clinical status 
on the 7-point ordinal scale from baseline to Day 22 in patients with a baseline IL-6 level 
>230 pg/mL and <230 pg/mL, by CRP tertile, and by neutrophil-to-lymphocyte ratio tertile 
10. Subgroup analysis of proportion of patients receiving mechanical ventilation or ECMO at 
Day 22 in patients with a baseline IL-6 level >230 pg/mL and <230 pg/mL, by CRP tertile, 
and by neutrophil-to-lymphocyte ratio tertile 
11. Subgroup analysis of proportion of patients discharged and alive at Day 22 in patients with 
a baseline IL-6 level >230 pg/mL and <230 pg/mL, by CRP tertile, and by neutrophil-to-
lymphocyte ratio tertile 
12. Time to discharge or to a NEWS2 of ≤2 and maintained for 24 hours, whichever occurs 
first 
Patients will not be recalled after discharge for any missing exploratory assessments.  
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
disease characteristics, medical history, and medication history for each patient. 
The site investigator will assess the patient for a history of chronic hypercapnic respiratory failure 
(eg, due to chronic obstructive pulmonary disease) at the screening visit.  Chronic hypercapnic 
respiratory failure is defined as the presence of both of the following criteria:  
1. Documented current or historical PaCO2 >45 mm Hg (measured from arterial blood gas 
analysis), and  
2. A clinician has documented a history of chronic hypercapnic respiratory failure in the 
medical record (Note that there are many ways to document this: chronic hypercapnic 
respiratory failure, CO2 retainer, chronic hypercapnia, chronic alveolar hypoventilation, 
etc). 
5.2. 
Efficacy Variables 
The efficacy variables include serum CRP, body temperature, gas exchange/oxygen requirement, 
requirement for ventilation support, ICU admissions, days of hospitalization, 7-point ordinal scale 
score (to assess clinical status), and NEWS2 specified in the study endpoints (Section 4.1.1), 
survival/mortality status.  
5.3. 
Safety Variables 
Safety variables include incidence of AESIs, SAEs, and laboratory safety test results (white cell 
count including ANC, hemoglobin, platelets, creatinine, total bilirubin, ALT, AST). 
5.4. 
Pharmacokinetic Variables 
The PK variable is the concentration of sarilumab and sIL-6R in serum at each time point specified 
in Table 5.  
5.5. 
Pharmacodynamic and Other Biomarker Variables 
Exploratory endpoint variables include measurement of SARS-CoV-2 in OP or NP swabs over 
time using RT-PCR. Qualitative (positive or negative) or relative quantitation of viral copies may 
be evaluated. Pharmacodynamic variables may include the time to reach a negative OP or NP 
RT-PCR result. 
Additional biomarker testing may include, but not be limited to, evaluation of inflammatory 
cytokines in serum, and ANC.  
Pharmacodynamic variables may include the time to nadir (or peak), mean and median change 
from baseline, mean and median percent change from baseline, and area under the curve (AUC) 
of mean change, median for IL-6 and ANC. 
These results may be reported outside the clinical study report (CSR). 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This study is an adaptive Phase 2/3, randomized, double-blind, placebo-controlled trial to evaluate 
the efficacy and safety of sarilumab in hospitalized adults with severe or critical COVID-19. As 
part of the Phase 3 adaptation plan, the Phase 3 portion of the study will include 3 cohorts. In 
Phase 2 and in Cohort 1 of the Phase 3 portion of the study, patients will be randomized in a 2:2:1 
allocation ratio to sarilumab 400 mg IV, sarilumab 200 mg IV, or placebo up to 26 Apr 2020. As 
of 27 Apr 2020 (as per recommendation of the IDMC), patients in Cohort 1 of the Phase 3 portion 
of the study will be randomized to sarilumab 400 mg or placebo only in the critical stratum in a 
2:1 manner.  Enrollment into Cohort 1 closed when approximately 170 patients in the critical 
stratum receiving mechanical ventilation at baseline who were randomized to receive either 
sarilumab 400 mg or placebo were enrolled.  Cohorts 2 and 3 began enrolling patients in parallel 
when Cohort 1 enrollment completed.  In Cohort 2, patients being treated with mechanical 
ventilation at baseline will be randomized 1:1 to receive sarilumab 800 mg IV or placebo., In 
Cohort 3, patients receiving high-intensity oxygen therapy without mechanical ventilation were 
randomized 1:1 to receive sarilumab 800 mg IV or placebo.  As of 06 Jun 2020, per 
recommendation of the IDMC, new patients will no longer be enrolled into Cohort 3.  Cohort 2 
will continue to enroll.  All patients will continue to be monitored and complete all assessments 
per protocol.  The study will be conducted in the United States in up to 150 sites.  The Sponsor 
may close enrollment into one or more severity categories, strata, or dose arms at any time to 
ensure adequate numbers of patients are enrolled into other categories or for other reasons related 
to safety, efficacy, futility, or new external information.  
Randomization 
For Phase 2 and Phase 3 Cohort 1, randomization will be stratified by: 
• Severity of illness at enrollment 
− Severe disease 
− Critical disease 
− Multi-system organ dysfunction 
− Immunocompromised 
• Systemic corticosteroids (Yes/No) 
The severity categories are: 
1. Severe disease  
• Requires supplemental oxygen administration by nasal cannula, simple face mask, or 
other similar oxygen delivery device  
2. Critical disease:  
• Requires supplemental oxygen requiring delivered by non-rebreather mask or 
high-flow nasal cannula, OR 
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• Use of invasive or non-invasive ventilation, OR 
• Requiring treatment in an ICU  
3. Multi-system organ dysfunction:  
• Multi-system organ dysfunction: use of vasopressors, extracorporeal life support, or 
renal replacement therapy 
4. Immunocompromised 
• Immunocompromised patients (or on immunosuppressant treatments) 
For Cohort 2, only patients as defined in Section 7.2.1 will be enrolled.  Randomization will be 
stratified by use of a non-IL6/6R therapy under an Emergency Use Authorization (EUA) at 
randomization (Yes/No) and use of systemic corticosteroids at randomization (Yes/No). 
Dosing  
Based on the IDMC recommendation, as of 27 Apr 2020, the severe and MSOD groups will no 
longer enroll or receive study drug.  Based on a 2nd IDMC recommendation, as of 06 Jun 2020, 
patients may only receive study drug while receiving mechanical ventilation. Throughout the 
study, study drug should be withheld if there is a high degree of suspicion of active bacterial or 
fungal infection.  Patients who received a prohibited medication will not be eligible for re-dosing.  
Phase 3 Cohort 1: 
Patients will receive a single dose of study drug on Day 1.  Patients can be re-dosed at 24 hours 
(±6 hours) if the patient is receiving mechanical ventilation and meets 1 of the following criteria: 
a. Remains febrile OR 
b. Fails to improve gas exchange (eg, as measured by ventilator settings or O2 
requirements) OR 
c. Is hemodynamically unstable OR 
d. Exhibits other objective evidence of clinical worsening (eg, mental status change, etc.) 
Additional doses may be administered weekly as early as Day 8 only for patients receiving 
mechanical ventilation at the time of re-dosing whose ANC is >500/mm3 and ALT is ≤5x ULN. If 
a patient received a 2nd dose other than Day 2, adjust subsequent weekly doses accordingly.  A 
maximum of 6 doses can be administered. 
Phase 3 Cohort 2: 
In Cohort 2, a maximum of 4 doses in total can be administered during the study.  The minimum 
dosing interval between any 2 doses is 18 hours. 
Day 1  
Patients will receive a single dose of study drug on Day 1 only if they are receiving mechanical 
ventilation at the time of dosing.   
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Day 2 through 7  
Patients will be re-dosed on Day 2 if they are receiving mechanical ventilation at the time of re-
dosing and meet at least 1 of the following criteria on the day the dose is administered:  
a. Remains febrile, OR 
b. Fails to improve gas exchange (eg, as measured by ventilator settings or oxygen 
requirements), OR 
c. Is hemodynamically unstable, OR 
d. Exhibits other objective evidence of clinical worsening (eg, mental status change, etc.) 
 
If the patient does not meet criteria for dosing on Day 2, study drug administration may be delayed 
up until Day 7. Study drug should be administered as early as possible between Days 2 and 7 
(preferably Day 2) on the earliest day that the patient meets dosing criteria.  Study drug should not 
be administered within 18 hours of the beginning of Day 8 (since scheduled dosing will occur on 
Day 8).  If the patient does not meet criteria for dosing on any day between Days 2 and 7, then no 
dose will be administered. 
Days 8 through 14  
A single dose of study drug will be administered on Day 8 if the patient meets all 3 of the following 
criteria on the day the dose is administered: 
a. Requires mechanical ventilation at the time of re-dosing AND 
b. ANC >500/mm3, AND 
c. ALT ≤5x ULN 
The minimum dosing interval between any 2 doses is 18 hours. If the patient does not meet criteria 
for dosing on Day 8, study drug administration may be delayed up until Day 14. Study drug should 
be administered as early as possible between Days 8 and 14 (preferably Day 8) on the earliest day 
that the patient meets dosing criteria.  Study drug should not be administered within 18 hours the 
beginning of Day 15 (since the scheduled dosing will occur on Day 15).  If the patient does not 
meet criteria for dosing on any day between Days 8 and 14, then no dose will be administered. 
Days 15 through 21  
A single dose of study drug will be administered on Day 15 if the patient meets all 3 of the 
following criteria on the day the dose is administered: 
a. Requires mechanical ventilation at the time of re-dosing, AND 
b. ANC >500/mm3, AND 
c. ALT ≤5x ULN 
The minimum dosing interval between any 2 doses is 18 hours. If the patient does not meet criteria 
for dosing on Day 15, study drug administration may be delayed up until Day 21. Study drug 
should be administered as early as possible between Days 15 and 21 (preferably Day 15) on the 
earliest day that the patient meets dosing criteria. If the patient does not meet criteria for dosing on 
any day between Day 15 and Day 21, then no dose will be administered. 
There is no dosing after Day 21. 
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Phase 3 Cohort 3: 
As of 06 Jun 2020, patients in Cohort 3 will no longer be enrolled or continue to receive study 
drug. 
Safety  
To maximize safety, the first approximately 12 patients who are randomized and receive the study 
drug will be monitored for safety (assuming a total of ~10 patients are dosed on the sarilumab 
doses of 200 mg IV or 400 mg IV).  Safety data on these 12 patients will be reviewed by an IDMC 
after the last of these patients dosed reaches Day 7.  Data on the first ~12, ~25, and ~50 patients 
(regardless of severity of illness) who reach at least Day 7 will be reviewed by the IDMC and 
Regeneron senior physicians to determine if a treatment arm should be discontinued for safety 
reasons.  Selected treatment groups in the Phase 2 portion may be continued forward in the 
remainder of the study.  In addition to these specific assessment times, the IDMC will actively 
monitor interim data to make recommendations about early study closure or changes to study arms 
throughout the course of the study. 
Assessments  
Patients will be assessed daily while hospitalized. Discharged patients will be contacted by 
telephone on Day 29 to assess status and occurrence of re-admission to a hospital.  Patients will 
undergo a series of efficacy, safety, and laboratory assessments while in the hospital.  Baseline 
serum IL-6 and other cytokines will be collected and analyzed in a central laboratory.  Baseline 
IL-6 levels will not be used as inclusion criteria or used for stratification at randomization. 
Oropharyngeal (OP) or NP samples to monitor viral infection and blood samples will be obtained 
on Day 1 (predose), 3, and 29 (or up until the day of discharge if the patient is discharged from the 
hospital before Day 29). The study is expected to last up to approximately 1 year, depending on 
the status of the COVID-19 outbreak.   
Figure 1: 
Study Flow Diagram for Phase 2 and Phase 3 
Phase 2 
 
