Clinical trial NCT04546581
Conditions: COVID COVID-19 SARS-CoV-2 SARS (Severe Acute Respiratory Syndrome)
Sponsor: University of Minnesota
Start date: 2020-10-08; Completion date: 2021-05-21
Enrollment: 593 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This protocol will serve as a platform for assessing treatments for adult patients hospitalized for medical management of COVID-19 without related serious end-organ failure. Trials will involve sites around the world strategically chosen to ensure rapid enrollment. This trial will compare hyperimmune intravenous immunoglobulin (hIVIG) with matched placebo, when added to standard of care (SOC), for preventing further disease progression and mortality related to COVID-19. SOC will include remdesivir unless it is contraindicated for an individual patient.

Detailed description:
The primary endpoint of this trial in hospitalized patients is an ordinal outcome based on the patient's clinical status on Day 7. It includes 7 mutually exclusive categories capturing the range of organ dysfunction that may be associated with progression of COVID-19, such as respiratory dysfunction and coagulation-related complications. The ordinal endpoint is defined as follows:

7\. Death

6\. End-organ failure

5\. Life-threatening end-organ dysfunction

4\. Serious end-organ dysfunction

3\. Moderate end-organ dysfunction

2\. Limiting symptoms due to COVID-19

1\. No limiting symptoms due to COVID-19

Secondary endpoints include time to the 3 least favorable categories, time to the 2 most favorable categories, and the pulmonary only and thrombotic only components of the primary ordinal outcome. Mortality, adverse events (AEs), including infusion reactions, and biological correlates of therapeutic activity are also assessed. Because there is no established endpoint for evaluating the clinical efficacy of treatments for COVID-19, other clinically relevant outcomes, including outcomes used in other COVID-19 treatment trials, will be recorded. Thus, the randomized groups (hIVIG + SOC versus placebo + SOC ) can be compared for multiple outcomes, and results can be compared or combined with other trials.

Participants will be randomized (1:1) to a single infusion of hIVIG + SOC or placebo + SOC on the day of randomization (Day 0). Participants taking remdesivir prior to randomization may be enrolled if eligibility criteria are met. Randomized participants who were not taking remdesivir before randomization will start taking remdesivir immediately following the infusion of hIVIG or placebo unless remdesivir is contraindicated. Participants will be followed for 28 days and, if the trial goes to completion, the primary analysis will be completed after all participants are followed for 28 days.

Arms: arm 1: Participants in this group will receive the investigational product and standard of care (SOC). arm 2: Participants in this group will receive a placebo and standard of care (SOC).
Interventions: intervention 1: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) intervention 2: Placebo intervention 3: Remdesivir
Intervention descriptions: intervention 1: Hyperimmune immunoglobulin to SARS-CoV-2 (hIVIG) is derived from the plasma of individuals who recover and develop neutralizing antibodies. Participants will receive a single infusion. intervention 2: Participants will receive a single infusion of the placebo (saline). intervention 3: Remdesivir will be given to participants in both groups as standard of care (SOC).

Protocol documents:
ICF_000.pdf: 
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INFORMED CONSENT FORM 
(FOLLOW-UP ENDING DAY 90) 
Sponsor / Study Title: 
  
University of Minnesota / “An International 
Multicenter, Adaptive, Randomized Double-Blind, 
Placebo-Controlled Trial of the Safety, Tolerability and 
Efficacy of Anti-Coronavirus Hyperimmune 
Intravenous Immunoglobulin for the Treatment of 
Adult Hospitalized Patients at Onset of Clinical 
Progression of COVID-19” 
 
Protocol Number: 
 
INSIGHT 013/ITAC 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
This form is for use in a research study that may involve participants who may or may 
not have the capacity to consent to take part in the study.  When the participant cannot 
legally consent to take part, pronouns “you” and “your” should be read as referring to 
the participant rather than the person (legally authorized representative) who is signing 
and dating this form for the participant. In cases where the participant’s representative 
gives consent, the participant should be informed about the study to the extent possible 
given his/her understanding. During the course of the study, if the participant regains 
the capacity to consent, informed consent will be obtained from the participant and the 
participant offered the ability to leave the study if desired. 
Key information: 
 
The following is a short summary to help you decide whether or not to be a part of this 
research study. More detailed information is listed later on in this form.  
We are asking you to join a research study about COVID-19. It is your choice whether 
or not you want to join. This form gives you information about the study that will help 
you make your choice. You can discuss this information with your regular doctor or 
family or anyone else you would like before you make your choice. Your choice will not 
affect the care you are getting for COVID-19. 
 
 
 


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What is the research question? 
We are trying to find out if giving anti-coronavirus hyperimmune intravenous 
immunoglobulin (hIVIG) can help people in the hospital with COVID-19 have fewer bad 
effects from COVID-19, get better faster, and get out of the hospital faster. Anti-
coronavirus hIVIG contains antibodies against the virus that causes COVID-19. We 
think this will help your body fight COVID-19 better, but we are not sure and so we are 
doing this study. We are asking you to join the study because you are in the hospital 
with COVID-19.  
What do you have to do if you decide to be in the study? 
The study staff at your hospital will make sure it is safe for you to be in the study. They 
will check your medical history. They will look at routine medical test results that you are 
probably already having done regularly in the hospital.  
If you agree to be in the study, we will randomize you to one of two study groups. It will 
be up to chance, like flipping a coin, and you will have an equal chance (50/50) of 
getting either hIVIG or a saline placebo (a salt solution with no active study drug). Your 
study doctor will not decide which of these you will get, and neither you nor your study 
doctor or study staff will know what study treatment you are getting. However, your 
study doctor can find out which group you are in if there is an emergency. 
You will get the usual supportive care for COVID-19 recommended by your hospital, just 
as you would if you do not join the study. In addition, the study will supply an antiviral 
study drug called remdesivir, unless there is a medical reason that you should not get 
remdesivir. Remdesivir has been shown in other studies to improve recovery from 
COVID-19 in persons who have been hospitalized. Remdesivir has an “emergency use 
authorization” in the US and many other countries.  This means that the regulatory 
authorities are allowing its use while the company that makes it is applying for FDA 
approval, because there are so few drugs available to treat COVID-19.   
You will get the study treatment (hIVIG or placebo) once, on the day you join the study. 
You will get it by a drip through a tube attached to a needle in your arm (intravenously, 
or IV). It will take about 1-2 hours, though it may sometimes take longer depending on 
how your body reacts to the infusion. This infusion together with the use of remdesivir is 
the only thing in the study that is experimental. Everything else is part of routine medical 
care for someone in the hospital with COVID-19. There are no treatments for COVID-19 
that are approved by the U.S. Food and Drug Administration (FDA), only best 
supportive care. 
You will get remdesivir once a day intravenously (IV) for up to 10 days while you are in 
the hospital, as part of this study. 
You will also need to agree not to participate in any other COVID-19 study for the first 7 
days you are in this study. 


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You will be in the study for 90 days. We will check on your health every day while you 
are in the hospital, and at regular intervals once you leave the hospital.  
We will collect the following information at these times:  
Up to 1 day 
before you 
get study 
treatment 
Day 0 (the day 
you get study 
treatment) 
Day 1, Day 2,  
Day 3, Day 28 
Day 5 and 
Day 14 
Day 7 
Day 90 
• Informed 
consent 
• Blood tests 
to check 
your health 
• Check to 
see how 
you are 
feeling 
• Pregnancy 
test 
• Your 
medical 
history 
• Infusion of 
study 
treatment  
• If you are 
taking certain 
other 
medicines 
• Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
• Nasal swab 
for future 
research 
• How you are 
feeling 
• Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
• How you 
are 
feeling 
• How you are 
feeling 
• If you are 
taking 
certain other 
medicines  
• Blood tests 
to check 
your health 
• Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
• Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
 
Day 90 is the last day you will be in the study. 
We may need to get some information from your medical record. By signing and dating 
this consent, you also agree to let us get information for this study from your medical 
record. You will be asked to sign a separate HIPAA form for this purpose as well. 
We will send the information we collect to the University of Minnesota (UMN) in the US 
where it will be stored and analyzed. In this information, only a code number, your year 
of birth, and a 3-letter code that you or the study staff chooses will be used on your 
information. We never give information that could identify you, such as your name, 
address, birth date, or medical record number, to anyone outside this site. The study 
staff at this site is responsible for keeping your identifying information safe from anyone 
who should not see it. We will send the blood samples to a laboratory in the US for 
storage. We will keep them for as long as we have the funding and space to do so, 
which we hope will be many years. We will use the samples in the future for tests to 
help understand more about COVID-19 and how people respond to treatment for 
COVID-19. You and your regular doctor will not get any results from these tests. We will 
not test your DNA (your genes). We will not sell your samples and they will not be used 
for research aimed at making money (commercial research). The samples will not have 
any information connected to them that could identify you. 


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Why would you want to be in the study? 
If you get the hIVIG, it may help you get better faster, although we do not know that for 
sure.  
It is important to remember that half (50%) of the people in this study will not get 
the hIVIG. 
By being in this study, you help study doctors learn more about how to treat COVID-19 
in people in the hospital. Because so many people are getting hospitalized with COVID-
19, this could be a big impact if a treatment proves to be effective. 
Why would you NOT want to be in the study? 
Only half (50%) of the people in this study will get the hIVIG. You may not get the hIVIG.  
If hIVIG turns out to be a good study treatment, you would not get that benefit.  It’s also 
possible that if you do get hIVIG, it may turn out not to be useful, or may cause side 
effects that are harmful to you. 
You do not have to be in this study to receive treatment for COVID-19. You will continue 
to receive the usual supportive care for COVID-19 recommended by your hospital. Your 
other options include other experimental treatments. Your study doctor or regular 
healthcare provider can explain your options and their risks and benefits to you.    
What are the side effects of the study hIVIG treatment? 
hIVIG is usually very safe to give. Similar immunoglobulin preparations have been used 
in many different diseases over many years, but immunoglobulin prepared solely from 
individuals who have recovered from COVID-19 has not been studied before. In an 
earlier study of influenza hIVIG in people in the hospital with the flu, over 150 people got 
hIVIG. There were no serious problems that occurred in people because they got hIVIG. 
All treatments cause side effects, and you may have some side effects from hIVIG.  
About 1% to 10% (1 in 100 people to 1 in 10 people) who get hIVIG get: 
• A fever 
• Chills 
• Nausea 
• Vomiting 
• Dizziness 
• Shortness of breath 
• Rash 
• Hives 
• Headache 
 
These side effects are usually not serious.  These can happen during the infusion or 
afterwards and usually go away on their own or with short-term treatment.  Although 
IVIG has been very safe for people with other diseases, less than 0.1% (less than 1 in 


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1,000) of people taking other types of IVIG for other illnesses have had very serious 
reactions to it, including a kind of lung injury called transfusion-related acute lung injury 
(TRALI). 
People can have allergic reactions to drugs, including hives, trouble breathing, or other 
allergic responses. This is very rare but is also a possible effect of any drug. Allergic 
reactions may be severe or life-threatening.   
In some laboratory studies, infusions of antibodies have made infections with viruses 
similar to the virus that causes COVID-19 worse. This is a very unlikely but possible 
side effect of the study treatment infusion in this study, and you will be closely 
monitored for any signs of this effect. 
It is also possible that getting the study treatment infusions could cause problems with 
your health because of the amount of fluid given to you for the study treatment if you 
have some other health condition that affects how your body handles fluids.  You will 
get up to about 400 mL of fluid for hIVIG or placebo, and about 100mL each day for 
remdesivir if you receive it. 
Some people may have some side effects after the hIVIG infusions.  Other people may 
have no side effects.  You will be monitored closely during the infusions, and short-term 
medical care will be provided if there are side effects from the infusions that can be 
treated. 
 
What are the benefits and risks or side effects of remdesivir treatment? 
Remdesivir was recently shown to help people who are in the hospital with COVID-19 to 
get better faster than people who got a placebo.  You may be given remdesivir to treat 
your COVID-19 even if you do not join this study if your regular doctor feels it is a good 
idea. If your study doctor considers that remdesivir is not a suitable study treatment for 
you, you can still join this study, and you will receive hIVIG or placebo without 
remdesivir. For example, remdesivir might be unsuitable for you if you have serious liver 
or kidney problems or an allergy to it. 
 
The most common side effects of remdesivir include: 
• Abnormal liver function test results 
• Abnormal kidney function test results 
• Fever 
• Elevated blood sugar 
• Constipation 
• Nausea 
• Vomiting 
• Decreased appetite 
• Headache  
 


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The abnormal liver and kidney function tests may last a few days or longer but came 
back to normal levels over time. 
 
People can have allergic reactions to drugs, including hives, trouble breathing, or other 
allergic responses. This is very rare but is also a possible effect of any drug. Allergic 
reactions may be severe or life-threatening.   
 
Some people may have some side effects after the infusion of remdesivir.  Other people 
may have no side effects.  You will be monitored closely during the infusions, and short-
term medical care will be provided if there are side effects from the infusions that can be 
treated. 
 
What are the side effects of the other study procedures? 
 
As shown in the table of what will happen at each visit, you will have some extra blood 
drawn for laboratory testing and storage.  You will also have an extra swab of your nose 
and throat that would not be done if you are not in the study.  The risks and discomforts 
of these extra blood draws and swab are no different than what you would have if they 
were performed as part of your regular hospital care for COVID-19. 
You may have pain or bruising at the site where the blood is drawn or the IV is inserted.  
You may feel faint.  An infection at the site of the blood draw or IV insertion is possible. 
The nose and throat swabs may cause discomfort, eyes watering, sneezing, or 
bleeding. 
What if you are pregnant or breastfeeding? 
If you are pregnant or breastfeeding, you can still join this study.  However, we do not 
have any information about how the study drug may affect your baby.  The risks to an 
unborn baby or a pregnant woman may possibly be serious.  Please take this into 
account as you make your decision about whether to join this study. 
Additional information: 
The following is more detailed information about this study in addition to the information 
listed above. 
Here is some additional information about the study that may help you make your 
choice about whether you want to be in the study. 
The US National Institutes of Health (NIH), an agency of the US Federal Government, is 
paying for this study. Because public money is paying for the study, we are required to 
comply with all rules and regulations about research. We are doing this study according 
to internationally recognized standards of research as well as the laws of each country 
where the study is taking place.  


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This study is taking place in several countries. We expect to enroll about 500 people 
around the world. 
You do not have to join this research study if you do not want to. If you choose to join 
the study, you can stop at any time by telling someone on the study team that you want 
to stop being in the study. If you choose not to join or to stop, your regular medical care 
will not change. 
If we get any new information that might change whether you want to join or stay in the 
study, we will tell you right away.  
Your study participation may be stopped without your consent if: 
• The groups overseeing the study decide the study should be stopped; 
• Your study team believes that being in the study is no longer in your best 
interests. 
 
If your participation is stopped, you will still get the usual care given at your hospital for 
COVID-19. 
If you do not want to be in this study, you will still get the usual care to treat COVID-19. 
However, you cannot get the hIVIG study treatment, because it is experimental. 
What are the costs to you? 
We will give you the study treatment (hIVIG or placebo) at no cost. We will also give you 
remdesivir at no cost.  We will pay for all clinic visits, lab work, and other tests that are 
part of this study. 
You, your insurance company, or some other third-party payer must pay for all other 
medicines and hospital costs, including other standard of care treatments for COVID-19. 
Will you be paid to be in the study? 
«Compensation» 
We will compensate you for your time and inconvenience participating in the study. 
[Specific details to be completed by site.] 
What if you are hurt as part of this study? 
If you are hurt because of being in this study, the study site will treat your injury right 
away. You or your insurance will have to pay for this treatment. The study cannot pay 
you or pay for any care for study-related injuries or for your illness. By signing and 
dating this document, you will not lose any of your legal rights or release anyone 
involved in the research from responsibility for mistakes. 
A new public health declaration, called the Public Readiness and Emergency 
Preparedness Declaration (PREP), was issued by the Department of Health and Human 


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Services on March 10, 2020.  This declaration limits the legal rights of a participant 
participating in a COVID-19 clinical study that uses a drug, device or vaccine designed 
to treat, diagnose, cure or prevent COVID-19. This includes the study Anti-Coronavirus 
Hyperimmune Intravenous Immunoglobulin (hIVIG) and Remdesivir used in this study.  
Participants using hIVIG and Remdesivir in this study will have limits on their right to 
sue the manufacturers, the study sponsor, healthcare providers and others for 
significant injuries and adverse reactions. 
What happens to the blood samples and respiratory swabs? 
We will send the blood and respiratory swab samples to a central laboratory in the 
United States of America. You and your study doctor will not get the results of any tests 
done on these samples. 
The blood samples will measure how many COVID-19 antibodies are in your blood. 
This will tell us how your immune system responded to your COVID-19.  The nasal 
swab will measure how much virus you have in your respiratory system. 
Any blood samples that are left over after these tests will be stored at the central 
laboratory for as long as we are able to keep them. We hope to use these in the future 
to answer other questions about COVID-19. You and your study doctor will not get any 
results from these tests. Some of the blood will also be given to the company that made 
the hIVIG to help them learn more about its effects. 
You can withdraw your consent for us to keep these specimens at any time.  Let your 
study team know if you do not want the study to keep your specimens anymore, and 
every effort will be made to destroy all of your specimens that are still at the central 
laboratory. 
How do we protect your privacy? 
We will take every reasonable step to keep your health information private and to keep 
anyone from misusing it. 
Your information (data) and samples will not be identified by name, or in any other way, 
in anything published about this study.  
We will do everything we can to keep your personal information private, but we cannot 
guarantee that nobody will get it. We may have to release your personal information if 
required by law. 
These people may see your medical and research information at your site: 
• Advarra Institutional Review Board (Advarra IRB) 
• The sponsor, other study research staff, and study monitors 
• US and other participating countries’ health regulatory agencies, including the US 
FDA 
• The US National Institutes of Health (NIH) which is funding the study 


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They are committed to protecting your privacy. 
As the research staff at the study site, we are required to make sure that people not 
involved with this study cannot see your research and medical information. We will keep 
your research files in a safe place and will handle your personal information very 
carefully.  
Your study data are sent electronically to the UMN in the US through a secure 
application. By signing and dating this consent, you agree to have your data sent to 
UMN. No information that could directly identify you is sent to UMN. This is called 
“pseudonymized data.” Access to the data at UMN is limited through security measures, 
and no data breach or unauthorized access has ever occurred in this system. After the 
study is over, the data will be stored securely for the period required by law. 
Your study data will be shared with the US National Institutes of Health (which is paying 
for this study), and with the regulatory authorities that oversee the studies, including the 
US FDA, as required by law. Your study data will also be shared with the drug company 
that provides the hIVIG to help them develop the study drug.  
UMN may share your data and specimens with other people who study COVID-19. 
UMN will remove any information that could possibly be used to identify you before 
sharing. This is called “anonymizing the data.” We will not ask you for additional consent 
for this sharing. UMN will only share data and specimens for research projects that are 
approved by the group that is conducting this study. 
This study has a Certificate of Confidentiality from the US Federal government. This 
means that UMN cannot share any data it has about you with national, state, or local 
civil, criminal, administrative, legislative, or other authorities unless you specifically allow 
us to share it, or it is being used as evidence, for example, if there is a court subpoena, 
unless you have consented for this use. Information, documents, or biospecimens 
protected by this Certificate cannot be disclosed to anyone else who is not connected 
with the research except, if there is a federal, state, or local law that requires disclosure 
(see below); if you have consented to the disclosure, including for your medical 
treatment; or if it is used for other scientific research, as allowed by federal regulations 
protecting research participants.  
The Certificate cannot be used to refuse a request for information from personnel of the 
United States federal or state government agency sponsoring the project that is needed 
for auditing or program evaluation by the agency which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food 
and Drug Administration (FDA).  You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about 
yourself or your involvement in this research. If you want your research information 
released to an insurer, medical care provider, or any other person not connected with 
the research, you must provide consent to allow the researchers to release it. 


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The Certificate of Confidentiality will not be used to prevent disclosure as required by 
federal, state, or local law of, for instance, child abuse or neglect, harm to self or others, 
and communicable diseases.  
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose 
you have consented to in this informed consent document. 
A description of this clinical trial will be available at 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. 
Information on this study will also be posted in a similar format on a European Web site 
at www.clinicaltrialsregister.eu 
To do this research, we will collect and use your personal data, as described above and 
in any HIPAA Authorization Form we have given you. Please tell us whether you agree 
to have us collect and use your personal data by placing your initials in front of your 
selection. 
 
____Yes, I agree to the collection and processing of my personal data. 
 
____No, I do not agree to the collection and processing of my personal data. 
It is your choice whether you allow us to collect and use your data. However, you will 
not be able to be in this research and have a chance to get the experimental treatment if 
we cannot collect and use your data. 
Whom to contact about this study 
During the study, if you experience any medical problems, suffer a research-related 
injury, or have questions, concerns or complaints about the study, please contact the 
study doctor at the telephone number listed on the first page of this consent document. 
If you seek emergency care, or hospitalization is required, alert the treating physician 
that you are participating in this research study.  
An institutional review board (IRB) is an independent committee established to help 
protect the rights of research participants. If you have any questions about your rights 
as a research participant, and/or concerns or complaints regarding this research study, 
contact: 
• By mail: 
Study Subject Adviser 


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Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00046242.


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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE RESEARCH STUDY  
I have read the consent or have had it explained to me. I am satisfied that I understand 
the information. By signing and dating this consent, I am stating that I want to join this 
study. I understand that I do not waive any of my legal rights as a study participant by 
signing and dating this consent. I understand that I will receive a copy of the signed and 
dated consent. 
If you agree to be in this study, please sign and date below. 
 
________________________________________  
Date: _______________ 
Signature of participant 
 
________________________________________ 
Printed name of participant 
 
_____________________________________   
Date: _______________ 
Signature of study doctor/designee 
 
_____________________________________ 
Printed name of study doctor/designee 
 
FOR ADULTS NOT CAPABLE of GIVING CONSENT  
 
________________________________________ 
 Date: _______________ 
Signature of Legally Authorized Representative (LAR)  
 
_____________________________________ 
Printed name of Legally Authorized Representative (LAR) 
 


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____________________________________ 
Relationship of Legally Authorized Representative (LAR) to Participant 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker 
under state or applicable local law) 
 
Witness to Consent Interview 
On the date given next to my signature, I witnessed the consent interview for the 
research study named above in this document. I attest that the information in this 
consent form was explained to the participant, and the participant indicated that his/her 
questions and concerns were adequately addressed. 
_______________________________________ 
Date: _______________ 
Signature of witness 
 
________________________________________ 
Printed name of witness 
 
NOTE: This consent form, with the original signatures, MUST be retained on file 
by the Investigator of Record. A copy of the signed and dated consent must be 
given to the participant. A copy should be placed in the participant’s medical 
record, if applicable.  
 

SAP_002.pdf: 
Statistical Data Analysis Plan 
 
An International Multicenter, Adaptive, Randomized Double-Blind, Placebo-
Controlled Trial of the Safety, Tolerability and Efficacy of Anti-Coronavirus 
Hyperimmune Intravenous Immunoglobulin for the Treatment of Adult 
Hospitalized Patients at Onset of Clinical Progression of COVID-19 
 
Short Title: Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) 
 
INSIGHT Protocol Number: 013 
 
 


SAP INSIGHT 013 
 
Version 2.0 
Inpatient Treatment with Anti-Coronavirus Immunoglobulin 
27 March 2021 
 
 
 
2
1 
Introduction .............................................................................................................. 3 
1.1 
Objective of the Statistical Analysis Plan ........................................................... 3 
1.2 
Trial Status and Information That Informed the Updated SAP ........................... 3 
1.2.1 
Trial Status .................................................................................................. 3 
1.2.2 
Enrollment Summary ................................................................................... 4 
1.2.3 
Summary of Baseline Characteristics .......................................................... 4 
1.2.4 
hIVIG/Placebo Assignment and Completeness of Infusions ........................ 5 
1.2.5 
Summary of Pooled (Both Treatment Groups Combined) Follow-up Results
 
5 
1.3 
Summary of Changes to SAP ............................................................................ 6 
1.4 
Description of the Study Design ......................................................................... 8 
2 
Interim DSMB Reviews: Goals and Format ............................................................ 13 
3 
Enrollment .............................................................................................................. 15 
4 
Analysis Populations .............................................................................................. 16 
5 
Baseline Characteristics ......................................................................................... 16 
6 
Administration of Study Treatment ......................................................................... 18 
7 
Statistical Analyses ................................................................................................ 20 
7.1 
Primary Efficacy Analysis ................................................................................. 20 
7.2 
Safety Analyses ............................................................................................... 23 
7.3 
Monitoring for Futility ........................................................................................ 24 
7.4 
Secondary Outcomes ....................................................................................... 25 
7.5 
Subgroup Analyses .......................................................................................... 28 
7.6 
Analyses of Stored Specimens ........................................................................ 31 
8 
Data Completeness and Study Conduct ................................................................ 32 
9 
The following data summaries will be provided: ..................................................... 32 
10 
Addendum to Statistical Analysis Plan for European Medicines Agency ............. 34 
 
 


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1 Introduction 
1.1 Objective of the Statistical Analysis Plan 
The objective of this statistical analysis plan (SAP) is to provide a description of the 
analytic strategy and the statistical methods that will be used to analyze the data for the 
Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) Phase III 
randomized, double-blind, placebo-controlled trial. The primary objective of the trial is to 
determine whether hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, 
derived from the plasma of individuals who recover and develop neutralizing antibodies, 
is a potentially safe and effective therapeutic approach to COVID-19 compared to 
placebo (each treatment is given with standard of care [SOC]). The primary endpoint of 
this trial is an ordinal outcome based on the patient’s clinical status on Day 7. 
In Version 1.0, this SAP provided: 
• A short description of the study design (Section 1.4) 
• Goals of the interim reviews by the independent DSMB and the planned format of 
the review meetings (Section 2) 
• A description of the planned data analyses presented in the reports to the DSMB 
(Sections 3-8). Guidelines for stopping the study because of early proof of 
efficacy, futility, or harm are described in Sections 7.1, 7.2, and 7.3, respectively.  
• A description of data summaries to be provided to study leadership to aid in 
monitoring trial conduct and data quality; these data summaries, which will be 
regularly updated and posted to the INSIGHT website, will be restricted to 
enrollment (Section 3), baseline data (Section 4), and summaries of follow-up 
data completeness (Section 8). 
Version 2.0 of the SAP was prepared prior to unblinding of the data by statisticians and 
other members of the core ITAC team who have been blinded to interim treatment 
comparisons for the duration of the trial.   
Below we briefly summarize the status of the trial and some key blinded data that 
informed the preparation of this updated SAP (Version 2.0). 
1.2 Trial Status and Information That Informed the Updated SAP 
1.2.1 Trial Status 
 
Version 1.0 of the protocol was used for the duration of the trial.  On November 24, 
2020 a letter of amendment was issued that extended the exclusion criteria in the trial to 
“Prior receipt of any SARS-CoV-2 monoclonal antibody treatments at any time.” The 
DSMB carried out two full reviews of the protocol, on November 24, 2020 and on 
January 5, 2021.  Following each review, the DSMB recommended the study continue 
as planned.  Between these full reviews and until enrollment was completed, the DSMB 
also reviewed safety data on a weekly basis that was provided to them by the unblinded 
statisticians. 


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Following the DSMB meeting on January 5, 2021, the DSMB approved the provision of 
the pooled (both treatment groups combined) category proportions to blinded 
statisticians in order to re-estimate sample size.  Using the observed pooled 
proportions, power was estimated to be 0.83 for the planned sample size of 500. Based 
on this, no change in sample size was recommended. 
1.2.2 Enrollment Summary 
The first participant was enrolled on October 8, 2020; the last participant was enrolled 
on February 10, 2021.  On February 3, 2021 we notified the central IRB for ITAC, 
Advarra, that the final accrual would be more than planned and that it likely would be 
between 550 and 600 participants.  A total of 593 participants were enrolled by 63 sites 
in 11 countries (93 more participants than were planned).  These 63 sites were provided 
study drug infusion bags following randomization by 47 study site pharmacies.  The 
number enrolled by site ranged from 1 to 41 participants. Twenty three sites enrolled 1-
4 participants; 17 sites enrolled 5-9 participants; 11 enrolled 10-14; and 12 sites 
enrolled 15 or more participants. 
Two participants did not meet strict eligibility criteria. One participant was enrolled 13 
days after symptom onset, and the second participant had a condition that did not allow 
venipuncture; this participant did not receive an infusion. 
1.2.3 Summary of Baseline Characteristics 
Selected baseline characteristics that were considered (as of March 23, 2021) in 
revising the SAP are given below. 
1. As noted above, participants are from 11 countries.  Numbers enrolled by country 
are: Denmark (77), Germany (10), Spain (65), Greece (70), UK (19), Indonesia 
(33), Argentina (4), Israel (6), Japan (15), Nigeria (41), and U.S. (253). 
2. Median (25th, 75th percentile) of age is 59 (50, 70) years. 
3. Median (25th, 75th percentile) of symptom onset is 8 (6, 10) days. 
4. Oxygen status (above pre-COVID-19 requirement): 28% were not receiving 
oxygen; 34% were receiving < 4 L/min; 28% were receiving ≥ 4 L/min; and 10% 
were receiving high-flow oxygen. 
5. 541 (93%) received remdesivir prior to randomization or on the same day as 
randomization as part of SOC. 
6. 329 (56%) were receiving corticosteroids at entry; 48 (84%) among those on 
high-flow oxygen and 229  (62%) among those on supplemental oxygen. 
7. 355 (60%) were receiving heparin (prophylactic, intermediate, or therapeutic 
dose) at entry. 
8. Median (10th, 25th, 75th, 90th percentile) BMI is 29.8 (23.0, 25.8, 34.7, 40.2) kg/m2.  
9. Selected diagnoses (% reported) collected as part of a medical history and an 
elevated BMI are summarized below: 
o Asthma (10%) 
o Cerebrovascular event (1%) 
o COPD (6%) 
o Diabetes (28%) 


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o Heart failure (4.6%) 
o Hepatic impairment (2%) 
o HIV (2%) 
o Hypertension requiring medication (42%) 
o Immunosuppressive disorder other than HIV (1%) 
o Malignancy (4%) 
o MI (3%) 
o Renal impairment (7%) 
o BMI ≥ 30 kg/m2 (49%) 
1.2.4 hIVIG/Placebo Assignment and Completeness of Infusions 
As indicated in the protocol, each study site pharmacy was assigned an hIVIG 
product/matching placebo to use.  The product assignment is summarized below: 
Product Manufacturer 
No. of Study Site 
Pharmacies 
No. of Lots of 
hIVIG Used 
No. of Participants 
CSL Behring 
11 
5 
155 
Emergent 
11 
3 
153 
Grifols 
11 
22 
146 
Takeda 
14 
14 
139 
Total 
47 
44 
593 
 
Lot potency was measured by Texcell for each of the 44 lots used. The potency 
measures were reported in AY/mL units; these levels were multiplied by 1.73674589 to 
obtain units in IU/mL.  The median (25th, 75th percentile) potency level of the 44 lots of 
hIVIG used was 1220 (893, 1442) IU/mL. 
Twelve participants did not receive an infusion.  Ten of these participants withdrew 
consent prior to being infused; for one participant, venous access could not be 
achieved; and one participant refused the infusion but continued in follow-up. 
1.2.5 Summary of Pooled (Both Treatment Groups Combined) Follow-up Results  
The last 28 day follow-up was to be completed by March 14, 2021. 
Selected follow-up data for both treatment groups combined were considered. 
The median (25th, 75th percentile) of time to discharge from randomization is 6 (4, 9) 
days. 
During regular investigator meeting, it became clear that some sites were retaining 
participants in the hospital for public health reasons and/or for the collection of the Day 
7 primary outcome data.  There were 7 sites (all that enrolled 5 or more participants) in 
6 countries that enrolled a total of 93 participants where no one was discharged before 
day 7. 


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The Day 3 NEW score is missing for 82 participants (13.8% of randomized participants).  
The score can only be determined for hospitalized participants and most of the missing 
data is for participants discharged before Day 3.   
A total of 581 participants received a full or partial infusion; as noted above, 12 (2%) 
participants were not infused. 
Among participants meeting the eligibility criteria and who received an infusion, there 
are 7 participants missing the 7-category primary ordinal endpoint that is assessed on 
Day 7 (see table below).  Six of these 7 participants were discharged prior to day 7 with 
no further contact.  One participant was transferred to another hospital before day 7.  
Details of the participants missing the Day 7 endpoint due to reasons other than missing 
forms are below.  
Pt 
Study Day 
of 
Discharge 
Discharged 
to 
Oxygen use on 
day of 
discharge 
Study Day 
last known 
alive 
Additional information 
1 
Day 2 
Home 
None 
Day 2 
 
2 
Day 4 
Home 
2.0 l/min 
Day 4 
 
3 
Day 3 
Home 
None 
Day 28 
Paramedics visited pt 
at home to collect Day 
7 and Day 28 
specimens. No other 
study data was 
collected. 
4 
Day 1 
Home 
1.5 l/min 
Day 5 
 
5 
Day 3 
Home 
4.0 l/min 
Day 7 
 
6 
Day 2 
Transferred 
to another 
hospital 
None 
Day 27 
Transferred to another 
hospital due to pt 
preference.  Known 
alive day 27, but no 
other contact. 
7 
Day 5 
Home 
None 
Day 25 
Pt did not want to be 
contacted anymore, 
but allowed access of 
medical records 
 
Among all randomized participants, 18 (3.0%) are missing the Day 7 primary endpoint, 
and 36 (6.1%) have unknown survival status on Day 28.  Of these, 11 withdrew 
consent, all before the infusion. 
1.3 Summary of Changes to SAP 
Based on the above information and additional data expected we made the following 
changes to the SAP: 
1. The secondary outcomes of hospitalization status at days 7, 14, and 28, time to 
discharge, and days alive outside of the hospital at Day 28 will be 
supplemented with the following additional outcomes: i) time to discharge or 
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symptoms; ii) time to being able to independently undertake usual activities with 
minimal or no symptoms (discharge status will be ignored); iii) the binary 
outcome of hospitalization will also be defined as alive and either discharged 
from the hospital or being able to independently undertake usual activities with 
minimal or no symptoms; iv) days alive and able to independently undertake 
usual activities with minimal or no symptoms at Day 28; and v) days alive and 
out of the hospital or able to independently undertake usual activities with 
minimal or no symptoms at Day 28 (whichever lead to greatest time). 
 
