Conditions: Covid19
Keywords: D-dimer Thromboprophylaxis Anti-coagulant Thrombotic Events Coagulation Inflammation Heparin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 160
Healthy volunteers: no

Brief summary:
Sequential randomized, multicenter, active comparator study to evaluate the hypothesis that rNAPc2 (AB201), a novel, potent and highly selective tissue factor inhibitor with anticoagulant, anti-inflammatory and potential antiviral properties, shortens time to recovery compared to heparin in hospitalized patients with COVID-19 and elevated D-dimer levels.

Detailed description:
Sequential randomized, multicenter, active comparator study to evaluate the hypothesis that rNAPc2, a novel, potent and highly selective tissue factor inhibitor with anticoagulant, anti-inflammatory and potential antiviral properties, shortens time to recovery compared to heparin in hospitalized patients with COVID-19 and elevated D-dimer levels. Study participants and Clinical Endpoint Committee (CEC) members assessing the clinical endpoints will be blinded to treatment assignment. The protocol comprises sequential Phase 2b and Phase 3 studies. Analysis of Phase 2b data could lead to study discontinuation, adjustment of eligibility criteria or sample size, and will inform the rNAPc2 dose level to be studied in Phase 3.

Arms:
arm 1: loading dose of 7.5 μg/kg SC on Day 1 followed by 5 μg/kg SC on Days 3 and 5 arm 2: loading dose of 5 ug/kg SC on Day 1 followed by 3 ug/kg SC on Days 3 and 5 arm 3: heparin at either prophylactic or therapeutic doses per Standard of Care at Institution

Interventions: intervention 1: rNAPc2 intervention 2: Heparin
Intervention descriptions: intervention 1: two dose levels of rNAPc2 intervention 2: standard of care heparin per institution (therapeutic or prophylactic regimen)

Protocol document:
ICF_002.pdf: 
ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 1 of 11 
 
 
INFORMED CONSENT FORM 
For Subject Participation in a Clinical Research Study 
 
Principal Investigator:  
Site Name: 
Address: 
24-Hour Site Phone Number:  
IRB/Ethics Committee Protocol #: 
Sponsor study #: NAPc-201/301 
Phase 2b/3 (Phase 2b consent only) 
Version Date: 07 July 2021 
 
Study Title: Assessing Safety, Hospitalization and Efficacy of rNAPc2 
in COVID-19 (ASPEN-COVID-19) 
 
 
Some people in this study may have a medical condition or a disability that does not allow them 
to make important decisions for themselves. If you have been asked to decide for someone else 
whether they should be in this study, please read this consent form carefully. You will be asked 
to sign this form if you agree that they should be in this study.  
 
In this form, we use the words “you” and “your.” If you are reading this form and deciding for 
someone else, the words ‘you’ and ‘your’ refer to that person, not to you. 
 
You are being asked to be in a clinical research study. This form provides you with information 
about the study. A member of the research team will describe this study to you and answer all of 
your questions. Please read the information below and ask questions about anything you don’t 
understand before deciding whether or not to participate. Once you understand the study and the 
other options that are available, you will be asked to sign this form if you wish to be in this 
study. You will be given a signed copy of this form to keep. 
 
Why is this study being done? 
People with COVID-19 infection (caused by the SARS-CoV-2 virus) are at high risk for 
problems caused by blood clotting too easily. When your blood clots too easily, it can form clots 
inside blood vessels that keep blood from reaching important body parts. These blood clots can 
be dangerous and even life-threatening. This study plans to learn more about the effects of 
rNAPc2, an investigational drug (study drug) that makes blood thinner and keeps it from clotting 
easily in people in the hospital with COVID-19 infection. This study will compare the study drug 
to heparin, a standard blood thinning medicine, to see if the study drug decreases the measures of 
blood clotting risk, health problems from blood clotting and the time to recover from COVID-19 
infection. 
 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 2 of 11 
 
 
You are being asked to be in this clinical research study because you are in the hospital due to 
COVID-19 infection and your blood tests show that you have an increased risk of blood clotting. 
 
How many subjects will take part in the study? 
About 160 people at approximately 20 international sites will be in this study.  
 
How long will I be in the study? 
Your participation will last up to 40 days.  
 
What happens if I join this study? 
If you join the study, the study doctor will first look at your medical records to make sure your 
blood tests show a high risk for blood clotting, interview you and conduct a physical exam to 
make sure you are eligible to continue in the study. 
 
If you are eligible to continue, you will be assigned to one of two different groups of research 
subjects. To decide which group you will be in, we will use a method of chance. This method is 
like flipping a coin. You will have an equal chance of being assigned to one group or the other 
group, and each group will get slightly different care: 
 
One group will receive the study drug as an injection just under the skin. If you are in this 
group, you will be assigned to receive one of two doses of the study drug. This decision will also 
be made by chance, like flipping a coin. 
 
The other group will receive heparin, a blood thinning medicine used as standard of care, as an 
injection just under the skin or through an IV line, as determined by the usual practice at your 
hospital. 
 
You will be given your assigned study drug or heparin while you are in the hospital. The 
different study groups have different dose schedules, and you might not receive a dose every day 
you are in the hospital. 
 
You will not be told which treatment group you are in. Your study doctor will know. In research 
studies treatment assignment information is usually kept secret to avoid the influence of that 
knowledge on the study results.However, we can give this information out if you have medical 
emergency. 
 
If an emergency arises, make sure you tell the emergency staff about this study. They can contact 
us, and we will give them all relevant information. 
 
While you are in the hospital, we will look at your medical records to collect information about 
your health. 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 3 of 11 
 
 
 
Schedule of activities for the clinical research study:  
 
Activity 
Screening 
Day -7 to 1  
Baseline 
Day 1 
Day 2 
(24h ± 
2h) 
Day 
3±1d 
Day 
5±1d 
Day 
8±1d 
Day of 
hospital 
discharge 
 
Day 
30±3d 
Informed Consent 
X 
 
 
 
 
 
 
 
Assess Eligibility 
X 
X 
 
 
 
 
 
 
Study Drug/Heparin 
 
 
* 
* 
* 
Medical History,  
Physical Exam, Vital Signs, 
Height and Weight 
 
X 
 
 
 
 
 
 
Review Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Draw 
X 
X 
X 
X 
 
X** 
X** 
X 
Urine Pregnancy Test, if 
applicable 
 
X 
 
 
 
 
 
 
Health Status Questions 
 
X 
X 
X 
X 
X 
X 
X 
*After Day 8, subjects assigned study drug may begin standard of care medication to prevent 
blood clotting, while heparin subjects will continue to receive treatment at the study doctor’s 
discretion. 
**Blood draw will be performed at either Day 8 or Day of Discharge for subjects who leave the 
hospital prior to the Day 8 visit. 
 
Health Status Questions: You will be asked questions about your health, and about any changes 
in your health since your last assessment. For example, whether you visited any hospitals or 
health care providers, whether you needed oxygen or had any problems, or whether you needed 
any assistance with your daily activities. 
 
Blood draws: Blood will be drawn on Days 1, 2, 3, 8 and 30 after you enter the study. Some of 
these blood draws will be done for the research and are not part of your hospital care. Blood will 
be drawn to check your general health and risk for blood clotting; and for research purposes 
including how much study drug is in your blood, certain measures of blood clotting, and whether 
the study drug causes antibody production. Antibodies are proteins that are part of the body’s 
natural defense system, called the immune system. The immune system can produce antibodies 
to remove unwanted substances such as bacteria, viruses or drugs. In this study we are interested 
in knowing whether the body produces antibodies related to the study drug. In addition, optional 
samples are requested which will be retained for future research use. If you leave the hospital 
before these blood draw days, your study doctor will arrange a way to collect this blood. This 
might mean you will be asked to come to the hospital from home on those days to have your 
blood drawn.  
 
If you are no longer in the hospital at Day 30, your study doctor will still check on your health 
and draw your blood. You might be asked to come to the hospital to see the study doctor for a 
visit, or the visit might be conducted over the phone. 
 
It is important that we monitor your health through Day 30. You will be receiving blood thinning 
medication as part of this study, and this information will help us monitor the safety and effects 
of these treatments. If we are not able to reach you by phone for the required follow up visit, we 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 4 of 11 
 
 
will use other methods to monitor your health. These methods might include contacting you 
through public records or social media, looking at your medical records, speaking with your 
primary health care provider, or speaking with a family member that you identify as a close 
contact. 
 
What are the possible discomforts or risks? 
Discomforts you may experience while in this study include the following: 
 
Bleeding. Because the study drug and heparin are both designed to thin your blood, bleeding is 
the main risk. Bleeding can be minor, like bruising, it can lead to low red blood cell counts, or it 
can be severe and life-threatening. Bleeding risk can also be further increased if other drugs that 
thin your blood are given at the same time. Being on these drugs can also increase the risk of 
bleeding from other medical procedures you might need. It is important to tell your study doctor 
about any bleeding you notice. 
 
Additional risks of the study drug:  
• Fever 
• Allergic reaction which could be severe or life-threatening 
• Immune reaction. It is possible that your immune system will make antibodies to attack 
the study drug, which could make the study drug less effective at thinning your blood or 
cause allergic reactions. 
 
Additional risks of heparin medications (standard blood thinner):  
• Low platelets. Heparin can cause your blood platelet levels to fall. Platelets help the 
blood clot. Low platelets can increase the chance of bleeding, but sometimes these low 
levels also are caused by increased clotting. Platelet levels usually go back to normal 
after stopping heparin. 
• Allergic reaction which could be severe or life-threatening 
• Immune reaction. It is possible that your immune system will make antibodies to attack 
the drug, which could make this drug less effective at thinning your blood. 
 
Blood Draws 
In this study we will collect between 0.3 and 2.6 tablespoons (5.4 to 38.9 ml) of blood from you 
during each blood draw. We will get blood by putting a needle into one of your veins and letting 
the blood flow into a glass tube. We will draw the blood through your existing intravenous (IV) 
line when possible. You may feel some pain when the needle goes into your vein. A day or two 
later, you may have a small bruise where the needle went under the skin. 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 5 of 11 
 
 
 
Other Risks 
There is a risk that people outside of the research team will see your research information.  We 
will do all that we can to protect your information, but it can not be guaranteed. 
 
You cannot participate in this study if you are pregnant. If you are a woman who can become 
pregnant, you must have a negative urine pregnancy test before starting study drug and must be 
willing to avoid sex or use an effective method of contraception for the duration of the study. If 
you become pregnant, the treatment or procedures involved in the study may involve risks to the 
embryo or fetus, which are not currently known. 
 
Male patients must agree to avoid partner pregnancy and sperm donation for at least 90 days 
after last dose of study medication. 
 
The study may include risks that are unknown at this time.  
 
Measures Taken to Minimize Risks, Discomforts, and Inconveniences 
 
You will be closely monitored to identify and minimize any side effects throughout the clinical 
research study.  The study team will tell you about new findings or other information that may 
affect your health, welfare, or willingness to stay in the study. 
 