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Phase 3 
 
a. If the patient has been discharged from the hospital before day 29, the study site staff will contact the patient 
for a follow-up phone call on Day 29 and Day 60.  
b. If the patient has been discharged from the hospital before day 60, the study site staff will contact the patient 
for a follow-up phone call 
c. The EOS will be on day 60 or day of death, whichever comes first 
EOS: End of study; R: Randomization; IV: intravenous 
6.1.1. 
Study Stopping Rules 
6.1.1.1. 
Individual Patient Stopping Rules 
For an individual patient, an investigator should assess potential benefit-risk to determine if study 
drug should be interrupted or discontinued for suspected drug-related events of infusion-related 
reactions.  Refer to Section 8.3 for details. 
6.1.1.2. 
Study Level Stopping Rules 
An independent data monitoring committee (IDMC) will actively monitor interim data to review 
the ongoing safety of patients and can make recommendations about early study closure or changes 
to the conduct of the study. The Sponsor may decide to stop or make adaptations to the study based 
upon the recommendations by the IDMC. 
A treatment arm may be dropped if there is a clinically meaningful imbalance between treatment 
arms in any of the following criteria: 
1. Incidence of SAEs 
2. Incidence of AESIs 
3. Progression of COVID-19 to more severe, critical, or multi-organ dysfunction 
4. Incidence of clinically significant recurrence of severe or critical disease after clinical 
improvement 
5. An obvious risk/benefit imbalance based upon any key efficacy endpoint of the study such 
that one dosing arm appears to be doing substantially better than another with an acceptable 
safety profile without requiring any specific statistical level of precision 
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6.1.2. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last study assessment (in the 
hospital or via a follow-up phone call if the patient was discharged from the hospital before 
Day 60), withdraws from the study, or is lost to follow-up (ie, the study patient can no longer be 
contacted by the investigator).  
6.2. 
Planned Timing of Analysis 
The first analysis of data is planned for safety and efficacy monitoring when the first approximately 
12 patients are randomized, receive a study drug, and have at least 7 days of follow-up. Data, 
including deaths, on these first 12 patients as well as all patients enrolled in the study at that time 
regardless of severity of illness will be reviewed by an IDMC and, separately, by unblinded senior 
physicians at Regeneron. Subsequently, separate reviews of data by the IDMC and Regeneron 
senior physicians will occur after the first 25 and first 50 patients regardless of severity of illness 
are enrolled and complete 7 days of follow-up. These analyses will include data, including deaths, 
from all randomized patients. These analyses will be performed to determine if a treatment arm 
should be discontinued for safety reasons. 
An analysis of the Phase 2 data is also planned when approximately 460 patients with all baseline 
IL-6 levels are randomized and treated, after which the Sponsor will make any appropriate updates 
to the Phase 3 study plan. 
Separate database locks for Cohorts 1 and 2 of the Phase 3 portion of the study are planned.   
Interim analyses may be performed as described Section 11.5.1. 
IDMC will continue to monitor the safety of patients throughout the study as specified in the IDMC 
charter.  
A description of the statistical methods to be employed is in Section 11, and blinding implications 
are discussed in Section 8.5. 
6.3. 
Study Committees 
6.3.1. 
Independent Data Monitoring Committee 
An IDMC will actively monitor interim data to review the ongoing safety of patients and can make 
recommendations about early study closure or changes to the protocol. The IDMC members will 
include 2 to 4 physicians with relevant medical specialty training and 1 statistician.  The operation 
of the IDMC is governed by a charter describing further details such as frequency of meeting, 
procedures (including but not limited to periodic safety monitoring) and requirements for reporting 
its observations to the Sponsor. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
The total sample size for Phase 2 will be approximately 460 to include patients with all baseline 
IL-6 levels.  Based on results from Phase 2 data, sample size for Phase 3 was re-calculated.  For 
Cohort 1 of the Phase 3 portion of this study, the total sample size will be approximately 
1,400 patients.  Enrollment into Cohort 1 will end when approximately 170 patients in the critical 
stratum receiving mechanical ventilation at baseline who were randomized to receive either 
sarilumab 400 mg or placebo are enrolled.  The total sample size for Cohort 2 will be 
approximately 225 patients.  The planned sample size for Cohort 3 was 225 patients, however, 
enrollment ended on 06 Jun 2020 at which time 9 patients enrolled. Cohorts 2 and 3 enrolled in 
parallel when Cohort 1 enrollment completed.   
7.2. 
Study Population 
Hospitalized adult (≥18 years old) male and female patients with COVID-19. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female adult ≥18 years of age at time of enrollment  
2. Hospitalized (or documentation of a plan to admit to the hospital if the patient is in an 
emergency department) with illness of any duration with evidence of pneumonia by chest 
radiograph, chest computed tomography or chest auscultation (rales, crackles), requires 
supplemental oxygen and/or assisted ventilation and meets 1 of the following criteria:   
Phase 2 and Phase 3 Cohort 1: must meet at least 1 of the following at baseline (patients 
meeting more than one criterion will be categorized in the most severely affected category): 
• Severe disease  
− Requires supplemental oxygen administration by nasal cannula, simple face mask, 
or other similar oxygen delivery device (ie, above pre-COVID baseline 
requirement, if any, by the patient)  
• Critical disease  
− Requires supplemental oxygen delivered by non-rebreather mask or high-flow 
nasal cannula, OR 
− Use of invasive or non-invasive ventilation, OR 
− Requiring treatment in an ICU  
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• Multi-system organ dysfunction 
− Multi-system organ dysfunction: use of vasopressors, extracorporeal life support, 
or renal replacement therapy 
Note: patients receiving vasopressors for reasons other than circulatory shock (eg, 
related to sedation or mechanical ventilation) may be randomized into the critical 
stratum  
• Immunocompromised 
− Immunocompromised patients (or on immunosuppressant treatments) 
Phase 3 Cohort 2: Patients must be receiving mechanical ventilation to treat respiratory 
failure due to COVID-19. 
3. Laboratory-confirmed SARS-CoV-2 infection as determined by a PCR result from any 
specimen (or other commercial or public health assay) within 2 weeks prior to 
randomization and no alternative explanation for current clinical condition  
4. Willing and/or able to comply with study-related procedures/assessments 
5. Provide informed consent signed by study patient or legally acceptable representative 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. In the opinion of the investigator, not expected to survive for more than 48 hours from 
screening. 
2. Presence of any of the following abnormal laboratory values at screening: ANC less than 
2000 mm3, AST or ALT >5x ULN, platelets <50,000 per mm3 
3. Treatment with anti-IL-6, anti-IL-6R antagonists, or with Janus kinase inhibitors (JAKi) in 
the past 30 days or plans to receive during the study period 
4. Current treatment with the simultaneous combination of leflunomide and methotrexate  
5. Exclusion criteria related to tuberculosis (TB) 
a. Known active TB or a history of incompletely treated TB 
b. Suspected or known extrapulmonary TB  
6. Patients with suspected or known active systemic bacterial or fungal infections 
Note:  Patients with a history of positive bacterial or fungal cultures but on enrollment does 
not have suspected or known active systemic bacterial or fungal infections may be enrolled. 
7. (Placeholder for Case Report Form [CRF]: Exclusion removed per Amendment 4) 
8. Participation in a double-blind clinical research study evaluating an investigational product 
or therapy within 3 months and less than 5 half-lives of investigational product prior to the 
screening visit.  
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Exception:  The use of remdesivir, hydroxychloroquine, or other treatments being used for 
COVID-19 treatments in the context of an open-label study, EUA, compassionate use 
protocol, or open-label use is permitted 
9. Any physical examination findings, and/or history of any illness, concomitant medications 
or recent live vaccines that, in the opinion of the study investigator, might confound the 
results of the study or pose an additional risk to the patient by their participation in the 
study 
10. Known systemic hypersensitivity to sarilumab or the excipients of the drug product 
Phase 3 Cohort 2 only: 
11. Known or suspected history of immunosuppression (eg, due to immunosuppressant 
medication) or immunodeficiency disorder  
Note: Patients receiving systemic corticosteroids for COVID-19 and patients receiving 
chronic low dose systemic corticosteroids at a dose less than or equal to 10 mg/day of 
prednisone (or an equivalent dose of another corticosteroid) may be eligible for inclusion. 
Well controlled HIV infection with a recent undetectable viral load is not an exclusion 
criterion 
12. Patients who require renal replacement therapy for acute kidney injury at randomization or 
who required renal replacement therapy within 72 hours prior to randomization 
Note: Patients who have chronic end-stage renal disease on chronic hemodialysis or 
peritoneal dialysis prior to their hospitalization may be eligible for inclusion. 
13. Patients who have circulatory shock requiring vasopressors at randomization or within 
24 hours prior to randomization 
Note: Patients who require vasopressors for sedation-related hypotension or reasons other 
than circulatory shock may be eligible for inclusion. 
14. Use of extracorporeal life support (eg, ECMO) or, in the opinion of the investigator, there 
is a high likelihood that extracorporeal life support will be initiated within 48 hours after 
randomization 
7.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who have taken study drug should be encouraged to remain in the study to allow for the 
collection of information and biological samples for study purposes. Patients who opt to withdraw 
from the study may be asked to provide a final blood draw sample for PK analysis before 
withdrawing from the study (Section 9.1.2) and to allow for re-contact at the end of the trial 
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(Day 60 follow-up phone call) in order to collect data on survival and history of hospital 
readmission. 
Rules for discontinuation of study treatment are discussed in Section 8.2.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational Treatment 
In Phase 2 and Phase 3 Cohort 1, all patients randomized and dosed will receive 1 of the following: 
• Sarilumab 200 mg IV for 1-hour  
• Sarilumab 400 mg IV for 1-hour 
• Placebo IV for 1-hour 
For Phase 3 Cohort 2, all patients randomized and dosed will receive 1 of the following: 
• Sarilumab 800 mg IV for 1-hour 
• Placebo IV for 1-hour 
Instructions on dose preparation are provided in the pharmacy manual.  
8.2. 
Dose Modification and Study Treatment Discontinuation Rules 
8.2.1. 
Dose Modification 
Eligible patients will receive repeat dosing per the criteria outlined in Section 6.1. Per the 
recommendation of the IDMC, as of 27 Apr 2020, patients will no longer receive 
sarilumab 200 mg or be eligible for repeat dosing of 200 mg and patients in the severe and MSOD 
strata will no longer receive sarilumab 400 mg or placebo.  As of 06 Jun 2020, based on an IDMC 
recommendation, only patients receiving mechanical ventilation at the time of dosing will receive 
study drug (Phase 3 Cohorts 1 and 2), including re-dosing.  Patients will no longer be enrolled or 
receive study drug in Phase 3 Cohort 3.  Patients will continue to be monitored and complete all 
assessments per protocol. 
8.2.2. 
Study Drug Discontinuation 
Study drug may be temporarily withheld if ANC <500/mm3 or ALT >5x ULN, or at the discretion 
of the investigator according to the instructions in Section 6.1.  Study drug may be continued if, 
upon repeat testing, ANC >500/mm3 and ALT ≤5x ULN. 
Patients who opt to withdraw from the study may be asked to provide a final blood draw sample 
for PK and other exploratory PD biomarker analysis before withdrawing from the study 
(Section 9.1.2). 
8.3. 
Management of Acute Reactions 
8.3.1. 
Acute Intravenous Infusion Reactions 
Emergency equipment and medication for the treatment of infusion reactions must be available for 
immediate use.  All Grade ≥2 infusion-related reactions must be reported as AESIs  (see 
Section 10.1.3 and Section 10.2.4) and graded using the grading scales as instructed in 
Section 10.2.5. 
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8.3.1.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• sustained/severe cough 
• rigors/chills 
• rash, pruritus (itching) 
• urticaria (hives, welts, wheals) 
• diaphoresis (sweating) 
• hypotension 
• dyspnea (shortness of breath) 
• vomiting 
• flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate. 
If investigators feel there is a medical need for treatment or discontinuation of the infusion other 
than described above, they should use clinical judgment to provide the appropriate response 
according to typical clinical practice. 
8.3.1.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following adverse events occur: 
• anaphylaxis* 
• laryngeal/pharyngeal edema 
• severe bronchospasm 
• chest pain 
• seizure 
• severe hypotension 
• other neurological symptoms (confusion, loss of consciousness, paresthesia, paralysis, 
etc.) 
• any other symptom or sign that, in the opinion of the investigator, warrants termination 
of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006): acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE 
FOLLOWING: 
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
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8.4. 
Method of Treatment Assignment 
In the Phase 2 study and Cohort 1 of the Phase 3 study, patients will be randomized in a ratio of 
2:2:1 to receive sarilumab 400 mg IV, or sarilumab 200 mg IV or placebo, in a stratified manner.  
In Phase 3, Cohort 2, patients will be randomized in a ratio of 1:1 to receive sarilumab 800 mg IV 
or placebo IV stratified by the use of systemic corticosteroids and by non-IL6/6R therapy 
administered under an EUA. Randomization will be performed according to a central 
randomization scheme using an interactive web response system (IWRS).   
Phase 2 and Phase 3 Cohort 1: 
Randomization will be stratified by: 
• Severity of illness at enrollment  
− Severe disease   
− Critical disease 
− Multi-system organ dysfunction 
− Immunocompromised 
• Systemic corticosteroids (Yes/No) 
For Cohort 2, only patients meeting criteria as defined in Section 7.2.1 will be enrolled.  
Randomization will be stratified by use of a non-IL6/6R therapy under an EUA at randomization 
(Yes/No) and use of systemic corticosteroids at baseline (Yes/No).   
While serum IL-6 and cytokines will be measured at a central laboratory predose on Day 1 and 
periodically after treatment, patients will not be stratified based on serum IL-6 levels. However, 
analyses will be conducted by baseline IL-6 levels. 
For this adaptive Phase 2/3 study, based on the planned analyses (see Section 6.2), the IDMC and 
Sponsor may decide to drop an arm due to safety reasons.  Accordingly, the randomization may 
be adjusted during the trial. 
8.5. 
Blinding 
A pharmacist or qualified personnel at the site, not otherwise associated with the conduct of the 
study, will reconstitute the drug for IV administration. The drug infusion solution must be provided 
in identical form for active and placebo treatments, so that they remain indistinguishable to both 
study personnel and patients. Study patients, the principal investigators, and study site personnel 
will remain blinded to all randomization assignments throughout the study. The Regeneron 
Medical/Study Director, Study Monitor, and any other Regeneron and contract research 
organization (CRO) personnel who are in regular contact with the study site will remain blinded 
to all patient randomization assignments. 
The study team directly involved with the study conduct will be blinded.  Selected individuals not 
involved in the conduct of the study may have access to unblinded data as needed for safety review 
or 
other 
data 
review. 
 