Additionally, as a sensitivity analysis for the analysis of time-to-discharge and 
days outside the hospital we will exclude participants from the 7 sites where no 
participants were discharged prior to Day 7.   
 
In all of the outcomes related to “discharge”, “discharge” will refer to home, to a 
rehabilitation center or to a post-acute care facility. 
2. The change in NEW score from baseline to Day 3 will not be considered as a 
secondary outcome because it is only collected for hospitalized participants, 
and the Day 3 New score is missing for 80 participants (nearly all the 
participants with missing data had been discharged before Day 3). 
 
3. A key subgroup analysis defined in the protocol is according to duration of 
symptoms.  The primary ordinal outcome will be summarized for the following 
approximately equal subgroups (<6, 6-7, 8-9, and 10-12 days).  The presence 
of a treatment by subgroup interaction will be estimated in 2 ways, with a 1 
degree of freedom (df) test with duration of symptoms included in the ordinal 
regression model as a continuous variable and with a 3 df test with indicators 
for categories of duration of symptoms in the regression model. 
 
4. Another important subgroup is by age.  The median (25th, 75th percentile) of age 
is 59 (50, 70) years.  Therefore, we will present age in approximate quartiles 
(<50, 50-59, 60-69, and ≥ 70) years. 
 
5. For the subgroup by geographic region the following subgroups will be defined: 
U.S.; Europe, UK, or Israel; and Argentina, Indonesia, Japan or Nigeria. 
 
6. Subgroup analyses by chronic conditions will be carried out for individual 
conditions which have prevalence at least 5% at baseline (asthma, COPD, 
diabetes, hypertension requiring medication, renal impairment, and BMI ≥ 40 
kg/m2). 
 
7. The following other subgroups that combine chronic conditions and concomitant 
treatments will be carried out: 
a. Participants with and without compromised immune function; participants 
with HIV, an immunosuppressive condition other than HIV, or taking 
antirejection medication, immune modulators, or biologic treatment for 


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autoimmune disease or cancer will be considered to have compromised 
immune function. 
b. BMI < 40 and ≥ 40 kg/m2 according to history of diabetes (4 groups) 
c. Hypertension with and without history of other metabolic and vascular co-
morbidity (4 groups): i) no hypertension or other metabolic/vascular co-
morbidity; ii) hypertension without metabolic/vascular co-morbidity; iii) 
metabolic/vascular condition without hypertension; and iv) hypertension 
and a metabolic/vascular co-morbidity.  Metabolic/vascular co-morbidities 
include a history of diabetes, a cerebrovascular event, heart failure, or an 
MI or acute coronary syndrome. 
d. Number of vascular co-morbidities (0, 1, 2, 3+) 
e. Quartile of Charlson Comorbidity Index (for conditions assessed) 
f. Risk calculator for vaccine prioritization (JHU) 
g. Quartile of disease progression risk score for Day 7 outcome that 
considers baseline antigen and antibody levels, age, gender, duration of 
symptoms, oxygen saturation, ordinal category, NEW score, and history 
of chronic health conditions. 
 
8. Subgroup analyses by concomitant medications will be carried out for 
corticosteroids, overall and in combination with oxygen requirements (baseline 
ordinal scale). 
 
9. Planned subgroup analyses by baseline antigen and antibody levels and 
antibody comparisons during follow-up have been added to the SAP as a new 
section. 
 
10. The analysis population for the efficacy outcomes has been changed from the 
intention-to-treat (ITT) population to a modified intention-to-treat (mITT).  
1.4 Description of the Study Design 
This section is adapted from the ITAC protocol version 1.0.  Italicized sections have 
been added as part of this update. 
Design 
This study is an adaptive, randomized, double-blind, placebo-controlled trial to evaluate 
the safety, tolerability and efficacy of hIVIG in adult participants who are hospitalized 
with COVID-19 with symptoms for no more than 12 days, and who do not have life-
threatening organ dysfunction or organ failure. Remdesivir will be provided to 
participants in both the hIVIG and placebo groups as SOC unless contraindicated for an 
individual participant.  
Primary Objective and Primary Outcome 
The primary objective is to compare the clinical status of participants in the hIVIG + 
SOC and placebo + SOC groups on Day 7 using an ordinal outcome with seven 
mutually exclusive categories. On Day 7, the worst of the seven categories the 


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participant was in that day will constitute the primary outcome. The seven categories 
are: 
7. Death 
6. End-organ failure 
5. Life-threatening end-organ dysfunction  
4. Serious end-organ dysfunction  
3. Moderate end-organ dysfunction 
2. Limiting symptoms due to COVID-19  
1. No limiting symptoms due to COVID-19 
Appendix F of the protocol provides clinical definitions of each category. 
The primary ordinal outcome captures the range of severity experienced by hospitalized 
patients with COVID-19, recognizing that end-organ manifestations in addition to 
pneumonia and acute respiratory distress syndrome are increasingly emerging as 
significant contributors to morbidity. The ordinal outcome includes both pulmonary 
manifestations as assessed in prior COVID-19 trials and additional components 
representing key non-pulmonary outcomes; the latter are highlighted as “extra-
pulmonary” in the guidance table (Appendix F). The primary endpoint will include both 
pulmonary and extra-pulmonary components, while the pulmonary manifestation scale 
only will be reported as a secondary endpoint. 
Day 7 was chosen for the timing of the primary endpoint for several reasons based on 
the following assumptions. The impact of hIVIG on disease progression may not be 
immediate; a few days may be needed to see the effects on clinical outcomes as 
measured by the ordinal outcome. Also, transient treatment effects that are no longer 
present at Day 7 may be clinically less relevant. Assessment of the ordinal outcome at a 
later time point may result in a diminished treatment difference because spontaneous 
recovery from COVID-19 may have begun in many participants. Also, antibody 
differences between the treatment groups, an important biologic mechanism for 
observing a clinical benefit, are assumed to be greatest during the first week after 
infusion.  
Lastly, use of Day 7 to characterize the clinical severity of participants in seven 
categories as studied here, results in a distribution of participants in the placebo group 
for the ordinal outcome that is sufficiently granular and not overly skewed to the most 
severe or least severe categories and, therefore, provides good power for comparing 
the two treatment groups with a feasible sample size given the difficulty in producing 
large quantities of hIVIG. 
The primary and secondary objectives of ITAC are addressed by pooling the four hIVIG 
products and making comparisons with the corresponding placebo groups. To justify 
this pooling, each hIVIG lot prepared has a neutralizing potency that provides an 


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appreciable dose margin over convalescent plasma.  A standard dose of 400 mg/kg is 
used for each hIVIG product (see section 8.1.2 of the protocol).  
Key Secondary Outcomes  
A number of secondary endpoints to assess safety and efficacy have been specified.  
Four endpoints are defined as key secondary outcomes: 1) a composite of death, end-
organ failure, or life threatening end-organ dysfunction (categories 5-7 of the primary 
ordinal outcome at Day 7); 2) time to the two most favorable categories of the primary 
ordinal outcome; 3) percentage in two most favorable categories of the ordinal outcome 
at Day 7; and hospitalization status at Day 14. 
Mortality, adverse events (AEs), including infusion reactions, and biological correlates of 
therapeutic activity are also assessed. Because there is no established endpoint for 
evaluating the clinical efficacy of treatments for COVID-19, other clinically relevant 
outcomes, including outcomes used in other COVID-19 treatment trials, will be 
recorded. Thus, the randomized groups (hIVIG + SOC versus placebo + SOC) can be 
compared for multiple outcomes, and results can be compared or combined with other 
trials. A list of secondary outcomes is given in Section 7.4.  
Study Treatments 
Anti-Coronavirus hIVIG is a human hyperimmune product of the purified gamma 
globulin (IgG) fraction of human plasma containing polyvalent neutralizing antibodies to 
SARS-CoV-2. hIVIG is prepared from pooled plasma collected from healthy, adult 
donors who have recovered from SARS-CoV-2 infection. Four hIVIG products 
(Emergent BioSolutions, Grifols Therapeutics, Inc., Takeda Pharmaceuticals, and CSL 
Bering) will be used in this trial. 
Duration 
All participants will be followed for 28 days. A subsample of participants is followed for 
90 days.  If the trial goes to completion, the primary analysis will be completed after all 
randomized participants are followed for 28 days. 
Randomization 
Randomization will be stratified by site pharmacy (clinical sites may share a pharmacy). 
Participants will be randomized (1:1) to a single infusion of hIVIG + SOC or placebo + 
SOC on the day of randomization (Day 0). 
Hyperimmune IVIG will be manufactured by four companies; to simplify logistics related 
to the supply of hIVIG to clinical sites and to take advantage of the randomization, which 
is stratified by site pharmacy, the same hIVIG product will be provided to a given site 
pharmacy for the duration of the trial to the extent possible. This is illustrated in Figure 1 
with an example that assumes that there are 24 site pharmacies and the supply of each 
of hIVIG products will be the same. 
Within each stratum permuted block randomization will be used to generate treatment 
assignments. 


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FIGURE 1. EXAMPLE OF ALLOCATION OF HIVIG TO 24 SITE PHARMACIES 
 
 
 
 
 
 
Sample Size  
The planned sample size is 500 participants (250 per group).  
The following assumptions were made in estimating the required sample size. 
a. The primary analysis will be modified intention-to-treat (mITT).  
b. A proportional odds model with indicators for the six cut-offs corresponding to 
using any of categories 1 to 6 as cut-offs for determining clinical 
improvement, treatment group (hIVIG versus placebo), baseline severity of 
illness as defined by the ordinal outcome, two-way interactions between 
baseline severity of illness and the six cut-offs, hIVIG product/matching 
placebo used, and two-way interactions between hIVIG product/matching 
placebo used and the six cut-offs will be used to estimate the odds ratio (OR).  
c. Type 1 error = 0.05 (2-sided) and power = 0.80. 
d. The clinical status of participants in the placebo group at Day 7 is assumed as 
shown in the third column in Table 1. Since both randomized treatment 
groups will receive remdesivir as SOC (unless contraindicated), these 
percentages were estimated using Day 7 data from the ACTT-1 trial for a 
subgroup of patients similar to ours (the subgroup of participants who entered 
ACTT-1 in categories 4 and 5 of their eight-category ordinal outcome for 
disease severity and were randomized to the remdesivir group). 
e. We assumed an OR (hIVIG/placebo) of 1.61 for a more favorable outcome. 
This corresponds to the percentage of participants in the hIVIG group at Day 
7 shown in each level of the ordinal scale given in the second column in Table 
1 below. For example, the percentage of participants in the two most 
favorable categories would be increased to 65.4% in the hIVIG group from 
54.0% in the placebo group (an 11.4 percentage point increase from the 
placebo group). Conversely, the percentage of participants in the four most 
severe categories would decrease to 19.4% from 28.1% in the placebo group. 
The same proportional improvement was assumed across the ordinal scale.  
f. Sample size depends on a number of assumptions, including the 
hypothesized odds ratio, the number of categories in the ordinal outcome, 
and the distribution of responses for the placebo group.i Hypothesized odds 
ratios closer to 1.0 correspond to a smaller treatment effect and require a 
larger sample size to maintain 80% power. The final sample size was chosen 
Pharmacies 
1-6 
IVIG1 
Placebo1 
Pharmacies 
19-24 
Placebo4 
IVIG4 
Pharmacies 
7-12 
IVIG2 
Placebo2 
Pharmacies 
13-18 
IVIG3 
Placebo3 


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after consideration of a range of odds ratios and of category percentages for 
the placebo group. 
g. Based on the category percentages in Table 1, the estimated sample size is 
494. This was increased to 500 to allow for a small number of participants 
who may be randomized but not receive the study infusion or meet strict 
eligibility criteria.  These participants will be excluded from the mITT analysis. 
  
A planned blinded sample size re-estimation that utilized the observed pooled (both 
treatment groups combined) category percentages confirmed that the sample size of 
500 participants would provide the planned power for detecting an odds ratio of 1.61.  
TABLE 1. HYPOTHESIZED PERCENTAGE OF PARTICIPANTS IN EACH CATEGORY ON DAY 7 
IN THE HIVIG AND PLACEBO GROUPS BASED ON AFOREMENTIONED 
ASSUMPTIONS 
Category 
hIVIG + SOC 
Group 
Placebo + SOC 
Group 
7. Death 
0.6 
1.0 
6. End-organ failure 
4.0 
6.3 
5. Life-threatening end-organ dysfunction  
4.2 
6.3 
4. Serious end-organ dysfunction  
10.6 
14.5 
3. Moderate end-organ dysfunction.  
15.1 
17.9 
2. Limiting symptoms due to COVID-19 
57.6 
49.0 
1. No limiting symptoms due to COVID-19 
7.8 
5.0 
Total 
100.0 
100.0 
 
For the key subgroup defined according to duration of symptoms at entry, in addition to 
analysis by quartile, the OR for the primary endpoint will be estimated for the 
participants in the lower 3 quartiles. Assuming the category percentages in Table 1, with 
an estimated 444 participants (75% of 593) (222 per treatment group), an OR of a more 
favorable outcome on hIVIG compared to placebo of 1.61 can be detected with 77% 
power. 
The study is not powered to detect treatment differences in mortality because the 
mortality is expected to be low given the eligibility criteria and duration of follow-up.  
The following outcomes are defined as key secondary outcomes:  
Composite of death, end-organ failure, or life-threatening end-organ dysfunction 
(categories 5-7 of the ordinal outcome) at Day 7: This composite outcome comprises 
the most severe three categories of the ordinal outcome. Decreasing the probability that 
a participant enters one of these disease states and remains there through Day 7 has 
high clinical significance. Comparing the hIVIG+SOC versus the placebo+SOC groups 
for the proportion of participants in the three worst categories on Day 7, a total sample 


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size of 579 participants (the estimated number of participants in the mITT analysis) is 
sufficient to detect a decrease to 6.6% in the hIVIG group compared with 13.6% in the 
placebo group (difference 7.0%) with 80% power.  A decrease from 13.6% to 8.8% as in 
Table 1 (OR = 1.61) can be detected with power of 45%. 
Time to the two most favorable categories of the primary ordinal outcome (first 
occurrence): We expect that by Day 28, almost all participants will be discharged from 
the hospital. Similarly, we expect most participants will be in in one of the two most 
favorable categories of the primary ordinal outcome by Day 28. In the ACTT-1 trial, in 
the subset of participants who entered the trial with disease severity similar to our 
eligibility criteria (ACTT-1 ordinal outcome categories 4 and 5), 94.7% had been 
discharged from the hospital by Day 28. This percentage was similar for the ACTT-1 
definition of “recovery” that includes a small percentage of participants who were 
hospitalized but no longer requiring medical care. Comparing the hIVIG versus placebo 
groups for time to the 2 most favorable categories, our study is powered to detect a 
relative rate ratio (RRR) of 1.3 with 80% power and a significance level of 0.05. The 
power calculations assume that the RRR is approximately constant to Day 28, the 
overall cumulative percentage in the two most favorable categories (pooled across 
treatment groups) by Day 28 is 81% and that between 2.5 and 3% withdraw consent or 
are lost to follow-up by Day 28.  
Two most favorable categories at Day 7:  Comparing the hIVIG versus the 
placebo+SOC groups for the percentage in the two most favorable categories (a binary 
outcome) on Day 7, the total sample size of 579 participants is sufficient to detect an 
increase in the this percentage from 54% in the placebo group to 65.4% in the placebo 
group (as in Table 1) with 80% power.  
Hospitalization status at day 14: The study has greater than 80% power to detect an 
increase to 87% in the hIVIG group compared with 77% in the placebo group for the 
percentage dischargedl at Day 14. Estimates from the ACTT-1 trial used for the placebo 
group were 51% discharged on Day 7, and 77% on Day 14, for participants that were 
similar to ours and who were randomized to the remdesivir arm (confidential data; 
personal communication). Power calculations assume that the treatment groups are 
compared by mITT. 
Data and Safety Monitoring 
An independent Data and Safety Monitoring Board (DSMB) will review interim data and 
use pre-specified guidelines for early termination of the trial or protocol modification.  
2 Interim DSMB Reviews: Goals and Format 
Goals of the interim reviews: 
- 
Protect the safety of study participants.  
- 
Advise on stopping or modifying the trial for efficacy, for patient safety in case of 
emerging data on harm, or for futility. 
- 
Review the conduct of the trial 


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The DSMB will conduct frequent safety reviews. The DSMB will review safety data for 
the first 20 to 30 participants randomized after they have been followed for 7 days. 
Thereafter, the DSMB will be asked to review safety data at 30 day intervals. The 
blinded sample size re-estimation will occur after 150 participants have been followed 
for 7 days. Futility reviews will be presented to the DSMB for the primary endpoint after 
50% of information time (based on the percentage of participants who have completed 7 
days of follow-up) is available.  
The DSMB may request interim reports on safety and efficacy at any time. 
Review meetings will typically consist of an Executive session (optional; closed), open 
session, closed session, and a second open session to give feedback to study 
leadership (optional).  
Masking of treatment group labels in interim reports: In the open reports, any data 
reports will be pooled across the two treatment groups. In the closed reports, treatment 
group labels will be masked; for example as “Group A” versus “Group B”. The treatment 
group labels will be consistent across all analyses and over subsequent reports. With 
each closed report, the DSMB will receive a separate, encrypted file that unmasks the 
treatment group labels. This procedure ensures that the DSMB has the full information 
to weigh benefit versus harm. 
Open report to the DSMB  
The open reports will contain: 
• A synopsis of the trial design and current status of the trial  
• Responses of the study team to DSMB recommendations  
• A summary prepared by the study leadership including any relevant emerging 
data from other studies 
• Data summaries for enrollment (including enrollment by hIVIG product/matching 
placebo group) and eligibility violations (Section 3), baseline characteristics 
(Section 5) and protocol deviations 
• Summary reports for data completeness and study conduct (including number 
infused), pooled across treatment groups (see Sections 6 and 8)  
• Unanticipated problems 
All data summaries in the open report will be pooled across treatment groups. The open 
report will be prepared by the blinded statisticians in cooperation with the unblinded 
statisticians. In addition to the DSMB, open reports will be provided to the study team, 
and posted on the study website following the DSMB meeting for access by study 
investigators.  
While the study is ongoing, summaries by treatment group, and comparisons of the 
hIVIG versus placebo are restricted to the confidential closed report to the DSMB. 


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Additionally, all summaries of follow-up data other than the data completeness and 
study conduct reports (pooled across the two treatment groups) will be restricted to the 
confidential closed report. For the planned sample size re-estimation, the pooled 
proportion of participants in each level of the seven-level ordinal outcome at Day 7 will 
be provided to the blinded study statisticians and study leadership. 
Closed report to the DSMB  
All data summaries in the closed report will be by (masked) treatment group. 
Comparisons between treatment groups will be by intention-to-treat among those 
randomized (efficacy outcomes) and among those receiving any infusion (safety 
outcomes). Specific details are given in the indicated sections. The closed reports for a 
full review will contain: 
• Specific data summaries requested by the DSMB or study leadership 
• Data summaries in the open report, by treatment group (enrollment, baseline 
characteristics, eligibility violations) 
• Data summaries to assess safety of the investigational treatment including 
infusion reactions, AEs, SAEs, deaths, composite primary safety outcome are 
described in Section 7.2. Data summaries for the primary “efficacy outcomes”, 
and selected secondary outcomes will also be included in each report because 
these data contain information about the risk/benefit profile of hIVIG. Analyses 
are described in Sections 7.1, 7.4, and 7.5.  
• Summaries on data completeness and study conduct, described in Section 8. 
• Interim monitoring boundaries for the primary safety outcomes (Section 7.2). 
• Interim monitoring boundaries for efficacy when sufficient data have accrued 
(Section 7.1). 
• Futility analyses when sufficient data have accrued (Section 7.3). 
• Listings of incident (new or increase in severity from baseline) grade 3 and 4 
adverse events, serious adverse events (SAE), unanticipated problems (UP), 
suspected unexpected serious adverse reactions (SUSAR), and deaths (Section 
7.2). 
3 Enrollment 
For the open report, the following enrollment and eligibility summaries will be provided: 
• Enrollment over calendar time: plot by day or week, cumulative and increments 
• Enrollment by country: number (%) 
These summaries will be provided overall and by study product/matching placebo 
randomization stratum. 


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For the closed report, enrollment will be summarized by treatment group. 
Eligibility violations will be reported as protocol deviations (see Section 8). 
4 Analysis Populations 
All analyses for both efficacy and safety outcomes, will be carried out for a modified 
intention-to-treat (mITT) population.  This mITT population will include all participants 
who met the eligibility criteria (2 participants did not) AND who received an infusion (12 
participants were not infused, 10 who withdrew consent before the infusion, one for 
whom venous access could not easily be achieved, and one who refused the infusion 
but continued in follow-up).  The mITT population includes 579 participants, 97.6% of 
the 593 participants randomized.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*6 were discharged with no further information, 1 was transferred to another hospital 
 
5 Baseline Characteristics 
Baseline characteristics will be based on information collected on baseline and 
screening forms.   
Baseline characteristics will be summarized by randomized treatment group and overall. 
Unless noted otherwise, categorical variables will be summarized with frequency 
(percentage) in each category, and continuous variables will be summarized with 
593 Randomized to ITAC 
591 Eligible 
579 Received Infusion 
579 in Primary Analysis 
2 did not meet strict  
eligibility criteria 
12 did not receive infusion 
-
10 withdrew consent 
prior to infusion  
-
1 could not be infused 
due to difficult venous 
access 
-
1 refused infusion 
572 with the Day 7 primary 
endpoint assessed and 7 with 
the Day 7 primary endpoint 
imputed.* 


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median (25th, 75th percentile) and/or mean (standard deviation). The following 
characteristics will be reported. Whether the variable will be summarized as a 
continuous or categorical covariate (and the categorization used) is given in brackets as 
needed.  
• Demographics 
o 
Age [<50, 50-59, 60-69, ≥70 years; and summary as continuous variable]  
o 
Sex at birth [male, female] 
o 
Race/Ethnic group: [Asian, Black, Latino/Hispanic, white, other] 
o 
Country of enrollment 
o 
Geographic region 
• COVID-19 related characteristics 
o 
Duration of symptoms prior to enrollment (<6, 6-7, 8-9, 10-12 days)   
o 
Use of remdesivir prior to enrollment  
o 
Ordinal outcome category 
o 
National Early Warning Score (NEWS) [summary as continuous variable] 
o 
Oxygen saturation 
o 
Respiratory function scale (modified Borg dyspnea scale; continuous outcome) 
o 
Receipt of SARS-CoV-2 vaccination (active or control) 
o 
Upper respiratory SARS-CoV-2 viral RNA 
• Other clinical characteristics 
o 
Concomitant treatments including corticosteroids and antiplatelet/anticoagulant 
medications 
o 
Corticosteroid use according to oxygen requirements  
o 
History of chronic conditions (heart failure, diabetes, asthma, chronic 
obstructive pulmonary disease, hypertension requiring medication, renal 
impairment, hepatic impairment, malignancy, MI, stroke)  
o 
Requirement of continuous chronic supplemental oxygen 
o 
Body mass index (BMI) [<25, 25.0-29.9, 30-39, 40+ kg/m2] 
o 
Pregnancy 
o 
Participants with and without compromised immune function; participants with 
HIV, an immunosuppressive condition other than HIV, or taking antirejection 


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medication, immune modulators, or biologic treatment for autoimmune disease 
or cancer will be considered to have compromised immune function. 
 
o 
BMI < 40 and ≥ 40 kg/m2 according to history of diabetes (4 groups) 
 
o 
Hypertension with and without history of other metabolic and vascular co-
morbidity (4 groups): i) no hypertension or other metabolic/vascular co-
morbidity; ii) hypertension without a metabolic/vascular co-morbidity; iii) 
metabolic/vascular co-morbidity without hypertension; and iv) hypertension and 
a metabolic/vascular co-morbidity.  Metabolic/vascular co-morbidities include a 
history of diabetes, a cerebrovascular event, heart failure, or an MI or acute 
coronary syndrome. 
 
o 
Number of vascular co-morbidities (0, 1, 2, 3+) 
 
o 
Quartile of Charlson Comorbidity Index (for conditions assessed) 
 
o 
Risk calculator for vaccine prioritization (JHU) 
 
o 
Quartile of risk score for Day 7 outcome that considers baseline antigen and 
antibody levels, age, gender, duration of symptoms, oxygen saturation, ordinal 
categorty, NEW score, and history of chronic health conditions. 
• Laboratory values [as continuous outcomes and grade 3 or 4 abnormalities 
according to the DAIDS AE Grading Table] 
6 Administration of Study Treatment 
These data are an important part of the safety reviews by the DSMB, with particular 
emphasis on infusion-related reactions and symptoms occurring during or within up to 2 
hours after the infusion. These reactions and symptoms will be graded according to the 
DAIDS AE Grading Table. 
The administration of study treatment is also an essential element of study conduct. 
Several summaries, pooled across treatment groups, will be included in the open report 
or provided to study leadership. Any summaries of adverse events or infusion-related 
reactions are restricted to the closed report.  
Following the completion of the trial, the summaries below will be used to describe the 
infusions given to each treatment group (hIVIG and control).  Some of the summaries 
will be carried out for all participants who meet the strict eligibility criteria; safety 
summaries will be summarized for participants in the mITT population. 
These summaries will be stratified by study product/matching placebo group.    
• Number and percentage of participants receiving complete infusion, partial infusion, 
or not infused among all randomized participants. 


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• Number and percentage of participants for whom infusion was interrupted.  
• Number and percentage of participants with infusion-related reactions and 
symptoms (reported during the infusion or within 2 hours after the infusion), by 
grade.  
• Number and percentage of participants with an incident grade 3 or 4 AE, SAE, UP or 
SUSAR on the day of infusion. Types of AEs will be summarized by system organ 
class and by grade.  
• Number and percentage of participants who received: 
o Prior to infusion, medication to prevent infusion reactions, and type of 
medication among all randomized participants 
o During or within 2 hours after infusion, medication to treat infusion reaction, 
and type of medication  
• The day the infusion began (same day as randomization, next day, > 1 day after 
randomization), and time between randomization and beginning of infusion (median 
hours, 25th, 75th percentiles). 
• Among participants receiving full infusion, duration of infusion (median minutes, 25th, 
75th percentiles). 
• Time from pooling of infusion bag (beginning of preparation of study 
product/matching placebo by the pharmacist) to the end of the infusion. 
• Actual dose received, infusion rate, infusion volume, and percentage who received 
the 400 mL dose (dose was capped at 400 mL corresponding to those who weighed 
100 kg or greater). 
• Remdesivir:  
o Number and percentage of participants who received (any) remdesivir, and 
number of days remdesivir was administered: median, 25th, 75th percentiles, 
distribution (< 5 days, 5 days, > 5 days). 
o Number and percentage of participants who received remdesivir prior to the day 
of randomization, and number of doses (median, 25th, 75th percentiles). 
o On the day of randomization: Number and percent of participants who received 
remdesivir prior to the hIVIG/placebo; after the hIVIG/placebo; no remdesivir.  
For these outcomes related to administration of study product, treatment groups will be 
compared using stratified Cochran Mantel Haenszel test stratified by study 
product/matching placebo group for binary outcomes and Wilcoxon rank-sum test for 
continuous outcomes.  
Section 7.2 outlines halting rules for pausing the trial due to infusion related adverse 
events.  


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7 Statistical Analyses 
All analyses will utilize 2-sided tests with a 0.05 significance level. Analyses will 
compare hIVIG treatment to placebo pooled across study products using the mITT 
population unless stated otherwise.  
7.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the seven-level ordinal outcome described in Section 
1.4. 
For the primary endpoint, the percent of participants in the seven categories of the 
ordinal outcome will be compared. A proportional odds model will be used to estimate a 
summary OR (the ratio of the cumulative odds of being in a better category of the 
ordinal outcome for hIVIG versus placebo). The model uses the cumulative probabilities 
of being in any of categories 1 up to a threshold (or cutoff) to define six cumulative odds 
corresponding to cutoffs at categories 1,2,..,6. The model will include a single indicator 
for treatment, indicators for the participant’s clinical state at entry (categories of ordinal 
outcome), and its two-way interactions with the six cutoffs for each of the six cumulative 
odds of improvement. The model will also include indicators for which of the four study 
product/matching placebo group was used and their two-way interactions with the six 
cutoffs. The primary test statistic will be a Wald test of the coefficient for the treatment 
indicator. 
For the primary endpoint analysis only, multiple imputation based on baseline and 
follow-up data will be used to estimate participant status at Day 7 for participants with 
missing data on the ordinal outcome. Imputation will not be performed for secondary 
endpoints or for subgroup analyses of the primary endpoint. 
Of the 7 participants with a missing Day 7 primary ordinal outcome, 6 were known to 
have been discharged.  For these participants it will be assumed that they are in one of 
the three most favorable categories (3 of the 6 discharged participants were on oxygen 
the day of discharge).  For this imputation, for those discharged by Day 7, in addition to 
treatment group, the following baseline covariates will be considered: age, clinical status 
based on the ordinal outcome at enrollment, duration of symptoms, presence of any 
comorbidity, and NEW score. In addition to the baseline covariates, the day of 
discharge after randomization, and oxygen status on the day of discharge will be used 
in the imputation.  
For the participant who was transferred to another hospital on Day 2 and who was 
known to be alive on Day 27, the ordinal category on Day 2 will be imputed for the Day 
7 primary outcome. 
We will impute ten data sets; parameter estimates (e.g., the summary odds ratio) from 
the 10 multiply imputed datasets will be combined using Rubin’s combining rules.  
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The DSMB is to consider a recommendation for stopping the trial early for 
efficacy only if there is clear and convincing evidence of superiority of the hIVIG 
versus the control group with respect to the primary outcome. 
For monitoring superiority, the Lan-DeMets spending function analogue of the O’Brien-
Fleming boundaries will be used, with a 1-sided 0.025 level of significance over multiple 
looks. The boundary for harm is asymmetric, requiring less evidence to stop for harm 
than for superiority, described in Section 7.2. For computing the Lan-DeMets boundary, 
the information fraction at each interim analysis will be the observed total number of 
participants with Day 7 ordinal outcome data divided by the planned number of 
participants. 
It is important that each hIVIG product is well-represented in the number of participants 
enrolled at the time of a recommendation by the DSMB to stop early due to convincing 
evidence of efficacy. Thus, we recommend that early termination for efficacy not be 
considered until at least 250 participants have been enrolled and at the time such a 
decision is made the DSMB also consider the number assigned each product. As a 
guideline we recommend that at least 20% of the information (number with a Day 7 
outcome), be from each hIVIG product. 
At each interim analysis the following will be provided:  
• The value of the primary test statistic (Wald test statistic defined as the 
standardized estimate of the summary log OR) from the cumulative logistic 
regression model, plotted over information time, at the current DSMB review, and 
the corresponding values of the test statistic presented at the previous reviews. 
The graph will also show the O’Brien-Fleming boundary with Lan-DeMets alpha-
spending function. Boundaries will be shown for a one-sided test with 
alpha=0.025 for superiority of hIVIG, and an asymmetric, Haybittle-Peto 
boundary for harm (2.5 standard deviations for the first 100 participants; 2 
standard deviations thereafter).  
• The primary safety outcome is a composite of grade 3 and 4 AEs, SAEs, or 
death through Day 7, as described in Section 7.2 below (primary safety 
outcome). Along with the overall primary outcome, this measure will be used to 
assess whether benefits of the treatment outweigh the risk.  
• Estimated proportion of participants in each level of the Day 7 ordinal scale by 
treatment group. 
• The summary ORs from fitting a similar cumulative logistic regression model for 
the ordinal outcome at Days 3, 5, 14, and 28. 
• History of the estimated ORs from the cumulative logistic regression model with 
95% CIs and p-values at previous DSMB reviews, as presented. 
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A test for the proportional odds assumption will be made from a model that allows 
different effect estimates for the hIVIG versus placebo according to the cut-off of the 
ordinal scale (a partial proportional odds model). That is, a cumulative logistic 
regression model with the same terms as above but including two-way interactions 
between the treatment indicator and the six cut-offs. A composite likelihood ratio test will 
be used to determine if any of the additional terms are significantly different from zero 
(i.e., a test of the proportional odds assumption). Even if the proportional odds 
assumption is violated, the overall summary OR will be the basis for inference for the 
primary analysis.  
Sample size re-estimation 
The sample size re-estimation was conducted by blinded statisticians and did not use 
any information on the treatment effect. The purpose was to re-estimate the sample size 
needed to obtain 80% power with an assumed odds ratio of 1.61 based on the 
distribution of the ordinal outcome at Day 7 observed in the trial pooled across study 
arms (as opposed to the hypothesized distribution informed by data from the ACTT-1 
trial).  
Sensitivity Analyses 
• In order to further characterize the summary OR and any deviations from 
proportional odds, separate ORs will be estimated for each of the six 
dichotomized definitions of improvement that can be formulated from the 
components of the ordinal outcome. That is, we will fit six separate logistic 
regression models for each of the six dichotomized definitions of improvement. 
These models will include an indicator for treatment arm, study product/matching 
placebo group, and baseline ordinal outcome group. 
• Categories 3 and 4 of the primary ordinal outcome differ in part by the amount of 
supplemental oxygen required, and a single cut point (4 liters/minute) defines the 
difference. Since, together, these two categories of the ordinal outcome are 
expected to include approximately 30% of participants, an analysis that combines 
these two categories (resulting in a six-category ordinal outcome) will be carried 
out to supplement the primary analysis using the same methods described 
above. 
• The adjusted cumulative logistic regression model for the final analysis will be 
refitted but exclude the 7 participants for whom the Day 7 outcome is missing 
(i.e., no multiple imputation will be performed). 
 