What are my responsibilities? 
By taking part in this clinical research study you agree to follow the study schedule and 
procedures. You agree to follow-up with your study doctor or study staff at the required times.  
You agree to report any signs of bleeding and any changes in health to your doctor or study staff. 
 
What are the possible benefits of the study? 
This study is designed for the researcher to learn more about the effects of the study drug in 
people with COVID-19 infection. However, there is no guarantee that your health will improve if 
you join this study. Also, there could be risks to being in this study. These risks are described in 
the section describing the discomforts or risks. 
 
Are there alternative treatments?  
There may be other ways of treating the high risk of blood clotting associated with COVID-19. 
These other ways include blood thinning medications which are currently approved and available 
outside of this study. You could also choose to get no treatment at all. 
 
You should talk to your doctor about your choices. Make sure you understand all of your choices 
before you decide to participate in this study. You may leave this study at any time and still have 
these other choices available to you.  
 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 6 of 11 
 
 
Who is paying for this study?  
This research is being sponsored by ARCA biopharma, Inc. (“Sponsor”), the manufacturer of the 
study drug. 
 
Will I be paid for being in the study?   
You will not be paid to be in the study. [Ex-US Countries – if subjects’ transportation will be 
paid for follow up clinic visits for blood collection or if they’ll be compensated for visits, specify 
here] 
 
Will I have to pay for anything? 
There are some medical treatments that you would have to get for your condition whether you 
were in this study or not. You will have to pay for these. There are other medical treatments that 
you will get because you are in this clinical research study. The Sponsor will pay for those. 
Those medical treatments are the study drug, and the blood tests that are for research purposes 
only. [For Ex-US Countries update per the agreement with the Sponsor.]  
 
Is my participation voluntary? 
Taking part in this study is voluntary.  You have the right to choose not to participate in this 
study.  If you choose to participate, you have the right to stop at any time.  If you refuse or 
decide to withdraw later, you will not lose any benefits or rights to which you are entitled.  
 
If you leave this study, you will still receive your normal medical care.  The only medical care 
that you will lose is the medical care you are getting as part of this study.  You might be able to 
get that same kind of medical care outside of the study.  Ask your study doctor.  
 
Can I be removed from this study?  
The study doctor may decide to stop your participation without your permission if the study 
doctor thinks that being in the study may cause you harm, or for any other reason. Also, the 
Sponsor may stop the study at any time. 
  
What happens if I am injured or hurt during the study?  
If you have an injury while you are in this study, you should call <insert name> immediately.  
[His/Her] phone number is <insert phone number>.  
 
If you are injured as a direct result of the study drug or any properly performed procedure 
(carried out according to the protocol), the Sponsor will pay for reasonable costs related to your 
treatment that is not covered by your health insurance, if your injury or illness is “research 
related”. The term “research-related injury” means physical injury caused by drugs or procedures 
required by the study that are different from the medical treatment you would have received if you 
had not participated in the clinical study. The Sponsor and the study doctor will determine if your 
injury or illness is research-related. Treatment must be authorized by the study doctor except in 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 7 of 11 
 
 
the event of an emergency (in which case the study doctor should be notified as soon as 
possible). Payment for lost wages, disability, discomfort, etc., due to injury is not available. 
 
Who do I call if I have questions? 
The researcher carrying out this clinical research study is <investigator name>. You may ask any 
questions you have now. If you have questions, concerns, or complaints later, you may call 
<investigator name> at <investigator phone number>. You will be given a copy of this form to 
keep. 
 
You may have questions about your rights as someone in this clinical research study. You can 
call <investigator name> with questions.  You can also call the responsible Institutional Review 
Board /Independent Ethics Committee.  You can call them at <IRB phone number>. 
 
A description of this clinical research study will be available on https://clinicaltrials.gov/, as 
required by U.S. Law. This website will not include information that can identify you. At most, 
the website will include a summary of the results. You can search this website at any time. 
 
Who will see my research information? 
The <institution> and its affiliated health systems have rules to protect information about you. 
Federal and state laws including the Health Insurance Portability and Accountability Act 
(HIPAA) also protect your privacy. [Ex-US Countries– replace with appropriate language] This 
part of the consent form tells you what information about you may be collected in this study and 
who might see or use it. 
 
The institutions involved in this study include: (list only local institutions) Institution/Covered 
Entity name 
 
We cannot do this study without your permission to see, use and give out your information.  You 
do not have to give us this permission.  If you do not agree, then you may not join this study.   
 
We will see, use and disclose your information only as described in this form or other privacy 
notices provided to you; however, people outside the [local institution] and its affiliate hospitals 
may not be covered by this obligation. 
 
We will do everything we can to maintain the confidentiality of your personal information, but 
confidentiality cannot be guaranteed.  
 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 8 of 11 
 
 
The use and disclosure of your information has no time limit.  You can cancel your permission to 
use and disclose your information at any time by writing to the study’s Principal Investigator, at 
the name and address listed below.  If you do cancel your permission to use and disclose your 
information, your part in this study will end and no further information about you will be 
collected.  Your cancellation would not affect information already collected in this study.   
 
PI Name 
Mailing Address 
 
Both the research records that identify you and the consent form signed by you may be looked at 
by others who have a legal right to see that information, such as: 
• Federal offices such as the Food and Drug Administration (FDA) and the Office of 
Human Research Protections (OHRP) that protect research subjects like you 
• The Institutional Review Board/Independent Ethics Committee that is responsible for 
overseeing this research 
• The study doctor and the rest of the study team 
• ARCA biopharma, Inc., who is the company paying for this clinical research study, and 
companies working for ARCA biopharma, Inc., to help run the study 
• Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow all of 
the rules for research 
• <add any other groups or entities that are applicable; this section is only for entities that 
have the legal right to audit study records> 
 
By signing this form, you are allowing the Sponsor, it’s related companies or independent 
companies monitoring the clinical research study and auditing results on behalf of the Sponsor, 
to have access to your original medical records for the purpose of collecting data, verifying the 
data are correct and checking that the clinical research study is conducted properly without 
violating the confidentiality of your records to the extent permitted by applicable laws and 
regulations. In addition, the  Sponsor’s employees, its related companies and other companies 
working with the Sponsor, the study doctor and study staff, the ethics committee and others 
responsible for overseeing research studies, and domestic and foreign regulatory authorities will 
have access to your study data in a form that does not mention your name in order to complete 
the research including the processing, analyzing, using, and storing data. 
 
We might talk about this clinical research study at meetings.  We might also print the results of 
this clinical research study in relevant journals.  But we will always keep the names of the 
research subjects, like you, private.  
 
You have the right to request access to your personal health information from the study doctor. 
To ensure proper evaluation of test results, your access to these study results may not be allowed 
until after the study is completed. 
You have the right to request correction of data if they are inaccurate or incomplete. 
 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 9 of 11 
 
 
The study doctor or staff acting on behalf of the study doctor, will use your information for 
the research outlined in this consent form. They will also make all or some of the following 
health information about you collected in this study available to: ARCA biopharma, Inc. 
(contact phone number 720-940-2100) and entities working for ARCA biopharma Inc., including 
University of Colorado Anschutz Medical Center, and CPC Clinical Research, an Academic 
Research Organization helping to conduct the clinical research study. 
Information about you that will be seen, collected, used and disclosed in this study, as 
allowed by local regulations: 
• Name and Demographic Information (age, sex, race, ethnicity, address, phone number, 
etc.) 
• Portions of your previous and current medical records that are relevant to this study, 
including but not limited to diagnosis(es), History and Physical, laboratory or tissue 
studies, radiology studies, procedure results 
• Research Visit and Research Test records 
• Blood samples and the data associated with the samples  
 
What happens to Data and Specimens that are collected in this clinical research study? 
Scientists at ARCA biopharma, Inc. and the University of Colorado Anschutz Medical Center 
work to find the causes and cures of disease.  The data and specimens collected from you during 
this clinical research study are important to this study and to future research.  If you join this 
study: 
• The data and other specimens given by you to the study doctor for this research no longer 
belong to you.   
• Both the study doctor and the Sponsor of this research may study your data and other 
specimens collected from you. 
• If data or other specimens are in a form that identifies you, the University or the health 
systems involved in this study may use them for future research only with your consent 
or Institutional Review Board approval. 
• Any product or idea created by the researchers working on this study will not belong to 
you. 
• There is no plan for you to receive any financial benefit from the creation, use or sale of 
such a product or idea.  
 
Optional Consent for Data and Sample Banking for Future Research 
 
ARCA biopharma, Inc., would like to keep some of the data and blood that is taken during the 
clinical research study to be used for other tests. If you agree, the data and samples will be kept 
and may be used in future research to learn more about COVID-19 or the study drug.  
• The research that is done with your data and samples is not designed to specifically help 
you. Reports about research done with your data and samples will not be given to you or 
your doctor. These reports will not be put in your health records. The research using your 
data and samples will not affect your care.  
• The choice to let the Sponsor keep the data and samples for future research is up to you. No 
matter what you decide to do, it will not affect the care that you will receive as part of the 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 10 of 11 
 
 
study. If you decide now that your data and samples can be kept for research, you can 
change your mind at any time and contact your study doctor to let him or her know that you 
do not want the Sponsor to use your data and samples any longer, and they will no longer be 
used for research. Otherwise, they may be kept until they are used up, or until the Sponsor 
decides to destroy them.  
• Your data and samples might be given to other researchers in the future. When this happens, 
the Sponsor will not give them your name, address, phone number or any other information 
that will let the researchers know who you are.  
• Data and samples will be used for genetic research (about diseases that are passed on in 
families). Even if your data and samples are used for this kind of research, the results will 
not be told to you and will not be put in your health records.  
• We may share data from our research with other researchers or data banks. One such data 
bank is called dbGAP, which collects genetic and other data and is sponsored by the 
National Institutes of Health (USA). By sharing data in data banks like this, we can make 
our discoveries more accessible to other researchers. Information which directly identifies 
you will not be sent to these data banks. Because your genetic information is unique to you, 
there is a small risk that someone could connect the information back to you. Also, genetic 
research and broadly sharing data may involve risks to you or people like yourself that are 
unknown at this time. 
• Your data and samples will only be used for research and will not be sold. The research 
done with your data and samples may help to develop new products in the future, but there 
is no plan for you to be paid.  
 
The possible benefits of research from your data and samples include learning more about what 
causes COVID-19 and other diseases, how to prevent them and how to treat them. The greatest 
risk to you is the release of your private information. The Sponsor will protect your records so 
that your medical information related to the study will be kept private. The chance that this 
information will be given to someone else is very small. There will be no cost to you for any data 
or sample collection and storage by the Sponsor. Please read each sentence below and think 
about your choice.  
 
After reading each sentence, write your initials on the line next to “Yes” or “No.” If you have 
questions, please talk to your doctor or nurse. No matter what you decide to do about the storage 
and future use of your data and samples, you may still participate in the study. 
 