An 
independent 
team 
at 
Regeneron, 
including 
senior 
physicians/management, will be unblinded and in communication with the IDMC and will make 
decisions for adaptations to the study during the Phase 2 portion of the study. 
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Blinding of CRP Assessment Results 
The study patients and select Regeneron study team members directly involved in the conduct of 
the study will remain blinded to post-treatment CRP values.  
8.6. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event and when a treatment decision is contingent on knowing the 
patient's treatment assignment. Study drug will be discontinued for patients whose treatment has 
been unblinded (Section 8.2.2).  
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the patient. Unblinding is performed using the 
IWRS which will notify Regeneron.   
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient's treatment 
assignment.  In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel.  
8.7. 
Treatment Logistics and Accountability 
8.7.1. 
Packaging, Labeling, and Storage 
Sarilumab for injection, 175 mg/mL will be provided as open-label supplies packaged in boxes. 
Each box will contain 1 prefilled syringe or vial. Each box will be labeled with a 1-panel, open 
label printed in black. The product identity and strength, container number, directions for use, 
route of administration and storage conditions will be indicated. 
Open-label study drug will display the product lot number on the label. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.7.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed/returned to the sponsor 
or designee. 
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8.7.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
• dispensed to each patient 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
8.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors.  
8.8. 
Concomitant Medications 
Any treatment administered from the first dose of study drug to the final study assessment will be 
considered concomitant medication. This includes medications that were started before the study 
and are ongoing during the study. 
If the local standard of care per written policies or guidelines includes lopinavir/ritonavir (Kaletra) 
or other agents, then continuing these during the study is permitted.  
CYP Substrates 
Interleukin-6 has been shown to reduce cytochrome (CY)P1A2, CYP2C9, CYP2C19, and 
CYP3A4 enzyme expression in in vitro studies. Therefore, it is expected that for a molecule that 
antagonizes cytokine activity, such as sarilumab, the formation of cytochrome P450 (CYP450) 
enzymes could be normalized, and as a result drugs that are metabolized by these CYP450 isoforms 
may have decreased levels when patients start receiving sarilumab. As a precautionary measure, 
drugs which are metabolized via these cytochromes and with a narrow therapeutic index should 
be closely monitored and adjusted if needed. Some examples of CYP450 substrates with a narrow 
therapeutic index requiring monitoring of effect are warfarin; examples of substrates that require 
monitoring of drug concentration include, but are not limited to, the following: warfarin, CsA, 
theophylline, digoxin, antiepileptics, such as carbamazepine (Carbatrol®, Tegretol®), divalproex 
(Depakote®), phenytoin (Dilantin®), or valproic acid (Depakene®); or antiarrhythmics, such as 
disopyramide (Norpace®), procainamide (Procan®, Pronestyl®), or quinidine (Quinidex®, Quin 
Release Quin- G®). 
Concomitant medications in a hospitalized population change daily and are difficult to collect and 
attribute to success and failure of therapy and impact on safety. Therefore, only select concomitant 
medications will be captured in this trial. The select list of medications will be assessed Day 1 to 
Day 29 (or until day of discharge from hospital if before Day 29) include corticosteroids, 
remdesivir, lopinavir-ritonavir, chloroquine, hydroxychloroquine, interferon beta, and 
convalescent serum. Refer to Section 9.2.3.4 for a complete list of concomitant medications that 
should be collected. 
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8.8.1. 
Prohibited and Permitted Medications 
Patients may continue their normal regimen of medications and procedures, except for those 
specified in the exclusion criteria for study enrollment (Section 7.2.2). Patients who receive a 
prohibited medication will not be eligible for re-dosing of study drug. 
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
Study assessments and procedures are presented by study period/day in Table 5. 
 
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Table 5: 
Schedule of Events 
Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 and 
discharge3,4 
60 
Window  
 
 
 
 
 
 
±7 days 
±7 days 
Screening/Baseline: 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Demographics and Medical History1 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Treatment: 
Study Drug Administration (only if receiving 
mechanical ventilation) 
 
X 
X5 
 
 
X5 
 
 
Assessments: 
Oxygen administration (FiO2) and 
Oxygenation (SpO2)6 
X 
X 
Phase 2 & Phase 3 Cohort 1 - 2 times a day 
Phase 3 Cohorts 2 and 3 - At least once per day and any time 
clinical status changes (eg, endotracheal intubation/extubation or 
requires change in oxygen delivery device) 
 
Clinical Status Assessment (7-point ordinal 
scale)7 
 
X 
Daily until discharge 
 
NEWS2 Score 
 
 
 
 
Air or oxygen 
 
X 
Daily in the morning until discharge 
 
Respiratory rate  
 
X  
Daily in the morning until discharge 
 
BP 
 
X 
Daily in the morning until discharge 
 
Pulse 
 
X 
Daily in the morning until discharge 
 
Consciousness 
 
X 
Daily in the morning until discharge 
 
Body temperature before antipyretics or 
4 hours after antipyretics8 
 
X 
Daily in the morning until discharge 
 
Imaging, microbiology results, and arterial 
blood gas results (as available)9 
 
 
If available in the medical record 
 
Limited physical examination (lung 
auscultation only) 
X 
 
 
 
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Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 and 
discharge3,4 
60 
Window  
 
 
 
 
 
 
±7 days 
±7 days 
Electrocardiogram (ECG), if feasible10 
X 
 
 
 
Record Targeted Medications11 
X 
 
Daily until discharge 
 
Adverse Events12 
X 
 
X 
Pregnancy Test (WOCBP)13 
X 
 
 
 