• The adjusted cumulative logistic regression model for the final analysis will be 
refitted and include all participants randomized with a Day 7 primary outcome. 
 
• The adjusted cumulative logistic regression model for the final analysis will be 
refitted and include a “worst case imputation”.  This was recommended by the 
FDA.  Among the 593 participants randomized, 18 (3.0%) are missing the Day 7 
outcome.  Of these 18 participants, partial follow-up data are available for 7 


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participants.  For 11 participants, all who were not infused, there are no follow-up 
data.  Given the double-blind nature of the trial, a worse case analysis (e.g., 
imputation of category 1 for those in the placebo group and category 7, death, in 
the hIVIG group) for these participants will not be done.  These 11 participants 
will be excluded from this sensitivity analysis.  Among the other 7 participants, 6 
were discharged before Day 7.  For these 6 participants, we assumed those in 
the placebo group were in category 1 and those in the hIVIG group were in 
category 4.  For the other participant who was transferred to another hospital on 
Day 2 and was known to be alive on Day 27, category 1 will be imputed on Day 7 
if assigned to the placebo group, and category 2 will be imputed on Day 7 if 
assigned to the hIVIG group.  This is the same category of ordinal outcome the 
participant was in on Day 2 (i.e., no change is assumed).      
 
• The adjusted cumulative logistic regression model will be refitted but will include 
geographic region as an additional covariate.  
7.2 Safety Analyses 
The following safety and tolerability outcomes will be analyzed: 
• The primary safety endpoint is a composite of grade 3 and 4 adverse events, 
SAEs, or death through Day 7. The percent of participants experiencing the 
composite safety outcome will be compared. A logistic regression model will be 
used to estimate an OR for hIVIG versus placebo. The logistic regression model 
will include indicators for treatment group, study product/matching placebo group, 
and baseline ordinal outcome category. Over the first 28 days, the cumulative 
proportion of participants with a SAE or death will be estimated using Kaplan-
Meier curves, by treatment group. The hazard ratio (HR) for hIVIG versus 
placebo will be estimated with a 95% CI using a Cox proportional hazards model 
with an indicator for treatment group, stratified by study product/matching 
placebo group and baseline ordinal outcome category. 
Stopping boundaries for harm: A Haybittle-Peto boundary of 2.5 standard 
deviations (SD) for the first 100 participants enrolled and 2.0 SD afterwards will 
be used as a guideline for harm. The SD refers to the standard deviation of the 
test statistic (standardized estimate of the summary log OR). With this boundary, 
less evidence is needed for stopping a trial early due to harm compared with 
stopping for efficacy.  
Similar to the efficacy analysis, the observed value of the test statistic for the 
primary safety outcome will be plotted over information time, for the current data, 
along with the boundaries and the values presented at previous DSMB reviews.  
• Safety analyses will also include infusion reactions collected during or within 2 
hours after the infusion of hIVIG/placebo. Percentages of participants who 
experience infusion reactions or prematurely terminated infusions will be 


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summarized by treatment groups and compared as described in the preceding 
section. 
• Other safety analyses will be conducted including the following outcomes: 
o Composite of grade 3 and 4 adverse events, SAEs, or death through Day 7 
excluding exempt events 
o Composite of grade 3 and 4 adverse events, SAEs, or death through Day 7 
by MedDRA system organ class (SOC) 
o Composite of SAE or death through Day 28 by MedDRA SOC 
o Each component of the primary safety outcome analysed separately (deaths, 
SAEs nonexmpt, SAEs exempt, and grade 3 and 4 adverse events)  
o A composite of SAEs and death through Day 28 (including and excluding 
exempt events and each component separately analyzed) 
o Prevalence of clinical AEs of any grade on Days 0, 1, 3, 7, and 28; AEs will 
be summarized by grade and day, and by MedDRA® system organ class and 
grade. (AEs present on those days). 
o Summaries of UPs and SUSARS, and listings of SAEs, UPs, SUSARs and 
deaths. 
o Change in laboratory test values from baseline to Day 7, and incidence of 
grade 3 and 4 laboratory abnormalities at Day 7. 
AEs will be coded with MedDRA, version 23.1.  In addition to the tables, listing of 
participants with grade 3 or 4 events, SAEs or deaths will be provided with the MedDRA 
preferred term (PT) and study day of AE. 
Further safety assessments may be considered including by study product/matching 
placebo group (see Section 7.5). 
Because the infusion volume in this protocol is significant (250 mL for remdesivir and up 
to 400 mL for hIVIG/placebo), as a guideline, the DSMB will be asked to consider 
halting enrollment if more than 5% of participants experience a grade 3 or 4 infusion AE 
or if more than 10% do not complete the infusion due to an AE(s). This will be informed 
by the lower bound of the 95% confidence interval which will not be adjusted for 
multiplicity. When this occurs, differences will be compared by randomized group. If the 
study is temporarily halted or stopped for safety reasons, institutional review 
boards/ethics committees will be informed. 
7.3 Monitoring for Futility 
To assess futility, conditional power calculations based on an unadjusted model (as was 
done for the original power calculations) for the Day 7 ordinal outcome will be presented 
under a range of scenarios. In the primary futility analysis, it will be assumed that the 
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the study design (adjusted OR = 1.61). As secondary analysis, the treatment effect for 
future follow-up will be assumed to be similar to the observed effect. Additional 
scenarios may be provided. Typical futility guidelines recommend stopping a trial when 
conditional power (assuming the originally hypothesized treatment effect for the future, 
as yet unobserved follow-up) is below 10%-20%. 
As a guideline, futility will first be assessed after 50% of the planned number of 
participants have Day 7 ordinal outcome data, and a value of 20% will be suggested as 
a threshold for the conditional power. Conditional power will be computed using the test 
statistic for the treatment indicator in a cumulative logistic regression model.  
Decisions to terminate the study for futility will include a broad assessment of the 
risk/benefit trade-off in addition to these guidelines. 
7.4 Secondary Outcomes 
The protocol defines a number of secondary endpoints in addition to the two key 
endpoints described in the previous section. These analyses will be carried out for the 
final report. No adjustment for multiplicity for all the treatment comparisons for the 
secondary outcomes will be made; they are supportive to the primary endpoint analysis. 
Selected secondary endpoints may also be analyzed for the interim monitoring report to 
help evaluate the safety and efficacy of hIVIG.  
Multiple imputation will only be used for data missing on the primary endpoint; all 
secondary endpoints will use complete case.  
Below, the secondary outcomes from the protocol are cited, with a short description of 
the analysis methods. The secondary outcomes are grouped by analysis methods and 
are not listed in order of importance.  
1. The primary ordinal outcome on Days 3, 5, 14 and 28. 
 
2. Pulmonary only components of the primary outcome measure at Days 3, 5, 7, 
14 and 28 
 
3. Thrombotic components of the primary outcome measure (stroke, myocardial 
infarction, venous and arterial thrombosis or embolism, plus disseminated 
intravascular coagulation) at Days 3, 5, 7, 14, and 28.  
 
4. Clinical organ dysfunction 
 
5. The ordinal outcome similar to the one used in the ACCT trial of remdesivir 
will be used to compare treatment groups at Day 7.  The ACCT ordinal 
outcome included 8 categories.  We can only approximate the categories 
because data were not collected concerning hospitalization for infection-
control reasons. It is similar to the ITAC primary ordinal outcome but 


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considers hospitalization status.  The following 8 categories will be defined for 
this ordinal outcome: 
 
• Not hospitalized, no limiting symptoms due to COVID-19 
• Not hospitalized, limiting symptoms due to COVID-19, home oxygen 
requirement, or both 
• Hospitalized, no limiting symptoms due to COVID-19, not requiring 
supplemental oxygen 
• Hospitalized, limiting symptoms due to COVID-19, not requiring 
supplemental oxygen 
• Hospitalized, requiring any supplemental oxygen 
• Hospitalized, requiring non-invasive ventilation or use of high-flow oxygen 
devices. 
• Hospitalized, requiring invasive mechanical ventilation or ECMO 
• Death 
 
6. Percentage in 2 most favorable categories at Day 7. 
 
7. Hospitalization status at Days 14 and 28. 
 
8. Hospitalization status (a binary outcome, alive and discharged from the 
hospital to home or rehabilitation OR able to independently undertake usual 
activities with minimal or no symptoms versus dead or hospitalized AND 
unable to independently undertake usual activities) at Days 7, 14 and 28. 
 
For outcomes 1-8, the proportion of participants in each category will be 
summarized by treatment group. For the ordinal outcomes, a summary OR 
will be estimated using a cumulative logistic regression model which includes 
a single indicator for treatment, indicators for the participant’s clinical state at 
entry (categories of ordinal outcome), its two-way interactions with the six 
cutoffs for each of the six cumulative odds of improvement, indicators for 
which of the four study product/matching placebo group was used and their 
two-way interactions with the six cutoffs. For the binary outcomes, a summary 
OR will be estimated using a logistic regression model which includes a single 
indicator for treatment, indicators for the participant’s clinical state at entry 
(categories of ordinal outcome), and indicators for which of the four study 
product/matching placebo group was used. For interim analyses we will 
consider clinical organ dysfunction as a binary composite endpoint at Day 7 
and Day 28. At the end of the trial we will take into account the severity of 
each organ dysfunction by developing a weighting scheme by examining the 
pooled association of each item with subsequent death. 
 
9. All-cause mortality through Day 28. 
 
10. Time to the three least favorable categories of the primary outcome measure. 


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For outcomes 9 and 10, the cumulative incidence of death (outcome 9) or the 
three least favorable categories (outcome 10) by treatment group will be 
estimated using Kaplan-Meier methods. The treatment groups will be 
compared using a log-rank test. A summary HR comparing the treatment 
groups will be estimated using a Cox proportional hazards model. These 
models will be stratified by study product/matching placebo group and 
baseline ordinal outcome group. 
 
11. Time to the two most favorable categories of the primary outcome measure. 
 
12. Time to discharge (this is similar to the recovery outcome used in the ACTT-1 
trial)  
 
13. Time to discharge or being able to independently undertake usual activities 
with minimal or no symptoms 
 
14. Time to being able to independently undertake usual activities with minimal or 
no symptoms (discharge status will be ignored) 
 
For outcomes 11-14, time-to-event methods that take into account the 
competing risk of death will be used. Specifically, Gray’s test with rho=0, the 
Fine-Gray model, and the Aalen-Johansen estimator for the cumulative 
incidence curve are the competing risk equivalents to the log-rank test, Cox 
proportional hazards model, and the Kaplan-Meier estimator for the 
cumulative proportion of participants with the event, respectively. Gray’s test 
and the Fine-Gray model will be stratified by study product/matching placebo 
group and baseline ordinal category. 
Additionally, as a sensitivity analysis for the analysis of time-to-discharge and 
days outside the hospital we will exclude participants from the 5 sites where 
no participants were discharged prior to Day 7.   
15. Days alive outside of a hospital through Day 28 
 
16. Days alive and able to independently undertake usual activities with minimal 
or no symptoms through Day 28 
 
17. Days alive and out of the hospital or able to independently undertake usual 
activities with minimal or no symptoms through Day 28 (whichever lead to 
greatest time) 
 
These outcomes (15-17) have been used in other trials of therapeutics for 
COVID-19. We will sum the number of days that each individual spends 
outside a short-term acute care hospital up to 28 days. A person who dies 
within 28 days will be assigned a value 0, consistent with the approach taken 


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in trials of intensive care-based interventions. We will present the mean and 
median days by group. We will test the hypothesis of no mean difference 
between arms using methods for continuous outcomes (ANCOVA models), 
with baseline baseline ordinal outcome group and study product/matching 
placebo group as covariates. Because the residual distribution is unlikely to 
be normally distributed, we will use robust or sandwich standard errors. This 
analysis will be undertaken only when complete follow-up data are available. 
The outcome does have limitations due to its handling of death and 
withdrawal. We expect that there will be minimal missing data but may use 
multiple imputation for the final analysis.  
 
18. Change in immunoglobulin levels (IgG, IgG subclasses, IgM, IgA) and 
neutralizing antibody titres from baseline to Days 1, 2, 3, 7, 28 and 90. 
 
Longitudinal random effects models will be used to summarize log-
transformed antibody level differences between the hIVIG and placebo 
groups at Days 1, 3, 7 and 28 of follow-up. Baseline antibody levels will be 
included as a covariate in these models. For the subset of participants for 
whom blood is collected at Day 90, antibody levels will be compared. 
 
Exploratory analyses will be carried out if hIVIG is efficacious to determine if 
antibody differences post-infusion on Days 1 and 3 predict the primary 
outcome. First, post-infusion antibody level (perhaps also considering the pre-
infusion level or change from baseline) will be considered as a predictor of the 
Day 7 ordinal outcome using a proportional odds model. If there is evidence 
that the post-infusion level or change predicts the Day 7 outcome, a model 
which includes the post-infusion level and treatment will be fit to determine 
the impact on the treatment estimate without the antibody level in the model. 
Second, we will examine the association between antibody treatment 
differences post-infusion by treatment group and the Day 7 summary OR from 
the cumulative logistic model. This could be done for each product separately 
(four data points) and/or according to the potency of each lot, grouped into 
more than four groups.   
7.5 Subgroup Analyses 
Subgroup analyses for the primary seven-category ordinal outcome (primary efficacy 
outcome), as well as for the primary safety outcome (Grade 3 and 4 adverse events, 
SAE or death through Day 7) will be performed to determine whether and how the 
treatment effect (hIVIG versus placebo) differs qualitatively across various subgroups 
defined at baseline, and whether there are safety concerns in specific subgroups.  
The protocol denotes the subgroup analysis by the duration of symptoms at study entry 
as the “key subgroup analysis.” In addition to the analysis by 4 categories of duration of 
symptoms (<6, 6-7, 8-9, 10-12 days), an analysis based on the upper quartile of 
symptom duration (e.g., less than or equal to the 75th percentile versus greater than the 


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75th percentile) (2 categories). The upper quartile is 10-12 days (75% of participants will 
have symptom duration < 10 days). In ACCT-1, a more severely ill target population 
than studied here, there was no limit to the duration of symptoms and the median was 9 
days (25th and 75th percentile, 6 – 12 days). The quartile definitions for duration of 
symptoms will be determined following the completion of enrollment. For interim 
analyses, the quartiles will be determined based on interim data. For those with shorter 
duration of time since symptom onset, the treatment effect is hypothesized to be greater 
than among participants who have had symptoms for a longer period of time. A global 
test for heterogeneity of the treatment effect across the symptom duration subgroups 
will be carried out in 2 ways: 1) by adding the interaction between symptom duration as 
a continuous variable (1 df test) and the treatment group to the model; and 2) by adding 
the interaction between categories of symptom duration and the treatment group to the 
model (3 df test). 
Other important subgroups include subgroups by disease severity, by age, and by pre-
existing conditions. A priori we have no reason to believe the clinical efficacy or safety 
of hIVIG compared to placebo will be substantially different in relative terms in any of 
the following subgroups considered. Subgroup analyses for the primary efficacy 
endpoint and safety endpoint will use the adjusted (cumulative) logistic models 
described earlier. ORs with 95% CIs comparing the treatment group versus control will 
be estimated for each subgroup. Global tests for heterogeneity of the treatment effect 
across subgroups will be carried out by adding the interaction between the subgroup 
indicator and the treatment group indicator to the model. In case the subgroup was 
formed by categorizing a continuous variable, the interaction term will be formed 
between the subgroup indicator and the continuous variable.  
Subgroup analyses will not be adjusted for multiple comparisons; they are supportive to 
the primary endpoint analysis. Subgroup analyses will be interpreted with caution due to 
limited power and uncontrolled type I error.  
Subgroup analyses will be performed for a number of baseline factors.  Unless 
otherwise stated, continuous outcomes will be summarized in quartiles.  The following 
subgroups will be considered: 
• Age (18-49, 50-59, 60-69, 70+ years) 
• Sex at birth (male, female) 
• Race/ethnicity (Asian, Black, Latino/Hispanic, White, other) 
• BMI [<25, 25.0-29.9, 30-39, 40+ kg/m2] 
• Presence of chronic medical conditions which had greater than 5% prevalence at 
baseline (diabetes, hypertension, COPD, asthma, renal impairment ) 
• Geographic location (U.S.; Europe, UK, or Israel; and Argentina, Indonesia, 
Japan or Nigeria) 
• Upper respiratory SARS-CoV-2 viral load 


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• Oxygen saturation level 
• Dyspnea severity (Modified Borg dyspnea scale) 
• Organ/respiratory dysfunction category based on ordinal primary outcome 
• NEWS 
• Participants with and without compromised immune function; participants with 
HIV, an immunosuppressive condition other than HIV, or taking antirejection 
medication, immune modulators, or biologic treatment for autoimmune disease or 
cancer will be considered to have compromised immune function. 
 
• BMI < 40 and ≥ 40 kg/m2 according to history of diabetes (4 groups) 
 
• Hypertension with and without history of other metabolic and vascular co-
morbidity (4 groups): i) no hypertension or other metabolic/vascular co-morbidity; 
ii) hypertension without metabolic/vascular co-morbidity; iii) metabolic/vascular 
condition without hypertension; and iv) hypertension and a metabolic/vascular 
co-morbidity.  Metabolic/vascular co-morbidities include a history of diabetes, a 
cerebrovascular event, heart failure, or an MI or acute coronary syndrome. 
 
• Number of vascular co-morbidities (0, 1, 2, 3+) 
 
• Quartile of Charlson Comorbidity Index (for conditions assessed) 
 
• Risk calculator for vaccine prioritization (JHU) 
 
• 
Corticosteroids, overall and in combination with oxygen requirements (ordinal 
category at baseline) 
 
• Use of antiplatelet/anticoagulant therapy (prophylactic heparin, intermediate or 
therapeutic heparin or other anticoagulant therapy, none) 
 
• Quartiles of disease progression risk score (defined using pooled treatment 
groups with the following baseline predictors of the Day 7 ordinal outcome: age, 
gender, antigen and antibody level, duration of symptoms, oxygen saturation 
level, ordinal outcome category at entry, NEWS, and chronic health conditions). . 
We will analyse the association between lot potency and the primary outcome for 
participants assigned active hIVIG using a cumulative logistic regression model 
adjusted for hIVIG product and baseline ordinal category. The aim of this analysis will 
be to determine if the primary outcome varies by range in potency among the various 
lots of hIVIG used.  
 
Additionally, we will explore if the association between lot potency and the primary 
outcome differs by baseline antibody titre. The potency of each lot will be measured by 


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Texcell. In addition to the subgroup analyses above, a subgroup analysis by lot potency 
(by tertiles) will be carried out. Participants in the placebo group will be classified 
according to the lot potency they would have received had they been randomly 
assigned to the hIVIG group.    
 
If there is a beneficial effect of hIVIG compared to placebo, in order to support 
regulatory claims for each hIVIG product used, sensitivity analyses comparing each 
hIVIG product to its matching placebo will be carried out for key efficacy and safety 
endpoints. First, we will assess the evidence for any difference in effect among the 
products. A test for heterogeneity of the treatment effect across study products will be 
carried out by adding the interaction between study product/matching placebo group 
and the treatment group indicator to the model. In addition to the models for efficacy 
and safety endpoints described above, we will also test for heterogeneity of the 
treatment effect across study product/matching placebo group after adjusting for lot 
potency. In one of the subgroup analyses by hIVIG product, the subgroups will be 
further divided by the potency level of the hIVIG lots used for that product (e.g., above 
and below the median level of lot potency for the product). 
 
Second, we will obtain estimates of the effect for each product using two general 
approaches. a) We will estimate the effect for each hIVIG product using only data from 
participants receiving that particular product/matching placebo (e.g., separate analyses 
for each study product). b) We will use multisource exchangeability modelsii (MEMs) to 
dynamically borrow information from other study products to improve estimation of the 
efficacy and safety of a single study product. MEMs work by enumerating all possible 
exchangeability patterns between the data sources (here data from different study 
products) and obtain a single posterior distribution for the parameter of interest using 
Bayesian model averaging. The key benefit of this approach is that it can borrow 
differentially from different study products. Estimates of the effect for each product will 
be done both adjusting for and not adjusting for lot potency.      
 
These analyses will consider that each hIVIG product will be used by a different group 
of clinical sites (i.e., each comparison will represent a small multi-center trial), and that 
power will likely be very low for all of the outcomes. Because the hIVIG product that 
each site receives is not randomized, any comparisons of the efficacy among hIVIG 
products should be interpreted cautiously. These analyses are referred to as sensitivity 
analyses because overall therapeutic efficacy and safety will be based on the pooled 
analysis of the four hIVIG products with placebo. 
7.6 Analyses of Stored Specimens 
NIH plans to measure antibody and antigen levels on plasma samples from ITAC.  
Antibody levels will be determined using kits made by Bio-Rad, which measures total 
(IgA, IgG, and IgM) anti-nucleoprotein (NP), and by GenScript (anti-spike neutralizing 
antibody surrogate), which measures a subset of antibodies capable of inhibiting 
binding by spike proteins.  Antigen levels will be determined in plasma using an assay 


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made by Quanterix. 
 
Results of the Bio-Rad antibody measurement are reported in terms of “specimen 
ratios”. Specimen ratios are defined as the specimen optical density (OD) divided by the 
optical density of the cut-off control R4 (ODMR4).  According to the manufacturer, 
specimen ratios less than 0.8 are considered negative, those with a specimen ratio 
between 0.8 and 1.0 are considered equivocal, and those greater than 1.0 are 
considered positive for the presence of anti-SARS-CoV-2 antibodies.   
 
Results of the GenScript antibody assay are reported as binding inhibition percentages.  
For this assay, levels less than 30% are considered negative and those ≥ 30% are 
considered positive.  
 
Results of the quantitative Quanterix assay are reported in pg/mL. The lower level of 
detection is 3 pg/mL. 
 
Subgroup analyses will be carried out using the antigen and antibody data at baseline 
and the Day 7 pulmonary and pulmonary+ ordinal outcomes at Day 7.   
 
Our hypothesis is as follows:  Patients with negative or lower positive antibody levels 
will benefit more from hIVIG compared to placebo than patients with higher antibody 
levels.  Furthermore, those with lower antibody levels AND with higher antigen levels, 
will benefit more from hIVIG compared to placebo than other subgroups categorized by 
both antibody and antigen levels. 
8 Data Completeness and Study Conduct 
The primary outcome (seven-level ordinal outcome) will be assessed daily through Day 
28. In-person visits are scheduled on Days 1, 2, 3, 7, and 28, when blood is collected 
(plasma and serum); other visits on Days 5 and 14 may be conducted by phone. 
Participants at selected sites will return for a visit 90 days after randomization to obtain 
a blood draw; this subset will comprise all participants at selected sites where return for 
a later visit is practical for participants.   
Data completeness and study conduct reports will be provided by treatment group (for 
the closed report) and pooled across treatment groups (for the open report). Data 
summaries for the infusion of hIVIG/placebo on Day 0 are described in Section 6; 
several of those reports are also relevant for monitoring study conduct and will be 
included in the open report or provided to study leadership, pooled across treatment 
groups. 
9 The following data summaries will be provided: 
• Number, percent and type of protocol deviations. Specific protocol deviations are 
reported in the protocol.  


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• Expected and observed number (% of expected) of participants who completed 
visits on Days 1, 2, 3, 5, 7, 14, 28, and 90.  
• Ascertainment of the primary outcome: Expected and observed number (% of 
expected) of participants with outcome status for the ordinal outcome (Days 0-7, 
14, and 28). 
• Expected and observed number (% of expected) of participants with known vital 
status at Days 0-7, 14, and 28.  
• Number and percent of participants who withdrew consent, or with missing 
primary outcome data for other reasons will be summarized.  
• Listing of participants who withdrew consent, including dates of randomization, 
study product/matching placebo group, receipt of study treatment, date of 
withdrawal, and reason of withdrawal.  
• Length of follow-up: Median, 25th, 75th percentiles, range and distribution 
• Collection of specimens: Expected and observed number (% of expected) of 
participants with specimens collected as specified by the protocol, by visit.  
A visit counts as “expected” if the visit window has closed or the data have been 
received.  
The summaries for the final report will be provided for the mITT population unless 
otherwise stated. 


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10 Addendum to Statistical Analysis Plan for European 
Medicines Agency 
During the review by EMA of INSIGHT 013 (ITAC), An International Multicenter, 
Adaptive, Randomized Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability 
and Efficacy of Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the 
Treatment of Adult Hospitalized Patients at Onset of Clinical Progression of COVID-19, 
it was requested that the data analysis plan be revised to make the 7-category 
pulmonary ordinal outcome at day 7 (a secondary endpoint) the primary endpoint for 
submissions to the EMA instead of the 7-category ordinal outcome specified in the 
protocol (see section 4 and Appendix F of the protocol) which also includes a range of 
organ dysfunction in addition to respiratory dysfunction.  The protocol-defined primary 
endpoint would be a secondary endpoint for EMA submissions. 
An addendum to Version 1.0 of the Statistical Analysis Plan was prepared on January 
11, 2021 to address this request from the EMA. It is reproduced here for ease of 
reference. 
The statistical data analysis plan based on the protocol, dated 25 September 2020, will 
not be changed as it reflects the protocol.  For the EMA submission, this document will 
be submitted with the protocol and the statistical data analysis plan.  Should the data 
analysis plan be modified before the end of the study, this document will be submitted 
with the updated statistical data analysis plan. 
For the EMA submission, the ordinal outcome shown in the table at the end of this 
section will be used as the primary endpoint.  Sample size assumptions, as stated in 
section 5.5 of the protocol, are not expected to differ for this outcome compared to 
those stated in the protocol for the primary endpoint.  This assumption is supported by 
results from another trial, INSIGHT 014 (TICO), for which similar endpoints were used.  
A paper describing the findings from TICO at day 5 for both ordinal outcomes reported 
that only 2 of 311 participants were in different categories of the two ordinal outcomes 
(ACTIV-3/TICO LY-CoV555 Study Group, N Engl J Med 2020, doi: 
10.1056/NEJMoa20331.30). 
The planned data analysis for the pulmonary ordinal outcome described in section 7 of 
the Statistical Data Analysis Plan for ITAC will be identical to those stated for the 
protocol-defined primary ordinal outcome.  Likewise, the assessment of model 
assumptions and sensitivity analyses specified in the Statistical Data Analysis Plan will 
be carried out for pulmonary ordinal outcome as well as the protocol-defined primary 
endpoint. 
Interim monitoring guidelines specified in the protocol for the primary endpoint will not 
change.  Stopping boundaries for substantial evidence of benefit, for harm, and for 
futility will be based on the protocol-defined primary endpoint. 


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Sample size re-estimation was recently carried out using pooled (both treatment groups 
combined) category percentages for the protocol-defined primary endpoint.  This re-
estimation confirmed that 500 participants will be sufficient to detect an OR of 1.61 with 
80% power. 
This document was prepared by blinded statisticians and reviewed by the blinded 
protocol team.  This document will be used with the protocol and the statistical data 
analysis plan to prepare the final study report for the EMA.        
 
 


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TABLE. CLINICAL CATEGORICAL DEFINITIONS FOR PULMONARY ORDINAL 
OUTCOME 
Each participant is categorized in the highest applicable category. 
Ordinal 
Category 
Categorical 
Description 
Categorical Definition* 
7 
Death 
Death 
6 
End-organ failure 
Currently requiring invasive assisted ventilation, 
extracorporeal membrane oxygenation, mechanical 
circulatory support, vasopressor therapy or renal 
replacement therapy 
5 
Life-threatening end-
organ dysfunction  
Currently requiring non-invasive assisted ventilation or 
high-flow oxygen or 
 
4 
Serious end-organ 
dysfunction  
Currently requiring supplemental oxygen (≥ 4 liters/min, or 
≥ 4 liters/min above premorbid requirements**) but not 
high-flow oxygen  
  
3 
Moderate end-organ 
dysfunction 
Requiring supplemental oxygen < 4 liters/min, or < 4 
liters/min above premorbid requirements** 
2 
Limiting symptoms 
due to COVID-19 
Symptomatic and currently unable to independently 
undertake usual activities 
1 
No limiting 
symptoms due to 
COVID-19 
Can independently undertake usual activities with minimal 
or no symptoms 
*Continued hospitalization or presence in a particular category of inpatient facility (e.g. 
intensive care or high dependency) is not used to divide these categories, as indication 
for continued hospitalization among recovering COVID patients is intrinsically 
subjective, in part determined by social and financial factors, and varies markedly 
across the globe.  
** Premorbid requirement refers to requirements prior to the development of COVID-19, 
for example in patients with chronic obstructive pulmonary disease, other chronic 
pulmonary diseases, or oxygen requirements related to altitude. 
 
 
 


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References 
i Whitehead J.  Sample size calculations for ordered categorical data.  Stat Med 1993; 12: 2257-2271. 
 
ii Kaizer AM, Koopmeiners JS, Hobbs BP. Bayesian hierarchical modeling based on multisource 
exchangeability. Biostatistics. 2018;19(2):169-184. doi:10.1093/biostatistics/kxx031 
 
Kaizer AM, Koopmeiners JS, Kane MJ, Roychoudhury S, Hong DS, Hobbs BP. Basket designs: Statistical 
considerations for oncology trials. JCO Precision Oncology. 2019; 3:1-9. 
 
Hobbs BP, Landin R. Bayesian basket trial design with exchangeability monitoring. Statistics in medicine. 
2018; 37(25):3557-72. 
                     