1. I give my permission for my data and blood samples to be kept by ARCA biopharma, Inc., 
for use in future research to learn more about how to prevent, detect, or treat COVID-19 
and how people respond to the study drug:     
 Yes_______              No_________ 
 
2. I give my permission for my data, blood and tissue samples to be used for research about 
other health problems (for example, causes of heart disease, osteoporosis, diabetes):     
Yes_______ 
 
No_________ 
 
 


ASPEN NAPc-201/301 Phase 2b ICF V8 20210707 FINAL     CONFIDENTIAL          Page 11 of 11 
 
 
 
Agreement to be in this study and use my data 
 
I have read this document about the clinical research study or it was read to me.  I understand the 
possible risks and benefits of this study and my responsibilities.  I understand and authorize the 
access, use and disclosure of my information as stated in this form.  I know that being in this 
study is voluntary.  I choose to be in this study.  
 
 
Signature of Subject:  
 
 
 
 
 
Date: ____________  
Subject’s Printed Name: 
 
 
 
 
 
 
 
Signature of Legally Authorized Representative (LAR) OR Proxy Decision Maker (if 
applicable):  
________________________________ 
    Date: ___________ 
LAR’s OR Proxy Decision Maker’s Printed Name:  
 
 
 
___________ 
(Select one: □ Legally Authorized Representative OR □ Proxy Decision Maker) 
 
Signature of Person Obtaining Consent: _______________________________ 
Date:   
 
 
Printed Name of Person Obtaining Consent: ________________________________ 
 
 
 
---------------------------------------Use the following only if applicable-------------------------------- 
 
Witness’s Signature: ______________________________________ 
 Date:   
 
 
Witness’s Printed Name: 
 
 
 
 
 
 
 
_ 
Witness of signature  
 
 
Witness of consent process 
 

Prot_000.pdf: 
 
 
 
 
 
Assessing Safety, Hospitalization and Efficacy of rNAPc2 
in COVID-19 (ASPEN-COVID-19) 
Subtitle: A Phase 2b Adaptive Study that Assesses the Efficacy in 
D-dimer Reduction and Safety of rNAPc2 Regimens versus Heparin in 
Hospitalized COVID-19 Patients 
 
 
 
Protocol Number: NAPc-201/301 
Principal Investigator: Marc Bonaca, MD, MPH 
Sponsor: ARCA biopharma, Inc. 
Version Number:  6.0 
07 July 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information provided herein contains Company trade secrets, commercial or financial information that the Company customarily holds close and treats as 
confidential. The information is being provided under the assurance that the recipient will maintain the confidentiality of the information under applicable statutes, 
regulations, rules, protective orders or otherwise. 
 


Protocol NAPc-201/301 
Version 6.0 Final 
 
07 July 2021 
CONFIDENTIAL 
 
Page 2 of 65 
Summary of Changes: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Protocol V2.00 31Aug2020 
Synopsis, 
Section 4  
 
 
 
 
• 
Sequential Phase 2/3 design with 
Phase 3 powered for standalone 
analysis 
• 
2nd dose level of rNAPc2 added to 
Phase 2b 
• 
Manage distribution of subjects to 
prophylactic vs therapeutic dose 
heparin in Phase 2b 
• 
Local clinical laboratory 
assessments, research samples 
adjusted 
• 
Day 15 visit removed  
• 
Enable unblinding, in depth analysis 
and possible amendments to Phase 
3 portion of the protocol  
• 
Assess dose-response for safety and 
biomarker effects in target 
population; inform dose selection 
for Phase 3 
• 
Facilitate assessment of heparin 
regimens vs rNAPc2 
• 
Safety 
• 
Operational Considerations 
Section 3 
• 
Clarify Phase 2b objective & 
endpoints 
• 
Clarity 
Sectionssections 
4.1, 6.3 
• 
Separate stratification for 
remdesivir and for other therapies 
with demonstrated efficacy in 
COVID-19 
• 
Distribute concurrent treatments 
among treatment groups 
Section 5 
• 
Exclusion criteria: platelet count, 
eGFR, bilirubin cutoffs added 
• 
Safety 
Section 6 
• 
Recommended low molecular 
weight heparin (LMWH) specified 
• 
Reduce variability 
Section 9 
• 
Statistical detail provided  
• 
Clarity 
Protocol V3.00 16Sep2020 
All 
• 
Minor administrative updates  
• 
Administrative/improve clarity 
Section 1.2 
• 
Updated schema to reflect all 
protocol v2.00 changes 
• 
Moved schedule of activities (SoA) 
to section 8.1.1 
• 
Administrative/improve clarity 
Section 3 
• 
Separated phase 2b and phase 3 
safety objectives in the table 
• 
Administrative/improve clarity 
Section 6.3 
• 
Updated blinding information 
(participants and CEC will be 
blinded) 
• 
Consistency throughout protocol 


Protocol NAPc-201/301 
Version 6.0 Final 
 
07 July 2021 
CONFIDENTIAL 
 
Page 3 of 65 
Section 8.1.1 
• 
SoA moved here and updated 
• 
Consistency with protocol v2.00 
changes and improve clarity 
Section 8.1.2 
• 
Section added 
• 
Clarify laboratory samples and 
values from SoA 
Section 8.1.3 
• 
Section added 
• 
Elaborate on SoA 
Section 8.2 
• 
Clarification around clinical events 
and efficacy outcomes 
• 
Administrative/improve clarity 
Section 10.1.5 
• 
Section added 
• 
Clarify study committees 
• 
Protocol V4.00 28Oct2020 
Throughout 
• 
Changed “coagulation and 
inflammatory biomarkers” to 
“biomarkers associated with 
outcomes including those related 
to coagulation and inflammation” 
• 
Clarity 
Throughout 
• 
Administrative updates 
• 
Consistency and clarity 
4.1 & 9.4.2 
• 
Stratification changed from 
“ongoing treatment with 
remdesivir and other agents with 
demonstrated efficacy in patients 
with COVID-19” to “participant’s 
local laboratory D-dimer level at 
screening” 
• 
Removed as agents with 
demonstrated efficacy have become 
standard of care. D-dimer reflects 
disease severity 
4.3 & 6.3 
• 
Removed clinical sites will be 
designated as prophylactic or 
therapeutic 
• 
Reflects evolution of standard of 
care 
5.1 
• 
Inclusion criterion 7  
• 
Exclusion criterion 2 
• 
Exclusion criterion 3  
• 
Align language with intent 
6.2.4 
• 
Storage of prepared syringes of 
rNAPc2 updated. 
• 
Clarity 
6.3 
• 
Site-based randomization 
• 
Clarity  
8.1.1 & 8.1.3 
• 
Schedule of Activities (SoA) and 
visit descriptions updated to reflect 
daily clinical assessments 
• 
Clarity 
8.1.2 
• 
Record local laboratory values for 
troponin, brain natriuretic peptide 
(BNP) and NT-proBNP 
• 
Capture cardiac biomarkers  
8.1.3 
• 
Demographics moved to Screening 
visit; sex, childbearing potential, 
and race added 
• 
Capture demographics for all 
screened participants 


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8.2 
• 
Section re-arranged  
• 
Clarity & consistency 
9.4.3 
• 
Analysis method for proportion of 
participants alive and out of the 
hospital at 30 days post-
randomization added 
• 
Clarity 
9.4.6 
• 
Alpha level for final analysis added 
• 
Clarity 
9.4.8 
• 
Executive Committee (EC) Chair or 
representative will be a member of 
the Unblinded Review Committee 
(URC) 
• 
Consistent with Data Safety 
Monitoring Committee charter 
10.1.5 
• 
DSMC unscheduled meetings and 
real-time notification for severe 
safety events 
• 
Safety 
• 
Protocol V5.00 01Feb2021 
Throughout 
• 
Revision of primary efficacy 
endpoint to change in D-dimer 
from baseline to Day 8 or day of 
discharge, if discharge prior to Day 
8 
• 
Change based on additional clinical 
information for duration of 
hospitalization in COVID-19 patients.  
Throughout 
• 
Revision of primary safety endpoint 
to major or non-major clinically 
relevant bleeding within 8 days of 
randomization  
• 
Changed to facilitate a more 
accurate assessment of bleeding 
events between rNAPc2 and heparin 
5.3 & 8.1.2 
• 
Revised to require negative 
pregnancy test for women of 
childbearing potential and 
clarification of effective 
contraception during the study 
• 
Health Regulatory agency feedback 
8.1 
• 
Visits and central lab assessments 
revised to align with endpoints: 
add Day 2; change Day 8 to Day 8 
or day of discharge, if discharge 
prior to Day 8; remove Day 10 
• 
Changed based on additional clinical 
information for duration  of 
hospitalization in COVID-19 patients 
6.1.2 
• 
Add clarification for standard of 
care thromboprophylaxis when 
fewer than 3 doses of rNAPc2 are 
prescribed (if patient is discharged 
prior to Day 5). 
• 
Safety 
6.5 
• 
Clarification to prohibited 
concomitant medication use during 
• 
Safety 


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trial and concurrently with study 
drug administration. 
8.4.5 
• 
Clarify AE/SAE reporting 
requirements, especially as related 
to expedited reporting 
• 
Safety 
Throughout 
• 
Administrative updates 
throughout, including 
incorporation of appendices 
• 
Clarity and consistency 
• 
Protocol V6.00 07Jul2021 
Throughout 
• 
Administrative updates 
• 
Consistency and clarity 
4.3 
• 
Justification for dose 
• 
Justification was expanded for clarity 
and to include additional detail from 
prior investigations 
5.0 
• 
Inclusion/Exclusion criteria 
clarifications 
• 
In agreement with regulatory agency 
requests, some inclusion/exclusion 
criteria were revised to include 
additional details/clarification while 
preserving the intention of each 
modified criterion 
5.1 & 5.3 
• 
Added language requiring male 
patients to avoid partner 
pregnancy and sperm donation 
• 
In agreement with regulatory agency 
request 
8.1.2 
• 
Removed central laboratory 
assessment of AST, ALT and 
bilirubin 
• 
Remove duplication of laboratory 
assessments in line with standard of 
care site COVID-19 practices 
8.5 
• 
Removed Unanticipated Problem 
Section and Unanticipated Problem 
Reporting Section 
• 
These sections did not inform clinical 
trial execution for ASPEN-COVID-19  
9.0 
• 
Increase to study sample size 
• 
Addition of an interim efficacy 
analysis and removal of Unblinded 
Review Committee 
• 
Clarification that primary endpoint 
analysis will evaluate proportional 
changes in D-dimer at Day 8; to be 
detailed in the statistical analysis 
plan 
• 
Given the evolution of COVID-19 
management since the start of 
ASPEN-COVID-19, the original 
rNAPc2 sample size and treatment 
effect assumptions were updated in 
order to increase experience in a 
diversity of COVID-19 patients. 
Changes in COVID-19 management 
that were considered include 1) 
evolving evidence for standard of 
care, 2) widespread use of several 
COVID-19 therapies of proven 


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benefit, and 3) changes in 
background therapy.  
 