Follow-up Phone Call 
 
 
 
 
 
 
X 
X 
Laboratory Testing: 
C-Reactive Protein (mandatory) 
X 
X 
 
X 
X  
 
 
 
 
 
 
Order CRP with all routine labs and obtain at the same time  
Record all results when available in medical chart 
 
Hematology14 
X 
 
Must be collected within 48 hours prior to redosing  
Record all results when available in medical chart 
 
Blood chemistry (including LFTs and 
creatinine)15 
X 
 
Must be collected within 48 hours prior to redosing  
Record all results when available in medical chart 
 
Ferritin, LDH, d-dimer 
 
X 
(mandatory) 
When available 
 
Blood cultures for bacteria and fungi16  
 
 
 
 
X 
X 
Weekly culture 
based on ANC16 
 
 
PK/Biomarkers/Research (defer to footnotes for sampling requirements): 
 
-1 or 1 
1 
2 
4 
7 
8 to 23 
(Only collect on 
day of dosing) 
29 or 
discharge3,4 
60 
Serum for PK/Sarilumab Concentration17 
 
X 
X 
X 
X 
X 
X 
 
Serum sIL-6R plus research17 
 
X 
X 
X 
X 
X 
X 
 
Serum cytokines including IL-6 and 
biomarker testing17 
 
X 
 
X 
X 
X 
X 
 
Blood for PCR SARS-CoV-217,18 
X 
X 
 
X 
 
 
X 
 
Oropharyngeal or nasopharyngeal swab for 
SARS-COV-2 detection and sequencing17,18 
X 
X 
 
X 
 
 
X 
 
Blood for research plasma17 
 
X 
 
 
 
 
X 
 
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Study Procedure 
Screening 
Visit1 
Baseline 
Visit1 
Daily Follow-up Until Hospital Discharge 
EOS2 
Day 
-1 or 1 
1 
2 
4 
7 
8 to 23 
29 and 
discharge3,4 
60 
Window  
 
 
 
 
 
 
±7 days 
±7 days 
 
 
 
X 
 
 
 
 
 
 
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9.1.1. 
Footnotes for the Schedule of Events Table 
1. Screening and baseline may occur on the same day. Assessments that are noted for both 
visits should only be assessed once. Medical history should include collecting onset of 
pneumonia symptoms.  Body temperature, SpO2, and FiO2 must be collected at 
randomization.   
2. Patients will have an end of study (EOS) assessment to collect data on survival and history 
of hospital re-admission.  This assessment may be performed by phone. 
3. Patients discharged prior to Day 29 will have a follow-up phone call on Day 29 to collect 
data on survival and history of hospital re-admission and do not need to be recalled to the 
hospital for a visit. 
4. Patients discharged prior to or after Day 29 should have a sample collected.  If day of 
discharge is not Day 29 and coincides with another visit, the Day 29 assessments should 
be performed. 
5. Patients will be re-dosed according to Section 6.1.  
6. Oxygen administration and oxygenation: refer to Section 9.2.2.3 of the protocol for details. 
SpO2 must be measured after 5 minutes of rest (sitting or supine) and must be measured 
simultaneously with oxygen administration and ventilation data. Record oxygen flow rate 
(L/min) for patients receiving nasal cannula, simple face mask, or non-rebreather mask. 
Record FiO2 for patients receiving high flow nasal cannula, non-invasive ventilation, 
mechanical ventilation, or extracorporeal membrane oxygenation.  
7. Clinical Status Assessment using the 7-point ordinal scale: refer to Section 9.2.2.4 of the 
protocol for details.  
8. Temperature may be measured using the following methods: oral, rectal, tympanic, or 
temporal according to local hospital protocols and according to the manufacturer’s 
instructions for use of the device. Body temperature should be measured using the same 
method each time. Temperature should be measured predose after at least 5 minutes of rest 
(supine or sitting).  
9. If available in the medical record, chest CT images will be collected as part of a separate 
effort related to this study for predictive exploratory analysis and may be provided in a 
separate study report. 
10. ECG only if feasible.  Historical ECG from current hospital admission is acceptable. 
11. Targeted medications: refer to Section 9.2.3.4 of the protocol for details.  
12. Adverse events: Only SAEs and AESIs will be recorded in eCRF. 
13. Pregnancy testing to be performed in women of childbearing potential (WOCBP) only. 
Serum or urine pregnancy test are both acceptable. 
14. Hematology: refer to Section 9.2.3.5 of the protocol for details. CBC is required prior to 
randomization (standard of care labs may be used). After Day 1, CBC will not be performed 
as a study procedure. When CBC is performed as part of the patient’s clinical care, the 
results will be entered in eCRF. 
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15. Blood Chemistry: refer to Section 9.2.3.5 of the protocol for details. LFTs and creatinine 
are required prior to randomization (standard of care labs may be used). After Day 1, LFTs 
and creatinine will not be performed as a study procedure. When chemistries are performed 
as part of the patient’s clinical care, the results will be entered in eCRF. 
16. Surveillance blood cultures for bacteria and fungi should be performed weekly for patients 
who have had a sustained ANC <1000/µL for >48 hours post-randomization.   
17. All samples should be collected before study drug administration except post-infusion PK 
and sIL-6R samples: 
• PK and sIL-6R samples collected on dosing days for the initial dose and for the FIRST 
repeat dose are mandatory.  Samples for subsequent doses are requested if sufficient 
PPE are available:  
⎯ 
One predose (as close to initiation of treatment as reasonable) and  
⎯ 
One within 60 minutes after the end-of-infusion (EOI).  The EOI sample or 
flush should be collected from the arm, contralateral to that used for IV 
infusion, if possible.  If not medically feasible, the sample can be drawn from 
the same arm.  If the sample cannot be obtained within 60 minutes of the end 
of infusion, the time from end of infusion should be provided in the CRF  
⎯ 
Day 4 samples are mandatory (if PPE and appropriate lab facilities are 
available). 
• The Day 1 predose sample and Day 29 or Early Termination PK sample may be used 
for ADA analysis. 
18. Swab and tests will be for exploratory analysis only not for inclusion or diagnosis. 
 
 
 
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9.1.2. 
Early Termination from the Study  
Patients who are withdrawn from the study before the primary endpoint assessment (Day 29) may 
be asked to provide a final blood draw sample for PK analysis before withdrawing from the study 
(Table 5) and to allow for re-contact at the end of the trial (Day 60 follow-up phone call) in order 
to collect data on survival and history of hospital re-admission.  
9.2. 
Study Procedures  
9.2.1. 
Procedures Performed Only at the Screening/Baseline 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline characteristics of the study population: demographics, medical 
history, timing of COVID-19 infection, prior therapy, pregnancy status.  
The investigator or sub-investigator will verify that the patient tests positive for SARS-CoV-19 
RT-PCR and record the result, specimen type, date of test, and the type of assay in the eCRF.  
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
C-Reactive Protein 
Serum CRP will be measured at each site’s local laboratory according to the schedule in Table 5.  
See Section 9.2.3.5 for details.  
9.2.2.2. 
Body Temperature 
Body temperature measurement will occur before taking antipyretics or more than 4 hours after 
last dose of antipyretics.  Body temperature will be measured to monitor the patient’s status 
regarding fever per the schedule in Table 5. Temperature may be measured using the following 
methods: axilla, oral, rectal, tympanic, or temporal according to local hospital protocols and 
according to the manufacturer’s instructions for use of the device. Body temperature should be 
measured using the same method each time. Temperature should be measured after at least 
5 minutes of rest (supine or sitting).  
9.2.2.3. 
Oxygen Administration and Oxygenation 
Supplemental oxygen/FiO2 use will be measured to monitor the patient’s status regarding gas 
exchange per the schedule in Table 5. As applicable, the following will be recorded: 
• Oxygen delivery device (eg, nasal cannula, simple face mask, non-rebreather mask, 
high flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, 
extracorporeal life support, etc) 
• Oxygen flow rate in Liters/min (if receiving nasal cannula, simple face mask, 
non-rebreather mask)  
• FiO2 (if receiving high flow nasal cannula, non-invasive ventilation, invasive 
mechanical ventilation, or extracorporeal life support) 
If a patient is using more than one device (eg, extracorporeal life support and invasive ventilation), 
information from both devices will be recorded separately.  
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Resting SpO2 will be measured to assess arterial oxyhemoglobin saturation. SpO2 will be measured 
using a fingertip or similar non-invasive device following 5 minutes of rest (inactivity) while 
supine, semi-recumbent, or sitting and will only be measured in the presence of a good SpO2 wave 
form. SpO2 must be measured simultaneously with recorded supplemental oxygen/FiO2 data. 
Additional data to be collected include (when available from the medical record): arterial pH, 
partial pressures of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide in arterial 
blood (PaCO2), oxyhemoglobin saturation in arterial blood from arterial blood gas analysis (SaO2).  
9.2.2.4. 
Clinical Status Assessment (7-Point Ordinal Scale) 
Cohort 1: A Clinical Status Assessment  (7-point ordinal scale) (Peterson, 2017) should be 
assessed in the morning to consider the worst assessments for the previous day (ie, midnight to 
midnight; 00:00 – 00:00 [24-hour clock]). If it is the first assessment and 24 hours of data are not 
available, report status at randomization. 
Cohort 2:   
• Ordinal Scale will be assessed (1) at the time of randomization and must match the 
stratum assigned by the investigator in the IRT, and (2) at the time of the administration 
of the first dose of study drug (which should be administered on Day 1 in most cases). 
Oxygen delivery device data may be used to calculate the ordinal scale.   
• Beginning on Day 3, the Ordinal Scale should be assessed in the morning to consider 
the worst assessments for the previous day (ie, midnight to midnight; 00:00 – 00:00 
[24-hour clock]). Therefore, the Day 3 assessment will reflect the patient’s clinical 
status on Day 2. 
The 7-point ordinal scale is: 
• Death; 
• Hospitalized, requiring invasive mechanical ventilation or ECMO; 
• Hospitalized, requiring non-invasive ventilation or high flow oxygen devices; 
• Hospitalized, requiring supplemental oxygen; 
• Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise) 
• Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical 
care 
• Not hospitalized 
9.2.2.5. 
NEWS2 Scoring System 
The NEWS2 scoring system (Table 6) is a composite score derived from respiratory rate (per 
minute), SpO2 Scale 1 (%) or SpO2 Scale 2 (%), Use of air or oxygen (?), Systolic blood pressure 
(mm Hg), Pulse (per minute), Consciousness, and Temperature (°C). 
The NEWS2 score will be assessed daily in the morning. 
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Table 6: 
The NEWS2 Scoring System 
 