Prot_001.pdf: 
Protocol INSIGHT 013 
 
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An International Multicenter, Adaptive, Randomized Double-Blind, Placebo-
Controlled Trial of the Safety, Tolerability and Efficacy of Anti-Coronavirus 
Hyperimmune Intravenous Immunoglobulin for the Treatment of Adult 
Hospitalized Patients at Onset of Clinical Progression of COVID-19 
 
Short Title: Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) 
 
INSIGHT Protocol Number: 013 
 
Version:  1.0, 20 August 2020 
 
Funded by the National Institute of Allergy and Infectious Diseases (NIAID), 
National Institutes of Health (NIH) and carried out by the International Network for Strategic 
Initiatives in Global HIV Trials (INSIGHT) 
Study Sponsor:  University of Minnesota 
 
In collaboration with four International Coordinating Centers (ICCs) of the INSIGHT 
Network: 
-Copenhagen HIV Programme (CHIP) - Copenhagen, Denmark 
-Medical Research Council (MRC) Clinical Trials Unit at University College London 
(UCL) -London, United Kingdom 
-The Kirby Institute, University of New South Wales - Sydney, Australia 
-The Institute for Clinical Research at the Veterans Affairs Medical Center - Washington, 
D.C., USA 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................... 2 
LIST OF TABLES ................................................................................................................... 5 
LIST OF FIGURES ................................................................................................................ 5 
1 
PROTOCOL SUMMARY ................................................................................................ 6 
 
Synopsis ................................................................................................................... 6 
1.1
1.1.1 
Rationale for Proposed Clinical Study ................................................................ 6 
1.1.2 
Study Design ...................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................ 8 
 
Study Rationale ........................................................................................................ 8 
2.1
 
Background ............................................................................................................... 9 
2.2
2.2.1 
SARS-CoV-2 Infection and Coronavirus Disease 19 (COVID-19) ...................... 9 
2.2.2 
Natural History of COVID-19 .............................................................................. 9 
2.2.3 
Risk Factors for Clinical Progression ................................................................ 11 
2.2.4 
Hospitalization of People with COVID-19 ......................................................... 12 
2.2.5 
Viral Kinetics of SARS-CoV-2 Infection ............................................................ 12 
2.2.6 
Immune Responses to SARS-CoV-2 Infection ................................................. 13 
2.2.7 
Current Treatment Strategies for COVID-19 .................................................... 14 
2.2.8 
Hyperimmune Intravenous Immunoglobulin (hIVIG)......................................... 16 
2.2.9 
Study Treatments ............................................................................................. 17 
3 
RISK/BENEFIT ASSESSMENT .................................................................................... 20 
 
Known Potential Risks ............................................................................................ 20 
3.1
3.1.1 
Blood Draw and IV Catheterization .................................................................. 20 
3.1.2 
Study Treatments ............................................................................................. 20 
3.1.3 
Confidentiality and Privacy ............................................................................... 23 
 
Known Potential Benefits ........................................................................................ 23 
3.2
4 
OBJECTIVES AND ENDPOINTS ................................................................................. 23 
 
Primary Objectives and Primary Endpoint .............................................................. 23 
4.1
4.1.1 
Rationale for Primary Endpoint at Day 7 .......................................................... 24 
 
Secondary Objectives ............................................................................................. 25 
4.2
5 
STUDY DESIGN ........................................................................................................... 28 


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Overall Study Design .............................................................................................. 28 
5.1
 
Randomization ........................................................................................................ 28 
5.2
 
Blinding ................................................................................................................... 28 
5.3
 
Distribution of Anti-Coronavirus hIVIG to Clinical Sites ........................................... 29 
5.4
 
Sample Size Assumptions ...................................................................................... 30 
5.5
5.5.1 
Primary Analysis............................................................................................... 30 
5.5.2 
Key subgroup analysis ..................................................................................... 31 
5.5.3 
Key secondary outcomes ................................................................................. 32 
 
Schedule of Assessments ....................................................................................... 33 
5.6
 
Approach to Intercurrent Therapies and Clinical Trial Co-enrollment ..................... 33 
5.7
6 
SCIENTIFIC RATIONALE FOR THE STUDY ............................................................... 34 
7 
STUDY POPULATION.................................................................................................. 34 
 
Inclusion Criteria ..................................................................................................... 34 
7.1
 
Exclusion Criteria .................................................................................................... 35 
7.2
 
Costs to Participants ............................................................................................... 36 
7.3
8 
STUDY PRODUCT ....................................................................................................... 36 
 
hIVIG and Placebo .................................................................................................. 36 
8.1
8.1.1 
hIVIG Description ............................................................................................. 36 
8.1.2 
hIVIG Dose ....................................................................................................... 36 
8.1.3 
hIVIG Administration ........................................................................................ 37 
8.1.4 
Preparation/Handling/Storage/Accountability ................................................... 38 
 
Remdesivir Background Therapy ............................................................................ 38 
8.2
8.2.1 
Rationale .......................................................................................................... 38 
8.2.2 
Description ....................................................................................................... 38 
8.2.3 
Administration .................................................................................................. 38 
8.2.4 
Contraindications.............................................................................................. 39 
8.2.5 
Dose Modification ............................................................................................. 39 
8.2.6 
Preparation/Handling/Storage/Accountability ................................................... 39 
 
Standard of Care Therapy ...................................................................................... 39 
8.3
8.3.1 
Thromboprophylaxis and diagnosis of thrombotic complications ..................... 39 
8.3.2 
Other Standard Supportive Care ...................................................................... 40 


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8.3.3 
Cautions and Contraindications ....................................................................... 40 
8.3.4 
Infection Control Measures .............................................................................. 41 
9 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 41 
 
Screening/Baseline, Follow-up and Endpoint Assessments ................................... 41 
9.1
9.1.1 
Screening/Baseline Assessments .................................................................... 41 
9.1.2 
Follow-up assessments .................................................................................... 43 
9.1.3 
Stored Samples and Future Research ............................................................. 44 
10 
SAFETY REPORTING ............................................................................................... 44 
 
Definitions ............................................................................................................ 45 
10.1
10.1.1 
Adverse Event (AE) ...................................................................................... 45 
10.1.2 
Criteria for Seriousness................................................................................. 46 
10.1.3 
Unanticipated Problems ................................................................................ 46 
10.1.4 
Severity ......................................................................................................... 46 
10.1.5 
Causality ....................................................................................................... 47 
10.1.6 
Expectedness ............................................................................................... 47 
 
Schedule for Data Collection and Reporting of Specific Events .......................... 48 
10.2
10.2.1 
Infusion-related reactions .............................................................................. 48 
10.2.2 
Targeted Laboratory abnormalities ............................................................... 48 
10.2.3 
Clinical adverse events of any grade severity on Days 0, 1, 3, 7 and 28 ...... 48 
10.2.4 
Incident Grade 3 and 4 clinical adverse events through Day 7 ..................... 48 
10.2.5 
Protocol-specified exempt events ................................................................. 49 
10.2.6 
Reportable SAEs .......................................................................................... 49 
10.2.7 
Unanticipated Problems (UPs) ...................................................................... 50 
10.2.8 
Deaths........................................................................................................... 50 
 
Medical Monitor ................................................................................................... 50 
10.3
 
Treatment Interruption or Discontinuation ........................................................... 50 
10.4
 
Halting Rules ....................................................................................................... 51 
10.5
11 
EVALUATION ............................................................................................................ 51 
 
Data Analysis ....................................................................................................... 51 
11.1
 
Ethical Conduct of the Study ............................................................................... 54 
11.2
 
Data Monitoring by an Independent DSMB ......................................................... 54 
11.3


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12 
PROTECTION OF HUMAN SUBJECTS AND ETHICAL CONSIDERATIONS .......... 55 
 
Participating Clinical Sites and Local Review of Protocol and Informed Consent 55 
12.1
 
Informed Consent of Study Participants .............................................................. 55 
12.2
 
Confidentiality of Study Participants .................................................................... 56 
12.3
 
Regulatory Oversight ........................................................................................... 56 
12.4
APPENDIX A 
SAMPLE INFORMED CONSENT FORM .................................................. 57 
APPENDIX B 
SCHEDULE OF ASSESSMENTS ............................................................. 85 
APPENDIX C 
INSIGHT 013 PROTOCOL TEAM ............................................................. 87 
APPENDIX D 
REFERENCES ON THE INSIGHT WEBSITE ........................................... 88 
APPENDIX E 
LIST OF ACRONYMS ............................................................................... 89 
APPENDIX F 
CLINICAL CATEGORICAL DEFINITIONS FOR ORDINAL OUTCOME .... 92 
APPENDIX G 
NATIONAL EARLY WARNING SCORE (NEWS) ...................................... 93 
13 
REFERENCES........................................................................................................... 95 
 
LIST OF TABLES 
Table 1. Hypothesized percentage of participants in each category on Day 7 in the hIVIG 
and placebo groups based on aforementioned assumptions ............................................... 31 
Table 2.  Adverse Event Data Collection Overview .............................................................. 45 
Table 3. Generic AE Grading Scale ..................................................................................... 47 
 
LIST OF FIGURES 
Figure 1. Natural History of COVID-19 ................................................................................. 11 
Figure 2. Example of Allocation of hIVIG to 24 Site Pharmacies ......................................... 30 
 
 


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 PROTOCOL SUMMARY 
1
 
Synopsis 
1.1
1.1.1 
Rationale for Proposed Clinical Study 
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of 
viral pneumonia cases of unknown cause. Coronavirus ribonucleic acid (RNA) was 
quickly identified in some of these patients. This novel coronavirus has been 
designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the 
disease caused by this virus has been designated coronavirus disease 2019 (COVID-
19). There were 59 confirmed cases on January 5, 2020, 2118 cases on January 26, 
2020, rising to more than 20 million confirmed cases and 750,000 deaths as of 
August 16, 2020 according to various international health reporting agencies.  
Hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from the 
plasma of individuals who recover and develop neutralizing antibodies, is a potentially 
useful therapeutic approach to COVID-19. Augmentation of the humoral immune 
(antibody) response using passive immunotherapy with hIVIG to SARS-CoV-2 at the 
onset of clinical progression before end-organ failure has developed may reduce the 
subsequent risk of further disease progression and death.  
1.1.2 
Study Design 
This protocol will serve as a platform for assessing treatments for adult patients 
hospitalized for medical management of COVID-19 without related serious end-organ 
failure. Trials will involve sites around the world strategically chosen to ensure rapid 
enrollment. Initially, this trial will compare hIVIG with matched placebo, when added 
to standard of care (SOC), for preventing further disease progression and mortality 
related to COVID-19. SOC will include remdesivir unless it is contraindicated for an 
individual patient.  
In future versions of the protocol, one or more drugs from a different class and with 
different mechanisms of action may be studied. Such treatments could be studied 
along with hIVIG if it is found effective and safe in this initial version of the protocol.  
The primary endpoint of this trial in hospitalized patients is an ordinal outcome based 
on the patient’s clinical status on Day 7. It includes 7 mutually exclusive categories 
capturing the range of organ dysfunction that may be associated with progression of 
COVID-19, such as respiratory dysfunction and coagulation-related complications 
(see Appendix F for full definition): 
7. Death 
 
6. End-organ failure 


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5. Life-threatening end-organ dysfunction  
 
4. Serious end-organ dysfunction  
 
3. Moderate end-organ dysfunction  
 
2. Limiting symptoms due to COVID-19 
 
1. No limiting symptoms due to COVID-19 
Secondary endpoints include time to the 3 least favorable categories, time to the 2 
most favorable categories, and the pulmonary only and thrombotic only components 
of the primary ordinal outcome.  Mortality, adverse events (AEs), including infusion 
reactions, and biological correlates of therapeutic activity are also assessed. Because 
there is no established endpoint for evaluating the clinical efficacy of treatments for 
COVID-19, other clinically relevant outcomes, including outcomes used in other 
COVID-19 treatment trials, will be recorded. Thus, the randomized groups (initially 
hIVIG + SOC versus placebo + SOC) can be compared for multiple outcomes, and 
results can be compared or combined with other trials.  
Participants will be randomized (1:1) to a single infusion of hIVIG + SOC or placebo + 
SOC on the day of randomization (Day 0). Participants taking remdesivir prior to 
randomization may be enrolled if eligibility criteria are met. Randomized participants 
who were not taking remdesivir before randomization will start taking remdesivir 
immediately following the infusion of hIVIG or placebo unless remdesivir is 
contraindicated. Participants will be followed for 28 days and, if the trial goes to 
completion, the primary analysis will be completed after all participants are followed 
for 28 days.  
The planned sample size is 500 participants (250 per group). After 150 participants 
are enrolled, sample size will be re-estimated, by investigators who are blinded to 
interim treatment results using pooled outcome data.  
The study population will include consenting hospitalized patients with COVID-19 
who have had COVID-19 symptoms ≤ 12 days, and who do not have life-threatening 
organ dysfunction or organ failure.  
Many other clinical trials evaluating treatments for COVID-19 are either ongoing or 
being planned. If findings from another trial have implications for the design and 
conduct of this trial, the protocol may be modified depending on the strength of the 
trial results and the target population studied.  


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An independent Data and Safety Monitoring Board (DSMB) will review interim data 
and use pre-specified guidelines for early termination of the trial or protocol 
modification. The DSMB will also be consulted concerning protocol modifications for 
reasons described above (e.g., sample size re-estimation or other aspects of the 
design resulting from emerging data). All protocol modifications will be discussed with 
the independent DSMB. Protocol amendments will be submitted to ethics committees 
(ECs) and a central institutional review board (IRB) in the United States of America 
(US). 
After consent and eligibility has been determined, a single infusion of hIVIG or 
placebo will be administered on the day of randomization (Day 0). Remdesivir 
infusions will follow the hIVIG/placebo infusion. Any infusion reactions and 
interruptions of the planned hIVIG/placebo infusion will be recorded. The ordinal 
outcome will be assessed throughout follow-up, including on Day 7 for the primary 
endpoint. On Day 0 (pre-hIVIG/placebo infusion), and on Days 1, 2, 3, 7, and 28, a 
blood sample will be obtained to centrally measure neutralizing antibody levels along 
with total immunoglobulin G (IgG) concentrations and its subclasses, immunoglobulin 
A (IgA), and immunoglobulin M (IgM); for participants at selected sites an additional 
blood sample for these measurements will be obtained at Day 90. Serious Adverse 
Events (SAEs), including deaths from any cause, will be collected through Day 28.  
hIVIG infusion related events of any grade will be collected.  Grade 3 and 4 AEs will 
be collected through Day 7.  AEs of any grade experienced on Days 1, 3, 7, and 28 
will be recorded. 
 INTRODUCTION 
2
 
Study Rationale 
2.1
COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2). 
While some cases are mild or asymptomatic, progressive disease can result in 
hospitalization, requirement for mechanical ventilation, and is a cause of substantial 
morbidity and mortality.1 While the most common mode of disease progression is 
progressive respiratory failure following the development of pneumonia, other severe 
complications including thrombosis and ischemia are increasingly recognized.2,3  
There is currently no vaccine to prevent infection with SARS-CoV-2 and no licensed 
therapeutic agent to treat COVID-19; emergency use authorizations and expanded 
access schemes have been instituted for certain interventions (including 
convalescent plasma and remdesivir, described below) prior to licensure. Several 
clinical trials utilizing novel drugs and repurposing older agents have been 
implemented to investigate the treatment of adults hospitalized with severe COVID-
19 (see Section 2.2.7).  


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Our understanding of the humoral immune response is evolving, with some evidence 
that responses are variable between individuals and delayed in some cases. It may 
therefore be that viral replication may lead to extensive tissue damage and 
inflammatory responses in the lungs and other organs before the development of 
neutralizing antibodies. Augmentation of the humoral immune response to SARS-
CoV-2 using passive immunotherapy with hIVIG to SARS-CoV-2 in hospitalized 
patients at the onset of clinical progression but before end-organ failure has 
developed may thus reduce the subsequent risk of further disease progression and 
death.  
 
Background 
2.2
2.2.1 
SARS-CoV-2 Infection and Coronavirus Disease 19 (COVID-19) 
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of 
viral pneumonia cases of unknown cause. A novel coronavirus was rapidly identified 
by sequencing and named severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2), and the illness caused by infection with SARS-CoV-2 has been named 
coronavirus disease 2019 (COVID-19).4 While SARS-CoV-2 mostly causes a mild 
respiratory illness, some individuals, particularly those who are elderly 5,6 and have 
comorbidities7 may progress to severe disease requiring hospitalization, mechanical 
ventilation in intensive care units, and death. As of 28 June 2020, just 14 weeks 
following the declaration of a pandemic on 11 March 2020 by the World Health 
Organization (WHO),4 there have been more than 20 million cases diagnosed and 
more than 750,000 deaths across 185 countries.1 Over 100,000 cases continue to be 
reported daily.4 
2.2.2 
Natural History of COVID-19 
SARS-CoV-2 has a median incubation period of 4 days (interquartile range 2-7 
days)8 and the mean serial interval defined as the time between a primary case-
patient (infector) having symptom onset and a secondary case-patient (infectee) 
having symptom onset for COVID-19 was calculated as 3.96 (95% confidence 
interval [CI] 3.53–4.39) days.9 COVID-19 illness is predominantly a respiratory 
disease typified by upper respiratory symptoms in mild cases and pneumonia, 
respiratory failure and acute respiratory distress syndrome (ARDS) in advanced 
disease. Initial symptoms typically involve the upper respiratory tract with cough, sore 
throat and malaise. Fever is present in approximately 44-98% of cases. Notably, 
persons with COVID-19 often complain of loss of smell or taste.  
Advanced complications of COVID-19 illness include cytopenias (lymphopenia, 
thrombocytopenia and anemia), and acute cardiac events (raised troponin, changes 
on electrocardiogram), acute renal injury and renal failure, liver impairment, and 
neurological events including acute cerebrovascular events, impaired consciousness 
and muscle injury and thrombotic events.  


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The natural history of COVID-19 as we understand it thus far is illustrated in Figure 1. 
In most patients (approximately 80%) symptoms resolve without the need for 
intervention within five to seven days of symptom onset up to a maximum of 14 days. 
However, approximately 20% of patients show signs of clinical disease progression, 
most notably pneumonia, around day 3 to 8 following symptom onset. Other 
manifestations of disease progression include thrombotic episodes including stroke 
and myocardial infarction (MI). This resembles the documented 6-8 fold excess risk 
of thrombosis when patients are infected with influenza.10  
A proportion of those who progress then further deteriorate, including with the 
development of ARDS around 1-5 days after pneumonic symptom onset.5,11,12,13  
Acute kidney injury necessitating dialysis and failure of other organs may also occur 
at this severe stage of disease. 
 
Of the nearly 1099 persons described in the Wuhan cohort, 16.0% had severe 
disease at presentation. 67 persons (6.1%) reached a composite primary endpoint of 
intensive care admission, mechanical ventilation and death; two-thirds had presented 
with severe disease.8,14 As described below, outcomes for those requiring 
mechanical ventilation and with other manifestations of end-organ failure are poor, 
and approaches to prevent this late stage of the disease among those with early 
evidence of progression are critically needed. 
 
In this trial, we aim to enroll patients hospitalized for medical management of COVID-
19 at the onset of clinical progression but before end-organ failure has developed: the 
time period of their infection which is shaded light orange in Figure 1. The majority of 
these patients will have emerging evidence of pneumonia, but recognizing the 
expanding range of organs involved in clinical progression of COVID-19, neither the 
inclusion criteria nor primary endpoint are limited only to assessment of pneumonia 
and related clinical progression.  
 


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FIGURE 1. NATURAL HISTORY OF COVID-19  
 
 
2.2.3 
Risk Factors for Clinical Progression  
Studies investigating risk factors for progression of COVID-19 and related hospital 
admission are currently few in the literature. Reports to date have predominately 
been conducted in individuals already hospitalized. These include a mix of descriptive 
information on the patients as well as estimates of associations between patient 
characteristics and disease severity. Older age has been found to be strongly related 
to greater severity14,15 and poorer outcome as has the presence of conditions such as 
hypertension, diabetes and coronary heart disease.12,14,16  Other risk factors identified 
include cigarette smoking14,15,17 and raised body mass index (BMI).18,19,20,21  Gender 
has not shown a consistent relationship with disease severity.14,22  Specific symptoms 
at presentation that have notably been associated with greater likelihood of 
progression to more severe disease include shortness of breath and elevated body 
temperature.14,23  
The COVID-19–Associated Hospitalization Surveillance Network (COVID-NET) report 
on 1482 persons who were hospitalized in 14 states in the United States of America 
(US) in March 2020 show nearly 75% were aged over 50 years, and nearly 90% had 
at least one or more underlying comorbid illness.24  
Based on 2.6 million users of the COVID Symptom Tracker App, predominantly in the 
United Kingdom, being older, obese, diabetic, or suffering from pre-existing lung, 
heart or renal disease placed participants at increased risk of visiting hospital with 
COVID-19.25 Pre-existing lung disease and diabetes were consistently associated 
with a higher risk of requiring respiratory support.25 A meta-analysis showed that 
cardiac injury as measured by a high sensitive troponin was associated with higher 
mortality, higher need for intensive care unit (ICU) care, and severe COVID-19 
disease.26 


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2.2.4 
Hospitalization of People with COVID-19 
Countries and jurisdictions differ in the clinical management of COVID-19 patients. 
Early in the epidemic, faced with small numbers of infected persons, some resource-
rich countries such as Singapore elected to admit all persons with COVID-19 illness 
regardless of symptom severity to facilitate strict isolation. Admission for reasons of 
public health or quarantine, rather than medical management, continues to be a 
requirement in some countries notably in Asia. Elsewhere, it is more common for 
those with mild illness to be advised to self-isolate at home, while only those severely 
unwell are admitted for medical management.  
Thresholds for ICU management also differ globally and are likely to vary significantly 
even within individual countries at different stages of the epidemic. For example, at 
the epidemic peak procedures commonly performed only in ICU may be extended to 
other care areas, while patients who might otherwise have been considered for ICU 
admission may be palliated if clinical services are overwhelmed. 
Reported mortality rates for those who develop end-organ failure requiring intensive 
support, including those admitted to ICU, differ widely. Amongst 1591 ICU patients 
from the Lombardy region in Italy, hardest hit by COVID-19, 88% required 
mechanical ventilation and 11% noninvasive ventilation.27 The ICU mortality rate was 
26%. Of 1043 patients with available data, 709 (68%) had at least 1 comorbidity and 
509 (49%) had hypertension, 21% had cardiovascular disease. Younger patients 
(≤63 years) compared to older patients, had lower ICU mortality and higher rates of 
discharge from ICU. The median length of stay in the ICU was 9 days though 58% 
remained in ICU at time of report.27 In one report of the Chinese experience in 
Wuhan, 31 of 32 persons who required mechanical ventilation died.5 In the United 
Kingdom, of the 4078 COVID-19 patients admitted into critical care with reported 
outcomes, 50.7% died in ICU; those requiring advanced respiratory support and renal 
support had worse outcomes.28 These data underline the importance of attenuating 
the disease in its early phase prior to the development of end-organ failure and the 
requirement of intensive care. 
2.2.5 
Viral Kinetics of SARS-CoV-2 Infection 
Viral kinetic studies have demonstrated extensive SARS-CoV-2 viral replication in the 
pharynx just before and early after symptom onset.29 Viral RNA shedding from 
pharynx gradually wanes as symptom resolve though viral RNA is still detectable 
weeks after symptom resolution.29,30,31 Median duration of viral shedding was 20 days 
in survivors (longest 37 days), but SARS-CoV-2 was detectable until death in non-
survivors.6 Whether this is viable virus with the potential for continued transmission 
remains uncertain. RNAemia has been reported but is relatively rare.30,32  Viral 
detection in sputum is higher and outlasts pharyngeal swabs in those with 
pneumonia.33  Persons with asymptomatic disease clear their virus faster than 
symptomatic individuals.34 


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The contribution of ongoing viral replication to disease progression in the third most 
severe stage of COVID-19 (i.e. on ventilator or extra-corporeal membrane 
oxygenation [ECMO]) is unclear, but likely minor as we hypothesize that any organ 
damage from the infection has likely occurred already and the predominant drivers of 
progression to severe disease/ARDS are those of the uncontrolled local and systemic 
immune response. 
2.2.6 
Immune Responses to SARS-CoV-2 Infection 
Notwithstanding the observed high viral loads, and progression of viral shedding from 
the upper to lower respiratory tract in those with progressive disease, the humoral 
immune response to SARS-CoV-2 appears variable and may be slow. While data are 
still emerging, it appears that in a significant proportion of cases, antibody responses 
are not yet evident at the time (day 5-7) when disease progression and 
hospitalization most commonly occur, supporting a role for supplementation of the 
antibody response at that time point.  
Two large series have described antibody responses (IgG and IgM). In the first, 
samples from 82 confirmed and 58 probable cases of COVID-19 in a cross-sectional 
analysis demonstrated IgG detection 14 (interquartile range [IQR] 10-18) days after 
symptom onset, with IgM detected median of 5 days (IQR 3-6) after symptom onset. 
Antibodies were absent in around 22% of individuals at assessment (IgM), and IgM 
was most commonly absent in those assessed early (within 7 days of symptom 
onset)].35 In the second study of 262 patients who provided 363 samples, antibody 
levels were examined by days from symptom onset. IgM antibodies were detectable 
in just under 40% of patients at day 5-7, rising to 50% at day 8-10, while interestingly 
IgG was detectable in a slightly higher proportion at those time points: just over 50% 
at day 5-7, rising to 60% at day 8-10.36 This series was drawn from hospitalized 
patients, but the severity of illness and any relationship with disease outcomes were 
not described. Both studies show considerable individual variation in antibody 
kinetics. Further longitudinal studies are underway and will better characterize the 
kinetics of these responses in individuals. 
SARS-CoV-2 infection may also induce significant changes in elements of the cellular 
immune response. As the disease process progresses, the peripheral lymphocyte 
count typically declines. The depletion of peripheral lymphocytes likely reflects 
translocation to the pulmonary tissue. The extent that this influx exclusively is helpful 
to the host, or possibly may contribute adversely to disease severity is currently 
unclear. In severe cases this decline in CD4+ and CD8+ lymphocytes is also 
associated with an increase in activated CD4+ and CD8+, increases in key 
proinflammatory cytokines including interleukin 6 (IL-6), and increases in natural killer 
(NK) cells.37,38 Trials assessing the use of various immunomodulatory agents with the 
aim of dampening this migration and systemic inflammation are underway, and may 
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2.2.7 
Current Treatment Strategies for COVID-19 
There has been no proven therapy for COVID-19, and no international standard of 
care has been established, though many clinical trials are underway. Approaches 
include direct anti-virals, including repurposed drugs found in vitro to have activity 
against SARS-CoV-2; immune modulators especially in patients with advanced 
disease, and modifiers of other pathophysiological pathways implicated in disease 
progression, including potentially anticoagulants and anti-platelet agents. In certain 
regions, local standards of care have been established, generally with agents 
hypothesized to have clinical activity but where robust comparative data are not yet 
available. For example, lopinavir, hydroxychloroquine, and favipiravir have all seen 
widespread use in hospitalized patients in different regions.  
The most promising current antiviral agent is remdesivir, a nucleotide analogue 
previously studied for Ebola.39  A preliminary report of the National Institute of Allergy 
and Infectious Diseases (NIAID) Adaptive COVID-19 Treatment Trial (ACTT) showed 
that participants receiving remdesivir had a shorter median time to recovery 
compared with those receiving placebo (11 vs 15 days; p<0.001). There was a trend 
toward a survival benefit after 14 days; estimates of mortality were 7.1% and 11.9% 
(hazard ratio [HR]=0.70; 95% CI: 0.47-1.04).40 In contrast, a smaller randomized 
study from China did not show a significant benefit for remdesivir in a similar 
hospitalized population (HR for time to clinical improvement 1.23 [95% CI 0.87–
1.75]); however that trial was stopped early due to slow enrollment and power was 
substantially less than planned (58% instead of 80%).41 A number of other remdesivir 
trials are ongoing and may clarify the extent of its therapeutic effect and other issues 
including optimal dosing and optimal timing of therapy. 
Based on the findings of ACTT, remdesivir will be provided to all study participants as 
SOC unless contraindicated for an individual patient. As in ACTT, remdesivir will be 
administered as a 200 milligram (mg) IV loading dose following the hIVIG/placebo 
infusion, followed by a 100 mg once-daily IV maintenance dose while hospitalized up 
to a 10 day total course. Participants taking remdesivir prior to randomization will 
continue their daily remdesivir infusions while hospitalized up to a 10 day course.  
Other chemotherapeutic agents with hypothesized direct antiviral activity undergoing 
clinical study include antimalarial agents, hydroxychloroquine and chloroquine, 
lopinavir-ritonavir (protease inhibitors) and favipiravir (an RNA-dependent RNA 
polymerase inhibitor). Despite some early trials that did not establish the efficacy of 
high-dose chloroquine42 and lopinavir-ritonavir,43 and uncontrolled studies showing 
minimal benefit and possible harm with hydroxychloroquine and azithromycin,44 these 
agents along with favipiravir have been incorporated into some local institutional 
protocols as SOC, especially in patients hospitalized with advanced and progressive 
disease.  


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Other agents under exploration modulate pathophysiological pathways implicated in 
disease progression. Given the apparent role of excessive IL-6 production in patients 
with advanced disease, tocilizumab and other inhibitors of IL-6 and associated 
cytokine pathways (such as Janus kinase, JAK, inhibitors) are all under evaluation, 
and off-label use of tocilizumab in critical illness is common in some settings. 
Similarly given the apparent role of platelet dysfunction and pro-coagulant effects of 
SARS-CoV-2 infection, there is interest in the use of antiplatelet agents and 
anticoagulants especially at the onset of progressive disease.  
A further promising line of approach is the use of passive immunotherapies to 
enhance the host immune response to SARS-CoV-2 infection, potentially enhancing 
viral control and limiting disease progression. Convalescent plasma, generic 
intravenous immunoglobulin (IVIG) and hIVIG to COVID-19 are all gaining interest. 
While their characteristics differ, convalescent plasma and hIVIG are examples of 
passive antibody therapy involving administration of antibodies against SARS-CoV-2 
as prevention or therapy. High doses of standard IVIG have also been hypothesized 
to be useful for their immunomodulatory effects (as for example in their use in 
immune thrombocytopenia) and are under evaluation as described below. The 
concept of passive immunotherapy is based on the historical concept of serotherapy 
developed in the 1890s where serum from immunized animals containing an antitoxin 
factor that could neutralize the toxin and be transferred onward to non-immune 
animals offered protection.45,46  
The most widely used of these agents at present is convalescent plasma containing 
COVID-19 antibodies (CCP). CCP is collected by apheresis from individuals who 
have recovered from COVID-19 and tested for the presence of SARS-CoV-2 
antibodies, preferably with a target neutralizing antibody titer. Despite relatively 
widespread use, data for its efficacy in SARS-CoV-2/COVID-19 is very limited. 
Convalescent sera were previously evaluated in an uncontrolled study for SARS-
CoV-1 illness in Hong Kong. This was shown to be more effective when given early, 
and in those who were polymerase chain reaction (PCR) positive and seronegative.47  
In a pilot uncontrolled study of CCP in China, one dose of 200 milliliters (mL) of CCP 
with neutralizing antibody titers ≥ 1:640 dilution was used in 10 patients with severe 
COVID-19.48 This was shown to be safe and showed a possible improvement in 
clinical outcomes. Another study in New York reported that 39 patients given 
convalescent plasma had improvements in supplemental oxygen requirements and 
survival compared to retrospectively matched controls.49  An initial report of the first 
5,000 hospitalized patients with COVID-19 given convalescent plasma through an 
expanded access program in the US reported that SAEs within 4 hours of infusion 
occurred in less than 1% of patients.50  This study was not controlled. 


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2.2.8 
Hyperimmune Intravenous Immunoglobulin (hIVIG) 
Anti-Coronavirus Hyperimmune IVIG contains polyvalent antibodies with neutralizing 
specificity for SARS-CoV-2. It has the potential to provide a standardized therapy to 
augment host immunity to SARS-CoV-2 and prevent disease progression in 
symptomatic patients. Hyperimmune IVIG differs from standard IVIG in its derivation 
from donors who have mounted an immune response to the infection of interest 
(natural infection as undertaken in this protocol, or following vaccination for other 
disease states), and its standardization as a product based on neutralizing antibody 
titers or similar assays demonstrating its activity against the infection of interest. 
Hyperimmune globulin requires plasma from otherwise healthy individuals in the 
convalescent phase of the infection, and it is clear that there will be many individuals 
fitting this criterion with most patients recovering from COVID-19 and therefore able 
to safely provide a plasma donation during convalescence. Therefore, this resource 
will be rapidly available and will serve as an accessible therapeutic modality across 
multiple jurisdictions globally. 
In other respects, hyperimmune and standard IVIG have similarities in their 
production, constituents, and safety profiles. Production of IVIG requires care when 
selecting donors, optimum screening of collected products for known infective agents, 
use of virus inactivation methods like fractionation, and physical and chemical 
treatment including solvent detergent treatment and caprylation (a short-chain 
saturated fatty acid which results in a product enriched for IgG) and nanofiltration.45 
Stabilizers currently used in IVIG are nonessential amino acids like glycine and L- 
proline unlike previous sucrose-containing preparations which could predispose to 
acute renal failure. 
Standard IVIG is by far the more widely used product compared with the various 
hyperimmune globulins, and contributes considerably to our understanding of the 
safety and administration of hyperimmune IVIG. Standard IVIG became a 
commercially available product in the early 1980s and remains an important 
therapeutic agent in those with primary immunodeficiencies, where it replaces absent 
or deficient immunoglobulins, and in immune thrombocytopenia and other 
autoimmune conditions, where it acts as an immunomodulator.45 Collected from large 
pools of human plasma, polyvalent and highly diverse monomeric IgG is the key 
product constituent. Very low levels of other plasma constituents such as other 
immunoglobulins including IgA and IgM and possibly IgE, solubilized membrane 
components, complement proteins, coagulation factors, and possibly other solubilized 
receptors, as well as specific antibodies to human leukocyte antigen (HLA) 
determinants and lymphocyte surface molecules are also present, and in some 
circumstances may contribute to its mechanism of action.51  
Standard IVIG is currently being studied as a therapy for COVID-19 illness in small 
trials, primarily as an immunomodulatory agent. For this purpose, it is given at 


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relatively high doses (in the range of 2 grams (g) per kilogram (kg) divided over 4 to 5 
days). Ongoing trials include NCT04261426, NCT04350580, and NCT04264858. 
Some efficacy for standard IVIG has also been reported in a retrospective 
comparison52 and a small case series.53 
Hyperimmune globulin preparations have been described to have therapeutic utility in 
varicella zoster, cytomegalovirus (CMV) pneumonitis,54 parvovirus induced red cell 
aplasia,55 and respiratory syncytial virus (RSV) infection56 in patients with underlying 
impairments of immunity. In addition, hyperimmune globulins for hepatitis A,57 
hepatitis B,58 and rabies59 have proven prophylactic efficacy and their use is 
recommended in clinical guidelines. The potential utility of this approach has also 
been explored in severe respiratory infections caused by other pathogens including 
influenza60 and severe acute respiratory syndrome (SARS).61,62,63 However, the 
evidence for efficacy of hyperimmune globulin in SARS infection is limited because in 
that disease outbreak, its use was assessed only in small, poorly controlled clinical 
studies.64 
While there are some mechanistic similarities between hIVIG and convalescent 
plasma,65 individual doses of convalescent plasma are inherently variable from unit to 
unit. Unlike hIVIG, convalescent plasma cannot be standardized as a therapeutic 
product at the required scale. In contrast to convalescent plasma where generally, a 
single unit of plasma obtained from a single ABO compatible donor is used, hIVIG is 
a highly purified preparation containing high titers of neutralizing antibodies pooled 
from multiple donors, and would be safer and have higher activity than CCP. 
Regulatory compliance and availability of assays to detect SARS-CoV-2 in serum and 
virologic assays to measure viral neutralization are critical. 
2.2.9 
Study Treatments 
Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin (hIVIG) 
Anti-Coronavirus hIVIG is a human hyperimmune product of the purified gamma 
globulin (IgG) fraction of human plasma containing polyvalent neutralizing antibodies 
to SARS-CoV-2. hIVIG is prepared from pooled plasma collected from healthy, adult 
donors who have recovered from SARS-CoV-2 infection.   
Multiple hIVIG products will be used in this trial. These hIVIG products are described 
below. Each hIVIG is labelled with the following name: “Anti-COVID-19 Hyperimmune 
Globulin (Human)”. An aliquot from each lot of hIVIG prepared for this trial will also be 
tested centrally at the NIAID Integrated Research Facility at Fort Detrick, Maryland. 
This batched central testing will not form part of the release criteria for hIVIG lots.  
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Emergent BioSolutions 
Emergent BioSolutions’ Anti-Coronavirus disease hIVIG, is a liquid product containing 
approximately 100 mg/mL (10g%) protein of which at least 96% is purified human 
IgG, stabilized with 250 millimoles (mmol) proline and 0.03% PS80 at pH 5.8. The 
vialed product will be clear to slightly opalescent, and colorless or pale-yellow liquid, 
essentially free of foreign particles.  
The manufacturing process for SARS-CoV-2 hIVIG contains two steps implemented 
specifically for virus clearance. The solvent and detergent step (using TnBP and TX-
100, respectively) is effective in the inactivation of enveloped viruses such as HBV, 
HCV, and HIV. Virus filtration, using a Planova™ 20N virus filter, is effective for the 
removal of viruses based on their size, including some non-enveloped viruses. These 
two viral clearance steps are designed to increase product safety by reducing the risk 
of transmission of enveloped and non-enveloped viruses. In addition to these two 
specific steps, the process of anion exchange chromatography was identified as 
contributing to the overall viral clearance capacity for small non-lipid enveloped 
viruses.  
Grifols Therapeutics, Inc. 
Grifols Therapeutics’ Anti-Coronavirus hIVIG is a ready-to-use sterile, preservative-, 
pyrogen-, and latex-free solution of human immune globulin for IV administration. The 
drug product consists of approximately 100 mg/mL (9.0 to 11.0%) protein in 0.16 to 
0.24 M glycine. The pH of the drug product is 4.0 to 4.5 and the osmolality is close to 
the physiologic range. The protein composition consists of not less than 98% purified 
IgG. The product is clear to opalescent and colorless to pale yellow liquid. 
The purification process used to manufacture hIVIG includes multiple segments with 
virus clearance capacity, such as caprylate-induced precipitation followed by filtration, 
caprylate incubation, ion-exchange chromatography, 35 nanometers (nm) 
nanofiltration, and low pH incubation. The capacity of these manufacturing segments 
to inactivate and/or remove virus was assessed via laboratory experiments in which a 
test virus was spiked into starting material that was then processed comparably to the 
commercial scale by means of a small-scale model, and the processed material was 
assayed for residual viral infectivity. The purification process demonstrated a large 
overall virus clearance capacity for enveloped and non-enveloped viruses of diverse 
physico-chemical properties, providing a very high margin of safety from the risk of 
transmission of infectious viruses. 
Takeda Pharmaceuticals 
Takeda’s anti-COVID-19 Hyperimmune Globulin (Human) is a ready-for-use sterile, 
liquid preparation of highly purified and concentrated IgG antibodies. The product 


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contains 100 mg/mL protein of which at least 98% is IgG; average IgA concentration 
is 37 micrograms (µg)/mL and IgM is present in trace amounts. Glycine (0.25 M) 
serves as a stabilizing and buffering agent. There is no added sugar, sodium, or 
preservatives. The pH is 4.6 to 5.1; the osmolality is 240 to 300 mOsmol/kg. Only 
clear or slightly opalescent and pale yellow solutions may be administered. Vials 
found to contain particles or discoloration must not be used.  
 The manufacturing process for anti-COVID-19 Hyperimmune Globulin (Human) 
contains three dedicated virus clearance steps, i.e., S/D treatment,66,67 nanofiltration 
(35 nm),68,69 and low pH incubation at elevated temperature.70,71 Viral safety studies 
used virus models and target viruses to evaluate the clearance of lipid enveloped and 
nonenveloped deoxyribonucleic acid (DNA) and RNA viruses by the manufacturing 
steps specific for viral reduction. These studies demonstrated that the 3 dedicated 
virus inactivation/removal steps provide effective and robust clearance of HIV, West 
Nile virus (WNV), hepatitis A virus (HAV), parvovirus B19 (B19V), as well as of model 
viruses for HCV, HBV, HAV, and B19V.  
  