 
 


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Protocol Amendment History 
Version 
Date 
Description of Change  
Brief Rationale 
2.00 
28Aug2020 
Design adjustments prior to study 
initiation 
Incorporate feedback 
3.00 
16Sep2020 
Administrative adjustments prior to 
study initiation 
Ensure consistency and 
clarity throughout the 
protocol 
4.00 
28Oct2020 
Adjustments prior to study 
initiation 
Incorporate feedback 
5.00 
01Feb2021 
Update to endpoints and revision 
of laboratory assessments; 
Clarification on requirements for 
women of child-bearing potential 
and safety reporting 
Scientific revision of 
endpoints; safety 
clarifications 
6.00 
07Jul2021 
Clarification of some 
inclusion/exclusion based on 
regulatory agency review; increase 
of study sample size 
Given the evolution of 
COVID-19 management 
since the start of ASPEN-
COVID-19, the original 
rNAPc2 sample size and 
treatment effect 
assumptions were 
updated in order to 
increase experience in a 
diversity of COVID-19 
patients 


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Protocol Approval Signature: 
 
The signatory has reviewed and agrees to the content of the final clinical study protocol as presented. 
 
 
 
 
 
 
 
Name:   
Marc Bonaca, MD, MPH 
 
Date 
Role:  
 
Study Principal Investigator 
 
 
 
 
 
 
Name:   
Michael Bristow, MD, PhD 
 
Date 
Role:  
 
Sponsor Representative 
 
 
 
 
 
 
 
 


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Site Principal Investigator Signature: 
 
The signatory has read the content of the final clinical study protocol and agrees to conduct the study as 
presented. 
 
 
 
 
 
Signature: 
 
 
Date:  
 
Name:  
 
 
 
 
Affiliation:  
 
 
 
 
 
 


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1 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ........................................................................................................................... 12 
STUDY ADMINISTRATION .................................................................................................................................... 12 
1 
PROTOCOL SUMMARY ............................................................................................................................. 12 
1.1 
Synopsis .............................................................................................................................................. 12 
1.2 
Schema ............................................................................................................................................... 15 
2 
INTRODUCTION .......................................................................................................................................... 16 
2.1 
Study Rationale .................................................................................................................................. 16 
2.2 
Background......................................................................................................................................... 17 
2.3 
Risk/Benefit Assessment .................................................................................................................. 20 
2.3.1 
Known Potential Risks ................................................................................................... 20 
2.3.2 
Known Potential Benefits .............................................................................................. 21 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 21 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 21 
4 
STUDY DESIGN ........................................................................................................................................... 23 
4.1 
Overall Design .................................................................................................................................... 23 
4.2 
Scientific Rationale for Study Design.............................................................................................. 24 
4.3 
Justification for Dose ......................................................................................................................... 24 
4.4 
End of Study Definition ..................................................................................................................... 25 
5 
STUDY POPULATION ................................................................................................................................ 25 
5.1 
Inclusion Criteria ................................................................................................................................ 25 
5.2 
Exclusion Criteria ............................................................................................................................... 25 
5.3 
Participants OF CHILD-BEARING POTENTIAL ........................................................................... 26 
5.3.1 
Contraception methods ................................................................................................. 26 
5.4 
Screen Failures .................................................................................................................................. 26 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 27 
6 
STUDY INTERVENTION ............................................................................................................................ 27 
6.1 
Study Intervention(s) Administration ............................................................................................... 27 
6.1.1 
Study Intervention Description ..................................................................................... 27 
6.1.2 
Dosing and Administration ............................................................................................ 27 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 28 
6.2.1 
Acquisition and accountability ...................................................................................... 28 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 29 
6.2.3 
Product Storage and Stability ....................................................................................... 29 
6.2.4 
Preparation ...................................................................................................................... 29 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 29 
6.4 
Study Intervention Compliance ........................................................................................................ 30 
6.5 
Concomitant Therapy ........................................................................................................................ 30 
6.5.1 
Management of Bleeding Events ................................................................................. 30 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 31 
7.1 
Discontinuation of Study Intervention ............................................................................................. 31 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 31 
7.3 
Lost to Follow-Up ............................................................................................................................... 32 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 32 
8.1 
Study Procedures .............................................................................................................................. 32 
8.1.1 
Schedule of Activities .................................................................................................... 33 


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8.1.2 
Laboratory Samples and Values .................................................................................. 34 
8.1.3 
Visit Description .............................................................................................................. 35 
8.2 
Efficacy Assessments ....................................................................................................................... 41 
8.3 
Safety and Other Assessments ....................................................................................................... 42 
8.4 
Adverse Events and Serious Adverse Events ............................................................................... 43 
8.4.1 
Definition of Adverse Events ........................................................................................ 43 
8.4.2 
Definition of Serious Adverse Events .......................................................................... 44 
8.4.3 
Classification of an Adverse Event .............................................................................. 44 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 45 
8.4.5 
Serious Adverse Event Reporting ............................................................................... 45 
8.4.6 
Reporting Events to Participants ................................................................................. 46 
8.4.7 
Events of Special Interest ............................................................................................. 46 
8.4.8 
Reporting of Pregnancy ................................................................................................ 46 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 47 
9.1 
Statistical Hypotheses ....................................................................................................................... 47 
9.2 
Sample Size Determination .............................................................................................................. 47 
9.3 
Populations for Analyses .................................................................................................................. 48 
9.4 
Statistical Analyses............................................................................................................................ 49 
9.4.1 
General Approach .......................................................................................................... 49 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 49 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 50 
9.4.4 
Safety Analyses .............................................................................................................. 50 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 51 
9.4.6 
Planned Interim Analyses ............................................................................................. 51 
9.4.7 
SubGroup Analyses ....................................................................................................... 52 
9.4.8 
phase 2b to 3 transition ................................................................................................. 52 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 52 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 52 
10.1.1 
Informed Consent Process ........................................................................................... 52 
10.1.2 
Study Closure ................................................................................................................. 54 
10.1.3 
Confidentiality and Privacy ........................................................................................... 54 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 54 
10.1.5 
Trial Committees ............................................................................................................ 55 
10.1.6 
Safety Oversight ............................................................................................................. 56 
10.1.7 
Clinical Monitoring .......................................................................................................... 56 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 56 
10.1.9 
Data Handling and Record Keeping ............................................................................ 56 
10.1.10 
Protocol Deviations ........................................................................................................ 57 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 57 
10.1.12 
Conflict of Interest Policy .............................................................................................. 58 
10.2 
Acronyms ............................................................................................................................................ 58 
10.3 
Heparin Guidance .............................................................................................................................. 60 
10.4 
Post-COVID Functional Status Scale ............................................................................................. 60 
11   REFERENCES .................................................................................................................................................. 64 
 
 
 


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STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with Good Clinical Practice (GCP) and applicable regulatory 
requirements. 
 
STUDY ADMINISTRATION 
 
Principal Investigator 
Sponsor representatives 
Marc Bonaca, MD, MPH  
Professor of Medicine, University of Colorado 
Executive Director, Colorado Prevention Center   
Michael Bristow, MD, PhD  
Chief Executive Officer, ARCA biopharma 
Professor of Medicine, University of Colorado 
2115 N Scranton St, Suite 2040 
Aurora, CO 80045  
Debra Marshall, MD 
Chief Medical Officer, ARCA biopharma 
marc.bonaca@cuanschutz.edu 
ARCA biopharma, Inc. 
10170 Church Ranch Way, Suite 100 
Westminster, CO 80021 
720-940-2100 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Assessing Safety, Hospitalization and Efficacy of rNAPc2 in COVID-19 
(ASPEN-COVID-19) 
Study Description: 
This protocol describes sequential randomized, multicenter, active 
comparator studies evaluating the hypothesis that rNAPc2, a novel, potent 
and highly selective tissue factor inhibitor with anticoagulant, anti-
inflammatory and potential antiviral properties, shortens time to recovery 
compared to heparin in hospitalized patients with COVID-19 and elevated 
D-dimer levels. The study utilizes a PROBE (Prospective Randomized Open-
label, Blinded End-point) design. Study participants and Clinical Endpoint 
Committee (CEC) members assessing the clinical endpoints will be blinded 
to treatment assignment. The protocol comprises sequential Phase 2b and 
Phase 3 studies. Analysis of Phase 2b data could lead to study 
discontinuation, adjustment of eligibility criteria or sample size, and will 
inform the rNAPc2 dose regimen to be studied in Phase 3.  
 
Objectives: 
 
Phase 2b: The primary safety and efficacy objectives are to identify an 
rNAPc2 dosing regimen with an acceptable bleeding profile and which 
reduces D-dimer levels compared to standard of care (SoC) heparin 
regimens. Secondary and exploratory objectives are to compare the 
treatment groups in terms of biomarkers associated with outcomes 
including those related to coagulation and inflammation, as well as clinical 
and functional outcomes that will also be assessed during Phase 3. 
Phase 3: The primary safety and efficacy objectives are to assess major or 


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non-major clinically relevant bleeding and whether rNAPc2 reduces time 
to recovery relative to heparin. Secondary and exploratory objectives are 
to compare the treatment groups in terms of a composite of thrombotic 
events and all-cause mortality; thrombotic events; all-cause mortality; 
biomarkers associated with outcomes including those related to 
coagulation and inflammation; health resource utilization; and post-
COVID-19 functional status.  
Endpoints: 
Phase 2b 
Primary efficacy endpoint: change in D-dimer level from Baseline to Day 8, 
or day of discharge if prior to Day 8.  
Primary safety endpoint: major or non-major clinically relevant bleeding 
within eight (8) days of randomization as compared to heparin.  
Secondary and exploratory efficacy endpoints: change in D-dimer level 
from baseline to 24h post-dose (Day 2) and Day 3, change in biomarkers 
associated with outcomes including those related to coagulation and 
inflammation from baseline through Day 8; other clinical and functional 
outcomes, including time to recovery as measured by the 8-point Adaptive 
COVID-19 Treatment Trial (ACTT) scale. 
Secondary safety endpoints: major or non-major clinically relevant 
bleeding with rNAPc2 vs. heparin, bleeding with higher vs. lower dose 
rNAPc2 through Day 30, and other adverse events (AEs). 
Phase 3 
Primary efficacy endpoint: time to recovery within thirty (30) days of 
randomization using the ACTT ordinal scale.  
Primary safety endpoint: major or non-major clinically relevant bleeding 
within eight (8) days of randomization as compared to heparin. 
Secondary and exploratory efficacy endpoints: time to first occurrence of a 
composite of thrombotic events and all-cause mortality within thirty (30) 
days of randomization; time to first occurrence of thrombotic events 
within 30 days of randomization; time to all-cause mortality within thirty 
(30) days of randomization; change in biomarkers associated with 
outcomes including those related to coagulation and inflammation from 
Baseline through Day 8; proportion alive and out of hospital at thirty (30) 
days post-randomization; days in intensive care unit, on ventilator, 
vasopressors, renal replacement therapy, and circulatory support; Post-
COVID Functional Status (PCFS) score at discharge and Day 30.  
Secondary safety endpoints: major or non-major clinically relevant 
bleeding with rNAPc2 or heparin, and other AEs. 