As part of the NEWS2 score, the patient’s mental status (ACVPU) will be assessed and categorized 
into one of the following categories: 
• Alert: A fully awake patient with spontaneous opening of the eyes, response to voice, 
and has motor function.  
• Confusion: A patient may be alert but confused or disorientated.  It is not always 
possible to determine whether the confusion is ‘new’ when a patient presents acutely 
ill.  Such a presentation should always be considered to be ‘new’ until confirmed to be 
otherwise. New-onset or worsening confusion, delirium or any other altered mentation 
should always prompt concern about potentially serious underlying causes and 
warrants urgent clinical evaluation. 
• Voice: The patient makes some kind of response when you talk to them, which could 
be in any of the three component measures of eyes, voice or motor – eg patient’s eyes 
open on being asked ‘Are you okay?’. The response could be as little as a grunt, moan, 
or slight movement of a limb when prompted by voice.  
• Pain: The patient makes a response to a pain stimulus. A patient who is not alert and 
who has not responded to voice (hence having the test performed on them) is likely to 
exhibit only withdrawal from pain, or even involuntary flexion or extension of the 
limbs from the pain stimulus. The person undertaking the assessment should always 
exercise care and be suitably trained when using a pain stimulus as a method of 
assessing levels of consciousness.  
• Unresponsive: This is also commonly referred to as ‘unconscious’. This outcome is 
recorded if the patient does not give any eye, voice or motor response to voice or pain. 
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9.2.3. 
Safety Procedures 
9.2.3.1. 
Vital Signs 
Vital signs, including blood pressure, pulse, and respiration, will be collected and recorded at the 
time points according to Table 5. Predose body temperature should be recorded on the vital signs 
eCRF. 
9.2.3.2. 
Limited Physical Examination 
A targeted physical examination including lung auscultation will be performed at time point 
according to Table 5. Care should be taken to examine and assess any abnormalities that may be 
present, as indicated by the patient’s medical history.  
9.2.3.3. 
Electrocardiogram 
If feasible, a standard 12-lead ECG will be performed at time points according to Table 5. An 
historical ECG from the present hospital admission (including ED stay) may be used.  The ECG 
strips or reports will be retained with the source.  
9.2.3.4. 
Targeted Medication Review 
The patient’s medications will be reviewed and recorded, including but not limited to use of: 
• antipyretics, such as aspirin, acetaminophen, ibuprofen, and other non-steroidal 
anti-inflammatory drugs (NSAIDs) 
• warfarin  
• cyclosporine A 
• theophylline 
• digoxin  
• antiepileptics, such as carbamazepine (Carbatrol®, Tegretol®), divalproex 
(Depakote®), phenytoin (Dilantin®), valproic acid (Depakene®);  
• antiarrhythmics, such as disopyramide (Norpace®), procainamide (Procan®, 
Pronestyl®), quinidine (Quinidex®, Quin Release Quin- G®) 
• antivirals, antibacterial, and antifungals 
• anti-parasitics (chloroquine or hydroxychloroquine) 
• interferon beta  
• corticosteroids 
• convalescent serum  
• angiotensin receptor blockers, such as Azilsartan (Edarbi), Candesartan (Atacand), 
Eprosartan (Teveten), Irbesartan (Avapro), Losartan (Cozaar), Olmesartan (Benicar), 
Telmisartan (Micardis), Valsartan (Diovan) 
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• angiotensin converting enzyme inhibitors: benazepril (Lotensin), captopril (Capoten), 
enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril 
(Univasc), perindopril (Aceon), quinapril (Accupril) 
9.2.3.5. 
Laboratory Testing 
Serum CRP will be measured at each site’s local laboratory according to the schedule in Table 5.  
All patients should have white blood cell count, platelet count, AST, and ALT measured prior to 
randomization (see Section 7.2.2). If these laboratory tests were not performed as part of the 
patient’s clinical care, they may be performed as study procedures in the site’s local laboratory.  
After randomization, when patients enrolled in this study undergo laboratory testing as part of their 
standard-of-care, the results of these tests will be provided to the Sponsor, as indicated.  
Certain tests that are not necessarily part of the patient’s standard-of-care will also be collected as 
part of this study, as indicated.  
Laboratory test results that may be recorded are Table 5. Tests may include: 
Blood Chemistry 
All patients should have a hepatic function panel, serum ferritin, and serum LDH at baseline prior 
to administering study drug. The results of blood chemistry testing that is performed as part of the 
patient’s standard-of-care will be shared with the Sponsor. These samples will be analyzed by a 
local laboratory.  LFTs and creatinine are required prior to randomization (standard of care labs 
may be used). After Day 1, LFTs and creatinine will not be performed as a study procedure. When 
chemistries are performed as part of the patient’s clinical care, the results will be entered in eCRF. 
A typical blood chemistry panel is shown below: 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Glucose 
Alkaline phosphatase 
Ferritin 
Albumin 
Lactate dehydrogenase (LDH) 
 
*(low-density lipoprotein [LDL] and high-density lipoprotein [HDL]) 
Hematology/Coagulation 
All patients would have a complete blood count with differential and a d-dimer performed at 
baseline prior to administering study drug. The results of hematology testing that is performed as 
part of the patient’s standard-of-care will be shared with the Sponsor. These samples will be 
analyzed by a local laboratory.  CBC is required prior to randomization (standard of care labs may 
be used). After Day 1, CBC will not be performed as a study procedure. When CBC is performed 
as part of the patient’s clinical care, the results will be entered in eCRF 
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A typical hematology panel is shown below: 
Hemoglobin 
Differential: 
Hematocrit 
Neutrophils 
Red blood cells (RBCs) 
Lymphocytes 
White blood cells (WBCs) 
Monocytes 
Platelet count 
Basophils 
 
Eosinophils 
Other Laboratory Tests 
Screening: 
Patients eligible for study participation will have tested positive for SARS-CoV-19 RT-PCR. This 
test will be performed as part of standard-of-care and the results will be provided to the Sponsor.  
Safety: 
Pregnancy testing will be performed using urine or serum samples at screening in women of 
childbearing potential. A positive pregnancy test is not exclusionary for study participation but 
will be recorded.  
Culture results (bacterial, fungal, or viral) including specimen source (BAL, tracheal aspirate, 
sputum, blood, urine, etc) performed as part of patients’ workup for new infection should be 
reported to the Sponsor. 
Phase 2 and Phase 3 Cohort 1:  Surveillance bacterial and fungal blood cultures: Blood samples 
will be collected on Day 7 and Day 15 for blood cultures. If the patient is discharged before Day 15, 
blood cultures will be collected on the day of discharge.    
Phase 3 Cohort 2: surveillance blood cultures for bacteria and fungi should be performed weekly 
for patients who have had a sustained ANC <1000/µL for >48 hours post-randomization. 
Biomarkers/Research Samples: 
Serum samples will be collected to measure cytokines and biomarkers such as IL-6, soluble IL-6R 
and will be analyzed by a central laboratory.  
Nasopharyngeal (NP)/oropharyngeal (OP) swabs will be used to collect secretions from patients 
to determine presence or absence of SARS-CoV-2 virus and to explore relative quantitation of 
viral load as an exploratory measure. In addition to RT-PCR to quantify viral load, viral sequencing 
may be performed if sufficient sample is available to determine the sequence and variations. 
Detailed instructions for blood/OP and NP swab sample collections are in the laboratory manual 
provided to study sites. 
9.2.4. 
Drug Concentration and Measurements 
Samples for measurement of sarilumab and sIL-6R in serum will be collected at visits listed in 
Table 5. These samples will be analyzed either by the Sponsor or a central laboratory.  
 
  
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9.2.5. 
Pharmacodynamic and Exploratory Biomarker Procedures 
In this study, research assessments will be performed to explore how sarilumab may modify the 
clinical manifestations and pathology associated with COVID-19 and how the IL-6 signaling 
pathway may be modulated.  
Biomarker samples will be collected at time points according to Table 5. PD marker/Biomarker 
measurements will be performed to determine the target pathway of IL-6 inhibition and the impact 
on pneumonia and respiratory illness associate with viral infection and pathology. Relative 
quantitation of viral load and viral sequencing may be evaluated using methodologies that include 
but may not be limited to RT-PCR and sequencing. Additional biomarkers related to anti-viral 
immunity, including but not limited to neutralizing antibodies may also be measured. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all serious clinical events and AESIs occurring during the 
study data collection, from the time of signing the ICF to the end of study. Medical conditions that 
existed or were diagnosed prior to the signing of the Informed Consent will be recorded as part of 
medical history. Abnormal laboratory values and vital signs observed at the time of Informed 
Consent should also be recorded as medical history.  
Throughout the study, the investigator will determine whether any AEs have occurred by 
evaluating the patient. Adverse events may be directly observed, reported spontaneously by the 
patient, or by questioning the patient at each study visit.  Patients should be questioned in a general 
way, without asking about the occurrence of any specific symptoms. The Investigator must assess 
all AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 10.2. The Investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature. The Investigator should follow up on SAEs (and 
AESIs) until they have resolved or are considered clinically stable; AEs should be followed until 
they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE.   
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance.  
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization).  A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior to 
signing the Informed Consent Form) procedures, treatments requiring hospitalization for 
pre-existing conditions that do not worsen in severity, and admission for palliative or social care 
should not be reported as SAEs (see Section 10.2 for Definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any SAE that may occur subsequent to the reporting period (end of study) that the Investigator 
assesses as related to study drug should also be reported. 
All serious adverse events (SAEs), AESIs, and pregnancy reports are to be reported according to 
the procedures in Section 10.1.3.   
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10.1.2. 
Reporting Procedure  
All SAEs and AESIs (serious and non-serious) must be reported with investigator’s assessment of 
the event’s seriousness, severity, and causality to the blinded study drug.  A detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome should be 
provided on the AE CRF. Specific or estimated dates of event onset, treatment, and resolution 
should be included, when available. Medical history, concomitant medications, and laboratory data 
that are relevant to the event should also be summarized in the narrative.  For fatal events, the 
narrative should state whether an autopsy was or will be performed and include the results if 
available. Information not available at the time of the initial report must be documented in a 
follow-up report. Source documents (including hospital or medical records, diagnostic reports, etc) 
will be summarized in the narrative on the AE CRF and retained at the study center and available 
upon request. 
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• Adverse Events of Special Interest (AESI; serious and nonserious): Adverse events 
of special interest for this study include the following: 
− Grade ≥2 infusion-related reactions 
− Grade ≥2 hypersensitivity reactions 
− Grade 4 neutropenia (ANC <500/mm3) 
− Grade 4 neutropenia with concurrent invasive infection (ANC <500/mm3) 
− Invasive bacterial or fungal infections of clinical significance with confirmed 
diagnosis based on the investigator’s assessment with appropriate diagnostic 
workups and consultations 
− Increase in alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥3X 
ULN (for patients with normal baseline) or >3X ULN AND at least 2-fold increase 
from baseline value (for patients with abnormal baseline) 
• Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility 
of the investigator to report to the sponsor (or designee), within 24 hours of 
identification, any pregnancy occurring in a female study patient, during the study or 
existing at the time of signing the informed consent form. Any complication of 
pregnancy affecting a female study patient, and/or fetus and/or newborn that meets the 
SAE criteria must be reported as an SAE. Outcome for all pregnancies should be 
reported to the sponsor. 
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10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994).  
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient re-hospitalization (readmission after discharge) or prolongation 
of existing hospitalization. In-patient hospitalization is defined as a hospital 
re-admission (any duration) or an emergency room visit for longer than 24 hours. 
Prolongation of existing hospitalization is defined as a hospital stay that is longer than 
was originally anticipated for the event or is prolonged due to the development of a 
new AE as determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
interest specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate.  Such an event might warrant 
further investigation in order to characterize and understand it.   
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10.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed.  
10.2.5. 
Severity  
The severity of AEs will be graded using the NCI-CTCAE v5.  Adverse events not listed in the 
NCI-CTCAE v5 will be graded according to the following scale: 
Table 7: 
Grading System for Adverse Events Not Listed in NCI-CTCAE  
Grade 
Severity 
Description 
1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.   
2  
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*.   
3  
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**. 
4  
Life–threatening 
Life-threatening consequences; urgent intervention indicated. 
5  
Death 
Death related to AE 
* Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
10.2.6. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions.  The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
For double blinded studies using an active comparator, the investigator should consider all study 
drugs in determining event causality.   
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug and same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when applicable  
• Patient’s medical and social history  
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Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study or its class of drugs or is predicted 
by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified procedure 
or can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments 
(eg, Pharmacovigilance; Risk Management; Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
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10.4. 
Notifying Health Authorities, Institutional Review Board, and 
Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, IRBs, and the 
participating investigators of any SUSARs (Suspected Unexpected Serious Adverse Reactions) 
occurring in other study centers using the active study drug (sarilumab), as appropriate per local 
reporting requirements. In addition, the sponsor and/or CRO will comply with any additional local 
safety reporting requirements. All notifications to investigators will contain only blinded 
information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the IRB unless delegated to the sponsor. 
 