CSL Behring 
Anti-COVID-19 hyperimmune globulin comes as a ready-for-use sterile, 10% protein 
liquid preparation in single-use vials. It contains 100 mg/mL protein stabilized with 
250 mmol/L L-proline. Anti-COVID-19 hyperimmune globulin has an osmolality of 320 
mOsmol/kg (range: 240 to 440 mOsmol/kg) and a pH of 4.8 (range: 4.6 to 5.0), with 
an IgG purity ≥ 98%. The vialed solution is clear or slightly opalescent and colorless 
to pale yellow. 
Production of Anti-COVID-19 hyperimmune globulin requires sourcing plasma from 
convalescent donors collected at qualified plasma collection centers, optimum 
screening of collected products for known infective agents, and use of virus reduction 
methods like low pH incubation, clarifying depth filtration, and 20 nm nanofiltration, 
which demonstrated a large overall virus clearance capacity for enveloped and non-
enveloped viruses of diverse physico-chemical properties. Stabilizers currently used 
in IVIG are nonessential amino acids like L-proline unlike sucrose-containing 
preparations which could predispose to acute renal failure. 
Placebo 
Participants assigned to the placebo group for hIVIG will be given infusions of a 
commercially available isotonic saline solution. There are color differences between 
the infusion preparations for hIVIG and placebo. Therefore, site pharmacists will be 
instructed to place a colored sleeve or other suitable covering over all infusion bags 
to mask the color of the contents and reduce the risk of unblinding. The volume used 
for hIVIG and for placebo will be comparable.  


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 RISK/BENEFIT ASSESSMENT 
3
 
Known Potential Risks 
3.1
Potential risks of participating in this trial are those associated with having blood 
drawn, IV catheterization, possible reactions to hIVIG infusions, thrombosis, the 
volume of fluid infused, and breach of confidentiality. These risks are discussed 
below. 
3.1.1 
Blood Draw and IV Catheterization 
Drawing blood may cause transient discomfort and fainting. Fainting is usually 
transient and managed by having the participant lie down and elevate his/her legs. 
Bruising at the blood collection sites may occur but can be prevented or lessened by 
applying pressure to the blood draw site for a few minutes after the blood is taken. IV 
catheterization may cause insertion site pain, phlebitis, hematoma formation, and 
infusate extravasation; less frequent but significant complications include 
bloodstream and local infections. The use of aseptic (sterile) technique will make 
infection at the site of blood draw or at catheterization less likely. 
3.1.2 
Study Treatments 
The hIVIG used in this study is manufactured in the same manner and to the same 
standards as commercially available IVIG. This includes screening for blood borne 
pathogens, and manufacturing steps including solvent/detergent to inactivate any 
viruses. The risks are anticipated to be the risks of standard IVIG preparations. 
Specific considerations related to the use of hIVIG in COVID-19, including thrombosis 
and the theoretical risk of antibody-dependent enhancement, are summarized at the 
conclusion of this section. 
As IVIG is made from human plasma, transmittable viral infections like hepatitis B, 
hepatitis C, and human immunodeficiency virus (HIV) are a potential risk (though 
steps are taken to screen for and inactivate such pathogens). In addition, there is a 
theoretical risk, although deemed very low, that hIVIG administration may be capable 
of transmitting other known or unknown infectious agents other than viruses, such as 
infectious prions (e.g., the agent of Creutzfeldt-Jakob disease). 
Immune globulin administration may impair the efficacy of live attenuated virus 
vaccines such as measles, rubella, mumps, and varicella. 
The safety of human IV immunoglobulins is well established. As described in the 
Investigational Brochures (IBs), a number of adverse events have been associated 
with the use of IVIG in both children and adults. In the range of 1 to 15%, usually less 
than 5%, of recipients experience some type of reaction, with the severity ranging 
from mild to severe. Most reactions occur during the initial 30 to 60 minutes of the 
infusion and are mild and self-limited.  


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Pyrogenic Reactions  
• 
These reactions are marked by a significant rise in temperature and are usually 
accompanied by systemic symptoms.  
Allergic Reactions  
• 
Allergic reactions often present with an uncomfortable feeling, especially a 
tightening around the neck, chest, or abdomen. There may be difficulty 
swallowing, a choking sensation, or difficulty breathing. Other symptoms of 
anaphylaxis include wheezing, rash, hives, rapid or weak pulse, hypotension, 
sweating, or an upset stomach with or without nausea, vomiting or diarrhea. 
Other more serious allergic reactions are rare, and include hemolysis and 
aseptic meningitis. 
Vasomotor Symptoms  
• 
These can occur with or without additional cardiac manifestations.  
• 
Blood pressure can either increase or decrease, and may be accompanied by 
flushing or tachycardia.  
• 
Patients experiencing such reactions may report shortness of breath or 
tightness in the chest.  
Non-allergic Systemic (Anaphylactoid) Reactions  
• 
These reactions most commonly include headache, dizziness, or 
lightheadedness. 
• 
Patients can also experience chills, nausea, vomiting, back or hip pain, 
malaise, myalgia and arthralgias. 
• 
Rigors are a rare infusion reaction that is an extreme form of chills that affects 
the whole body with vigorous shaking. 
• 
The most frequent cause of such reactions is infusion at an excessively rapid 
rate. 
• 
These types of reactions are more common in a patient naïve to IgG treatment 
and/or who harbor chronic infection. These reactions may be marked by 
flushing and warmth of the skin, chills, headache, dizziness, nausea, vomiting, 
and muscle aches. 
• 
Frequently the patient reports anxiety and in some cases, “a sense of 
impending doom.” Often, the patient will have elevated blood pressure rather 
than hypotension, distinguishing this type of reaction from true anaphylaxis.  


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Post-infusion Reactions  
• 
These reactions can occur immediately or up to 48 to 72 hours following the 
infusion. 
• 
Symptoms associated with post-infusion reactions are usually less severe in 
nature, but can interfere with a patient’s quality of life.  
• 
Common post-infusion reactions may include headache, low-grade fever, 
nausea, arthralgias, and generalized malaise. 
Other Reactions 
• 
Renal dysfunction, acute renal failure, and osmotic nephropathy may occur with 
immune globulin intravenous products in predisposed patients. Renal 
dysfunction and acute failure occur more commonly in patients receiving IVIG 
products containing sucrose. The hIVIG products in this study do not contain 
sucrose. 
• 
Transfusion-related acute lung injury (TRALI), although very rare, may occur 
and is characterized by severe respiratory distress, pulmonary edema, 
hypoxemia, normal left ventricular function, and fever. 
• 
The infused volumes of study product may be as high as 200 mL, so there is the 
risk of volume overload in the recipient which could cause pulmonary edema. 
Transfusion-associated circulatory overload (TACO) has been associated with 
plasma infusion and may be clinically indistinguishable from TRALI even though 
the physiologic mechanisms differ. TACO is hydrostatic, not permeability, 
edema and more responsive to diuresis when it occurs. Patients with pre-
existing conditions who may not tolerate the volume of hIVIG/placebo to be 
given will be excluded from this study, but this condition could still occur in 
recipients. 
• 
There are case reports of pulmonary emboli occurring after administration of 
IVIG and plasma therapy, though definitive studies assessing risk are lacking.72 
Pulmonary emboli have been shown to develop in approximately 10-15% of 
critically ill adults.73 Other thrombotic events, including myocardial infarction, 
cerebral vascular accident, and deep vein thrombosis may also occur. 
Specific Considerations in COVID-19 
There is potentially a slight elevation in the risk of thrombosis with standard IVIG 
therapy, and in some cases COVID-19 is associated with thrombotic complications. 
Hence participants with pre-existing prothrombotic tendencies will not be included 
and any thrombotic events will form part of the primary endpoint assessment and be 
monitored during interim safety analyses by the DSMB.  


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There is a theoretical risk the antibody infusion may worsen the disease course of 
COVID-19 via antigen-dependent enhancement (ADE). It is unclear if this 
phenomenon is relevant and clinically significant in COVID-19, but to ensure 
detection of any such phenomenon (which could be manifested by disease 
progression soon after hIVIG infusion) close monitoring of clinical disease outcomes 
will be maintained in the randomized groups, including in the days prior to the primary 
endpoint assessment at Day 7. 
3.1.3 
Confidentiality and Privacy 
Participants will be asked to provide personal health information (PHI). All attempts 
will be made to keep this PHI confidential within the limits of the law. However, there 
is a chance that unauthorized persons will see the participant’s PHI. All source 
records including electronic data will be stored in secured systems in accordance with 
institutional policies and government regulations.  
All study data that leave the site (including any electronic transmission of data) will be 
identified only by a coded number that is linked to a participant through a code key 
maintained at the clinical site. Names or readily identifying information will not be 
released. Electronic files will be password protected. 
Only people who are involved in the conduct, oversight, monitoring, or auditing of this 
trial will be allowed access to the PHI that is collected. Any publication from this trial 
will not use information that will identify study participants. Organizations that may 
inspect and/or copy research records maintained at the participating site for quality 
assurance and data analysis include groups such as the IRB, NIAID and applicable 
regulatory agencies (e.g. US Food and Drug Administration [FDA]).  
 
Known Potential Benefits 
3.2
While the trial is conducted to test the hypothesis that hIVIG will reduce the risk of 
further disease progression, hIVIG may or may not prevent this outcome in any 
individual who participates in this trial. However, there is benefit to society from their 
participation in this trial resulting from insights gained about the therapeutic agent 
under study as well as the natural history of the disease. While there may not be 
benefits for an individual, there will be benefits to society if a safe, efficacious 
therapeutic agent can be identified during this global COVID-19 outbreak. 
 OBJECTIVES AND ENDPOINTS 
4
 
Primary Objectives and Primary Endpoint 
4.1
The primary objective is to compare the clinical status of participants in the hIVIG + 
SOC and placebo + SOC groups on Day 7 using an ordinal outcome with 7 mutually 


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exclusive categories. On Day 7, the worst of the 7 categories the participant was in 
that day will constitute the primary outcome. The 7 categories are: 
7. Death 
6. End-organ failure 
5. Life-threatening end-organ dysfunction  
4. Serious end-organ dysfunction  
3. Moderate end-organ dysfunction 
2. Limiting symptoms due to COVID-19  
1. No limiting symptoms due to COVID-19 
Appendix F provides clinical definitions of each category. In addition to the overall 
summary odds ratio (OR) that will be estimated as described in Section 11.1, ORs 
will be estimated for the 6 dichotomized definitions of improvement that can be 
formulated from the categories of the ordinal outcome. 
4.1.1 
Rationale for Primary Endpoint at Day 7   
The goals of this study are to assess the safety, tolerability and efficacy of a single 
infusion of hIVIG in preventing further progression and mortality related to COVID-19 
when administered at the onset of clinical progression, with the aim of improving the 
long term outcome of the disease process. There is as yet no consensus on the 
optimal endpoint for determining clinical benefit from COVID-19 therapies, including 
the constituent elements of the endpoint and the timing of its assessment after 
randomization. Both may differ depending on the target population and the nature of 
the treatment studied. 
The primary ordinal outcome captures the range of severity experienced by 
hospitalized patients with COVID 19, recognizing that end-organ manifestations in 
addition to pneumonia and ARDS are increasingly emerging as significant 
contributors to morbidity. The ordinal outcome includes 7 well-defined mutually 
exclusive categories that assess further progression of disease as well as recovery 
from COVID-19.  
The ordinal outcome includes both pulmonary manifestations as assessed in prior 
COVID-19 trials and additional components representing key non-pulmonary 
outcomes; the latter are highlighted as “extra-pulmonary” in the guidance table 
(Appendix F). The primary endpoint will include both pulmonary and extra-pulmonary 
components, while the pulmonary manifestation scale only will be reported as a 
secondary endpoint. 
Day 7 was chosen for the timing of the primary endpoint for several reasons based 
on the following assumptions. The impact of hIVIG on disease progression may not 


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be immediate; a few days may be needed to see the effects on clinical outcomes as 
measured by the ordinal outcome. Also, transient treatment effects that are no longer 
present at Day 7 may be clinically less relevant. Assessment of the ordinal outcome 
at a later time point may result in a diminished treatment difference because 
spontaneous recovery from COVID-19 may have begun in many participants. Also, 
antibody differences between the treatment groups, an important biologic mechanism 
for observing a clinical benefit, are assumed to be greatest during the first week after 
infusion.  
Lastly, use of Day 7 to characterize the clinical severity of participants in 7 categories 
as studied here, results in a distribution of participants in the placebo group for the 
ordinal outcome that is sufficiently granular and not overly skewed to the most severe 
or least severe categories and, therefore, provides good power for comparing the two 
treatment groups with a feasible sample size given the difficulty in producing large 
quantities of hIVIG (see Section 5.5).  
 
Secondary Objectives 
4.2
Secondary objectives will be assessed by comparing hIVIG + SOC with placebo + 
SOC over the 28 day follow-up period for outcomes listed below. Because there is no 
established endpoint for evaluating the clinical efficacy of treatments for COVID-19, 
other clinically relevant outcomes, including outcomes used in other COVID-19 
treatment trials, will be recorded. Thus, the randomized groups can be compared for 
multiple outcomes, and results can be compared or combined with other trials. Many 
of the endpoints used in other trials are ordinal outcomes or are defined based on a 
dichotomy of an ordinal outcome and assessed at a single follow-up time point or as 
a time-to-event outcome. 
1. All-cause mortality through Day 28. 
 
2. The primary ordinal outcome on Days 3, 5, 14 and 28. 
 
3. Change in National Early Warning Score (NEWS) (see Appendix G) from baseline 
at Day 3. 
 
4. Time to the 3 least favorable categories of the primary outcome measure. 
 
5. Time to the 2 most favorable categories of the primary outcome measure. 
 
6. Hospitalization status (a binary outcome, alive and discharged from the hospital to 
home or rehabilitation versus dead or hospitalized) at Days 7, 14 and 28. 
 
7. Time to discharge (this is similar to the recovery outcome used in the ACTT-1 
trial40)   


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8. Days alive outside of a hospital through Day 28 
 
9. Pulmonary only components of the primary outcome measure at Days 3, 5, 7, 14 
and 28 
 
10. Thrombotic components of the primary outcome measure (stroke, myocardial 
infarction, venous and arterial thrombosis or embolism, plus disseminated 
intravascular coagulation) at Days 3, 5, 7, 14, and 28.   
 
11. Outcomes assessed in other treatment trials of COVID-19 for hospitalized 
participants in order to facilitate cross trial comparisons and overviews, e.g., 6-, 7- 
and 8- category ordinal scales at days 7, 14 and 28; and binary outcomes defined 
by improvement or worsening based on the primary ordinal outcome and ordinal 
outcomes used in other trials. 
 
12. Clinical organ dysfunction defined by new onset of any one or more of the 
following conditions (or requirement for the following therapies) through Day 28: 
a. Respiratory: 
1. Extracorporeal membrane oxygenation (ECMO) 
2. Invasive ventilation 
3. Non-invasive ventilation or high flow oxygen 
b. Cardiac and vascular: 
1. Myocardial infarction 
2. Myocarditis or pericarditis  
3. NYHA Class III/IV congestive cardiac failure 
4. Vasopressor therapy 
c. Renal: 
1. Renal replacement therapy (dialysis) 
d. Hepatic: 
1. Hepatic decompensation 
e. Neurological  
1. Cerebrovascular event (stroke) 
2. Encephalitis, meningitis or myelitis 
3. Acute delirium 
f. Hematological: 
1. Disseminated intravascular coagulation 
2. New thrombotic events, including pulmonary embolism, deep venous 
thrombosis, or arterial thrombosis 
g. Infective: 
1. Microbiologically-proven severe infection (not including SARS-CoV-
2) 
 
13. Safety and tolerability will be assessed using outcomes described above (e.g., 
mortality and thrombotic outcomes) and also assessed by the following outcomes: 


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a. A composite of incident grade 3 and 4 events (not limited to a laboratory 
abnormality), SAEs (see Section10.1.2), or death through Day 7 (primary 
safety endpoint) 
b. Infusion reactions of any grade severity during the infusion and 2 hours 
post-infusion, and percentage of participants for whom the infusion was 
interrupted or stopped prior to completion 
c. SAEs or deaths through Day 28 
d. Prevalence of adverse events of any grade on Days 1, 3, 7 and 28. 
 
14. Change in immunoglobulin levels (IgG, IgG subclasses, IgM, IgA) and neutralizing 
antibody titers from baseline to Days 1, 2, 3, 7, 28 and 90. 
 
15. The primary endpoint by duration of symptoms at study entry. This is a key 
subgroup analysis.  For those with shorter duration of time since symptom onset, 
the treatment effect is hypothesized to be greater than among participants who 
have had symptoms for a longer period of time.  This hypothesis assumes that 
disease progression among those with longer duration of symptoms at study entry 
will be primarily determined by organ damage that has already occurred instead of 
ongoing viral replication.  In addition, it is assumed that the natural antibody 
response to SARS-CoV-2 infection is likely to be greater at entry for those with 
longer symptom duration, and this would diminish the treatment difference 
between the hIVIG and placebo groups over the week following infusion. Given 
the inclusion criteria of ≤ 12 days, we anticipate the upper quartile will be 8-10 
days (75% of participants will have symptom duration < 8 to 10 days).  In ACCT-1, 
a more severely ill target population than studied here, there was no limit to the 
duration of symptoms and the median was 9 days (interquartile range, 6 to 12).40   
The quartile definitions for duration of symptoms will be determined following the 
completion of enrollment, and will be stated in the data analysis plan.   
 
16. The primary endpoint for other subgroups defined by the characteristics measured 
at baseline will also be assessed: 
 Age 
 Biological sex 
 Race/ethnicity 
 BMI 
 Presence of selected chronic medical conditions (cardiovascular disease, 
diabetes, asthma, chronic obstructive pulmonary disease, hypertension, 
cancer) 
 Geographic location 
 hIVIG product administered 
 hIVIG lot potency of administered product 
 Upper respiratory SARS-CoV-2 viral load 
 Neutralizing antibody level 


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 Oxygen saturation level 
 Dyspnea severity 
 Organ/respiratory dysfunction category based on ordinal primary outcome 
 NEWS 
 Disease progression risk score (defined using pooled treatment groups 
with the following baseline predictors of the day 7 ordinal outcome: age, 
gender, duration of symptoms, oxygen saturation level, ordinal outcome 
category at entry, NEWS, and chronic health conditions). 
 STUDY DESIGN 
5
 
Overall Study Design 
5.1
This study is an adaptive, randomized, double-blind, placebo-controlled trial to 
evaluate the safety, tolerability and efficacy of hIVIG in consenting hospitalized 
patients with COVID-19 who have had COVID-19 symptoms ≤ 12 days, and who do 
not have life-threatening organ dysfunction or organ failure. Remdesivir will be 
provided to participants in both the hIVIG and placebo groups as SOC unless 
contraindicated for an individual participant.   
Participants may co-enroll in INSIGHT observational studies (e.g. INSIGHT 004 
Genomics, FLU-003+) or have been previously enrolled in such studies prior to 
hospitalization (e.g. ICOS). 
 
Randomization 
5.2
Randomization will be stratified by site pharmacy (clinical sites may share a 
pharmacy). Participants will be randomized in a 1:1 ratio to receive a single infusion 
of hIVIG or placebo.  
Hyperimmune IVIG will be manufactured by multiple groups and the specific hIVIG 
distributed to each site will be determined in a way that considers factors discussed in 
Section 5.4. 
Within each stratum permuted block randomization will be used to generate treatment 
assignments. 
 
Blinding 
5.3
Hyperimmune IVIG or placebo will be prepared by a pharmacist who is unblinded to 
the treatment assignment.  
Blinding of the participant and clinical staff will be achieved by placing a colored 
sleeve over the infusion bags used for hIVIG and placebo. Placebo will consist of 
normal saline.  


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In the event that the blind is broken for safety reasons, this will be recorded, and the 
protocol co-chair(s) will be notified. In that situation, every attempt will be made to 
minimize the number of people unblinded. 
 
Distribution of Anti-Coronavirus hIVIG to Clinical Sites   
5.4
It is critical to establish whether Anti-Coronavirus hIVIG is safe and effective as 
rapidly as possible. To accomplish this, hIVIG will be manufactured for use in this trial 
by 3 different groups. Four hIVIG products, two produced by an Alliance of several 
companies including Takeda Pharmaceuticals and CSL Behring, and one each 
produced by Emergent BioSolutions and Grifols Shared Services North America, Inc., 
will be used. No single group can prepare sufficient quantity of hIVIG product to 
rapidly complete this trial. Thus, for practical reasons, the primary analysis (see 
Section 11.1) which compares the hIVIG and placebo groups on Day 7 for the 
primary ordinal endpoint will pool the outcome results for the 4 different hIVIG 
products and matching placebos. 
 
To simplify logistics related to the supply of hIVIG to clinical sites and to take 
advantage of the randomization, which is stratified by site pharmacy, the same hIVIG 
product will be provided to a given site pharmacy for the duration of the trial to the 
extent possible. This is illustrated in Figure 2 with an example that assumes that 
there are 24 site pharmacies and the supply of each of hIVIG products will be the 
same. 
The site pharmacy allocation of hIVIG will take into account estimates of the number 
of participant doses each manufacturer will provide and estimates of the number of 
participants to be enrolled by sites using each site pharmacy (i.e., it may not be an 
equal number of site pharmacies or participants for each hIVIG product). 
 
It is likely that the hIVIG provided by each manufacturer will be from more than one 
lot during the study. For each individual participant, all hIVIG vials used will come 
from the same lot. This plan for distributing the hIVIG will simplify the tracking of lots 
used by each site pharmacy. This plan also simplifies the pharmacy plans prepared 
for each site pharmacy.  
 
More generally, with this plan, one can consider this as parallel multi-center trials of 
different hIVIG products for which planned analyses that compare the hIVIG and 
placebo groups for primary and secondary outcomes will be pooled across the hIVIG 
products used. With such a plan, depending on the number of doses of each hIVIG 
product provided, there may be adequate power to compare each hIVIG product with 
matching placebo for some outcomes other than the primary efficacy outcome, 
including potentially change in anti-SARS-CoV-2 IgG levels from baseline (Day 0), 
safety outcomes, such as AEs and infusion interruptions, and selected secondary 
efficacy outcomes. 
 


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FIGURE 2. EXAMPLE OF ALLOCATION OF HIVIG TO 24 SITE PHARMACIES 
 
 
 
 
 
 
 
 
 
Sample Size Assumptions 
5.5
5.5.1 
Primary Analysis 
The planned sample size for the trial is 500 participants (250 in each group). The 
following assumptions were made in estimating the required sample size. 
a. The primary analysis will be intention to treat.  
b. A proportional odds model with indicators for the six cut-offs corresponding to 
using any of categories 1 to 6 as cut-offs for determining clinical improvement, 
treatment group (hIVIG versus placebo), baseline severity of illness as defined by 
the ordinal outcome, two-way interactions between baseline severity of illness and 
the six cut-offs, hIVIG product/matching placebo used, and two-way interactions 
between hIVIG product/matching placebo used and the six cut-offs will be used to 
estimate the OR.  
c. Type 1 error = 0.05 (2-sided) and power = 0.80. 
d. The clinical status (% distribution) of participants in the placebo group at Day 7 is 
assumed as shown in the 3rd column in Table 1. Since both randomized treatment 
groups will receive remdesivir as SOC (unless contraindicated), these 
percentages were estimated using Day 7 data from the ACTT-1 trial for a 
subgroup of patients similar to ours (the subgroup of participants who entered 
ACTT-1 in categories 4+5 of their 8-category ordinal outcome for disease severity 
and were randomized to the remdesivir group). 
e. We assumed an OR (hIVIG/placebo) of 1.61 for a more favorable outcome.  This 
corresponds to the % distribution of the clinical status of participants in the hIVIG 
group at Day 7 shown in the 2nd column in Table 1 below.  For example, the 
percentage of participants in the 2 most favorable categories would be increased 
to 65.4% in the hIVIG group from 54.0% in the placebo group (an 11.4% increase 
from the placebo group).  Conversely, the percentage of participants in the 4 most 
severe categories would decrease to 19.4% from 28.1% in the placebo group. 
The same proportional improvement was assumed across the ordinal scale.  
f. Sample size depends on a number of assumptions, including the hypothesized 
odds ratio, the number of categories in the ordinal outcome, and the distribution of 
responses for the placebo group.74 Hypothesized odds ratios closer to 1.0 
correspond to a smaller treatment effect, and require a larger sample size to 
Pharmacies 
1-6 
IVIG1 
Placebo1 
Pharmacies 
19-24 
Placebo4 
IVIG4 
Pharmacies 
7-12 
IVIG2 
Placebo2 
Pharmacies 
13-18 
IVIG3 
Placebo3 


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maintain 80% power.  The final sample size was chosen after consideration of a 
range of odds ratios and of category percentages for the placebo group. 
g. Based on the category percentages in Table 1, the estimated sample size is 494.  
This was increased to 500 to allow for a small number of participants who may be 
randomized but not receive the study infusion or be lost to follow-up.  
We are planning a blinded sample size re-estimation using pooled data (both the 
hIVIG and placebo groups combined) for the primary endpoint that will be made after 
approximately 150 participants have completed the Day 7 follow-up assessment. The 
goal of the re-estimation is to retain 80% power to detect the hypothesized summary 
odds ratio of 1.61. The re-estimation will use the observed (pooled) distribution of the 
ordinal outcome at day 7, pooled across study arms.  
TABLE 1. HYPOTHESIZED PERCENTAGE OF PARTICIPANTS IN EACH CATEGORY ON DAY 7 IN 
THE HIVIG AND PLACEBO GROUPS BASED ON AFOREMENTIONED ASSUMPTIONS 
Category 
hIVIG + SOC 
Group 
Placebo + SOC 
Group 
7. Death 
0.6 
1.0 
6. End-organ failure 
4.0 
6.3 
5. Life-threatening end-organ 
dysfunction  
4.2 
6.3 
4. Serious end-organ dysfunction  
10.6 
14.5 
3. Moderate end-organ dysfunction.  
15.1 
17.9 
2. Limiting symptoms due to COVID-
19 
57.6 
49.0 
1. No limiting symptoms due to 
COVID-19 
7.8 
5.0 
Total 
100.0 
100.0 
 
5.5.2 
Key subgroup analysis 
For the key subgroup defined according to duration of symptoms at entry, 375 
participants will be in the lower 3 quartiles.  Assuming the category percentages in 
Table 1, with 375 participants, an OR of a more favorable outcome on hIVIG 
compared to placebo of 1.61 can be detected with 70% power.  For this subgroup, an 
OR of 1.73 can be detected with 80% power and type 1 error = 0.05 (2-sided). 


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5.5.3 
Key secondary outcomes  
The study is not powered to detect treatment differences in mortality, because the 
mortality is expected to be low given the eligibility criteria.  
The following outcomes are defined as key secondary outcomes:  
Composite of death, end-organ failure, or life-threatening end-organ 
dysfunction (categories 5-7 of the ordinal outcome) at Day 7:  This composite 
outcome comprises the most severe three categories of the ordinal outcome. 
Decreasing the probability that a participant enters one of these disease states and 
remains there through Day 7, has high clinical significance.  Comparing the 
hIVIG+SOC versus the placebo+SOC groups for the proportion of participants in the 
three worst categories on Day 7, a total sample size of 500 participants is sufficient to 
detect a decrease to 6.1% in the hIVIG group compared with 13.6% in the placebo 
group (difference 7.5%, OR=2.4) with 80% power, under the following assumptions:  
a. The analysis will be intention to treat.   
b. Type 1 error = 0.05 (2-sided) and power = 0.80. 
c. The proportion of participants who are in categories 5-7 of the ordinal outcome on 
Day 7 in the placebo + SOC group is 13.6% (Table 1).  In the ACTT-1 study, the 
proportion was 10.8%, among participants in baseline categories 4+5 of the 
ACTT-1 ordinal outcome who were randomized to the remdesivir group 
(confidential data, personal communication).  
A decrease from 13.6% to 8% (OR 1.8) could be detected with power of 47%. 
Time to discharge from hospital, time to the 2 most favorable categories of the 
primary ordinal outcome: We expect that by Day 28, almost all participants will be 
discharged from the hospital.  Similarly, we expect most participants will be in in one 
of the 2 most favorable categories of the primary ordinal outcome by Day 28. In the 
ACTT-1 trial, in the subset of participants who entered the trial with disease severity 
similar to our eligibility criteria (ACTT-1 ordinal outcome categories 4+5), 94.7% had 
been discharged from the hospital by Day 28. This percentage was similar for the 
ACTT-1 definition of “recovery” that include a small percentage of participants who 
were hospitalized but no longer requiring medical care. Comparing the hIVIG versus 
placebo groups for time to hospital discharge, our study is powered to detect a 
relative rate ratio (RRR) of 1.3 with 80% power and a significance level of 0.05.  The 
power calculations assume that the RRR is approximately constant to Day 28, the 
overall cumulative percentage discharged (pooled across treatment groups) by Day 
28 is 94% and that between 2.5 and 3% withdraw consent or are lost to follow-up by 
Day 28.  We assume power is similar for time to the 2 most favorable outcomes of 
the primary ordinal outcome.   
Hospitalization status: Comparing the hIVIG versus the placebo+SOC groups for 
the hospitalization status (a binary outcome, alive and discharged from the hospital to 
home or rehabilitation versus dead or hospitalized) on Day 7, the total sample size of 
500 participants is sufficient to detect an increase in the proportion discharged to 


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58% in the hIVIG group from 45% in the placebo group (OR=1.7), with 80% power.  
Similarly, the study has 80% power to detect an increase to 81% in the hIVIG group 
compared with 70% in the placebo group (OR=1.85) at Day 14.  Corresponding 
estimates from the ACTT-1 trial were 51% discharged on Day 7, and 77% on Day 14, 
for participants that were similar to ours and randomized to the remdesivir arm 
(confidential data; personal communication).  Our hypothesized percentages are 
slightly lower, because our eligibility criteria allow for use of high-flow oxygen, in 
addition to the ACTT-1 ordinal categories 4+5. Power calculations assume that the 
treatment groups are compared by intent-to-treat. 
 