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Study Population: 
Phase 2b: Approximately 160 men or women enrolled at approximately 20 
sites, 18 to 90 years of age with COVID-19 documented by a validated test 
such as polymerase chain reaction (PCR) within one (1) week of 
hospitalization or screening and D-dimer above the upper limit of normal.  
 
Phase 3: Approximately 450 additional participants (same criteria as listed 
for Phase 2b) at up to approximately 80 sites.  
 
Phase: 
2b/3 
Description of 
Sites/Facilities Enrolling 
Participants: 
Approximately 80 global clinical sites (in total between Phases 2b and 3) 
will be selected based on prior performance in randomized clinical trials 
and access to patients with COVID-19. 
 
Description of Study 
Intervention: 
 
Phase 2b: Participants will be randomly assigned 1:1:2 to receive rNAPc2 
at 1 of 2 dose regimens, or a heparin regimen per site SoC (prophylactic or 
therapeutic). The higher rNAPc2 dose regimen will include a 7.5 μg/kg 
subcutaneous (SC) loading dose on Day 1 followed by 5μg/kg SC on Days 3 
and 5; the lower dose regimen will be administered as a 5 μg/kg SC loading 
dose on Day 1 followed by 3μg/kg SC on Days 3 and 5. Prophylactic or 
therapeutic doses of low molecular weight heparin (LMWH) or 
unfractionated heparin (UFH) will be administered according to local SoC 
in the control group. Participants will be stratified by local laboratory D-
dimer level at screening. 
 
Phase 3: Participants will be randomly assigned to receive rNAPc2 at a 
dose regimen selected based on Phase 2b data or to heparin (1:1).  
 
Participant Duration: 
Up to 40 days 
 
 


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1.2 
SCHEMA 
Figure 1. Schematic of study design: Phase 2b (Study NAPc-201) in upper panel. Phase 3 (Study 
NAPc-301) in lower panel  
 
 
 
 
 
 
 
 


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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared 
a pandemic by the World Health Organization and is responsible for significant morbidity and mortality 
worldwide.1 Mortality is predominantly related to progressive pneumonia and acute respiratory distress 
syndrome which may progress to thrombotic events and multi-organ failure. Pathologic examination of 
pulmonary vasculature from patients with COVID-19 pneumonia has demonstrated vessel wall edema 
and immune cell infiltration, small vessel and capillary thrombosis, and infarction.2,3 The underlying 
pathophysiology of COVID-19 is incompletely understood but appears to involve a severe inflammatory 
response and coagulopathy promoting venous and arterial thrombosis despite conventional 
anticoagulation.4 Supporting this is the observed association between elevated D-dimer levels and 
mortality.5 The prevalence and clinical impact of COVID-19-associated coagulopathy highlight the need 
for novel antithrombotic therapies. 
One such novel therapy is rNAPc2, an 
85 amino acid recombinant peptide 
with anticoagulant, anti-inflammatory, 
and potential antiviral effects 
originally cloned from the saliva of 
canine hookworm Anclyostoma 
caninum.6 rNAPc2 is a potent inhibitor 
of the tissue factor (TF)-activated 
factor VII (fVIIa) complex that initiates 
the extrinsic coagulation pathway 
(Figure 2) and activates members of 
the protease activated receptor (PAR) 
family that plays a role in inflammatory disorders such as sepsis.7,8,9 TF appears to be the major activator 
of the coagulation cascade during viral infection,10 providing a mechanistic rationale for rNAPc2 in 
COVID-19. Preclinical evidence supporting examination of rNAPc2 includes its effect on D-dimer levels, 
which predict adverse COVID-19 outcomes including death.11 rNAPc2 reduced D-dimer response to 
Ebola virus infection in non-human primates by approximately 70% compared with placebo.12 
TF also plays a central role in inflammatory signaling and dysregulated immunity related to viral 
infections.13,14 Because of rNAPc2’s mechanism of action as a TF inhibitor, it was evaluated as a potential 
therapeutic agent to counteract haemorrhagic viral infections in which disseminated intravascular 
coagulation was a key pathophysiologic element. rNAPc2 showed evidence of survival benefit against 
lethal Ebola and Marburg virus challenges in non-human primates,12 attenuated inflammatory biomarker 
response and, in Ebola, reduced viral load.12 
TF also enhances viral dissemination.15 In experimental models, rNAPc2 has been shown to reduce 
vascular dissemination of viruses that incorporate host TF into their envelopes,16 a characteristic which 
may be beneficial in COVID-19. Taken together, the anticoagulant, anti-inflammatory, and potential 
antiviral effects of rNAPc2 support its evaluation for treatment of patients with COVID-19. 
rNAPc2 was originally in development for the prevention of thrombotic complications following 
orthopedic surgery, percutaneous coronary intervention (PCI) and non-ST elevation acute coronary 


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syndrome (NSTE-ACS).17,18,19 During this cardiovascular development program, rNAPc2 was tested in 
multiple Phase 1 and 2 clinical trials involving more than 700 human participants. Due to commercial 
factors unrelated to safety or efficacy, cardiovascular development of rNAPc2 did not proceed to pivotal 
studies. Availability of safety data in several patient populations including those with acute illness, in 
conjunction with immediate availability of investigational product for human use, enables immediate 
initiation of a pivotal study in patients with COVID-19. 
2.2 
BACKGROUND  
rNAPc2 is a novel, potent (Ki =10 pM), highly selective TF inhibitor with anticoagulant, anti-
inflammatory, and potential antiviral properties. 
Mechanism of action 
rNAPc2 inhibits the quaternary complex of TF/activated factor X (fXa) /fVIIa that catalyzes thrombin 
formation, by a unique mechanism requiring initial binding of rNAPc2 to zymogen or fXa before 
formation of the final quaternary inhibitory complex (Figure 3). The TF/fXa/fVIIa complex also activates 
the pro-inflammatory protease activated receptors PAR1 and PAR2; 
inhibition of this signaling is the likely basis for 
the anti-inflammatory effects of rNAPc2 in 
humans.20,21 Cell derived TF incorporated into 
virus envelope substantially promotes 
infectivity15 and is inhibited by rNAPc2 through 
the same mechanism of forming an inhibitory 
quarternary complex which is presumably why 
rNAPc2 reduced viral load in Ebola-infected 
monkeys and Herpes simplex virus 1 (HSV1)-
infected mice.12,16 
 
Clinical data with rNAPc2 
Pharmacokinetics: Systemic exposure to rNAPc2 
increased with increasing doses from 1.5 to 5.0 
μg/kg SC with no significant differences in Tmax 
among doses. The mean t1/2 values ranged from 
47.0 to 64.1 hours following the first dose on Day 1 and from 70.8 to 78.9 hours following the third dose 
on Day 5 and are independent of route of administration (intravenous [IV] or SC). The prolonged t1/2 in 
humans has been determined to be a result of stoichiometric binding of rNAPc2 to fX in plasma.22 SC 
bioavailability, estimated in the dog and cynomolgus monkey, was in excess of 95% and rNAPc2 was 
undetected in urine.  
 
There have been six Phase 1 and 3 Phase 2 trials of rNAPc2 that enrolled 800 participants. A total of 704 
participants have received rNAPc2 via IV (N=235) and SC (N=469) administration. In these trials, there 
were 174 participants who received a single dose of rNAPc2 and 530 participants who received multiple 
doses of rNAPc2. Early phase clinical studies with rNAPc2 are summarized (Table 1).  
Figure 3. rNAPc2 mechanism of action: 1) rNAPc2 binds 
tightly to zymogen factor X; 2) docking of the rNAPc2-fX 
complex to TF/fVIIa assembled on a procoagulant 
phospholipid surface; and 3) presentation of the reactive 
loop of rNAPc2 to the active site of fVIIa, resulting in a 
tightly bound quarternary inhibitory complex. c2  rNAPc2; 
TF  tissue factor; VIIa  fVIIa; X  factor X19 


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Table 1: Summary of Previous Clinical Trials of rNAPc2 
 
Study 
Description 
Dose 
N Total 
(N on drug) 
Finding 
CVS/A-0101 
Phase 1 SAD  
in HS 
3-7.5 µg/kg IV 
Single dose 
28 
(20) 
Well tolerated 
CVS/A-9704 
Phase 1 SAD  
in DIC 
0.7 – 5 µg/kg SC  
Single dose 
13 
(10) 
Well tolerated 
CVS/G-9704 
Phase 1 SAD  
in HS 
0.3-5 µg/kg SC 
Single dose 
29 
(20) 
Well tolerated 
CVS/A-9801 
Phase 1 
Coadministered  
with fVIIa in HS 
3.5 µg/kg SC 
Single dose 
6 
(6) 
fVIIa normalized rNAPc2 PT elevations 
CVS/C-9802 
Phase1 MAD  
in HS 
1.5-5 µg/kg SC 
Multiple dose 
18 
(12) 
Drug accumulation  
with multiple dosing 
rNAPc2 antibodies observed in 3 pts 
CVS/MC-9803 
Phase 2 in knee 
replacement 
1.5-5 µg/kg SC 
Multiple dose 
293 
(293) 
Dose-related increase  
in major bleeds 
No drug neutralizing antibodies 
observed 
CVS/NL-9901 
Phase 2 in 
elective PCI 
3.5-10 µg/kg SC 
Single dose 
154 
(124) 
Dose-related increase  
in minor bleeds 
NUVO-0201 
ANTHEM/TIMI-
32 
Phase 2  
in NSTE-ACS 
1.5-10 µg/kg IV 
Multiple dose* 
255 
(215) 
Trend for less ischemia 
13% of pts had 
 rNAPc2 antibodies  
NAP-0601 
Phase 1  
in colon cancer 
2.5-10µg/kg SC 
Multiple dose 
4 
(4) 
Stopped for poor recruitment  
(40 planned) 
DIC disseminated intravascular coagulation, fVIIa activated factor VII, HS healthy subjects, IV intravenous, MAD 
multiple ascending dose, nAb neutralizing antibody, NSTE-ACS non-ST elevation-acute coronary syndrome, PCI 
percutaneous coronary intervention, PT prothrombin time, SAD single ascending dose, SC subcutaneous. 
*183 pts had single dose of rNAPc2, and 32 pts had multiple doses of rNAPc2. Source: rNAPc2 IB 
Pharmacodynamic effect: rNAPc2 prolonged prothrombin time (PT) in a dose-dependent manner 
(Figure 4).  
 