 
 
. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report to health authorities and IRB as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plans (SAPs) for the study.  There will 
be 2 separate SAPs for this study; one will be for Phase 2 and second for Phase 3. The SAPs will 
be revised prior to the end of each portion of the study (Phase 2 or Phase 3) to accommodate 
amendments to the clinical study protocol and to make changes to adapt to unexpected issues in 
study execution and data that may affect the planned analyses. The final SAPs will be issued before 
the first database lock in each portion of the study (Phase 2 or Phase 3). 
Endpoints are listed in Section 4. Analysis variables are listed in Section 5. 
This adaptive Phase 2/3 study is intended to allow for adaptations such as follows: dropping of a 
treatment group for safety reasons; confirmation or modification of the endpoints for Phase 3; and 
sample size re-estimation in Phase 3.  Therefore, treatment groups in Phase 3 and analyses for 
Phase 3 portion will depend on the final endpoints and treatment groups selected based on Phase 2 
results.   
The Phase 3 portion will be powered and analyzed independently of the Phase 2 portion, in order 
to ensure that the Phase 3 portion is confirmatory and to avoid inflating the Type I error rate of the 
Phase 3 portion of the study.  
As mentioned in Section 3.2.2, the adaptations to the Phase 3 cohorts include: 1) dropping of the 
sarilumab 200-mg dose group, 2) modification of the Phase 3 endpoints, 3) addition of Cohorts 2 
and 3, ie, new cohorts of patients randomized to sarilumab 800 mg or placebo, and 4) justification 
of sample size for Cohort 1 and establishing sample sizes for Cohorts 2 and 3.  
11.1. 
Statistical Hypothesis 
Phase 2 Portion of the Study 
For the Phase 2 portion of the study, the hypothesis to be tested is the superiority of sarilumab 
versus placebo with respect to the primary endpoint of percent change from baseline in CRP levels 
at Day 4 (Section 4.1.1 and Section 11.4.3.1). 
The statistical hypotheses (null H0 vs. alternative H1) for the primary endpoint are: 
𝐻0: 𝜇1 = 𝜇2     versus    𝐻1: 𝜇1 ≠𝜇2 
where μ1 and μ2 are mean percent changes from baseline in CRP-levels at Day 4 (based on natural 
logarithm scale) in the 2 treatment groups.  
The statistical hypotheses (null H0 vs. alternative H1) for the Phase 2 key secondary efficacy 
endpoint of time-to-improvement (2 points) in clinical status from baseline using the 7-point 
ordinal scale, time-to-resolution of fever and time-to-improvement in oxygenation (Section 4.1.2) 
are stated below. 
𝐻0: 𝑆1(𝑡) = 𝑆2(𝑡) for all time 𝑡     versus    𝐻1: 𝑆1(𝑡) ≠𝑆2(𝑡) for some time 𝑡  
where S1 (t) and S2 (t) are the survival probability functions of the above endpoints.   
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Phase 3 Portion of the Study (Prior to Adaptation) 
For the Phase 3 portion, the study is intended to allow for adaptation of the primary endpoint based 
on results from the Phase 2 data, ie, confirmation or modification of the primary endpoint. Hence 
the final endpoint may be different.  The currently specified primary endpoint for Phase 3 is 
time-to-improvement (2 points) in clinical status from baseline on the 7-point ordinal scale 
(Section 4.1.1).  The statistical hypotheses for this endpoint are the same as stated above for 
Phase 2 time-to-event endpoint. 
Phase 3 Portion of the Study (Post-Adaptations) 
Based on the adaptations to the Phase 3 study design, the null hypotheses to be tested (separately) 
in each of the 3 Phase 3 Cohorts corresponding to the final primary endpoint are: 
Cohort 1 
H10:  Sarilumab 400 mg IV is not different than placebo in terms of proportion of patients with at 
least a 1-point improvement in clinical status from baseline to Day 22 using the 7-point ordinal 
scale in patients with critical COVID-19 receiving mechanical ventilation at baseline. 
Cohort 2 
H20:  Sarilumab 800 mg IV is not different than placebo in terms of proportion of patients with at 
least a 1-point improvement in clinical status from baseline to Day 22 using the 7-point ordinal 
scale in patients with COVID-19 receiving mechanical ventilation at baseline.   
 
The statistical hypotheses (null H0 vs. alternative H1) for each of these can be stated as: 
𝐻10: 𝑝1
(1)=𝑝0
(1)     versus    𝐻11: 𝑝1
(1)≠𝑝0
(1) 
𝐻20: 𝑝1
(2)=𝑝0
(2)    versus    𝐻21: 𝑝1
(2)≠𝑝0
(2) 
where 𝑝1
(1)(𝑝1
(2)) and 𝑝0
(1)(𝑝0
(2)) are the proportions of responders in the sarilumab and placebo 
treatment groups  within Cohorts 1 and 2, respectively. 
 
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11.2. 
Justification of Sample Size 
For the Phase 2 portion of the study, approximately 200 patients (80 in each of the 2 sarilumab 
dose groups and 40 on placebo) are required in all disease severity strata with high baseline IL-6 
levels to test for superiority of sarilumab versus placebo with respect to percent change from 
baseline CRP levels at Day 4.  This sample size will provide 90% power using a 2-sample t-test to 
detect an effect size (ie, difference/SD) of 0.633 at the 0.05 (2-sided) significance level.  The effect 
size of 0.633 assumes that the mean treatment difference in percent change from baseline using 
natural logarithm of CRP levels (sarilumab minus placebo) would be -6.6% with a standard 
deviation of 10.43% (percent change from baseline in sarilumab is estimated to be mean = -45.98% 
and SD=10.43% based on tocilizumab data from China study in COVID-19; See Figure 2 in 
(Xu, 2020).  If the effect in the placebo group is assumed to be negligible (~0%) and variability in 
CRP is high, then the power could be much greater than 90% for larger effect sizes (eg, treatment 
difference = -50% and SD = 30%, effect size = 1.667).  Total sample size for Phase 2 is expected 
to be larger than 200 to include patients with all baseline IL-6 levels.  
Additional patients are being included in Phase 2 to allow for adequate estimation and improve 
precision of the treatment effect using the Phase 3 clinical endpoint—time to improvement 
(2 points) in clinical status (7-point ordinal scale)—prior to making adaptations to Phase 3 study 
design.  The total sample size for Phase 2 is updated to be approximately 460 patients, to include 
patients with all baseline IL-6 levels. 
Phase 3 Portion of the Study (Prior to Adaptations) 
Sample size calculations for the Phase 3 portion of the study prior to adaptations were based on 
the Phase 3 primary endpoint of time-to-improvement (2 points) in clinical status from baseline on 
the 7-point ordinal scale, using the log-rank test of superiority.  Median time-to-improvement 
(2 points) in clinical status was assumed to follow an exponential survival distribution with 
difference between sarilumab and placebo median times assumed to be 2 days (5 days in placebo 
and 3 days in sarilumab group). 
With a 2:2:1 randomization ratio (sarilumab 400 mg IV:sarilumab 200 mg IV:placebo) and 
assuming that accrual duration is 1 year (~365 days) with each patient followed for a period of at 
least 29 days, the Phase 3 portion of the study would require a total of approximately 300 patients 
in the severe and critical strata with high baseline IL-6. For a pairwise comparison between each 
sarilumab dose (400 mg IV or 200 mg IV) and placebo using a log-rank test, a sample size of 
approximately 123 on sarilumab and 61 on placebo (184 total) will provide 90% power at a 2-sided 
significance level of 0.05. 
This study plans to enroll approximately 400 patients in Phase 3 Cohort 1 (across all IL-6 levels 
and severity of illness) in order to have 300 patients in the severe and critical strata to test the 
primary hypothesis in high IL-6 patients.  The number of patients enrolled may be revised based 
on the observed distribution of baseline IL-6 levels in Phase 2.   
Due to the novel nature of the COVID-19 pandemic, the ordinal scale primary efficacy endpoint 
planned in Phase 3 is not well established and will require confirmation based on Phase 2 data. At 
the end of the Phase 2 portion, power calculations will be reassessed, and Phase 3 sample size may 
be re-estimated.  
 