Schedule of Assessments 
5.6
Participants will be randomized and given their infusion of study drug/placebo on Day 
0, in addition to standard of care therapy. All participants will be followed through 28 
days. Consenting participants at selected sites will return for a visit 90 days after 
randomization to obtain a blood draw; this subset will comprise all participants at 
selected sites where return for a later visit is practical for participants. While in the 
hospital, evaluations will be made each day (Appendix B). SAEs and deaths should 
be immediately reported. Participants who are discharged will be asked to return to 
the site at Day 1, 2, 3, 7 and Day 28 (if already discharged) for a blood draw and 
health status assessment.  Additional visits after discharge at Days 5 and 14 can be 
completed by telephone contact. 
 
Approach to Intercurrent Therapies and Clinical Trial Co-
5.7
enrollment 
In general, the study will take a pragmatic approach to the use of intercurrent, 
concomitant medications. With the exception of convalescent plasma or IVIG 
(hyperimmune or standard, other than study drug) which is not permitted prior to entry 
or through Day 7, there are few restrictions.  
Participants will be asked at screening to agree to refrain from participation in other 
clinical trials until after the assessment of the primary endpoint (Day 7). However, it is 
recognised that, in the case of progression to life-threatening disease and end-organ 
failure (broadly categories 5 and 6 of the outcome measure) there will be 
considerable clinical concern, and participation in an additional clinical trial at that 
time will not be restricted.  
Prior participation in clinical trials (except receipt of IVIG, hIVIG or convalescent 
plasma) is not restricted, recognising for example that participants may have enrolled 
in a study for mild disease prior to progression and then may wish to participate in 
this study at the onset of progression. 
The planned analyses are by intention to treat. All participants will be compared at 
Day 7 irrespective of use of concomitant treatments. Concomitant treatments at 
baseline and Day 7 will be recorded. The study randomization and site stratification 
will balance the use of concomitant medications on average at baseline and these will 
be summarized with other baseline characteristics. Follow-up use of concomitant 


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treatments may differ by treatment group reflecting different efficacy/safety of the 
study treatments. Use of concomitant treatments will be summarized at Day 7 by 
treatment group. 
 SCIENTIFIC RATIONALE FOR THE STUDY 
6
The clinical course of SARS-CoV-2-infected individuals tends to diverge around day 3 
to 8, with a fraction of patients showing progression (most notably pneumonia) while 
others recover. A proportion of those progressing then further progress to end-organ 
failure, including respiratory failure, and in some cases death. Humoral immunity to 
SARS-CoV-2 is not yet well understood, and may be variable or delayed in some 
individuals (including potentially those progressing). Augmentation of the antibody 
response using passive immunotherapy with hIVIG to SARS-CoV-2 around the onset 
of clinical progression but before end-organ failure has developed may reduce the 
subsequent risk of further disease progression and death.  
 STUDY POPULATION 
7
The total sample size is projected to be 500 adults ≥18 years of age with COVID-19 
and who meet all eligibility criteria. These participants will be enrolled at clinical trial 
sites globally. Each site pharmacy may supply several clinical sites; approximately 
20-30 site pharmacies will participate (see Section 5.4). The estimated time from 
screening (Day -1 or Day 0) to the end of the study for an individual participant is 
approximately 28 days.  Consenting participants at selected sites will return at Day 90 
for a final blood draw. 
Patient eligibility must be confirmed by a study clinician named on the delegation log. 
There is no exclusion for receipt of SARS-CoV-2 vaccine (experimental or licensed). 
 
Inclusion Criteria 
7.1
In order to be eligible to participate in this study, a participant must meet all of the 
following criteria: 
1. SARS-CoV-2 infection documented by PCR or other nucleic acid test (NAT) within 
3 days prior to randomization OR documented by NAT more than 3 days prior to 
randomization AND progressive disease suggestive of ongoing SARS-CoV-2 
infection 
 
2. Symptomatic COVID-19 disease 
 
3. Duration of symptoms attributable to COVID-19 ≤ 12 days 
 
4. Requiring inpatient hospital medical care for clinical manifestations of COVID-19 
(admission for public health or quarantine only is not included) 
 


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5. Age ≥ 18 years 
 
6. Willingness to abstain from participation in other COVID-19 treatment trials until 
after study Day 7 
 
7. Provision of informed consent by participant or legally authorized representative 
 
 
Exclusion Criteria 
7.2
1. Prior receipt of SARS-CoV-2 hIVIG or convalescent plasma from a person who 
recovered from COVID-19 at any time 
 
2. Prior receipt of standard IVIG (not hyperimmune to SARS-CoV-2) within 45 days 
 
3. Current or predicted imminent (within 24 hours) requirement for any of the 
following: 
 
 Invasive ventilation 
 Non-invasive ventilation 
 Extracorporeal membrane oxygenation 
 Mechanical circulatory support 
 Continuous vasopressor therapy 
 
4. History of allergy to IVIG or plasma products 
 
5. History of selective IgA deficiency with documented presence of anti-IgA 
antibodies 
 
6. Any medical conditions for which receipt of the required volume of intravenous 
fluid may be dangerous to the patient  
 
 Includes New York Heart Association Class III or IV stage heart failure 
 
7. Any of the following thrombotic or procoagulant disorders: 
 Acute coronary syndromes, cerebrovascular syndromes and pulmonary or 
deep venous thrombosis within 28 days of randomization 
 
History of prothrombin gene mutation 20210, homozygous Factor V Leiden 
mutations, antithrombin III deficiency, protein C deficiency, protein S 
deficiency or antiphospholipid syndrome  
 
8. Any condition for which, in the opinion of the investigator, participation would not 
be in the best interest of the participant or that could prevent, limit, or confound 
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Costs to Participants 
7.3
There is no cost to participants for the research tests, procedures/evaluations, and 
study product while taking part in this trial. Procedures and treatment for clinical care 
including costs associated with hospital stay may be billed to the participant, 
participant’s insurance or third party. 
 STUDY PRODUCT 
8
 
hIVIG and Placebo 
8.1
8.1.1 
hIVIG Description 
Summary characteristics of the individual hIVIG products and placebo are 
summarized in Section 2.2.9, with information on handling and preparation found in 
the Study Procedure Modules 
8.1.2 
hIVIG Dose 
The hIVIG product is administered as a single dose of 400 mg/kg (or 0.4 g/kg) body 
weight, to a maximum dose of 40 g or 400 mL (i.e. capped at a body weight of 
100kg). 
The safety profile of hIVIG is anticipated to be comparable to licensed IVIGs for which 
doses of well above 400 mg/kg are safe and well tolerated. Licensed IVIGs are used 
with doses up to 400mg/kg for immune replacement and up to 2 g/kg for 
immunomodulatory induction, with an established favourable safety profile in which 
adverse events are not closely dose related. 
The selected dose is derived from measures of anti-SARS-CoV-2 neutralizing 
potency from hIVIG, in comparison with that observed in convalescent plasma pools. 
Convalescent plasma pools used to produce hIVIG contain approximately 10 mg/mL 
of IgG immunoglobulin. Analysis of hIVIG shows an expected 10-fold increase in anti-
SARS-CoV-2 binding IgG, but a lower than expected (5-fold) enrichment in anti- 
SARS-CoV-2 neutralizing potency. This suggests that only 50% of anti-SARS-CoV-2 
neutralizing potency of plasma pools utilized to produce hIVIG is associated with 
IgGs. Based on this comparison, the neutralizing potency associated with the 
selected dose of 400 mg/kg hIVIG is significantly higher than in a fixed dose of 400 
mL of convalescent plasma (3.5-5 fold higher than that dose of plasma when 
administered to 70-100 kg). This dose was therefore selected as providing an 
appreciable dose margin over convalescent plasma (in addition to the other 
advantages of hIVIG versus plasma), while remaining well within the accepted safe 
dose range for other IVIG products, and observing the limitations of hIVIG product 
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There are no data so far to define target therapeutic titers for anti-SARS-CoV-2 
antibody which would support dose derivation from target titers rather than the 
approach to dose selection described above. Although not considered for dose 
selection in the present study, the hIVIG products’ potencies, and circulating levels of 
immunoglobulins (IgG, IgG subclasses, IgM, IgA) and neutralizing antibody titers 
following treatment will be measured. The analysis of the relationship between 
neutralizing titers and clinical outcomes may help to define a target therapeutic 
neutralizing titer for hIVIG+SOC and therefore may support dose optimization for 
future clinical investigations. 
8.1.3 
hIVIG Administration 
The hIVIG product is administered as a single dose of 400 mg/kg (or 0.4 g/kg) current 
actual (not ideal) body weight, to a maximum dose of 40 g or 400 mL (i.e. capped at a 
body weight of 100 kg). The product as supplied should not be diluted. The infusion 
line may be flushed with normal saline.  
Infusion of hIVIG/placebo should commence at an infusion rate of 0.5 mg/kg/minute 
for approximately 30 minutes. If the infusion is well tolerated, the rate of 
administration may be increased to a maximum of 4 mg/kg/minute as follows: the rate 
may be increased by doubling the infusion rate after intervals of not less than 30 
minutes, so long as the infusion remains well tolerated. Participants should remain 
under close clinical observation during the infusion and for at least 60 minutes 
following completion of the infusion.  
For participants judged to be at risk for volume overload (including but not limited to 
those with pre-existing cardiac failure), or who have for renal dysfunction (estimated 
creatinine clearance <60ml/min), administer hIVIG at the minimum infusion rate 
practicable.  
For all participants, use of diuretics may be considered as clinically appropriate to 
avoid or treat fluid overload, with the goal of maintaining participants in a euvolemic 
state following completion of the infusion. 
If adverse events occur, such as flushing, headache, nausea, changes in pulse rate 
or blood pressure, the rate of infusion should be slowed or infusion should be 
temporarily stopped. When events resolve, the infusion may be resumed at a rate 
that is comfortable to the participant (start at half of the last tolerated rate and 
increase gradually). 
The hIVIG treatment should be immediately stopped should new onset or worsening 
of any of the following occur: 
• Profound hypotension (systolic blood pressure < 80 mmHg) 


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• Severe shortness of breath, wheezing, or sustained (i.e., ≥ 10 seconds) new 
decrease in oxygen saturation to < 90% on room air 
• Severe (Grade ≥ 3) local infusion site reactions, including pain, tenderness, 
erythema, or swelling as defined in the protocol-specified toxicity grading scale 
• Sustained body core temperature exceeding 38.5°C or increase in body core 
temperature >2.0°C from baseline prior to infusion 
• Suspected intercurrent sepsis (not manifestations of COVID-19) 
• Severe chest pain 
• Suspected anaphylaxis 
8.1.4 
Preparation/Handling/Storage/Accountability 
This information is found in the Study Procedure Modules. 
 
Remdesivir Background Therapy 
8.2
8.2.1 
Rationale 
The antiviral drug remdesivir is being provided to all participants in this study, unless 
contraindicated.  Remdesivir was shown to improve time to recovery in moderately-
to-severely ill individuals hospitalized with COVID-1940.  It is being provided to 
standardize background therapy in this study; while considered standard of care in 
hospitalized patients, due to shortages and regulatory status the drug may not be 
available at some participating sites during the study period. 
8.2.2 
Description 
Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the 
intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition 
to the active ingredient, the lyophilized formulation of remdesivir contains the 
following inactive ingredients: water for injection, sulfobutylether-β-cyclodextrin 
(SBECD), and hydrochloric acid and/or sodium hydroxide. 
8.2.3 
Administration 
Remdesivir will be administered as a 200 mg IV loading dose (100 mL volume) on the 
first day of its infusion followed by 100mg daily for the course described below; 
remdesivir may have commenced prior to randomization. For participants starting 
remdesivir after randomization to hIVIG/placebo, the loading dose should be given 
immediately after the infusion of hIVIG/placebo, once any infusion reactions from that 
infusion have resolved; for those who commenced remdesivir prior to randomization, 
the usual maintenance dose of 100 mg can be given after the hIVIG/placebo infusion 
on Day 0 in the same manner. After the first remdesivir infusion, a 100 mg once-daily 
IV maintenance dose (also 100 mL volume) is given each day while hospitalized for 


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up to a 10 day total course; shorter durations of 5 days may be considered by the 
clinical investigator as appropriate in patients who are not ventilated. Infusions will not 
be given to participants after discharge. The total treatment course should not exceed 
10 calendar days even if an infusion is missed.  
The dose should be given at approximately the same time each day (+/- 2 hours for 
medication scheduling). 
Any dose that is delayed may be given later that calendar day. Any dose that is 
missed (not given that calendar day) is not made up. The treatment course continues 
as described above for hospitalized patients even if participants become PCR 
negative.  
8.2.4 
Contraindications 
Remdesivir is contraindicated in participants with a history of hypersensitivity to 
remdesivir or any ingredient of the solution for injection.75 Clinical caution should be 
exercised in individuals with hepatic or renal dysfunction, and hepatic and renal 
function should be checked prior to dosing and monitored during therapy.75  
Remdesivir has not been studied in pregnancy, and use in pregnancy should be 
based on an individual assessment of risk/benefit by the treating physician.  
8.2.5 
Dose Modification 
If the estimated glomerular filtration rate (eGFR) decreases to < 25 mL/min, the 
remdesivir infusion should not be given on that day. The infusion may be resumed on 
the next day if the eGFR returns to ≥ 30 mL/min. If the participant’s renal function 
worsens to the point that they require hemodialysis or hemofiltration, remdesivir will 
be discontinued. 
If the ALT and/or AST increases to > than 5 times the upper limit of normal, the dose 
of remdesivir should be withheld and not be restarted until the ALT and AST reduces 
to ≤ 5 times the upper limit of normal. 
8.2.6 
Preparation/Handling/Storage/Accountability 
This information is found in the Study Procedure Modules. 
 
Standard of Care Therapy 
8.3
8.3.1 
Thromboprophylaxis and diagnosis of thrombotic complications 
Consideration should be given to the use of pharmacological thromboprophylaxis 
(thrombosis prevention) in line with local clinical guidelines as appropriate for an 
individual participant, in addition to approaches to maintain mobility and minimize 
other thrombotic risks. Standard approaches to thromboprophylaxis supported by 
high quality evidence include the use of low molecular weight heparin (for example, 
enoxaparin 0.5m/kg daily; high quality evidence), which is the preferred agent in 


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some COVID-19 treatment guidelines.76,77,78 However other standard approaches in 
accordance with local and institutional guidelines and the medical circumstances of 
an individual participant may also be considered, including the use of low 
(prophylactic) dose unfractionated heparin (high quality evidence), or higher doses 
than prophylactic doses as judged appropriate (low quality evidence). Specialist 
advice should be sought for participants who are pregnant. 
An appropriate degree of clinical suspicion should be maintained for the development 
of new thrombotic complications, including deep venous thrombosis, pulmonary 
embolism, and other vascular events. Use of laboratory testing such as D-dimer may 
be confounded in the presence of acute COVID-19 infection. Consideration should be 
given to use of definitive imaging strategies for diagnosis wherever possible (for 
example, limb ultrasonography, computed tomography pulmonary angiograms), as 
appropriate for an individual participant.  
8.3.2 
Other Standard Supportive Care 
Participants will be offered supportive care of complications of COVID-19 as clinically 
appropriate for the individual.  
This includes appropriate management of pneumonia, hypoxemic respiratory 
failure/ARDS, sepsis and septic shock, cardiomyopathy and arrhythmia, acute kidney 
injury, and complications from prolonged hospitalization, including secondary 
bacterial infections, thromboembolism, gastrointestinal bleeding, and critical illness 
polyneuropathy/myopathy. Such care includes treatment with anti-bacterial agents for 
patients believed to have bacterial infection (high quality evidence), and guidelines-
compliant management of sepsis when it is present (moderate quality evidence). 
For participants requiring intensive care measures, consideration should be given to 
supportive care measures including lung-protective ventilation for patients who 
require invasive ventilation (high quality evidence) and prone positioning for 
mechanically ventilated patients with more than moderate ARDS (high quality 
evidence).79,80 
As noted in section 8.1.3, hIVIG administration, use of diuretics may be considered 
as clinically appropriate to avoid or treat fluid overload. 
Links to details of such care can be found in Appendix D.   
8.3.3 
Cautions and Contraindications 
It is not recommended to use high dose chloroquine (600 mg twice daily) due to 
studies showing excess harm and no demonstrable benefit. (Hydroxy)chloroquine 
has no documented clinical benefit, and hence should not be used as part of SOC for 
COVID-19. Of note, the effectiveness of remdesivir may also be reduced if combined 
with (hydroxy)chloroquine, and hence it is not advisable to combine these two drugs; 


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in patients who are on pre-existing hydroxychloroquine for therapy of other diseases 
such as systemic lupus erythematosus, specialist advice should be sought.81  
8.3.4 
Infection Control Measures 
Minimum standards of protection to reduce the risk of SARS-CoV-2 transmission 
from trial participants to research personnel, participants in other trials, or patients 
treated in the same facility can be found in links displayed in Appendix D. 
 STUDY ASSESSMENTS AND PROCEDURES 
9
 
Screening/Baseline, Follow-up and Endpoint Assessments 
9.1
Data collection at each visit is outlined below and summarized in Appendix B. Day 0 
refers to the day on which randomization occurs and on which the hIVIG/placebo 
infusion is given.  Screening and baseline assessments can be done on the same 
day.  The term “baseline” refers to data that are collected prior to randomization. 
9.1.1 
Screening/Baseline Assessments 
After obtaining informed consent, the following assessments are performed within 24 
hours prior to randomization to determine eligibility and to collect baseline data: 
 Confirm EITHER: 
 
-    the positive SARS-CoV-2 test result (PCR or other NAT) was performed within 
3 days prior to randomization or,  
- 
if more than 3 days prior to randomization, the prospective participant 
demonstrates progressive disease suggestive of ongoing SARS-CoV-2 
infection 
 Take a focused medical history, including the following information:  
− Demographics including age, biological sex 
− Day of onset of COVID-19 signs and symptoms 
− History of chronic medical conditions, including targeted conditions for 
outcome analysis  
− Medication allergies 
− Current use of targeted concomitant medications 
− Prior use of monoclonal antibody treatment or SARS-CoV-2 vaccine trial 
participation 
 
 Perform a focused physical examination: 
− Height and weight;  
− Vital signs: Blood pressure, heart rate 
− Respiratory rate, oxygen requirements and saturation 
 
 Obtain blood for local laboratory evaluations: 


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− White blood cell count 
− Hemoglobin 
− Platelets 
− Lymphocytes 
− C-reactive protein (CRP)  
− Serum creatinine 
− Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
 
 Determine disease status at entry (includes SpO2, oxygen requirements) for the 
constituents of the ordinal outcome categories. 
 
 Plasma and serum specimens for central testing for immunoglobulin levels, SARS-
CoV-2 neutralizing antibody determination and storage for future COVID-19 related 
research (four [4] 1 mL aliquots of serum and four [4] 1 mL aliquots of plasma).  
Two 9mL tubes, SST and EDTA, of blood (18 mL total) will be drawn in order 
obtain the 8 aliquots.  
 
 Mid-turbinate swab for determination of SARS-CoV-2 viral load in central 
laboratory 
 Urine or serum pregnancy test (in women of childbearing potential) (not an 
exclusion criterion but performed to ensure any pregnancy is recognized at entry) 
Note: If a woman is either postmenopausal (i.e., is age ≥ 45 years and has had ≥12 
months of spontaneous amenorrhea) or surgically sterile (i.e., has had a 
hysterectomy, bilateral ovariectomy (oophorectomy), or bilateral tubal ligation), she is 
not considered to be of childbearing potential.  
 
The overall eligibility of the patient for the study will be assessed once all screening 
values are available. The screening process can be suspended prior to complete 
assessment at any time if exclusions are identified by the study team. 
Participants who qualify will be randomized within 24 hours of obtaining the baseline 
assessments.  Post-randomization on Day 0 the following will be recorded: 
 Adverse events of any grade severity prior to starting the infusion 
 Start and stop times of the infusion of hIVIG/placebo and remdesivir 
 Infusion related reactions 
 Whether the completion of the infusion was as planned 
 Medication used prophylactically or therapeutically to manage infusion-
related reactions 
 Adverse events (AEs) of any grade severity during and for 2 hours after the 
infusion 


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9.1.2 
Follow-up assessments 
Participants will be followed through Day 28 following randomization for collection of 
study data. Clinical data targeted to components of the primary and secondary 
endpoints will be collected daily during hospitalization, and at scheduled visits to day 
28 after discharge. This will include discharge status, development of key medical 
conditions, vital signs including SpO2. On Day 7, interim targeted physical exam and 
concomitant medications will be collected along with the results of blood tests for 
serum creatinine, ALT or AST, white blood cell count, hemoglobin, platelets, 
lymphocytes, and C-reactive protein (CRP).  
AEs of any grade severity will be collected on Day 0 prior to infusion and on Days 1, 
3, 7, and 28 (AEs present on those days).  Incident AEs of grade 3 or 4 severity will 
be collected through Day 7 and all SAEs will be collected through Day 28. 
The primary ordinal outcome measure will be assessed daily while the participant is 
hospitalized and on Day 3, 5, Day 7 (primary endpoint), Day 14 and Day 28 for all 
participants.  Items necessary for determination of NEWS will be collected on Day 3. 
The Borg dyspnea score will be evaluated at baseline and day 7. 
For participants who are no longer hospitalized, in-person visits will be done on study 
days where blood is collected (Days 1, 2, 3, 7, and 28). For other visits (Day 5 and 
Day 14), contact with the participant for the purpose of study data collection may be 
performed by telephone, recognizing that certain components of the endpoints (e.g. 
SpO2) are not likely available from outpatients. Other information as possible will be 
gathered.  
On Days 1, 2, 3, 7, and 28, plasma and serum samples (four 1 mL aliquots of both 
plasma and serum at each visit) will be obtained for central testing of antibody levels 
(including neutralizing antibodies) to SARS-CoV-2 and for storage for future related 
research. Two 9 mL tubes, SST and EDTA, of blood (18 mL total) will be drawn in 
order obtain the 8 aliquots. 
In consenting participants at selected sites (determined at site level prior to opening; 
selected sites will endeavor to follow all participants to day 90), plasma and serum 
samples (four 1 mL aliquots of both plasma and serum) will be obtained at Day 90 for 
central testing of antibody levels (including neutralizing antibodies) to SARS-CoV-2 
and for storage for future related research. Two 9mL tubes, SST and EDTA, of blood 
(18 mL total) will be drawn in order obtain the 8 aliquots. 
For patients co-enrolled on INSIGHT 004 Genomics, where genomics samples have 
not already been collected prior to enrollment in this protocol they may be collected at 
any time during follow-up. 


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9.1.3 
Stored Samples and Future Research 
The plasma and serum specimens collected as outlined above and the inoculum from 
the baseline mid-turbinate nasal swab will be stored at a central specimen repository 
in the US.  In addition to the specified testing to be done per protocol, the specimens 
will be available for later use in research concerning COVID-19, SARS-CoV-2, and 
the impact of the study treatment.  Proposed research utilizing these specimens will 
be reviewed and approved by the trial oversight committee.  Results of research tests 
on individual specimens will not be given to participants or their clinicians.  Aggregate 
research results will be made available. 
 SAFETY REPORTING 
10
The safety evaluation of the study intervention includes several components, all of 
which will be regularly reviewed by the independent DSMB.  For this protocol, the 
term “study intervention” refers to the hIVIG/placebo and to remdesivir.  
With the exception of infusion related reactions of any grade, which are only collected 
for the hIVIG/placebo, all other AEs are collected for the study intervention (either the 
hIVIG/placebo or study-provided SOC treatment).  Selected events will be reported to 
regulators and IRBs/ethics committees in addition to being regularly reviewed by the 
DSMB.  
The following information will be collected to evaluate safety: 
 Infusion-related reactions of any grade severity during and within 2 hours post-
infusion of the hIVIG/placebo. 
 Clinical AEs of any grade severity will be collected on Days 0, 1, 3, 7, and 28 
(AEs present on those days).  
 Targeted laboratory abnormalities of any grade severity at Day 7. 
 Incident grade 3 and 4 clinical adverse events occurring through Day 7 
(isolated laboratory abnormalities that are not associated with signs or 
symptoms are not recorded). 
 Clinical events that are collected as part of the primary ordinal outcome or as 
secondary outcomes through Day 28. These are protocol exempt events and 
are not reported as SAEs unless they are considered as related to the study 
intervention. 
 Serious adverse events, including laboratory-only serious events, considered 
related to the study intervention (either the hIVIG/placebo or a study-provided 
SOC treatment) through Day 28. 
 Serious adverse events that are not collected as part of the primary ordinal 
outcome or as a secondary outcome through Day 28.   
 Unanticipated problems through Day 28. 
 Deaths through Day 28.  
An overview of safety data collected during the study is given in Table 2. 


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Table 2.  Adverse Event Data Collection Overview  
 
Day 0* 
Infusion 
+2 hrs 
Day 
1 
Day 3 
Day 5 
Day 7 
Day 
14 
Day 
28 
Infusion-related 
reactions and 
symptoms 
 
X 
 
 
 
 
 
 
Incident Grade 3 and 4 
clinical AEs** 
Collected through day 7 
 
Clinical AEs of any 
grade severity  
X 
X 
X 
X 
 
X 
 
X 
Targeted laboratory 
abnormalities of any 
grade 
 
 
 
 
 
X 
 
 
Targeted clinical events 
collected as study 
endpoints*** 
 
Collected through Day 28 
Serious clinical AEs 
not reported as a study 
endpoint*** 
 
Collected through Day 28 
Unanticipated 
problems 
 
Collected through Day 28 
Any serious adverse 
event related to study-
provided treatment 
 
Collected through Day 28 
 
* pre-infusion AE collection 
** Incident grade 3 and 4 AEs are new (not present at baseline) AEs or AEs that have 
increased in grade 
*** see section 10.2.5 for specific events 
 
Definitions and methods of reporting each type of event are given below. 
 
Definitions 
10.1
10.1.1 Adverse Event (AE) 
An adverse event is any untoward or unfavorable medical occurrence in a study 
participant, including any abnormal sign (e.g., abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with their participation in 


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research, whether or not considered related to the research. If a diagnosis is clinically 
evident (or subsequently determined), the diagnosis, rather than the individual signs 
and symptoms or lab abnormalities, will be recorded as the AE. AEs are reported on 
the appropriate case report form (CRF) when prompted. 
10.1.2 Criteria for Seriousness 
Events are serious if they lead to one of the following outcomes:  
 Death 
 Life-threatening (i.e., an immediate threat to life)  
 Hospitalization or prolongation of hospitalization 
 Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
 Congenital abnormalities/birth defects 
 Other important medical evens that may jeopardize the participant and/or may 
require intervention to prevent one of the outcomes listed above  
10.1.3 Unanticipated Problems 
An unanticipated problem (UP) is any incident, experience or outcome that is: 
1. 
Unexpected in terms of nature, severity, or frequency in relation to: 
a. the research risks that are described in the IRB-approved research protocol 
and informed consent document; Investigator’s Brochure (IB) or other study 
documents; and 
b. the characteristics of the population being studied; and 
2. 
Possibly, probably, or definitely related to participation in the research; and 
3. 
Places study participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized. 
 
Furthermore, a UP could be an expected event that occurs at a greater frequency 
than would be expected based on current knowledge of the disease and treatment 
under study. The DSMB providing oversight to the study may make such an 
assessment based on an aggregate analysis of events. 
10.1.4 Severity 
The investigator will evaluate all AEs with respect to both seriousness (results in 
outcomes as above) and severity (intensity or grade). AEs will be graded for severity 
according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, (also known as the DAIDS AE Grading Table; see Appendix D for the URL).  


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For specific events that are not included in the DAIDS AE Grading Table, the generic 
scale below is to be used: 
TABLE 3. GENERIC AE GRADING SCALE 
Grade 1 
Symptoms causing no or minimal interference with usual social and 
functional activities 
Grade 2 
Symptoms causing greater than minimal interference with usual social 
and functional activities 
Grade 3 
Symptoms causing inability to perform usual social and functional 
activities 
Grade 4 
Symptoms causing inability to perform basic self-care functions, or 
medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death 
Grade 5 
Events resulting in death 
 
10.1.5 Causality 
Causality refers to the likelihood that the event is related to the study intervention.  It will 
be assessed for SAEs and UPs.  This assessment will be made for both the agent under 
investigation (hIVIG) and the study-provided background therapy of remdesivir using the 
following guidelines: 
 Reasonable possibility – There is a clear temporal relationship between the study 
intervention and the event onset, and the AE is known to occur with the study 
intervention or there is a reasonable possibility that the study intervention caused the 
AE. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
 
 No reasonable possibility – There is no evidence suggesting that the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
The causality assessment is based on available information at the time of the 
assessment of the event.  The investigator may revise these assessments as additional 
information becomes available. 
10.1.6 Expectedness 
Expectedness will be assessed for SAEs using the Reference Safety Information section 
of the IBs for the hIVIG and remdesivir. 


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The expectedness assessment is based on available information at the time of the 
assessment of the event.  The investigator may revise these assessments as additional 
information becomes available. 
 
Schedule for Data Collection and Reporting of Specific 
10.2
Events 
10.2.1 Infusion-related reactions 
Infusion related signs/symptoms of any grade that are new or have increased in 
grade compared to their pre-infusion level are reported for the hIVIG/placebo if they 
occur during or within 2 hours post infusion.  Any infusion related reaction assessed 
as meeting SAE criteria will be reported as an SAE.  Similarly, any grade 3 or 4 
infusion related reaction will be reported as an AE. 
 
10.2.2 Targeted Laboratory abnormalities 
Selected laboratory tests are performed prior to infusion and on Day 7. These values 
are associated with a severity grade centrally using the laboratory test results 
reported on the eCRFs with normal ranges, and with the DAIDS AE Grading Table. 
 
Other laboratory abnormalities identified in the course of the participant’s clinical care 
are not reported as AEs (e.g., an isolated elevated glucose level) unless they are 
associated with a specific clinical diagnosis/syndrome, in which case they are 
reported if they meet the reporting criteria of one of the other safety outcomes.  In 
addition, if an isolated laboratory test result meets SAE reporting criteria (e.g., a 
serious event related to the study intervention), it should be reported as an SAE. 
 
10.2.3 Clinical adverse events of any grade severity on Days 0, 1, 3, 7 and 28 
On Day 0 prior to infusion and on Days 1, 3, 7 and 28 the prevalence of AEs of any 
grade severity that the participant reports that day will be collected.  This information 
supplements the information on grade 3 and 4 events through Day 7 that is collected. 
10.2.4 Incident Grade 3 and 4 clinical adverse events through Day 7 
From the time of randomization on Day 0 through Day 7, clinical events reaching 
Grade 3 or 4 severity level will be reported as AEs unless they are a protocol-
specified exempt event (see below).   
 
Any medical condition of grade 1 and 2 that is present at Day 0 will be reported as an 
AE if it increases to Grade 3 or 4 by Day 7. 
 
Isolated laboratory abnormalities will not be recorded on the eCRF for grade 3 and 4 
events.  However, as noted above, if an isolated laboratory result meets SAE criteria, 
it should be reported as an SAE. 


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10.2.5 Protocol-specified exempt events 
These events are listed in sections 4.1 and 4.2 and are collected systematically 
during study follow-up on eCRFs. These events will not be reported as Grade 3 or 4 
AEs even if they occur at that severity grade.  They also will not be reported as SAEs, 
even if they meet one or more of the criteria for seriousness, unless the investigator 
considered that there was a reasonable possibility that the study intervention 
caused the event.  These events may occur during the initial hospitalization, lead to 
a re-admission, or occur in a later hospitalization during follow-up.  
The following are protocol-specified exempt events: 
 
Death 
 
Stroke 
 
Meningitis 
 
Encephalitis 
 
Myelitis 
 
Myocardial infarction 
 
Myocarditis 
 
Pericarditis 
 
New onset of worsening of CHF (NYHA class 3 or 4) 
 
Arterial or deep venous thromboembolic events 
 
Respiratory failure defined as receipt of high flow nasal oxygen, noninvasive 
ventilation, or invasive ventilation 
 
Hypotension requiring vasopressor therapy 
 
Renal dysfunction requiring renal replacement therapy 
 
Hepatic decompensation 
 
Acute delirium  
 
Disseminated intravascular coagulation 
 
Microbiologically-proven severe infection (not including SARS-CoV-2) 
 
10.2.6 Reportable SAEs 
Reportable SAEs for this study are: 
 Serious clinical AEs not reported as a study endpoint; and 
 Any serious AE related to the study intervention 
Deaths, life-threatening events, and others SAEs considered related to the 
investigational agent, irrespective of whether the event is mentioned above as a 
protocol-specified exempt event, that occur from the time of infusion of the 
hIVIG/placebo begins through the Day 28 visit must be reported by sites on the SAE 
eCRF to the sponsor via the INSIGHT Safety Office.   These events must be reported 
within 24 hours of site awareness.  All other SAEs must be reported within 3 days 
of site awareness. 