Figure 4. PT versus time from study CVS/C-9802, 
multiple ascending dose administration in healthy 
subjects. Mean + standard deviation, N=4 or 6 per 
dose group (IB) 


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Efficacy: The initial clinical development program for rNAPc2 explored its utility as an anticoagulant, 
focusing on clinical settings associated with increased risk for arterial and venous thrombosis (Table 1). 
In a dose-escalation trial of 154 patients undergoing elective PCI randomized to placebo or 4 doses of 
rNAPc2, systemic thrombin generation, assessed by 
prothrombin fragment 1.2, was suppressed in all 
rNAPc2 dose groups to levels below baseline 
values.18 rNAPc2 was also assessed in a sequential 
dose-ranging study in patients undergoing total 
knee replacement.17 The mean rate of deep vein 
thrombosis (DVT) among patients receiving three 
regimens of rNAPc2 within 6-12 hours post-
operatively was 21.5%.  Administration of rNAPc2 
(3.0 µg/kg) within 1 hour after surgery reduced the 
rate of DVT to 12.2% (95% CI 5.7%-21.8%).  In 
comparison, rates of DVT after knee replacement 
among patients treated with LMWH range from 
8%-36%.23,24,25 In 203 patients presenting with 
NSTE-ACS treated with early coronary angiography, 
rNAPc2 (7.5 ug/kg) suppressed prothrombin fragment 1.2 generation (Figure 5) and reduced ischemia by 
50% compared with placebo.19 
Safety: Among patients undergoing knee replacement surgery, no dose-related increase in minor 
bleeding was observed. Major bleeding events were observed in 0, 3.4%, and 10.6% of patients 
receiving 1.5, 3.0, and 5.0 μg/kg SC at 6-12 hours postoperatively, respectively.17 None of the major 
bleeds were considered serious. In 203 patients presenting with NSTE-ACS treated with early coronary 
angiography, rNAPc2 at 7 increasing IV doses from 1.5 μg/kg to 10 μ/kg or placebo most of whom who 
were also receiving heparin and aspirin plus clopidogrel did not significantly increase major bleeding vs. 
placebo (3.7% vs. 2.5%; p=NS) despite increasing the international normalized ratio in a dose-related 
fashion.19 Among patients undergoing elective PCI, the frequency of minor bleeding in the 3.5 and 5.0 
μg/kg dose groups was comparable to placebo, increasing to 11% and 31% in the 7.5 and 10 μg/kg SC 
dose groups, respectively.18 Occurrence of major bleeding was not dose-dependent in this population 
which was also receiving a variety of antiplatelet and other anticoagulant therapies. Following rNAPc2 
administration, infusion of rfVIIa normalized PT in healthy subjects, suggesting rfVIIa may be useful in 
transiently reversing the anticoagulant effects of rNAPc2.26 In Phase 1 and 2 studies anti-rNAPc2 
antibody formation was observed in 33 of 324 (10%)  treated participants, without any  neutralizing 
antibody formation or associated AEs (refer to the Investigator Brochure). 
Preclinical studies with rNAPc2 
In rhesus monkeys infected with Ebola, a virus that induces overexpression of TF in primate monocytes 
and macrophages, treatment with rNAPc2 lowered D-dimer levels (p<0.0001) compared with placebo 
and improved survival (p=0.0184) (Figure 6). Interleukin-6 (IL-6) elevation appeared less frequent in the 
rNAPc2-treated monkeys and viral load was decreased.12 
Figure 5. Prothrombin fragment 1.2 (F1.2), a marker of new thrombin 
generation, was reduced significantly at 2 to 6 and 48 h with 7.5 μg/kg 
rNAPc2 compared with placebo. Lower-dose rNAPc2 (1 to 5 μg/kg) 
blunted the increase in F1.2 seen at 48 h in the placebo group (JACC 
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Figure 6. Effect of rNAPc2 treatment on D-dimer, survival, interleukin-6 (IL-6) and virus titer in non-human 
primates (rhesus macaque). rNAPc2 ("treated") n=9, placebo ("control, n=3 investigated contemporaneously with 
rNAPc2 and 4 historical controls, total N = 7), rNAPc2 treated survivors ("Survivors", a subset of Treated, N = 3). For 
survival analysis, the placebo group was supplemented with 7 additional historical controls for a total N of 14. 
Prior data have shown that host cell-derived TF on viral envelopes enhances cell infection in vitro.15 
Antiviral effects of rNAPc2 were evaluated in BALB/c mice inoculated with HSV1 which has TF as a 
constituent of its envelope. The viral load, quantified by plaque forming assay, in different organ 
systems including brain, liver, heart, and lung, was significantly reduced (p<0.05) when mice were 
concurrently treated with rNAPc2 compared with HSV1 alone.16 
Taken together, these clinical and preclinical data suggest that rNAPc2 may have potential advantages 
over marketed anticoagulants for which COVID-19 trials are planned or underway.  
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Due to the anticoagulant action of rNAPc2, there is a risk of bleeding. Dose-related increased bleeding, 
with associated anemia in some cases, was observed in Phase 2 studies of patients undergoing knee 
replacement and in patients undergoing elective PCI who were concurrently receiving a variety of anti-
platelet and other anti-thrombotic therapies.17,18 A potential risk with rNAPc2 is fever which was 
observed in a study of patients undergoing knee replacement in whom fever was attributed to 
inflammation associated with the surgery (refer to the Investigator Brochure). Other potential risks 
include generic risks with biologic drugs: formation of neutralizing antibodies and allergic reactions 
including anaphylaxis. If any signs or symptoms of serious hypersensitivity reactions occur after rNAPc2 
D-dimer
Survival
Virus titer
IL-6


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administration, discontinue further treatment with rNAPc2, treat according to the standard of care, and 
monitor until signs and symptoms resolve. This includes patients who may present with a 
hypersensitivity to the investigational medication components.  
2.3.2 KNOWN POTENTIAL BENEFITS  
rNAPc2 has no established clinical benefits. Participants enrolled in the proposed study will have COVID-
19 with elevated D-dimer, which predicts a higher risk of thrombosis and death.5 Potential benefits with 
rNAPc2 include reduced risk of thrombosis during COVID-19 and shorter time to recovery due anti-
thrombotic effects, as well as reduced inflammation and viral load.  
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The risk/benefit profile for the proposed study is expected to be favorable as eligibility criteria are 
designed to select a population at increased risk of thrombosis and death and rNAPc2 doses are selected 
to reduce bleeding risk while retaining anti-thrombotic efficacy.  
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Phase 2b- Safety 
 
 
The Phase 2b safety objective is 
to identify an rNAPc2 dosing 
regimen with an acceptable 
bleeding profile compared to 
SoC heparin regimens 
 
 
Primary safety endpoint:  
major or non-major clinically 
relevant bleeding (Section 8.3 Safety 
and Other Assessments) within eight 
(8) days of randomization as 
compared to heparin  
 
Secondary safety endpoints are:  
• 
major or non-major clinically 
relevant bleeding with rNAPc2 
vs. heparin 
• 
bleeding with higher vs. lower 
dose rNAPc2 through Day 30  
• 
Other AEs  
Both rNAPc2 and heparin 
cause bleeding 
Phase 3 – Safety 
 
 
The Phase 3 safety objective is 
to assess tolerability of rNAPc2 
compared with heparin 
Primary safety endpoint:  
major or non-major clinically 
relevant bleeding within eight (8) 
days of randomization as compared 
to heparin (Section 8.3 Safety and 
Other Assessments)     
 
Secondary safety endpoints are:  
• 
major or non-major clinically 
relevant bleeding with rNAPc2 
vs. heparin through Day 30 
Both rNAPc2 and heparin 
cause bleeding 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
• 
Other AEs  
Phase 2b – Primary efficacy 
 
 
The primary efficacy objective 
is to identify a rNAPc2 dosing 
regimen which reduces D-
dimer levels compared to SoC 
heparin regimens  
Primary efficacy endpoint: change in 
D-dimer level from baseline to Day 
8, or day of discharge if prior to Day 
8 
D-dimer reflects the rNAPc2 
mechanism of action and 
predicts survival in patients 
with COVID-19 
Phase 2b – Secondary and exploratory 
 
Secondary objectives are to 
compare the rNAPc2 and 
heparin groups in terms of 
biomarkers associated with 
outcomes including those 
related to coagulation and 
inflammation 
 
Exploratory objectives are to 
compare the treatment groups 
in terms of clinical and 
functional outcomes that will 
also be assessed during Phase 3 
Secondary efficacy endpoints: 
• 
change in D-dimer level from 
baseline to 24 hours post-dose 
(Day 2) and Day 3 
• 
change in biomarkers associated 
with outcomes including those 
related to coagulation and 
inflammation from baseline 
through Day 8 
Exploratory efficacy endpoints: 
• 
clinical and functional outcomes 
(including time to recovery as 
measured by the ACTT ordinal 
scale) 
 
Inflammatory biomarkers 
reflect rNAPc2 mechanism 
of action and inflammation 
is believed to play a 
pathophysiologic role in 
COVID-19. Time-to-event 
outcomes from the overall 
study will determine the 
definitive efficacy of 
rNAPc2. Functional 
assessments will determine 
the effect of rNAPc2 on 
functional recovery. 
Phase 3 – Primary efficacy 
 
 
The primary objective is to 
assess whether rNAPc2 reduces 
time to recovery relative to 
heparin  
Primary efficacy endpoint: time to 
recovery within thirty (30) days of 
randomization using the ACTT 
ordinal scale 
Time to recovery is a 
clinically meaningful 
outcome for patients. 
Phase 3 – Secondary and exploratory 
 
Secondary objectives are to 
compare the treatment groups 
in terms of a composite of 
thrombotic events and all-
cause mortality; thrombotic 
events; and all-cause mortality. 
 
 
 
 
 
Exploratory objectives are to 
compare the treatment groups 
in terms of: 
• 
Biomarkers associated with 
outcomes including those 
Secondary efficacy endpoints:  
• 
time to first occurrence of a 
composite of thrombotic events 
and all-cause mortality within 
thirty (30) days of 
randomization 
• 
time to first occurrence of 
thrombotic events within thirty 
(30) days of randomization 
• 
time to all-cause mortality 
within thirty (30) days of 
randomization  
 
Exploratory endpoints are: 
• 
change in biomarkers associated 
with outcomes including those 
rNAPc2 anticoagulant 
activity may reduce arterial 
and venous 
thromboembolic events in 
patients with COVID-19. 
Healthcare resource 
utilization is a meaningful 
outcome to patients and the 
health system, as is 
functional recovery. 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
related to coagulation and 
inflammation  
• 
Health resource utilization 
• 
Post-COVID-19 functional 
status  
 
related to coagulation and 
inflammation from baseline 
through Day 8 
• 
proportion alive and out of 
hospital at thirty (30) days post-
randomization 
• 
days in intensive care unit, on 
ventilator, vasopressors, renal 
replacement therapy, and 
circulatory support, e.g. 
extracorporeal membrane 
oxygenation 
• 
PCFS scale score at discharge 
and Day 30  
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
Hypothesis: rNAPc2, a novel, potent and highly selective tissue factor inhibitor with anticoagulant, anti-
inflammatory and potential antiviral properties, shortens time to recovery in hospitalized patients with 
COVID-19. 
This protocol describes sequential Phase 2b/3 randomized, active comparator, multicenter superiority 
studies comparing rNAPc2 to heparin in hospitalized patients with COVID-19 and elevated D-dimer level. 
The study utilizes a PROBE (Prospective Randomized Open-Label, Blinded End-point) design 27,28. Study 
participants and Clinical Endpoint Committee (CEC) members assessing the clinical endpoints will be 
blinded to treatment assignment. Randomization will be stratified by the participant’s local laboratory 
D-dimer level at screening (> or ≤ 2X the assay’s upper limit of normal (ULN)).  
The primary objective of the Phase 2b study is to identify a rNAPc2 dosing regimen with an acceptable 
bleeding profile and which reduces D-dimer levels compared to SoC heparin regimens. The primary 
safety endpoint is major or non-major clinically relevant bleeding within 8 days of randomization and 
the primary efficacy endpoint is change in D-dimer level from Baseline to Day 8, or day of discharge if 
prior to Day 8. Secondary and exploratory objectives and endpoints are detailed in Section 3 OBJECTIVES 
AND ENDPOINTS. 
 