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Phase 3 Portion of the Study (Post-Adaptations) 
Sample size calculations for the Phase 3 portion of the study after the adaptations are based on the 
Phase 3 primary endpoint of the percentage of patients who were on mechanical ventilation at 
baseline and had at least a 1-point improvement in the ordinal scale (ie, alive and off of ventilation). 
In Cohort 1, the hypothesis is tested only in patients in the critical stratum, first in the subgroup of 
patients on mechanical ventilation at baseline and then, as an enrichment strategy, in the overall 
critical stratum (ITT).  In the Phase 2 portion of the study, approximately 17% of patients treated 
with placebo (ie, standard of care) and 57% of patients treated with sarilumab (on top of standard 
of care) achieved at least 1-point improvement by Day 22. 
Cohort 1: With a 2:1 randomization ratio (sarilumab 400 mg IV: placebo), an effect size the same 
as that observed in Phase 2, and 170 patients in the critical stratum on mechanical ventilation, then 
the pairwise comparison between sarilumab 400 mg (n~113) and placebo (n~57) would have 
>99% power. Assuming the response rate on placebo is 17% and the rate on sarilumab 400 mg is 
37% (ie, a difference in proportions is one-half that observed in Phase 2), then the sample size of 
170 would provide approximately 80% power to detect this reduced difference.  These calculations 
assume alpha=0.045, allowing for an interim analysis at the 0.005 level (see Section 11.5.1.  
Therefore, this study plans to enroll approximately 450 critical patients in order to have 
approximately 170 patients within the critical stratum who are on mechanical ventilation and 
randomized to 400 mg or placebo.  Note that the total number of patients enrolled in Phase 3 
Cohort 1 is larger than that to account for the patients who had been randomized to the severe 
stratum, MSOD stratum, or to the 200-mg dose group before the IDMC decision to discontinue 
further enrollment into those strata and dose groups. 
Cohort 2: With a 1:1 randomization ratio (sarilumab 800 mg IV: placebo), an effect size the same 
as that observed in Phase 2 for 400 mg, and 225 patients total, then the pairwise comparison 
between sarilumab 800 mg (n=113) and placebo (n=112) would have >99% power to detect the 
difference observed in Phase 2, and would have 92% power if the effect were half of that observed 
in Phase 2 (ie, 20% difference).  These calculations assume alpha=0.045, allowing for an interim 
analysis at the 0.005 level.  A sample size re-estimation may occur after Phase 3 Cohort 1 results 
are determined.   
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
ITT population:  The intention-to-treat (ITT) population includes all randomized patients who 
received at least one dose of the study drug.  Analysis of the ITT population will be done according 
to the initial treatment assigned to the patient (as randomized). ITT population will be used for 
sensitivity analysis of the efficacy endpoints in Phase 2, as well as for analysis of data including 
(but not limited to) demographics and baseline characteristics.  ITT population will be the primary 
analysis population for the Phase 3 Cohorts 1 and 2.  For Cohort 1, the specific primary population 
will be the subset of patients on mechanical ventilation at baseline. 
mITT population:  The modified intention-to-treat (mITT) population includes all randomized 
patients who received at least one dose of the study drug and have high baseline IL-6 levels. 
Analysis of the mITT population will be done according to the initial treatment assigned to the 
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patient (as randomized). The mITT population will be the primary population for analysis of 
primary and secondary efficacy endpoints in Phase 2, as well as for data including (but not limited 
to) demographics and baseline characteristics. 
PPS:  The per protocol population set (PPS) includes all ITT patients who did not have any 
relevant major protocol deviations. A relevant major protocol deviation is one that may affect the 
interpretation of study efficacy results. The final determination of the definition of PPS will be 
made prior to the first database lock.  Analysis of the PPS will be done according to the treatment 
the patient actually received (as treated). Determination of “as treated” will be based on the actual 
study drug received on Day 1. The PPS will be used only in Phase 3 Cohorts 1 and 2for sensitivity 
analysis of the primary efficacy endpoints. 
11.3.2. 
Safety Analysis Set 
Safety population: The safety population includes all randomized patients who received at least 
one dose of the study drug. Analysis of the Safety population will be done according to the 
treatment received (as treated). Determination of “as treated” will be based on the actual study 
drug received on Day 1. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Subgroups will be defined by key baseline factors (eg, demographics, disease characteristics). 
Subgroup analyses will be performed on efficacy endpoints and safety endpoints, as needed.  
Details will be described in the Statistical Analysis Plan (SAP). 
Statistical analyses will be performed using Statistical Analysis Software (SAS) Version 9.4 or 
higher. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized patients:  received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
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• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
• The ITT population, mITT population, and PPS (defined in Section 11.3.1) 
• The Safety population (defined in Section 11.3.2) 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
11.4.3. 
Efficacy Analyses 
The study analysis plan is based on the analysis of 2 populations, an mITT and an ITT population, 
within specific strata or combinations of strata.  Supportive analyses may also be performed using 
the PPS population. 
11.4.3.1. Primary Efficacy Analysis 
Phase 2 portion of study (COVID-19 patients in all disease severity strata): 
For the Phase 2 portion of the study, the primary efficacy analysis will be a pairwise comparison 
between sarilumab 400 mg IV and placebo with respect to the primary endpoint of percent change 
from baseline in CRP levels (natural logarithm scale) at Day 4.   
Percent change from baseline in CRP levels is estimated using the natural log-transformed data.  
Missing values of CRP levels at Day 4 will be imputed by Day 3 or Day 5 levels when available, 
in this order of priority. CRP levels measured by local labs will be used to compute the primary 
endpoint.  If local lab data is missing, then data from central labs will be used.  Sensitivity analysis 
will be conducted using the CRP data from central labs.  Additional details on missing data 
handling will be specified in the SAP. 
Hypothesis test of superiority of sarilumab versus placebo will be done using an ANCOVA model 
with change from baseline in CRP at Day 4 as dependent variable; treatment group, severity of 
illness and systemic corticosteroid use as fixed effects, and ln(Baseline CRP) as covariate.  
Estimation of treatment effect will be provided in terms of percent change from baseline in CRP 
levels at Day 4 along with 2-sided 95% confidence intervals.  P-values will be compared to the 
2-sided 5% significance level.  
To determine the success of the Phase 2 portion of the trial, first the data in patients with high 
baseline IL-6 will be analyzed (mITT).  If the treatment difference is statistically significant, 
similar analysis will be done between sarilumab 400 mg IV and placebo on the data for the full 
Phase 2 ITT population (that is, without regard to baseline IL-6 levels).  In addition, the key 
secondary endpoint, time to improvement (2 points) in clinical status from baseline on the 7-point 
ordinal scale, will also be analyzed as below using Phase 2 data. These analyses will be used to 
inform selection of the primary endpoint for Phase 3 portion.  Comparison between sarilumab 
200 mg IV and placebo will also be performed descriptively. 
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Phase 3 portion of the study (COVID-19 patients in Cohort 1 critical disease severity 
stratum; and COVID-19 patients in Cohort 2): 
Post adaptations to the Phase 3 study design, the primary efficacy analyses will be 2 separate 
pairwise comparisons, namely:  
1. One in Cohort 1 critical patients with mechanical ventilation at baseline comparing 
sarilumab 400 mg IV versus placebo, and 
2. Second in Cohort 2 patients receiving mechanical ventilation at baseline comparing 
sarilumab 800 mg IV versus placebo. 
 
Primary endpoint for each comparison will be proportion of patients with a 1-point improvement 
in clinical status from baseline to Day 22 using the 7-point ordinal scale.  Hypothesis tests of 
superiority of sarilumab (400 mg or 800 mg-dose) versus placebo will be done using the stratified 
Cochran-Mantel-Haenszel (CMH) test for 2 proportions.  For Cohort 1, the stratification factor 
will be use of corticosteroids (yes/no). For Cohort 2, the stratification factors will be use of non-
IL-6/6R therapies administered under an EUA at baseline (yes/no) and use of corticosteroids 
(yes/no).   
Estimation of the treatment effect will be provided as differences in proportions and confidence 
intervals calculated using the strata-adjusted confidence intervals from CMH method 
(Zhang, 2016). Stratification factors are as mentioned above. 
For each cohort, p-values and confidence intervals will be reported with overall Type 1 error 
controlled at 0.05 (2-sided). 
11.4.3.2. Secondary Efficacy Analysis 
Analysis for Phase 2 Key Secondary Endpoints: 
The key secondary endpoint of time-to-improvement (2 points) in clinical status assessment with 
7-point ordinal scale will be analyzed for Phase 2 similarly as described above for the Phase 3 
primary endpoint in COVID-19 patients (all disease severity strata) with high baseline IL-6 
(ie, mITT) as well as in the ITT population of all baseline IL-6 levels. 
Testing of the key secondary endpoint for the Phase 2 portion of the study will be done at the 
significance level of 0.05 (2-sided).  P-values for other secondary endpoints will also be reported 
and compared with 0.05 (2-sided) significance level for descriptive purpose. 
Analysis for Phase 3 Key Secondary Endpoints: 
The following key secondary endpoints in Phase 3 will be tested similarly as the Phase 3 primary 
endpoint described in Section 11.4.3.1.  See Table 4 for details for secondary endpoints.   
Cohort 1 
1. Proportion of patients with at least 1-point improvement in clinical status assessment from 
baseline to Day 22 in patients with critical COVID-19  
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2. Proportion of patients who recover (discharged, or alive without supplemental oxygen use 
or at pre-COVID oxygen use) by Day 22 in patients with critical COVID-19 receiving 
mechanical ventilation at baseline 
3. Proportion of patients who die through Day 29 in patients with critical COVID-19 
receiving mechanical ventilation at baseline 
4. Proportion of patients who die through Day 29 in patients with critical COVID-19 
Cohort 2 
1. Proportion of patients who recover (discharged, or alive without supplemental oxygen use 
or at pre-COVID oxygen use) by Day 22 in patients with COVID-19 receiving mechanical 
ventilation at baseline 
2. Proportion of patients who die through Day 29 in patients with COVID-19 receiving 
mechanical ventilation at baseline 
Key secondary endpoints for the Phase 3 portion of the study will be tested sequentially in a 
hierarchical manner, while preserving the overall significance level at 0.05 (2-sided). 
Analysis for Other Secondary Endpoints (Phase 2 and Phase 3): 
1. Differences in time-to-event endpoints by treatment (eg, time to a one category 
improvement in ordinal scale, and other time-to-event endpoints) will be summarized with 
Kaplan-Meier estimates and 95% confidence intervals on medians will be reported. P-
values and confidence intervals for hazard ratios comparing treatment groups will also be 
reported using Cox proportional hazards model with stratification factors mentioned 
earlier.  Cumulative incidence rates will be plotted with comparisons between groups 
descriptively tested using log-rank test. 
2. Change in ordinal scale at specific time points will be summarized by proportions 
(eg, proportion who have a 1-, 2-, 3-, or 4-point improvement or 1-, 2-, 3-, 4-point 
worsening). 
3. Duration of event (eg, duration of mechanical ventilation, ventilator-free days, days of 
hospitalization) will be summarized through descriptive statistics including mean, standard 
deviation, and median days with quartiles.  P-values using 2-sample t-test and 95% 
confidence intervals using normal approximation will also be reported. 
4. Continuous endpoints and their changes from baseline will be summarized through 
descriptive statistics including mean, standard deviation, median and quartiles, and 95% 
confidence intervals of means, as needed. 
5. Categorical data (eg, 28-day mortality or ordinal scale by day) will be summarized 
according to proportions with confidence intervals on the difference or odds ratios for a 
binary or multiple category scale, respectively. 
Missing data procedures will be described in the SAP. 
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11.4.4. 
Control of Multiplicity 
Phase 2 Portion of the Study (Prior to Adaptations) 
For the Phase 2 portion of the study, hypothesis test will be conducted for the Phase 2 primary 
endpoint of percent change from baseline in CRP levels at Day 4 in patients across all disease 
severity strata in mITT population (ie, high baseline IL-6).  If there is substantial overlap between 
mITT (eg, ≥95%, then ITT will be the primary population).  Otherwise, ITT population will be 
tested sequentially.   
The key secondary endpoint of time-to-improvement (≥2 points) in clinical status assessment will 
only be descriptively analyzed in Phase 2.  P-values will be reported for descriptive purpose.   
Overall Type 1 error will be controlled at 0.05 level (2-sided) in Phase 2. 
Based on Phase 2 results, adaptations may be made to Phase 3, such as to change Phase 3 endpoints 
and re-estimate the size of the Phase 3 portion of the study.  The final Phase 3 analyses will be 
independent from Phase 2 and possess an independent 5% significance level.  
Phase 3 Portion of the Study (Post-adaptations): 
Primary analyses in Cohorts 1 and 2 will be conducted separately.  Overall type 1 error will be 
controlled within each cohort at 0.05 (2-sided) level.   
Multiplicity adjustment will be made for interim looks and significance level will be adjusted for 
final analysis of the primary endpoint within each cohort.  Overall type 1 error for testing primary 
and key secondary endpoints within each cohort will be controlled using a hierarchical testing 
order as shown in Table 8. 
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Table 8: 
Testing Strategy for Control of Multiplicity in Phase 3 Cohorts 1 and 2 
(Overall Type 1 Error in Each Cohort is 0.05 [2-sided]) 
Order 
Timing of 
Analysis 
Type of 
Endpoint 
Endpoint 
Population 
Example 
Nominal 
Significance 
level, α 
Cohort 1 
 