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SAEs are followed until the outcome of the SAE is known.  If the outcome of an SAE 
is still unknown at the time of the final follow-up visit (Day 28), the outcome will be 
entered in the database as “unknown.” 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are 
assessed as related to a study-provided treatment and are unexpected per the 
Reference Safety Information of the IB for that treatment.  SUSARs are reported from 
the INSIGHT Safety Office to applicable regulators in an expedited fashion.  SUSARs 
that result in death or are immediately life-threatening are reported to regulators 
within 7 calendar days of receipt.  All other SUSARs are reported to regulators within 
15 calendar days.  The INSIGHT Safety Office will generate a Safety Report for each 
SUSAR for distribution to investigators and other parties.  Investigators are 
responsible for submitting Safety Report summaries that are received from the 
sponsor to their overseeing IRB/EC.  Investigators must also comply with all reporting 
requirements of their overseeing IRB/EC. 
Safety reports for SUSARs indicate the study intervention (i.e., are unblinded). 
SAEs that are not protocol-specified exempt events and that are not related to the 
study intervention (investigational agent or treatment provided as SOC) must be 
reported on the SAE eCRF within 3 days of site awareness. 
 
10.2.7 Unanticipated Problems (UPs) 
UPs must also be reported via the appropriate eCRF to the INSIGHT Safety Office no 
later than 7 calendar days after site awareness of the event. Investigators are 
responsible for submitting UPs that are received from the sponsor to their overseeing 
IRB/EC.  Investigators must also comply with all reporting requirements of their 
overseeing IRB/EC. 
 
10.2.8 Deaths 
Deaths that are considered unrelated to the study intervention are reported on the 
eCRF for deaths.  Deaths considered related to the study intervention (investigational 
agent or study-supplied SOC) must also be reported as an SAE.   
 
Medical Monitor 
10.3
A Medical Monitor appointed by the sponsor will be responsible for reviewing all 
SAEs, making an independent assessment of causality and expectedness, preparing 
sponsor safety reports, and communicating as needed with the DSMB and the 
Investigational New Drug (IND) holder.  
 
 
Treatment Interruption or Discontinuation 
10.4
An infusion may be interrupted or discontinued at any time at the participant’s request 
or at the discretion of the Investigator or Sponsor. Reasons for interruption or 
discontinuation and the total volume administered will be recorded.  


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Halting Rules 
10.5
The sponsor medical monitor or the DSMB may request that enrollment be halted for 
safety reasons (e.g., unacceptably high rate of infusion-related reactions or other 
unanticipated AEs).  As a guideline, the DSMB will be asked to consider halting 
enrollment if more than 5% of participants experience a grade 3 or 4 infusion AE or if 
more than 10% do not complete the infusion due to an AE(s). This will be informed by 
the lower bound of the confidence interval. If the study is temporarily halted or 
stopped for safety reasons, IRBs/ethics committees will be informed.  
The IND holder and sponsor, in collaboration with the protocol chair and the DSMB 
will determine if it is safe to resume the study. The sponsor will notify the Site 
Investigators of this decision. The conditions for resumption of the study will be 
defined in this notification. The Site Investigators will notify their local IRBs/ethics 
committees of the decision to resume the study. 
 EVALUATION 
11
 
Data Analysis 
11.1
A brief summary of the statistical considerations is provided here, full details will be 
described in a statistical analysis plan (SAP) that will be finalized prior to unblinding 
of the data. Data unblinding will either occur after a recommendation from the 
independent DSMB or after all participants complete the Day 28 follow-up visit. 
The primary analysis will be by intention to treat comparing all participants 
randomized to hIVIG with those randomized to placebo. The different hIVIG products 
will be pooled for this analysis.  
This analysis plan applies to the primary efficacy and safety outcomes, and important 
secondary outcomes. 
For the primary endpoint, the percent of participants in the 7 categories of the ordinal 
outcome will be compared. A proportional odds model will be used to estimate a 
summary OR.82 The model will include a single indicator for treatment, indicators for 
the participant’s clinical state at entry (categories of ordinal outcome), and its two-way 
interactions with the six cut-offs. The model will also include indicators for which of 
the four hIVIG product/matching placebo product was used and their two-way 
interactions with the six cutoffs for each of the six cumulative odds of improvement. A 
test for the proportional odds assumption will be carried out. Even if the proportional 
odds assumption is violated, the overall summary OR will be the basis for inference 
based on the primary analysis. In order to further characterize the summary OR and 
any deviations from proportional odds, separate ORs will be estimated for each of the 
six dichotomized definitions of improvement that can be formulated from the 
components of the ordinal outcome.  


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For the primary endpoint analysis only, multiple imputation based on baseline and 
follow-up data will be used to estimate participant status at day 7 for participants with 
missing follow-up data.  For this imputation the following baseline covariates will be 
considered in addition to an indicator for treatment group: age, geographic region, 
clinical status based on the ordinal outcome at enrollment, presence of comorbidities, 
NEW score, and oxygen saturation. In addition to these baseline covariates, the last 
NEW score and the last value of the ordinal outcome measured will be used in the 
imputation. 
We will impute ten data sets; parameter estimates (e.g., the summary odds ratio) 
from the 10 multiply imputed datasets will be combined using Rubin’s combining 
rules. The imputation will take into account whether partial information concerning the 
ordinal outcome at Day 7 is known (e.g., it is known that the patient is alive and no 
longer hospitalized and receiving supplemental oxygen and only which of the best 2 
categories the patient is in is unknown). 
Categories 3 and 4 of the primary ordinal outcome differ in part by the amount of 
supplemental oxygen required, and a single cut point (4 liters/minute) defines the 
difference. Since, together, these 2 categories of the ordinal outcome are expected to 
include approximately 30% of participants, an analysis that combines these two 
categories (a 6-category ordinal outcome) will be carried to supplement the primary 
analysis using the same methods described above.  
SAEs and grade 3 and 4 events (excluding isolated laboratory abnormalities) will be 
classified by system organ class according to MedDRA. The composite of incident 
grade 3 or 4 events, an SAE or death over 7 days of follow-up will be summarized 
with Mantel Haenszel chi-square tests stratified by hIVIG/matched placebo group. 
Time to event methods (e.g., Kaplan-Meier estimates and Cox regression) will be 
used to summarize deaths and SAEs through Day 28. 
Safety analyses will also include infusion reactions collected during or within 2 hours 
after the infusion of hIVIG/placebo.  Percentages of participants who experience 
infusion reactions or prematurely terminated infusions will be summarized by 
treatment groups, and Cochran Mantel Haenszel tests will be used to compare 
groups. 
For secondary endpoints such as time to discharge and time to the 2 most favorable 
categories of the primary ordinal outcome, time to event methods that take into 
account the competing risk of death will be used. Specifically, Gray’s test with rho=0, 
the Fine-Gray model, and the Aalen-Johansen estimator for the cumulative incidence 
curve are the competing risk equivalents to the log-rank test, Cox proportional 
hazards model, and the Kaplan-Meier estimator for the cumulative proportion of 
participants with the event, respectively.83,84,85 
Longitudinal random effects models will be used to summarize log-transformed 
antibody level differences between the hIVIG and placebo groups at Days 1, 3, 7 and 
28 of follow-up. Baseline antibody levels will be included as a covariate in these 


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models. For the subset of participants for whom blood is collected at Day 90, 
antibody levels will be compared.  
Subgroup analyses for the primary 7-category ordinal outcome (primary efficacy 
outcome), as well as for the primary safety outcome (Grade 3 and 4 events, SAE or 
death through Day 7) will be performed to determine whether the treatment effect 
(hIVIG versus placebo) differs across baseline-defined subgroups. The key subgroup 
analysis is by duration of symptoms at study entry.  For the subgroup of participants 
in the lower 3 quartiles, the OR for the primary ordinal outcome at Day 7 is 
hypothesized to be greater than the overall result and those in the upper quartile 
(longest duration of symptoms at study entry).  The difference in ORs will be 
compared for those in the lower 3 quartiles versus the upper quartile.  In addition, the 
trend across the four quartiles will be assessed.   
The following other baseline-defined subgroups will be considered: age, gender, 
race/ethnicity, BMI, history of chronic conditions, geographic region, hIVIG product 
administered, neutralizing antibody level, baseline upper respiratory SARS-CoV-2 
viral load,  oxygen saturation level, ordinal outcome category at entry, NEWS, 
dyspnea severity, and a disease progression score. A priori we have no reason to 
believe the clinical efficacy or safety of hIVIG compared to placebo will be 
substantially different in any of the subgroups considered. These analyses will be 
approached cautiously because random differences can occur (type 1 error is inflated 
due to the number of subgroups examined), confounding due to other factors in 
defining each subgroup is possible, and power is limited. To partially control the 
inflation of type 1 error and to guide the interpretation of subgroup summaries, an 
overall test of heterogeneity of treatment effect (treatment by subgroup interaction) 
will be constructed to assess how strong the evidence is that the treatment effect 
varies across the baseline subgroups. 
In addition to these subgroup analyses, a subgroup analysis by lot potency will be 
carried out.  The aim of this analysis will be to determine if the primary outcome 
varies by range in potency among the various lots of hIVIG used.  The potency of 
each lot will be measured by a central laboratory.  Participants in the placebo group 
will be classified according the lot potency they would have received had they been 
randomly assigned to the hIVIG group. The methods used for this subgroup analysis 
will be as described above.  
If there is a beneficial effect of hIVIG compared to placebo, in order to support 
regulatory claims for each hIVIG product used, sensitivity analyses comparing each 
hIVIG product to its matched placebo will be carried out for key efficacy and safety 
endpoints. These analyses will consider that each hIVIG product will be used by a 
different group of clinical sites (i.e., each comparison will represent a small multi-
center trial), and that power will likely be very low for all of the outcomes. These 
analyses are referred to as sensitivity analyses because overall therapeutic efficacy 
and safety will be based on the pooled analysis of the four hIVIG products with 
placebo. 


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If the hIVIG and placebo groups differ for the primary ordinal outcome at Day 7, the 
extent to which a favourable treatment difference for hIVIG can be explained by 
antibody levels measured at baseline and Days 1, 3, 7, and 28 of follow-up will be 
investigated.  
 
Ethical Conduct of the Study  
11.2
The study will be conducted according to the Declaration of Helsinki in its current 
version; the requirements of Good Clinical Practice (GCP) as defined in Guidelines, 
EU Clinical Trials Directive (2001/20/EC), and EU GCP Directive (2005/28/EC); 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Guidelines; Human Subject Protection and 
Data Protection Acts; the US Office for Human Research Protections (OHRP); or with 
the local law and regulation, whichever affords greater protection of human subjects. 
 
 Data Monitoring by an Independent DSMB 
11.3
An independent DSMB will review the study prior to initiation and at frequent intervals 
during the trial. The DSMB will review safety data for first 20 to 30 participants 
randomized after they have been followed for 7 days.  Thereafter, the DSMB will 
review safety data at 30 day intervals. Safety summaries will include the safety 
outcomes in section 4.2. The DSMB may also convene additional reviews as 
necessary. After each meeting they will recommend continuing the study as planned, 
modifying the study, or terminating the study.  
The DSMB will be asked to recommend early termination or modification only when 
there is clear and substantial evidence of a treatment difference. As a guideline, 
asymmetric boundaries will be provided to the DSMB to monitor the primary endpoint 
comparison. For monitoring early benefit of hIVIG, the Lan-DeMets spending function 
analogue of the O’Brien-Fleming boundary will be used86,87; a Haybittle-Peto type 
boundary using a 2.5 standard deviation (SD) difference for the first 100 participants 
enrolled and 2.0 SD afterwards will used as a guideline for harm.88 The Lan-DeMets 
boundary used will be chosen to preserve a 1-sided 0.025 level of significance. For 
computing the Lan-DeMets boundary, the information fraction at each interim 
analysis will be the number of participants who have completed 7 days of follow-up 
divided by the target sample size (currently 500). With this guideline for early 
termination, less evidence will be required for crossing a boundary for harm than 
benefit.  
Futility analyses will also be presented to the DSMB for the primary endpoint 
comparison by the unblinded statisticians based on conditional power estimates. 
Conditional power incorporates the observed results by treatment group thus far (and 
uses the originally assumed treatment effect for future data) to calculate the 
conditional probability of obtaining a significant result by the end of the trial. If 
conditional power, given the observed data and assuming the originally hypothesized 
treatment effect thereafter, is less than 20% after 50% of information (primary 
endpoints) is available, consideration should be given to stopping the trial. 


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A SAP will be developed to guide DSMB interim analyses. The SAP will include 
recommended analyses for the DSMB to consider in addition to the primary endpoint 
analysis in the event early termination for efficacy or futility is considered. For 
example, the primary endpoint at Day 7 for the key previously defined subgroup of 
those in the lower 3 quartiles of symptom duration at entry will be routinely 
summarized in the closed interim report to the DSMB. 
All of these analyses will consider the timeliness of reporting primary outcome data, 
secondary efficacy and safety outcomes, and subgroups.  
 PROTECTION OF HUMAN SUBJECTS AND ETHICAL 
12
CONSIDERATIONS  
 
Participating Clinical Sites and Local Review of Protocol and 
12.1
Informed Consent 
This study will be conducted by major medical centers participating in the 
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). It is 
anticipated that potential participants will be recruited by the site investigators and/or 
that positive SARS-CoV-2 laboratory testing will be used to enquire about potential 
enrollment. Information about this study will be disseminated to health care providers 
in these settings. 
Prior to the initiation of the study at each clinical research site, the protocol, informed 
consent form and any participant information materials will be submitted to and 
approved by a central/national IRB or EC and/or the site’s local IRB/EC. Likewise, 
any future amendments to the study protocol will be submitted and approved by the 
same IRB(s) or EC(s). After IRB/EC approval, sites must register for this study before 
screening potential participants and must register for any protocol amendments. 
Specific protocol registration information can be found in the Study Procedure 
Modules. 
 
Informed Consent of Study Participants  
12.2
Informed consent must be obtained (see sample in Appendix A) prior to conducting 
any study-related procedures.  For patients who are incapacitated, informed consent 
may be obtained from a legally authorized representative.  Capacity will be assessed 
according to local standards and policies.  Local standards and policies will also 
determine who is legally authorized to consent for an individual who is incapacitated.  
Should the individual regain capacity during the study, their direct consent should be 
obtained at the earliest opportunity.  Electronic consent methods may be used if 
approved by the IRB/EC. Procedures for recording of written consent may be 
modified for infection control purposes as approved by the IRB/EC. 


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Confidentiality of Study Participants  
12.3
The confidentiality of all study participants will be protected in accordance with GCP 
Guidelines and national regulations.  
 
Regulatory Oversight 
12.4
Sites in the US will conduct this trial under the terms of the IND and will adhere to 
FDA regulations found in 21 CFR 312, Subpart D. Sites in countries other than the 
US will not conduct the trial under the IND. All sites will conduct the trial in 
accordance with the requirements of GCP as codified in their local law and 
regulation, under the oversight of their institution and competent regulatory authority. 
A specific protocol monitoring plan will be developed.  The plan will outline the 
frequency of monitoring visits based on such factors as study enrollment, data 
collection status, and regulatory obligations.  


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APPENDIX A-1 
SAMPLE INFORMED CONSENT FORM 
(FOLLOW-UP ENDING DAY 28) 
Short Title: Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) 
Sponsored by: The University of Minnesota  
A Multicenter Study of the 
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)  
Full Title of the Study:  An International Multicenter, Adaptive, Randomized 
Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability and Efficacy of 
Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the Treatment of 
Adult Hospitalized Patients at Onset of Clinical Progression of COVID-19 
CONSENT FOR PARTICIPATING IN A NATIONAL INSTITUTES OF HEALTH (NIH)-
FUNDED RESEARCH STUDY  
SITE INVESTIGATOR: ________________________________ PHONE: __________  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
OHRP Requirements to be read by the sites: 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL 
IRB/EC REVIEW AND APPROVAL.  INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL 
IRB/EC WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH THE LANGUAGE INTENDED 
FOR LOCAL USE.  LOCAL IRBs/ECs ARE REQUIRED TO WEIGH THE UNIQUE RISKS, 
CONSTRAINTS, AND POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  
ANY DELETION OR SUBSTANTIVE CHANGE OF INFORMATION CONCERNING RISKS OR 
ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY THE INVESTIGATOR, APPROVED BY THE 
LOCAL IRB/EC, AND NOTED IN THE IRB/EC MINUTES.  JUSTIFICATION AND IRB/EC APPROVAL 
OF SUCH CHANGES MUST BE FORWARDED TO THE INTERNATIONAL COORDINATING 
CENTER.  SPONSOR-APPROVED CHANGES IN THE PROTOCOL MUST BE APPROVED BY THE 
LOCAL IRB/EC BEFORE USE UNLESS INTENDED FOR THE ELIMINATION OF APPARENT 
IMMEDIATE HAZARD.  NEW INFORMATION SHALL BE SHARED WITH EXISTING SUBJECTS AT 
NEXT ENCOUNTER, WITH ALL NEW SUBJECTS PRIOR TO INVOLVEMENT, OR AS THE LOCAL 
IRB/EC MAY OTHERWISE ADDITIONALLY REQUIRE. 
ALL SITE INSTRUCTION THAT IS INCLUDED IN A TEXT BOX SHOULD BE 
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Key information: 
 
We are asking you to join a research study about COVID-19. It is your choice whether or not 
you want to join. This form gives you information about the study that will help you make 
your choice. You can discuss this information with your doctor or family or anyone else you 
would like before you make your choice. Your choice will not affect the care you are getting 
for COVID-19. 
What is the research question? 
We are trying to find out if giving anti-coronavirus hyperimmune intravenous immunoglobulin 
(hIVIG) can help people in the hospital with COVID-19 have fewer bad effects from COVID-
19, get better faster, and get out of the hospital faster. Anti-coronavirus hIVIG contains 
antibodies against the virus that causes COVID-19. We think this will help your body fight 
COVID-19 better, but we are not sure and so we are doing this study. We are asking you to 
join the study because you are in the hospital with COVID-19.  
What do you have to do if you decide to be in the study? 
The study staff at your hospital will make sure it is safe for you to be in the study. They will 
check your medical history. They will look at routine medical test results that you are 
probably already having done regularly in the hospital.  
If you agree to be in the study, we will randomize you to one of two study groups. It will be 
up to chance, like flipping a coin, and you will have an equal chance (50/50) of getting either 
hIVIG or a saline placebo (a salt solution). Your doctor will not decide which of these you will 
get, and neither you nor your doctor or study staff will know what treatment you are getting.  
You will get the usual supportive care for COVID-19 recommended by your hospital, just as 
you would if you do not join the study. In addition, the study will supply an antiviral drug 
called remdesivir, unless there is a medical reason that you should not get remdesivir. 
Remdesivir has been shown in other studies to improve recovery from COVID-19 in persons 
who have been hospitalized. 
You will get the study treatment (hIVIG or placebo) once, on the day you join the study. You 
will get it by a drip through a tube attached to a needle in your arm (intravenously). It will 
take about 1-2 hours, though it may sometimes take longer depending on how your body 
reacts to the infusion. This is the only thing in the study that is experimental. Everything else 
is part of routine medical care for someone in the hospital with COVID-19. 
You will get remdesivir once a day intravenously for up to 10 days while you are in the 
hospital, as part of standard care for your COVID-19. 
You will also need to agree not to participate in any other COVID-19 study for the first 7 
days you are in this study. 


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You will be in the study for 28 days. We will check on your health every day while you are in 
the hospital, and at regular intervals once you leave the hospital.  
We will collect the following information at these times:  
Up to 1 day 
before you 
get study 
treatment 
Day 0 (the day 
you get study 
treatment) 
Day 1, Day 2, 
and 
Day 3 
Day 5 
and Day 
14 
Day 7 
Day 28 
 Informed 
consent 
 Blood tests 
to check 
your health 
 Check to 
see how 
you are 
feeling 
 Pregnancy 
test 
 Your 
medical 
history 
 Infusion of 
study treatment 
 If you are taking 
certain 
medicines 
 Blood for future 
research (18 
mL, about 2 
tablespoons) 
 Nasal swab for 
future research 
 How you are 
feeling 
 Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
 How 
you are 
feeling 
 How you are 
feeling 
 If you are 
taking 
certain 
medicines  
 Blood tests 
to check 
your health 
 Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
 How you are 
feeling 
 Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
 
Day 28 is the last day you will be in the study. 
We may need to get some information from your medical record. By signing this consent, 
you also agree to let us get information for this study from your medical record. 
 


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We will send the information we collect to the University of Minnesota (UMN) in the US 
where it will be stored and analyzed. In this information, only a code number, your year of 
birth, and a 3-letter code that you or the study staff chooses will be used on your 
information. We never give information that could identify you, such as your name, address, 
birth date, or medical record number, to anyone outside this site. The study staff at this site 
is responsible for keeping your identifying information safe from anyone who should not see 
it. We will send the blood samples to a laboratory in the US for storage. We will keep them 
for as long as we have the funding and space to do so, which we hope will be many years. 
We will use the samples in the future for tests to help understand more about COVID-19 and 
how people respond to treatment for COVID-19. You and your doctor will not get any results 
from these tests. We will not test your DNA (your genes). We will not sell your samples and 
they will not be used for research aimed at making money (commercial research). The 
samples will not have any information connected to them that could identify you. 
Why would you want to be in the study? 
If you get the hIVIG, it may help you get better faster, although we do not know that for sure. 
Remember that half (50%) of the people in this study will not get the hIVIG. 
By being in this study, you help doctors know more about how to treat COVID-19 in people 
in the hospital. Because so many people are getting hospitalized with COVID-19, this could 
be a big impact if a treatment proves to be effective. 
Why would you NOT want to be in the study? 
Only half (50%) of the people in this study will get the hIVIG. You may not get the hIVIG.  If 
hIVIG turns out to be a good treatment, you would not get that benefit.  It’s also possible that 
if you do get hIVIG, it may turn out not to be useful, or may cause side effects that are 
harmful to you. 
What are the side effects of the study hIVIG treatment? 
hIVIG is usually very safe to give. Similar immunoglobulin preparations have been used in 
many different diseases over many years, but immunogloblin prepared solely from 
individuals who have recovered from COVID-19 has not been studied before. In an earlier 
study of influenza hIVIG in people in the hospital with the flu, over 150 people got hIVIG. 
There were no serious problems that occurred in people because they got hIVIG. 
All treatments cause side effects, and you may have some side effects from hIVIG.  About 
1% to 10% (1 in 100 people to 1 in 10 people) who get hIVIG get a fever, chills, nausea, 
vomiting, dizziness, shortness of breath, rash, hives, or headache, but these are usually not 
serious.  These can happen during the infusion or afterwards and usually go away on their 
own or with short-term treatment.  Although IVIG has been very safe for people with other 
diseases, less than 0.1% (less than 1 in 1,000) of people taking other types of IVIG for other 
illnesses have had very serious reactions to it, including a kind of lung injury called TRALI. 


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People can have allergic reactions to drugs, including hives, trouble breathing, or other 
allergic responses. This is very rare but is also a possible effect of any drug. Allergic 
reactions may be severe or life-threatening.   
In some laboratory studies, infusions of antibodies have made infections with viruses similar 
to the virus that causes COVID-19 worse. This is a very unlikely but possible side effect of 
the treatment infusion in this study, and you will be closely monitored for any signs of this 
effect. 
It is also possible that getting the study treatment infusions could cause problems with your 
health because of the amount of fluid given to you for the study treatment if you have some 
other health condition that affects how your body handles fluids.  You will get up to about 
400 mL of fluid for hIVIG or placebo, and about 100mL each day for remdesivir if you 
receive it 
Some people may have some side effects after the hIVIG infusions.  Other people may have 
no side effects.  You will be monitored closely during the infusions, and short-term medical 
care will be provided if there are side effects from the infusions that can be treated. 
 
What are the benefits and risks or side effects of remdesivir treatment? 
Remdesivir was recently shown to help people who are in the hospital with COVID-19 to get 
better faster than people who got a placebo.  You may be given remdesivir to treat your 
COVID-19 even if you do not join this study. If your doctor considers that remdesivir is not a 
suitable treatment for you, you can still join this study, and you will receive hIVIG or placebo 
without remdesivir. For example, remdesivir might be unsuitable for you if you have serious 
liver or kidney problems or an allergy to it. 
 
The most common side effects of remdesivir include abnormal liver function test results, 
abnormal kidney function test results, fever, elevated blood sugar, constipation, nausea, 
vomiting, decreased appetite, and headache. The abnormal liver and kidney function tests 
may last a few days or longer but came back to normal levels over time. 
 
People can have allergic reactions to drugs, including hives, trouble breathing, or other 
allergic responses. This is very rare but is also a possible effect of any drug. Allergic 
reactions may be severe or life-threatening.   
 
Some people may have some side effects after the infusion of remdesivir.  Other people 
may have no side effects.  You will be monitored closely during the infusions, and short-term 
medical care will be provided if there are side effects from the infusions that can be treated. 
 
What are the side effects of the other study procedures? 
 
As shown in the table of what will happen at each visit, you will have some extra blood 
drawn for laboratory testing and storage.  You will also have an extra swab of your nose and 
throat that would not be done if you are not in the study.  The risks and discomforts of these 


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extra blood draws and swab are no different than what you would have if they were 
performed as part of your regular hospital care for COVID-19. 
Additional information: 
Here is some additional information about the study that may help you make your choice 
about whether you want to be in the study. 
The US National Institutes of Health (NIH), an agency of the US Federal government, is 
paying for this study. Because public money is paying for the study, we are required to 
comply with all rules and regulations about research. We are doing this study according to 
internationally recognized standards of research as well as the laws of each country where 
the study is taking place.  
This study is taking place in several countries. We expect to enroll about 500 people around 
the world. 
You do not have to join this research study if you do not want to. If you choose to join the 
study, you can stop at any time by telling someone on the study team that you want to stop 
being in the study. If you choose not to join or to stop, your regular medical care will not 
change. 
If we get any new information that might change whether you want to join or stay in the 
study, we will tell you right away.  
Your study participation may be stopped without your consent if: 
 The groups overseeing the study decide the study should be stopped; 
 Your study team believes that being in the study is no longer in your best interests. 
 
If your participation is stopped, you will still get the usual care given at your hospital for 
COVID-19. 
If you do not want to be in this study, you will still get the usual care to treat COVID-19. 
However, you cannot get the hIVIG treatment, because it is experimental. 
 
What are the costs to you? 
We will give you the study treatment (hIVIG or placebo) at no cost. We will also give you 
remdesivir at no cost.  We will pay for all clinic visits, lab work, and other tests that are part 
of this study. 
 
 
 
THE NEXT PARAGRAPH IS FOR UNITED STATES SITES ONLY.  SITES IN 
OTHER COUNTRIES SHOULD DELETE THE NEXT PARAGRAPH. 


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You, your insurance company, or some other third-party payer must pay for all other 
medicines and hospital costs. 
 
 
 
Will you be paid to be in the study? 
We will compensate you for your time and inconvenience participating in the study. [Specific 
details to be completed by site.] 
What if you are hurt as part of this study? 
If you are hurt because of being in this study, [insert the name of the hospital/clinic] will treat 
your injury right away. You or your insurance will have to pay for this treatment. The study 
cannot pay you or pay for any care for study-related injuries or for your illness. 
 
 
 
What happens to the blood samples and respiratory swabs? 
We will send the blood and respiratory swab samples to a central laboratory in the United 
States of America. You and your doctor will not get the results of any tests done on these 
samples. 
The blood samples will measure how many COVID-19 antibodies are in your blood. This will 
tell us how your immune system responded to your COVID-19.  The nasal swab will 
measure how much virus you have in your respiratory system. 
Any blood samples that are left over after these tests will be stored at the central laboratory 
for as long as we are able to keep them. We hope to use these in the future to answer other 
questions about COVID-19. You and your doctor will not get any results from these tests. 
Some of the blood will also be given to the company that made the hIVIG to help them learn 
more about its effects. 
How do we protect your privacy? 
We will take every reasonable step to keep your health information private and to keep 
anyone from misusing it. 
SITES OUTSIDE THE UNITED STATES:  Please replace the paragraph 
above with language appropriate for your location 
If the above is not true for your site, i.e., if trial insurance covers such 
cost, please replace the above with appropriate language. 


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Your information (data) and samples will not be identified by name, or in any other way, in 
anything published about this study.  
We will do everything we can to keep your personal information private, but we cannot 
guarantee that nobody will get it. We may have to release your personal information if 
required by law. 
These people may see your medical and research information at your site: 
 the [insert the name of the hospital/clinic] ethics committee (institutional review board 
[IRB]); 
 the sponsor, other study research staff, and study monitors 
 US and other participating countries’ health regulatory agencies 
 the US National Institutes of Health which is funding the study 
They are committed to protecting your privacy. 
As the research staff at [inset the name of the hospital/clinic], we are required to make sure 
that people not involved with this study cannot see your research and medical information. 
We will keep your research files in a safe place and will handle your personal information 
very carefully.  
Your study data are sent electronically to the UMN in the US through a secure application. 
By signing this consent, you agree to have your data sent to UMN. No information that could 
directly identify you is sent to UMN. This is called “pseudonymized data.” Access to the data 
at UMN is limited through security measures, and no data breach or unauthorized access 
has ever occurred in this system. After the study is over, the data will be stored securely for 
the period required by law. 
Your study data will be shared with the regulators that oversee the studies, as required by 
law. Your study data will also be shared with the drug company that provides the hIVIG to 
help them develop the drug.  
UMN may share your data and specimens with other people who study COVID-19. UMN will 
remove any information that could possibly be used to identify you before sharing. This is 
called “anonymizing the data.” We will not ask you for additional consent for this sharing. 
UMN will only share data and specimens for research projects that are approved by the 
group that is conducting this study. 
This study has a Certificate of Confidentiality from the US Federal government. This means 
that UMN cannot share any data it has about you with national, state, or local civil, criminal, 
administrative, legislative, or other authorities unless you specifically allow us to share it.  
A description of this clinical trial will be available at http://www.ClinicalTrials.gov as required 
by U.S. law, and on the EudraCT website (https://eudract.ema.europa.eu/). These websites 
will not include your name or any other direct identifiers such as your contact information. 


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These websites will include a summary of the results of this research once the study has 
been completed. You can search either website at any time. 
[Note for US sites: The following brief HIPAA authorization is provided. Your site-specific 
consent should be modified to reflect the HIPAA authorization language requirements at 
your site.] 
To do this research, we will collect and use your personal data, as described above and in 
any HIPAA Authorization Form we have given you. Please tell us whether you agree to have 
us collect and use your personal data by placing your initials in front of your selection.


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____Yes, I agree to the collection and processing of my personal data. 
 
____No, I do not agree to the collection and processing of my personal data. 
It is your choice whether you allow us to collect and use your data. However, you will not be 
able to be in this research and have a chance to get the experimental treatment if we cannot 
collect and use your data. 
[The following section (up to “What if you have problems or questions?”) is for countries 
subject to the General Data Protection Regulation (GDPR) or similar legislation requiring 
this information. It should only be included in consents for sites subject to such legislation. It 
will vary from place to place whether it must be in this consent document, a separate 
consent document, or an information sheet that does not require signature. The amount of 
information provided may be reduced to meet the requirements of a particular country (e.g., 
not all countries/ECs require an enumeration of all of a data subject’s rights).] 
What are your rights regarding your data? 
The UMN is a public research university, and this study is funded primarily by a grant from 
the US Federal government. UMN and the study funding source require the sponsor (UMN) 
to follow regulations and policies that are meant to protect your privacy. UMN is also 
required to comply with the General Data Protection Regulation (GDPR), because it 
processes data obtained from people in Europe.  
 
There is no specific independent supervisory authority overseeing the processing of data in 
the US. Any complaint you might have about the use of your data would be made to your 
national data protection authority. 
 
The GDPR gives you additional rights which we would like to inform you about below. 
 
Right to Information 
You have the right to know what data about you is being processed. You can also get a free 
copy of this data provided. 
 
Right to Correction 
You have the right to correct any information about you which is incorrect or had become 
incorrect. 
 
Right to Erasure/Anonymization 
The sponsor is required under both EU and US law to retain data from research studies like 
this one for many years. However, you have the right to request that your personal data be 
completely anonymized. This is done by destroying the information at your study center that 


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links your identity to the pseudonymized data held by the sponsor. This means that no one 
would ever be able to link the data held by the sponsor to you personally.  
 
Right to Restriction of processing 
Under certain conditions, you have the right to demand processing restrictions, i.e. the data 
may then only be stored, not processed. You must apply for this. Please contact your study 
physician or the data protection officer of the study center if you want to do so. This right 
may be limited if the restriction would affect the reliability of the study results. 
 
Right to Data portability  
You have the right to receive the personal data that you have provided to the study center. 
This will allow you to request that this information be transmitted either to you or, where 
technically possible, to another agency designated by you. 
 
Right to Contradiction 
You have the right to object at any time to any specific decision or action taken to process 
your personal data. This right is limited for data that have already been processed and may 
be limited if your objection would affect the reliability of the study results. 
 