During Phase 2b, an interim efficacy analysis will be conducted when 120 participants have completed 
Day 8 assessments, or Day of Discharge assessments if the participant is discharged prior to Day 8. To 
account for early recovery, deaths, and lab errors which may lead to lack of Day 8 D-dimer in 
approximately 20% of patients, 120 participants will provide for approximately 100 participants to be 
evaluated in the interim efficacy analysis. The interim efficacy analysis will test for futility based on the 
primary study hypothesis. Additionally, at the interim efficacy analysis, the Data Safety Monitoring 
Committee will be empowered to adjust sample size as pre-specified in the Phase 2b interim analysis 


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plan. While this review is taking place, the study will continue to enroll. Upon completion of Phase 2b, 
the database will be locked for analysis of clinical and biomarker data.  
The primary objective of the Phase 3 trial is to test the hypothesis that the rNAPc2 dose regimen 
identified in Phase 2b reduces time to recovery relative to heparin. The Phase 3 primary efficacy 
endpoint is time to recovery within 30 days of randomization using the ACTT ordinal scale. The primary 
safety endpoint is major and non-major clinically relevant bleeding within 8 days of randomization.  
Secondary and exploratory objectives and endpoints are detailed in Section 3 OBJECTIVES AND 
ENDPOINTS. Although the Phase 3 primary endpoint is being measured in the Phase 2b study as a 
secondary endpoint, the primary analysis of Phase 3 will not include the Phase 2b data. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Accumulating data linking COVID-19 to thrombotic events has shifted equipoise away from inclusion of a 
placebo group. Consequently, rNAPc2 will be compared to heparin administered according to local SoC. 
Clinical pathways for anticoagulation of hospitalized patients with COVID-19 vary from institution to 
institution reflecting the current state of clinical uncertainty. To avoid potential confusion and error due 
to deviation from these pathways, heparin-allocated participants will receive regimens according to 
local institutional practice. As many hospitalized patients with COVID-19 participate in trials of antiviral 
and other therapies, concurrent participation in interventional trials that do not include anti-thrombotic 
or anti-platelet therapy is permitted. Based on data that D-dimer levels are related to patient outcomes 
in hospitalized COVID-19 patients,5 randomization will be stratified by local laboratory D-dimer level at 
screening.  
4.3 
JUSTIFICATION FOR DOSE 
 
Dose selection is based on data from three (3) Phase 2 dose-ranging studies which collectively enrolled 
more than 700 patients with acute coronary syndrome, undergoing knee replacement surgery, or after 
PCI. Based on the extensive pharmacokinetic (PK) data from the previous trials of rNAPc2 showing a 
consistently long half-life that increased with repeat dosing and produced escalating dose levels after 
both the 2nd (Day 3) and 3rd (Day 5) doses, a loading dose is used for both rNAPc2 regimens. The 
rationale is that with rNAPc2’s long half-life, steady state is not reached within the 8 days of the ASPEN-
COVID-19 efficacy follow-up period, as areas under the curve (AUCs) increase following each dose during 
that interval. As COVID-19 patients ill enough to be hospitalized are at immediate risk for the conditions 
that lead to micro- or macrovascular thromboses, the therapeutic goal is rapid attainment of rNAPc2 
plasma levels approximating those achieved at steady state, thus the decision was made to start the 
regimen with a loading dose.  
Pharmacokinetic and pharmacodynamic studies following single doses of rNAPc2 demonstrated a dose 
dependent increase in international normalized ratio (INR) ranging from 1.5 at 3.0 µg/kg to 1.75 at 5.0 
µg/kg and 2.1 at 7.5 µg/kg. Based on these data, an initial dose of 5 µg/kg followed by 3.0 µg/kg on Days 
3 and 5 (where the long T 1/2 produces greater levels than for the initial dose) was estimated to be 
equivalent to prophylactic dose heparin. A dose of 7.5 µg/kg followed by 5 µg/kg on days 3 and 5 was 
estimated to correlate with a higher intensity of anticoagulation approximating therapeutic heparin. 
In Phase 2b, 2 rNAPc2 dose regimens will be evaluated:  
• 
Higher dose: loading dose of 7.5 μg/kg SC on Day 1 followed by 5 μg/kg SC on Days 3 and 5 


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• 
Lower dose: loading dose of 5 µg/kg SC on Day 1 followed by 3 µg/kg SC on Days 3 and 5.  
 
The dose regimen for Phase 3 will be selected based on Phase 2b data.  
 
The active comparator will be heparin at either prophylactic or therapeutic doses per SoC. SoC may 
evolve to reflect emerging data from COVID-19 anti-thrombotic trials and clinical experience. 
 
4.4 
END OF STUDY DEFINITION 
Participants will complete their study participation after their final or Day 30 contact. The end of the 
study is defined as completion of the last enrolled participant’s final visit or contact.  
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for randomization in this study: 
 
1. Age ≥ 18 years and ≤ 90 years at the Screening assessment  
2. Weight ≥ 50 kg at randomization 
3. Hospitalized with a diagnosis of COVID-19 and in need of inpatient medical care 
4. Positive for SARS-CoV-2 on nasopharyngeal, oropharyngeal or other tissue/body fluid samples by 
PCR or validated other test of ongoing infection (not an antibody test for prior exposure), within 
seven (7) days of hospitalization or screening assessment 
5. D-dimer level > upper limit of normal at screening (local lab; initial value as collected at the time of 
hospital admission, prior to initiation of heparin treatment preferred) 
6. Provided electronic or written informed consent, either personally or through a legally authorized 
representative (LAR) 
7. Must agree not to participate in a concurrent interventional study involving anticoagulation or anti-
platelet therapy 
8. Female patients of reproductive or childbearing potential must be willing to use an effective method 
of contraception for the duration of the study (see section 5.3.1), and male patients must be willing 
to use an effective method of contraception to avoid partner pregnancy and abstain from sperm 
donation for at least 90 days after last dose. 
 
5.2 
EXCLUSION CRITERIA 
Patients who meet any of the following exclusion criteria are not eligible for randomization in this study: 
 
1. High bleeding risk, e.g. major surgery within prior 1 month, history of a major bleed while receiving 
anticoagulation, recent hemorrhagic stroke, current or planned (during current hospitalization) dual 
anti-platelet therapy, platelet count <25,000/µL, current therapeutic anticoagulation for a medical 
indication other than COVID, e.g. atrial fibrillation, known thrombosis, hereditary or acquired 
coagulopathy treated with therapeutic anticoagulation. Patients receiving prophylactic 
anticoagulation are eligible if they are willing to discontinue current anticoagulation.  
2. Sustained systolic blood pressure < 90 mmHg considered to be clinically significant 


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3. Persistent eGFR <20 ml/min/1.73m2  
4. Known severe liver disease (e.g. bilirubin >3.5 mg/dL (60 umol/L))  
5. Life expectancy estimated to be < 72 hours based on current clinical condition 
6. Anticipated hospital discharge or transfer within 5 days based on current clinical condition 
7. Known anti-phospholipid syndrome 
8. Unable to receive heparin, e.g. history of heparin-induced thrombocytopenia and thrombosis (HITT) 
9. Participation in any interventional clinical study with an investigational product within seven (7) days 
of the Screening assessment or within 5 half-lives of the investigational agent, whichever is longer 
5.3 
PARTICIPANTS OF CHILD-BEARING POTENTIAL 
There are no studies of rNAPc2 in pregnant women. Therefore, a urine pregnancy test will be required 
prior to study drug initiation (Baseline/Day 1 visit) for all female participants of child-bearing potential. A 
female who is surgically sterile or post-menopausal for at least 12 months is not considered to be of 
childbearing potential.  Female participants of child-bearing potential must be willing to use a highly 
effective method of contraception for the duration of the study, otherwise they will be excluded from 
study participation. 
Male patients must be willing to use effective method of contraception to avoid partner pregnancy and 
abstain from sperm donation for at least 90 days after last dose. 
5.3.1 CONTRACEPTION METHODS 
Examples of effective contraception methods include the following: 
• Contraceptive pill or transdermal patch (established at least 30d prior to screening) 
• Single barrier plus spermicide 
• Intrauterine device 
• Implants for contraception 
• Injections for contraception (with prolonged release) 
• Hormonal vaginal device 
• Sterilization, surgical tubal ligation 
• Sole sexual partner consisting of surgically sterilized male partner with appropriate post-surgical 
documentation of the absence of spermatozoa in the ejaculate 
• Same sex partner 
 
5.4 
SCREEN FAILURES 
The study will screen and enroll hospitalized patients with documented COVID-19, in the US and other 
countries with high rates of COVID-19. Each potential participant will be assigned a screening 
identification number. Only patients who test positive for SARS-CoV-2 will be randomized. 