 
 
 
 
 
1 
Final 
Primary 
Proportion of patients with a 
1- point improvement in 
clinical status from baseline 
to Day 22 
Critical COVID-19 
patients receiving 
mechanical ventilation at 
baseline 
0.049† 
2 
Final 
Key 
Secondary 
Proportion of patients with a 
1- point improvement in 
clinical status assessment 
from baseline to Day 22  
All Critical stratum 
COVID-19 patients 
(including ventilated or 
ECMO or not ventilated 
at baseline) 
0.049† 
3 
Final 
Key 
Secondary 
Proportion of patients who 
recover (discharged, or alive 
without supplemental oxygen 
use) by Day 22 
Critical COVID-19 
patients receiving 
mechanical ventilation at 
baseline 
0.049† 
4 
Final 
Key 
Secondary 
All-cause mortality at Day 29 
Critical COVID-19 
patients receiving 
mechanical ventilation at 
baseline 
0.049† 
5 
Final 
Key 
Secondary 
All-cause mortality at Day 29 
All Critical stratum 
COVID-19 patients 
(including ventilated or 
ECMO or not ventilated 
at baseline) 
0.049† 
Cohort 2  
1 
Final 
Primary 
Proportion of patients with a 
1- point improvement in 
clinical status from baseline 
to Day 22 
COVID-19 patients 
receiving mechanical 
ventilation at baseline 
0.049‡ 
2 
Final 
Key 
Secondary 
Proportion of patients who 
recover (discharged, or alive 
without supplemental oxygen 
use) by Day 22 
COVID-19 patients 
receiving mechanical 
ventilation at baseline 
0.049‡ 
3 
Final 
Key 
Secondary 
All-cause mortality at Day 29 
COVID-19 patients 
receiving mechanical 
ventilation at baseline 
0.049‡ 
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Order 
Timing of 
Analysis 
Type of 
Endpoint 
Endpoint 
Population 
Example 
Nominal 
Significance 
level, α 
† If the interim analysis results for primary endpoint are statistically significant, then the Sponsor may decide to 
stop the cohort earlier for efficacy and the alpha used at interim will be reallocated to test the key secondary 
endpoints at the full α=0.05 (2-sided). If the interim analysis on the primary endpoint is not significant, the 
Sponsor will continue the follow-up of cohort and any interim results on the secondary endpoints will be 
exploratory.  The Sponsor may present nominal p-values for key secondary endpoints at the interim without 
formal testing at interim. 
‡ Interim analyses for Cohort 2.  In case of interim analyses, similar alpha spending and alpha re-allocation rules 
will be used for Cohort 2. 
11.4.5. 
Safety Analysis 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, the following observation period is defined: 
• The on-treatment period is defined as the day from first dose of study drug (Day 1) to 
study Day 29 (patients who are discharged prior to Day 29 will receive a follow-up 
phone call to collect data on SAEs (if any), survival and history of hospital re-
admission). 
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment period. In this 
study, only SAEs and AESIs are collected.  As such TEAEs will reflect this data. 
In addition, there will be an end of study (EOS) phone call follow-up to collect data on survival 
and history of hospital re-admission. 
Analysis 
All SAEs and AESIs reported in this study will be coded using the currently available version of 
the Medical Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level 
terms. The preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all reportable TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.5), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group.  
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11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
11.4.5.3. Treatment Exposure 
Exposure to study drug will be examined for each patient.  The total number of doses administered 
to each patient and exposure related parameters (eg, duration of IV infusion, total volume of drug 
administered etc.) will be analyzed and summarized using descriptive statistics by treatment group 
in the Safety population. 
11.4.5.4. Treatment Compliance 
Treatment compliance in a given patient for this study is defined as the number of fully completed 
infusions of study drug divided by number of doses administered (applicable, both, to patients who 
receive only single dose or multiple doses since protocol amendment #4).  
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The concentrations of sarilumab and sIL-6R over time and selected PK parameters, as appropriate, 
will be summarized using descriptive statistics. 
No formal statistical hypothesis testing will be performed.  
11.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The concentrations of exploratory PD/Biomarkers over time will be summarized using descriptive 
statistics and may be reported separately from the CSR. 
11.5. 
Timing of Analysis 
The timing of the analyses for this study are detailed in Section 6.2. 
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11.5.1. 
Interim Analysis in Phase 3 
Because of the unmet medical need for effective medicines in this global COVID-19 pandemic 
situation, interim analyses are planned for efficacy in the Phase 3 portion of the study.  The timing 
of the first interim analysis will be determined once approximately 110 patients in the Phase 3 
Cohort 1 critical stratum receiving mechanical ventilation at baseline and randomized to 400 mg 
or placebo are enrolled, with a data lock point 22 days later.  Interim analysis for this data lock 
will be conducted in all critical Phase 3 Cohort 1 patients who were enrolled until the first dose 
date of the last 110th patient in Cohort 1 critical stratum randomized to sarilumab 400 mg or 
placebo who was on a ventilator at baseline. 
To preserve the overall Type 1 error at 0.05 in the Phase 3 Cohort 1, the primary efficacy endpoint 
will be tested at interim analysis at the 0.005 level (2-sided), leaving the remaining significance 
level of 0.049 (2-sided) for the final analysis should the interim results not be statistically 
significant.  The information fraction at this first interim analysis will be 65% (ie, 110 patients out 
of 170 at final).  Under the Hwang-Shih-DeCani alpha spending function (Hwang, Shih, DeCani, 
1990, Anderson 2020 [gsDesign R package]) (assume gamma family with parameter γ = -6.5), if 
the interim analysis is not significant, then the nominal significance level for testing the final 
analysis of primary endpoint will be 0.049 (2-sided). 
Should the interim analysis be positive, the alpha from the interim analysis will be recycled and 
added to the alpha for the planned key secondary endpoints which will allow them to be tested at 
a significance level of 0.05.  Similar interim analyses are planned for the Phase 3 Cohort 2 and 
will be specified in the SAP in more detail. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, SAEs, baseline findings, medication, medical history, etc) will be done using 
internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) Medidata 
Rave. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
The study monitor and/or designee will visit each site prior to enrollment of the first patient, and 
periodically during the study. This study will use the principles of risk-based monitoring (ICH).  
This means that the number of visits for any given site may vary based on site risk indicators. The 
investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
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12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate, and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel. All required CRFs must be 
completed for each and every patient enrolled in the study. The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the sponsor in the CRFs. After 
review of the clinical data for each patient, the investigator must provide an electronic signature.  
A copy of each patient CRF casebook is to be retained by the investigator as part of the study 
record and must be available at all times for inspection by authorized representatives of the sponsor 
and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
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12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB. A copy of the IRB -approved ICF and documentation of 
approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient.   
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients must be informed of the new information and provide their written 
consent if they wish to continue in the study. The original signed revised ICF must be maintained 
in the patient’s study record and a copy must be given to the patient. 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator’s personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
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13.4. 
Institutional Review Board 
An appropriately constituted IRB, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB should be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical study. 
A copy of the IRB approval letter with a current list of the IRB members and their functions must 
be received by the sponsor prior to shipment of drug supplies to the investigator.  The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site 
thereafter. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB-approved amendment. Where required per local legislation, regulatory authority approval will 
also be sought.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines 
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB and Health Authorities must be informed according to applicable 
regulatory requirements, and adequate consideration must be given to the protection of the 
patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA Approval Summary: 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: An adaptive phase 2/3, Randomized, Double-Blind, 
Placebo-Controlled Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients 
with COVID-19 and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study 
Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients with COVID-19 
Protocol Number: 
6R88-COV-2040 
Protocol Version: 
6R88-COV-2040 Amendment 7 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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Signature Page for VV-RIM-00114290 v1.0
Signature Page for VV-RIM-00114290 v1.0 Approved
ESig Approval
10-Jun-2020 22:09:57 GMT+0000
ESig Approval
10-Jun-2020 22:23:47 GMT+0000
ESig Approval
ment
10-Jun-2020 22:39:29 GMT+0000
ESig Approval
10-Jun-2020 23:17:18 GMT+0000
ESig Approval
11-Jun-2020 14:36:25 GMT+0000
                                        VV-RIM-00114290-1.0 Approved - 11 Jun 2020 GMT-5:00