Right to Withdrawal of this consent 
You may withdraw your consent at any time with effect for future data collection. This 
withdrawal may be in an informal or verbal communication to your investigator. If you 
withdraw your consent this will not affect the lawfulness of the data processing that has 
been or will be done with data collected until you withdraw consent. Data already collected 
will be anonymized. 
 
If you would like to use one of these rights, please first contact the person responsible for 
the data collection at your study center: 
 
Person responsible for data collection at the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 
 
For concerns about data processing and compliance with data protection requirements you 
can also contact the data protection officer responsible for the study center: 
Data protection officer responsible for the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 


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In addition, you have the right to lodge a complaint with the competent authority if you 
believe that the processing of personal data concerning you is contrary to the GDPR: 
Data protection authority responsible for the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 
 
What if you have problems or questions? 
If you ever have questions about this study, or about the storage or use of your data or 
samples, or if you are hurt by being in the study, contact: 
 [name of the investigator or other study staff] 
 [telephone number of the above] 
 
If you have questions about your rights as a research participant, you can call: 
 [name or title of person on the ethics committee (IRB) or other organization 
appropriate for the site] 
 [telephone number of the above]  


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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE INSIGHT 013 STUDY 
(Inpatient Treatment with Anti-Coronavirus Immunoglobulin, ITAC)  
I have read the consent or have had it explained to me. I am satisfied that I understand the 
information. By signing this consent, I am stating that I want to join this study. I understand 
that I do not waive any of my legal rights as a study participant by signing this consent. I 
understand that I will receive a copy of the signed and dated consent. 
If you agree to be in this study, please sign below. 
 
________________________________________  
Date: _______________ 
Signature of participant 
 
________________________________________ 
Printed name of participant 
 
_____________________________________   
Date: _______________ 
Signature of investigator/designee 
 
_____________________________________ 
Printed name of investigator/designee 
 
FOR ADULTS NOT CAPABLE of GIVING CONSENT  
 
________________________________________ 
 Date: _______________ 
Signature of Legally Authorized Representative (LAR)  
 
_____________________________________ 
Printed name of LAR 
 


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____________________________________ 
Relationship of LAR to Participant 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under state or applicable local law) 
 
Witness to Consent Interview 
 
On the date given next to my signature, I witnessed the consent interview for the research 
study named above in this document. I attest that the information in this consent form was 
explained to the subject, and the subject indicated that his/her questions and concerns were 
adequately addressed. 
_______________________________________ 
Date: _______________ 
Signature of witness 
 
________________________________________ 
Printed name of witness 
 
NOTE: This consent form, with the original signatures, MUST be retained on file by 
the Investigator of Record. A copy of the signed and dated consent must be given to 
the participant. A copy should be placed in the participant’s medical record, if 
applicable.  
If no-touch / electronic consent is used, the participant must be provided with a copy 
of the consent in a manner appropriate to the method used to obtain it.  A record of 
the act of consent must also be appropriately retained in the participant’s medical 
record. 
 
 
 


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APPENDIX A-2 
SAMPLE INFORMED CONSENT FORM 
FOR SITES COLLECTING DAY 90 SAMPLES 
Short Title: Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) 
Sponsored by: The University of Minnesota  
A Multicenter Study of the 
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)  
Full Title of the Study:  An International Multicenter, Adaptive, Randomized 
Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability and Efficacy of 
Anti-Coronavirus Hyperimmune Intravenous Immunoglobulin for the Treatment of 
Adult Hospitalized Patients at Onset of Clinical Progression of COVID-19 
CONSENT FOR PARTICIPATING IN A NATIONAL INSTITUTES OF HEALTH (NIH)-
FUNDED RESEARCH STUDY  
SITE INVESTIGATOR: ________________________________ PHONE: __________  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
OHRP Requirements to be read by the sites: 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL 
IRB/EC REVIEW AND APPROVAL.  INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL 
IRB/EC WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH THE LANGUAGE INTENDED 
FOR LOCAL USE.  LOCAL IRBs/ECs ARE REQUIRED TO WEIGH THE UNIQUE RISKS, 
CONSTRAINTS, AND POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  
ANY DELETION OR SUBSTANTIVE CHANGE OF INFORMATION CONCERNING RISKS OR 
ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY THE INVESTIGATOR, APPROVED BY THE 
LOCAL IRB/EC, AND NOTED IN THE IRB/EC MINUTES.  JUSTIFICATION AND IRB/EC APPROVAL 
OF SUCH CHANGES MUST BE FORWARDED TO THE INTERNATIONAL COORDINATING 
CENTER.  SPONSOR-APPROVED CHANGES IN THE PROTOCOL MUST BE APPROVED BY THE 
LOCAL IRB/EC BEFORE USE UNLESS INTENDED FOR THE ELIMINATION OF APPARENT 
IMMEDIATE HAZARD.  NEW INFORMATION SHALL BE SHARED WITH EXISTING SUBJECTS AT 
NEXT ENCOUNTER, WITH ALL NEW SUBJECTS PRIOR TO INVOLVEMENT, OR AS THE LOCAL 
IRB/EC MAY OTHERWISE ADDITIONALLY REQUIRE. 
ALL SITE INSTRUCTION THAT IS INCLUDED IN A TEXT BOX SHOULD BE 
REMOVED FROM THE SITE’S INFORMED CONSENT FOR PARTICIPANTS 


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Key information: 
 
We are asking you to join a research study about COVID-19. It is your choice whether or not 
you want to join. This form gives you information about the study that will help you make 
your choice. You can discuss this information with your doctor or family or anyone else you 
would like before you make your choice. Your choice will not affect the care you are getting 
for COVID-19. 
What is the research question? 
We are trying to find out if giving anti-coronavirus hyperimmune intravenous immunoglobulin 
(hIVIG) can help people in the hospital with COVID-19 have fewer bad effects from COVID-
19, get better faster, and get out of the hospital faster. Anti-coronavirus hIVIG contains 
antibodies against the virus that causes COVID-19. We think this will help your body fight 
COVID-19 better, but we are not sure and so we are doing this study. We are asking you to 
join the study because you are in the hospital with COVID-19.  
What do you have to do if you decide to be in the study? 
The study staff at your hospital will make sure it is safe for you to be in the study. They will 
check your medical history. They will look at routine medical test results that you are 
probably already having done regularly in the hospital.  
If you agree to be in the study, we will randomize you to one of two study groups. It will be 
up to chance, like flipping a coin, and you will have an equal chance (50/50) of getting either 
hIVIG or a saline placebo (a salt solution). Your doctor will not decide which of these you will 
get, and neither you nor your doctor or study staff will know what treatment you are getting.  
You will get the usual supportive care for COVID-19 recommended by your hospital, just as 
you would if you do not join the study. In addition, the study will supply an antiviral drug 
called remdesivir, unless there is a medical reason that you should not get remdesivir. 
Remdesivir has been shown in other studies to improve recovery from COVID-19 in persons 
who have been hospitalized. 
You will get the study treatment (hIVIG or placebo) once, on the day you join the study. You 
will get it by a drip through a tube attached to a needle in your arm (intravenously). It will 
take about 1-2 hours, though it may sometimes take longer depending on how your body 
reacts to the infusion. This is the only thing in the study that is experimental. Everything else 
is part of routine medical care for someone in the hospital with COVID-19. 
You will get remdesivir once a day intravenously for up to 10 days while you are in the 
hospital, as part of standard care for your COVID-19. 
You will also need to agree not to participate in any other COVID-19 study for the first 7 
days you are in this study. 


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You will be in the study for 90 days. We will check on your health every day while you are in 
the hospital, and at regular intervals once you leave the hospital.  
We will collect the following information at these times:  
Up to 1 day 
before you 
get study 
treatment 
Day 0 (the day 
you get study 
treatment) 
Day 1, Day 2,  
Day 3, Day 28 
Day 5 and 
Day 14 
Day 7 
Day 90 
 Informed 
consent 
 Blood 
tests to 
check your 
health 
 Check to 
see how 
you are 
feeling 
 Pregnancy 
test 
 Your 
medical 
history 
 Infusion of 
study 
treatment 
 If you are 
taking certain 
medicines 
 Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
 Nasal swab 
for future 
research 
 How you are 
feeling 
 Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
 How 
you are 
feeling 
 How you are 
feeling 
 If you are 
taking 
certain 
medicines  
 Blood tests 
to check 
your health 
 Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
 Blood for 
future 
research (18 
mL, about 2 
tablespoons) 
 
We may need to get some information from your medical record. By signing this consent, 
you also agree to let us get information for this study from your medical record. 
 


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We will send the information we collect to the University of Minnesota (UMN) in the US 
where it will be stored and analyzed. In this information, only a code number, your year of 
birth, and a 3-letter code that you or the study staff chooses will be used on your 
information. We never give information that could identify you, such as your name, address, 
birth date, or medical record number, to anyone outside this site. The study staff at this site 
is responsible for keeping your identifying information safe from anyone who should not see 
it. We will send the blood samples to a laboratory in the US for storage. We will keep them 
for as long as we have the funding and space to do so, which we hope will be many years. 
We will use the samples in the future for tests to help understand more about COVID-19 and 
how people respond to treatment for COVID-19. You and your doctor will not get any results 
from these tests. We will not test your DNA (your genes). We will not sell your samples and 
they will not be used for research aimed at making money (commercial research). The 
samples will not have any information connected to them that could identify you. 
Why would you want to be in the study? 
If you get the hIVIG, it may help you get better faster, although we do not know that for sure. 
Remember that half (50%) of the people in this study will not get the hIVIG. 
By being in this study, you help doctors know more about how to treat COVID-19 in people 
in the hospital. Because so many people are getting hospitalized with COVID-19, this could 
be a big impact if a treatment proves to be effective. 
Why would you NOT want to be in the study? 
Only half (50%) of the people in this study will get the hIVIG. You may not get the hIVIG.  If 
hIVIG turns out to be a good treatment, you would not get that benefit.  It’s also possible that 
if you do get hIVIG, it may turn out not to be useful, or may cause side effects that are 
harmful to you. 
What are the side effects of the study hIVIG treatment? 
hIVIG is usually very safe to give. Similar immunoglobulin preparations have been used in 
many different diseases over many years, but immunogloblin prepared solely from 
individuals who have recovered from COVID-19 has not been studied before. In an earlier 
study of influenza hIVIG in people in the hospital with the flu, over 150 people got hIVIG. 
There were no serious problems that occurred in people because they got hIVIG. 
All treatments cause side effects, and you may have some side effects from hIVIG.  About 
1% to 10% (1 in 100 people to 1 in 10 people) who get hIVIG get a fever, chills, nausea, 
vomiting, dizziness, shortness of breath, rash, hives, or headache, but these are usually not 
serious.  These can happen during the infusion or afterwards and usually go away on their 
own or with short-term treatment.  Although IVIG has been very safe for people with other 
diseases, less than 0.1% (less than 1 in 1,000) of people taking other types of IVIG for other 
illnesses have had very serious reactions to it, including a kind of lung injury called TRALI. 


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People can have allergic reactions to drugs, including hives, trouble breathing, or other 
allergic responses. This is very rare but is also a possible effect of any drug. Allergic 
reactions may be severe or life-threatening.   
In some laboratory studies, infusions of antibodies have made infections with viruses similar 
to the virus that causes COVID-19 worse. This is a very unlikely but possible side effect of 
the treatment infusion in this study, and you will be closely monitored for any signs of this 
effect. 
It is also possible that getting the study treatment infusions could cause problems with your 
health because of the amount of fluid given to you for the study treatment if you have some 
other health condition that affects how your body handles fluids.  You will get up to about 
400 mL of fluid for hIVIG or placebo, and about 100mL each day for remdesivir if you 
receive it 
Some people may have some side effects after the hIVIG infusions.  Other people may have 
no side effects.  You will be monitored closely during the infusions, and short-term medical 
care will be provided if there are side effects from the infusions that can be treated. 
 
What are the benefits and risks or side effects of remdesivir treatment? 
Remdesivir was recently shown to help people who are in the hospital with COVID-19 to get 
better faster than people who got a placebo.  You may be given remdesivir to treat your 
COVID-19 even if you do not join this study. If your doctor considers that remdesivir is not a 
suitable treatment for you, you can still join this study, and you will receive hIVIG or placebo 
without remdesivir. For example, remdesivir might be unsuitable for you if you have serious 
liver or kidney problems or an allergy to it. 
 
The most common side effects of remdesivir include abnormal liver function test results, 
abnormal kidney function test results, fever, elevated blood sugar, constipation, nausea, 
vomiting, decreased appetite, and headache. The abnormal liver and kidney function tests 
may last a few days or longer but came back to normal levels over time. 
 
People can have allergic reactions to drugs, including hives, trouble breathing, or other 
allergic responses. This is very rare but is also a possible effect of any drug. Allergic 
reactions may be severe or life-threatening.   
 
Some people may have some side effects after the infusion of remdesivir.  Other people 
may have no side effects.  You will be monitored closely during the infusions, and short-term 
medical care will be provided if there are side effects from the infusions that can be treated. 
 
What are the side effects of the other study procedures? 
 
As shown in the table of what will happen at each visit, you will have some extra blood 
drawn for laboratory testing and storage.  You will also have an extra swab of your nose and 
throat that would not be done if you are not in the study.  The risks and discomforts of these 


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extra blood draws and swab are no different than what you would have if they were 
performed as part of your regular hospital care for COVID-19. 
Additional information: 
Here is some additional information about the study that may help you make your choice 
about whether you want to be in the study. 
The US National Institutes of Health (NIH), an agency of the US Federal government, is 
paying for this study. Because public money is paying for the study, we are required to 
comply with all rules and regulations about research. We are doing this study according to 
internationally recognized standards of research as well as the laws of each country where 
the study is taking place.  
This study is taking place in several countries. We expect to enroll about 500 people around 
the world. 
You do not have to join this research study if you do not want to. If you choose to join the 
study, you can stop at any time by telling someone on the study team that you want to stop 
being in the study. If you choose not to join or to stop, your regular medical care will not 
change. 
If we get any new information that might change whether you want to join or stay in the 
study, we will tell you right away.  
Your study participation may be stopped without your consent if: 
 The groups overseeing the study decide the study should be stopped; 
 Your study team believes that being in the study is no longer in your best interests. 
 
If your participation is stopped, you will still get the usual care given at your hospital for 
COVID-19. 
If you do not want to be in this study, you will still get the usual care to treat COVID-19. 
However, you cannot get the hIVIG treatment, because it is experimental. 
 
What are the costs to you? 
We will give you the study treatment (hIVIG or placebo) at no cost. We will also give you 
remdesivir at no cost.  We will pay for all clinic visits, lab work, and other tests that are part 
of this study. 
 
 
 
THE NEXT PARAGRAPH IS FOR UNITED STATES SITES ONLY.  SITES IN 
OTHER COUNTRIES SHOULD DELETE THE NEXT PARAGRAPH. 


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You, your insurance company, or some other third-party payer must pay for all other 
medicines and hospital costs. 
 
 
 
Will you be paid to be in the study? 
We will compensate you for your time and inconvenience participating in the study. [Specific 
details to be completed by site.] 
What if you are hurt as part of this study? 
If you are hurt because of being in this study, [insert the name of the hospital/clinic] will treat 
your injury right away. You or your insurance will have to pay for this treatment. The study 
cannot pay you or pay for any care for study-related injuries or for your illness. 
 
 
 
What happens to the blood samples and respiratory swabs? 
We will send the blood and respiratory swab samples to a central laboratory in the United 
States of America. You and your doctor will not get the results of any tests done on these 
samples. 
The blood samples will measure how many COVID-19 antibodies are in your blood. This will 
tell us how your immune system responded to your COVID-19.  The nasal swab will 
measure how much virus you have in your respiratory system. 
Any blood samples that are left over after these tests will be stored at the central laboratory 
for as long as we are able to keep them. We hope to use these in the future to answer other 
questions about COVID-19. You and your doctor will not get any results from these tests. 
Some of the blood will also be given to the company that made the hIVIG to help them learn 
more about its effects. 
How do we protect your privacy? 
We will take every reasonable step to keep your health information private and to keep 
anyone from misusing it. 
SITES OUTSIDE THE UNITED STATES:  Please replace the paragraph 
above with language appropriate for your location 
If the above is not true for your site, i.e., if trial insurance covers such 
cost, please replace the above with appropriate language. 


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Your information (data) and samples will not be identified by name, or in any other way, in 
anything published about this study.  
We will do everything we can to keep your personal information private, but we cannot 
guarantee that nobody will get it. We may have to release your personal information if 
required by law. 
These people may see your medical and research information at your site: 
 the [insert the name of the hospital/clinic] ethics committee (institutional review board 
[IRB]); 
 the sponsor, other study research staff, and study monitors 
 US and other participating countries’ health regulatory agencies 
 the US National Institutes of Health which is funding the study 
They are committed to protecting your privacy. 
As the research staff at [inset the name of the hospital/clinic], we are required to make sure 
that people not involved with this study cannot see your research and medical information. 
We will keep your research files in a safe place and will handle your personal information 
very carefully.  
Your study data are sent electronically to the UMN in the US through a secure application. 
By signing this consent, you agree to have your data sent to UMN. No information that could 
directly identify you is sent to UMN. This is called “pseudonymized data.” Access to the data 
at UMN is limited through security measures, and no data breach or unauthorized access 
has ever occurred in this system. After the study is over, the data will be stored securely for 
the period required by law. 
Your study data will be shared with the regulators that oversee the studies, as required by 
law. Your study data will also be shared with the drug company that provides the hIVIG to 
help them develop the drug.  
UMN may share your data and specimens with other people who study COVID-19. UMN will 
remove any information that could possibly be used to identify you before sharing. This is 
called “anonymizing the data.” We will not ask you for additional consent for this sharing. 
UMN will only share data and specimens for research projects that are approved by the 
group that is conducting this study. 
This study has a Certificate of Confidentiality from the US Federal government. This means 
that UMN cannot share any data it has about you with national, state, or local civil, criminal, 
administrative, legislative, or other authorities unless you specifically allow us to share it.  
A description of this clinical trial will be available at http://www.ClinicalTrials.gov as required 
by U.S. law, and on the EudraCT website (https://eudract.ema.europa.eu/). These websites 
will not include your name or any other direct identifiers such as your contact information. 


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These websites will include a summary of the results of this research once the study has 
been completed. You can search either website at any time. 
[Note for US sites: The following brief HIPAA authorization is provided. Your site-specific 
consent should be modified to reflect the HIPAA authorization language requirements at 
your site.] 
To do this research, we will collect and use your personal data, as described above and in 
any HIPAA Authorization Form we have given you. Please tell us whether you agree to have 
us collect and use your personal data by placing your initials in front of your selection.


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____Yes, I agree to the collection and processing of my personal data. 
 
____No, I do not agree to the collection and processing of my personal data. 
It is your choice whether you allow us to collect and use your data. However, you will 
not be able to be in this research and have a chance to get the experimental treatment if 
we cannot collect and use your data. 
[The following section (up to “What if you have problems or questions?”) is for countries 
subject to the General Data Protection Regulation (GDPR) or similar legislation 
requiring this information. It should only be included in consents for sites subject to such 
legislation. It will vary from place to place whether it must be in this consent document, 
a separate consent document, or an information sheet that does not require signature. 
The amount of information provided may be reduced to meet the requirements of a 
particular country (e.g., not all countries/ECs require an enumeration of all of a data 
subject’s rights).] 
What are your rights regarding your data? 
The UMN is a public research university, and this study is funded primarily by a grant 
from the US Federal government. UMN and the study funding source require the 
sponsor (UMN) to follow regulations and policies that are meant to protect your privacy. 
UMN is also required to comply with the General Data Protection Regulation (GDPR), 
because it processes data obtained from people in Europe.  
 
There is no specific independent supervisory authority overseeing the processing of 
data in the US. Any complaint you might have about the use of your data would be 
made to your national data protection authority. 
 
The GDPR gives you additional rights which we would like to inform you about below. 
 
Right to Information 
You have the right to know what data about you is being processed. You can also get a 
free copy of this data provided. 
 
Right to Correction 
You have the right to correct any information about you which is incorrect or had 
become incorrect. 
 
Right to Erasure/Anonymization 
The sponsor is required under both EU and US law to retain data from research studies 
like this one for many years. However, you have the right to request that your personal 
data be completely anonymized. This is done by destroying the information at your 


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study center that links your identity to the pseudonymized data held by the sponsor. 
This means that no one would ever be able to link the data held by the sponsor to you 
personally.  
 
Right to Restriction of processing 
Under certain conditions, you have the right to demand processing restrictions, i.e. the 
data may then only be stored, not processed. You must apply for this. Please contact 
your study physician or the data protection officer of the study center if you want to do 
so. This right may be limited if the restriction would affect the reliability of the study 
results. 
 
Right to Data portability  
You have the right to receive the personal data that you have provided to the study 
center. This will allow you to request that this information be transmitted either to you or, 
where technically possible, to another agency designated by you. 
 
Right to Contradiction 
You have the right to object at any time to any specific decision or action taken to 
process your personal data. This right is limited for data that have already been 
processed and may be limited if your objection would affect the reliability of the study 
results. 
 
Right to Withdrawal of this consent 
You may withdraw your consent at any time with effect for future data collection. This 
withdrawal may be in an informal or verbal communication to your investigator. If you 
withdraw your consent this will not affect the lawfulness of the data processing that has 
been or will be done with data collected until you withdraw consent. Data already 
collected will be anonymized. 
 
If you would like to use one of these rights, please first contact the person responsible 
for the data collection at your study center: 
 
Person responsible for data collection at the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 
 
For concerns about data processing and compliance with data protection requirements 
you can also contact the data protection officer responsible for the study center: 
Data protection officer responsible for the study center: 
Name: 
 


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Address: 
 
Phone: 
 
Email 
 
 
In addition, you have the right to lodge a complaint with the competent authority if you 
believe that the processing of personal data concerning you is contrary to the GDPR: 
Data protection authority responsible for the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 
 
What if you have problems or questions? 
If you ever have questions about this study, or about the storage or use of your data or 
samples, or if you are hurt by being in the study, contact: 
 [name of the investigator or other study staff] 
 [telephone number of the above] 
 
If you have questions about your rights as a research participant, you can call: 
 [name or title of person on the ethics committee (IRB) or other organization 
appropriate for the site] 
 [telephone number of the above]  


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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE INSIGHT 013 STUDY 
(Inpatient Treatment with Anti-Coronavirus Immunoglobulin, ITAC)  
I have read the consent or have had it explained to me. I am satisfied that I understand 
the information. By signing this consent, I am stating that I want to join this study. I 
understand that I do not waive any of my legal rights as a study participant by signing 
this consent. I understand that I will receive a copy of the signed and dated consent. 
If you agree to be in this study, please sign below. 
 
________________________________________  
Date: _______________ 
Signature of participant 
 
________________________________________ 
Printed name of participant 
 
_____________________________________   
Date: _______________ 
Signature of investigator/designee 
 
_____________________________________ 
Printed name of investigator/designee 
 
FOR ADULTS NOT CAPABLE of GIVING CONSENT  
 
________________________________________ 
 Date: _______________ 
Signature of Legally Authorized Representative (LAR)  
 
_____________________________________ 
Printed name of LAR 
 


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____________________________________ 
Relationship of LAR to Participant 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under state or applicable local 
law) 
 
Witness to Consent Interview 
 
On the date given next to my signature, I witnessed the consent interview for the 
research study named above in this document. I attest that the information in this 
consent form was explained to the subject, and the subject indicated that his/her 
questions and concerns were adequately addressed. 
_______________________________________ 
Date: _______________ 
Signature of witness 
 
________________________________________ 
Printed name of witness 
 
NOTE: This consent form, with the original signatures, MUST be retained on file 
by the Investigator of Record. A copy of the signed and dated consent must be 
given to the participant. A copy should be placed in the participant’s medical 
record, if applicable.  
If no-touch / electronic consent is used, the participant must be provided with a 
copy of the consent in a manner appropriate to the method used to obtain it.  A 
record of the act of consent must also be appropriately retained in the 
participant’s medical record. 


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APPENDIX B 
SCHEDULE OF ASSESSMENTS 
 
Screen 
or Day 0 
Day 0 
Follow-up Study Day 
 Shaded columns denote in-person visits 
Day 
−1/01 
01 
1 
2 
3 
4 
5 
6 
7 
14 
28 
Acceptable deviation from day 
0 
0 
0 
0 
0 
0 
0 
0 
0 
+3 
+4 
ELIGIBILITY & BASELINE DATA 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
Baseline medical history (including 
day of illness from symptom onset) 
X 
 
 
 
 
 
 
 
 
 
 
Baseline medications 
X 
 
 
 
 
 
 
 
 
 
 
Symptom-directed  
physical exam 
X 
 
 
 
 
 
 
 
 
 
 
Review SARS-CoV-2 test results 
X 
 
 
 
 
 
 
 
 
 
 
Mid-turbinate swab for central 
SARS-CoV-2 viral load testing 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test or other 
documentation of pregnancy status 
X 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Study Drug/Placebo Administration 
 
X 
 
 
 
 
 
 
 
 
 
Assess infusion completion and 
AEs 
 
X 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment for ordinal 
outcomes2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs for NEW score 
assessment3 
X 
 
 
 
X 
 
 
 
 
 
 
Hospitalization status 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Interim medical history 
 
 
 
 
 
 
 
 
X 
X 
X 
Interim medications 
 
 
 
 
 
 
 
 
X 
 
 
Borg dyspnea scale 
X 
 
 
 
 
 
 
 
X 
 
 
Clinical adverse events of any 
grade (present on day of 
assessment) 
 
X 
X 
 
X 
 
 
 
X 
 
X 
Incident grade 3 and 4 adverse 
events (all through Day 7) 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
Local laboratory testing 
X 
 
 
 
 
 
 
 
X 
 
 


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Research sample storage (plasma 
and serum) and central testing for 
immunoglobulin levels and 
neutralizing antibody titers4 
X 
 
X 
X 
X 
 
 
 
X 
 
X 
SAEs and unanticipated problems 
Report as they occur 
Deaths 
Report as they occur 
Hospitalization Summary 
Report upon hospital discharge 
1 Screening and randomization can be done in same session. 
2 Collected every day for inpatients and at Days 7, 14 and 28 for outpatients. 
3 Collected while hospitalized only 
4Consenting participants at selected sites will also be seen at Day 90 (+10 days) to obtain a blood sample 
for central testing and storage  


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APPENDIX C 
INSIGHT 013 PROTOCOL TEAM 
To oversee the implementation of this treatment study, membership on the protocol 
team will include: 
 Protocol co-chair(s) 
 NIAID, Division of Clinical Research representatives 
 INSIGHT University of Minnesota representatives 
 INSIGHT International Coordinating Center representatives 
 Collaborating laboratory representatives 
 Collaborating hIVIG manufacturers 
 Site investigators 
 Study biostatisticians  
 Community representative 
 
A core team consisting of the co-chair(s), ICC leaders, NIAID representatives, study 
statisticians and other representatives and the INSIGHT Principal Investigator (PI) will also 
regularly convene to review study progress and address study conduct and administrative 
issues that arise. 


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APPENDIX D 
REFERENCES ON THE INSIGHT WEBSITE 
 
The INSIGHT website (www.insight-trials.org) will maintain updated links to the 
following documents referenced in the INSIGHT 013 protocol and to other information 
pertinent to the study: 
 
 
DAIDS toxicity table: (https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-
event-grading-tables) 
 
 
INSIGHT Publications and Presentations Policy 
((http://insight.ccbr.umn.edu/resources/P&P_policy.pdf) 
 
 CDC and ECDC guidance on how to handle infection control measures 
(https://www.cdc.gov/sars/guidance/i-infection/healthcare.html) and 
https://www.ecdc.europa.eu/en/publications-data/infection-prevention-and-control-
and-preparedness-covid-19-healthcare-settings)). 
 
 Treatment guidelines from NIH and WHO 
(https://www.covid19treatmentguidelines.nih.gov/, 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-
guidance/patient-management, https://www.idsociety.org/practice-guideline/covid-
19-guideline-treatment-and-management/, and https://www.ersnet.org/covid-19-
guidelines-and-recommendations-directory)  


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APPENDIX E 
LIST OF ACRONYMS 
µL 
microliter 
ADE 
Antibody-dependent enhancement 
AE 
adverse event 
ACTT 
Adaptive COVID-19 Treatment Trial  
ALT 
alanine aminotransferase 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
B19V 
parvovirus B19 
BMI 
body mass index 
CCP 
convalescent plasma containing COVID-19 antibodies  
CDC 
Centers for Disease Control and Prevention (US) 
CI 
confidence interval 
CMV 
cytomegalovirus 
COVID-19 
coronavirus disease 2019  
CVA 
cerebrovascular accident 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board  
DVT 
deep vein thrombosis 
EC 
ethics committee 
ECMO 
extra-corporeal membrane oxygenation  
eGFR 
estimated glomerular filtration rate 
EU 
European Union 
FDA 
US Food and Drug Administration  
g 
gram(s) 
 
GCP 
Good Clinical Practice 


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GDPR 
General Data Protection Regulation 
HAV 
hepatitis A virus 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hIVIG 
hyperimmune intravenous immunoglobulin 
HR 
hazard ratio 
IB 
investigator’s brochure 
ICC 
International Coordinating Center 
ICH 
 The International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use 
ICU 
 
intensive care unit 
IEC 
Institutional Ethics Committee 
IgA, IgE, IgG, IgM 
immunoglobulin A, E, G, M 
IL-6 
interleukin 6 
INSIGHT 
International Network for Strategic Initiatives in Global HIV Trials 
IQR 
interquartile range 
IRB 
Institutional Review Board 
IVIG 
intravenous immunoglobulin 
kg 
kilogram 
mg 
milligram 
MI 
myocardial infarction 
mL 
milliliter 
mmol 
millimole(s) 
NEWS 
National Early Warning Score 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH (US) 
NIH 
National Institutes of Health (US) 
nm 
nanometer(s) 


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OHRP 
Office for Human Research Protections (US) 
OR 
odds ratio 
PCR 
polymerase chain reaction 
PHI 
personal health information 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS 
severe acute respiratory syndrome 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TACO 
transfusion-associated circulatory overload  
TRALI 
transfusion-related acute lung injury 
UMN 
University of Minnesota 
UP 
unanticipated problem 
US 
United States of America 
WHO 
World Health Organization 
WNV 
West Nile virus 
 
 


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APPENDIX F 
CLINICAL CATEGORICAL DEFINITIONS FOR 
ORDINAL OUTCOME 
Each participant is categorized in the highest applicable category. 
Ordinal 
Category 
Categorical 
Description 
Categorical Definition* 
7 
Death 
Death 
6 
End-organ failure 
Currently requiring invasive assisted ventilation, extracorporeal 
membrane oxygenation, mechanical circulatory support, 
vasopressor therapy or renal replacement therapy 
5 
Life-threatening end-
organ dysfunction  
Currently requiring non-invasive assisted ventilation or high-
flow oxygen or 
Extra-pulmonary: 
Symptoms and signs of an acute stroke (NIHSS > 14)   
4 
Serious end-organ 
dysfunction  
Currently requiring supplemental oxygen (≥ 4 liters/min, or ≥ 4 
liters/min above premorbid requirements**) but not high-flow 
oxygen or 
Any of symptoms or signs of the following extra-pulmonary 
conditions: 
Stroke (NIH Stroke Scale/Score [NIHSS] ≤ 14), meningitis, 
encephalitis, or myelitis, myocardial infarction, myocarditis, 
pericarditis, or New York Heart Association Class III or IV 
congestive heart failure, arterial or deep venous thrombosis 
including pulmonary embolism.  
3 
Moderate end-organ 
dysfunction 
Requiring supplemental oxygen < 4 liters/min, or < 4 liters/min 
above premorbid requirements** 
2 
Limiting symptoms due 
to COVID-19 
Symptomatic and currently unable to independently undertake 
usual activities 
1 
No limiting symptoms 
due to COVID-19 
Can independently undertake usual activities with minimal or no 
symptoms 
*Continued hospitalization or presence in a particular category of inpatient facility (e.g. intensive care or 
high dependency) is not used to divide these categories, as indication for continued hospitalization 
among recovering COVID patients is intrinsically subjective, in part determined by social and financial 
factors, and varies markedly across the globe.  
** Premorbid requirement refers to requirements prior to the development of COVID-19, for example in 
patients with chronic obstructive pulmonary disease, other chronic pulmonary diseases, or oxygen 
requirements related to altitude. 


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APPENDIX G 
NATIONAL EARLY WARNING SCORE (NEWS)  
Criteria 
Point Value 
Respiratory Rate (breaths per minute) 
≤8 
+3 
9-11 
+1 
12-20 
0 
21-24 
+2 
≥25 
+3 
Oxygen Saturation (%) 
≤91 
+3 
92-93 
+2 
94-95 
+1 
≥96 
0 
Any Supplemental Oxygen 
Yes 
+2 
No 
0 
Temperature in °C (°F) 
≤35.0 (95) 
+3 
35.1-36.0 (95.1-96.8) 
+1 
36.1-38.0 (96.9-100.4) 
0 
38.1-39.0 (100.5-102.2) 
+1 
≥39.1 (≥102.3) 
+2 
Systolic BP 
≤90 
+3 
91-100 
+2 
101-110 
+1 
111-219 
0 
≥220 
+3 
Heart Rate (beats per minute) 


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≤40 
+3 
41-50 
+1 
51-90 
0 
91-110 
+1 
111-130 
+2 
≥131 
+3 
AVPU 
A 
0 
V, P, or U 
+3 
AVPU - Alert, Voice, Pain, Unresponsive. 
 


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