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Ineligible individuals may be rescreened. At the time of rescreening, a new informed consent must be 
obtained, and a new screening number will be assigned.  
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
The target sample size for Phase 2b is approximately 160 participants, with an additional approximately 
450 planned during Phase 3. Eligibility criteria are broad to facilitate enrollment, the primary 
requirement being elevated D-dimer.  In published data, 68% of patients hospitalized with COVID-19 had 
D-dimer > 0.5 ng/mL.32 
Enrolled participants are anticipated to reflect the epidemiology of COVID-19. In May 2020, 46%, 30% 
and 24% of hospitalized patients with COVID-19 in the US were >65, 50-64 and <50 years of age, 
respectively. Race/ethnicity was reported as 37% Non-Hispanic White, 40% Non-Hispanic Black and 14% 
Hispanic. Concomitant medical conditions included hypertension 59%, CV disease 35%, metabolic 
disease 42%, obesity 50% and renal disease 16%.29  
We anticipate enrolling at approximately 20 sites in Phase 2b and 80 clinical sites in Phase 3, selected for 
experience providing high quality clinical trial data and for the prevalence and ability to recruit the 
target population. Sites will be selected in geographic areas with high rates of COVID-19 in the US and 
abroad. Because of the rapid timeline, regulatory approval and drug importation time will be considered 
during site selection.  
Adherence is facilitated by planned administration of all study medication in-hospital. Retention should 
be facilitated due to the short duration of follow up and limited number of study-related activities. 
Follow up for clinical outcomes and AEs may be conducted remotely.  
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
rNAPc2 is a non-glycosylated, single-chain, 85 amino acid peptide manufactured according to Good 
Manufacturing Practices using fermentation in yeast and subsequent purification. Heparin will be 
provided by hospitals according to their local policies and investigator-determined SoC. 
6.1.2 DOSING AND ADMINISTRATION 
 
Participants will be randomized to either rNAPc2 or heparin. In Phase 2b, rNAPc2-allocated participants 
will be assigned to receive either the higher dose (7.5 μg/kg SC on Day 1, and 5 μg/kg SC on Days 3 and 
5) or lower dose regimen (5 μg/kg SC on Day 1, and 3 μg/kg SC on Days 3 and 5). For Phase 3, a single 
dose regimen will be selected based on Phase 2b data. Participants who are discharged after 1 rNAPc2 
dose may receive SoC thromboprophylaxis, if clinically indicated, 48 hours after receipt of rNAPc2. Those 
discharged after 2 or more rNAPc2 doses may receive SoC thromboprophylaxis, if clinically indicated, 72 
hours after receipt of second rNAPc2 dose. Hospitalized rNAPc2 allocated participants may receive SoC 


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thromboprophylaxis, if clinically indicated, starting on Day 8, after the D-dimer and other Day 8 central 
laboratory measurements are drawn.  
 
Example of rNAPc2 dose calculation: a patient weighing 80 kg randomized to the higher dose would 
receive 0.6 mg SC (0.6 ml at 1 mg/ml) on Day 1 and 0.4 mg SC (0.4 ml) on Days 3 and 5. As each vial 
contains 0.5 ml, the Day 1 dose would require 2 vials, Day 3 would require 1 vial and Day 5 would 
require 1 vial, with the excess volume discarded on each day. This is an example; each participant’s 
weight-based dose should be calculated based on their individual weight at baseline. Weight-based 
dosing is capped at 115 kg, so participants with higher body weight will receive the dose for weight of 
115 kg. 
 
Participants randomized to heparin will be treated with LMWH or UFH per local SoC.30 Enoxaparin and 
dalteparin are the preferred LMWH. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
rNAPc2 study drug will be shipped from the drug depot using dry ice, and with a temperature-
monitoring device (TempTale or equivalent). This device will record the temperature maintained during 
shipment.  
At the time of or immediately after study initiation, and as needed thereafter, study drug will be shipped 
to the site. The site will be responsible for confirming the supplies received match the shipping record. 
Each time a participant is enrolled, the carton and vial number used must be documented. A Study Drug 
Accountability Form is to be completed for every participant being treated with the study drug. All 
accountability logs must be available to authorized Sponsor representatives (auditors) for inspection. 
Each site will initially be supplied with adequate quantities of rNAPc2 to ensure study medication supply 
for timely randomization. Study drug will be tracked through a Drug Accountability system.  
If the study drug is lost or damaged or is exposed to a temperature which is outside of the required 
study drug storage range the Sponsor should be notified immediately. The final decision regarding 
whether a site will be re-supplied with study drug, or if further action is required, will be determined by 
the Sponsor. 
After a participant has been treated, the drug vial with the remainder of the study drug must be 
retained until the study coordinator or designee obtains approval from the Coordinating Center or 
Sponsor to return or destroy the drug. Following completion of drug accountability and confirmation by 
the site monitor (Clinical Research Associate [CRA]), the vials can be destroyed in accordance with all 
local, state, and federal laws and in accordance with the destruction policies at the participating site. 
Documentation of destruction must be provided to the Sponsor. A copy of the documentation of 
destruction should be kept with the sites’ pharmacy documentation. 
At the end of the study and following final drug accountability, any unused vials should be destroyed in 
accordance with all local, state, and federal laws and in accordance with destruction policies at the 
participating site. Documentation of destruction must be provided to the Sponsor.  If the participating 
site does not have properly documented or appropriate destruction policies in place, the used and 
unused study drug should be returned to the distribution depot, after verification of drug accountability. 


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The Coordinating Center will assess the adequacy of the policies and procedures and collect necessary 
documentation.  
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
rNAPc2 is supplied in labelled glass vials as a frozen, sterile, clear, colorless solution (1 mg/mL) in 65 mM 
sodium phosphate/80 mM NaCl, pH 7.0. Each 2 mL vial is filled to a volume of 0.5 mL and contains 0.5 
mg of active rNAPc2. Vials contain no preservative and are designed for single use only. 
Vials will be supplied in labeled cartons (1 vial per carton), and each vial will be labelled with a unique 
vial number identifier, together with the study number, the lot number, expiration date, and Sponsor 
information.  
6.2.3 PRODUCT STORAGE AND STABILITY 
All study medication must be stored in a secure location under controlled -20⁰C frozen conditions 
(acceptable temperature range is between -30oC and -10oC). Records of the storage conditions must be 
maintained throughout the study by continuous temperature recording systems, regularly maintained 
temperature alarm systems, or by visual inspection of a calibrated thermometer. The temperature, date, 
and time must be recorded daily and initialed by the appropriate study-site personnel.  
The rNAPc2 study drug contains no antibacterial preservatives and should be thawed immediately 
before use. Vials should be thawed at room temperature and should not be heated or shaken. Vials may 
be gently swirled and inverted to promote thawing and mixing. After thawing, if necessary, vials can be 
stored at ambient temperature (15⁰C - 25⁰C, with excursions up to 30⁰C) for up to twenty-four (24) 
hours, or under refrigerated conditions (2 - 8⁰C) for up to 3 months. Exposure or storage at elevated 
ambient temperature (> 25⁰C) should be limited to < 2 hrs.   
6.2.4 PREPARATION 
After vial thawing, the appropriate volume of rNAPc2 drug product, based on the calculated dose for a 
patient, should be drawn from the vial into a polypropylene syringe for SC injection. Vials of drug 
product should be used for preparing one dose for one participant only. rNAPc2 in polypropylene 
syringes may be stored at refrigerated conditions (2 - 8⁰C) for up to 24 hours, or at room temperature 
for up to 4 hours. The product should be allowed to equilibrate to ambient temperature before 
administration.  
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Intervention Allocation 
Site-based randomization will be implemented in this study. Participants will be randomly assigned to 
treatment groups based on a computer-generated randomization schedule prepared before the study 
by or under the supervision of the Sponsor. The randomization will be balanced by using randomly 
permuted blocks for each site and the D-dimer level stratification. After confirming eligibility, the 
requestor will obtain the participant’s randomization assignment.  
Blinding 
To minimize the potential for bias, data that may potentially unblind the intervention assignment will be 
handled with special care to maintain the integrity of blinding for the participant and the CEC. This 
includes discouraging speculation and avoiding verbal disclosure to the participant and redacting the 


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data in question from medical records reviewed by the CEC. Study site investigators assessing potential 
clinical efficacy and safety events should be blinded to treatment allocation, if possible. Neither the 
study site, Sponsor, CEC, nor study participants will have access to the central laboratory results during 
the conduct of the trial with the exception of clinical safety alerts.  
The investigator will not be provided with randomization codes. The study site will know the treatment 
assignment, however; participants should not be made aware of their treatment assignment. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Both rNAPc2 and heparin should be administered and documented in-hospital by hospital staff. Dates, 
doses and mode of administration will be recorded in the electronic Case Report Form (eCRF).  
6.5 
CONCOMITANT THERAPY 
 
Use of the following prohibited concomitant therapy is excluded at any time during the study: 
• 
Treatment with an investigational drug or device, defined as one not approved for any 
indication in the US, Europe or Japan. If treatment with an investigational drug or device is 
initiated, study medication should be discontinued. Follow up procedures continue as shown on 
the Schedule of Activities (SoA). 
 
If the patient requires the following therapies for medical indications, rNAPc2 should be not be 
concomitantly administered: 
• 
Dual antiplatelet therapy, e.g., aspirin + ticagrelor, clopidogrel, or prasugrel 
• 
Systemic anticoagulation, e.g., warfarin, factor Xa inhibitors, direct thrombin inhibitors 
 
Appropriate investigator discretion based upon the prior therapy should apply for washout timelines of 
these therapies in advance of rNAPc2 administration. As per standard pharmacokinetic studies, a delay 
of 4 to 5 half-lives should be allowed to washout most drugs. 
6.5.1 MANAGEMENT OF BLEEDING EVENTS 
rNAPc2 is expected to be dosed in-hospital on Days 1, 3 and 5; half-life of rNAPc2 following the day 5 
dose is approximately 72 hours. Heparin is expected to be dosed in-hospital; half-life of LMWH is 
approximately 4½ hours, half-life of UFH is approximately 1 hour. If serious bleeding occurs in-hospital 
the following routine measures should be considered: 
• 
Delay the next study drug administration or discontinue treatment if indicated.  
• 
Consider the usual treatment measures for bleeding events, including fluid replacement and 
hemodynamic support, blood transfusion, and fresh frozen plasma, if physical examination and 
laboratory testing suggest benefit could be obtained. 
If rescue management is required, participant should remain blinded to treatment assignment if 
possible. For uncontrolled major bleeding in a patient receiving rNAPc2 for whom usual treatment 
measures have been ineffective, recombinant activated clotting factor VII (rfVIIa) may be 
administered.26 In a Phase 1 study in healthy volunteers, administration of rfVIIa 4 hours after rNAPc2 
normalized PT, which was correlated with the activation of the coagulation cascade as measured using 


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biochemical markers of factor X and factor IX activation. This study suggests that rfVIIa may be useful in 
transiently reversing the anticoagulant effects of rNAPc2. However, the effect of rfVIIa in an actively 
bleeding patient who has received rNAPc2 is currently unknown (refer to the Investigator Brochure). 
If the participant is not hospitalized, a serious bleeding event should be referred for evaluation at the 
appropriate facility such as an urgent care center or emergency department depending on the severity 
of the bleeding.  
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
A participant's study medication must be discontinued if: 
• 
The participant withdraws consent to receive study medication 
• 
The investigator believes that for safety reasons or tolerability reasons (e.g. AE) it is in the best 
interest of the participant to discontinue study medication 
• 
The participant develops any condition, which in the investigator’s judgment requires long-term 
therapeutic anticoagulation or fibrinolysis 
• 
The participant initiates treatment with an investigational drug or device, defined as one not 
approved for any indication in the US, Europe or Japan 
• 
The participant becomes pregnant. 
If a participant discontinues study medication for any reason before the end of the study, study 
assessments should continue in accordance with the SoA to ascertain full safety and efficacy 
information.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. Data 
collected in the database and research samples collected up to the date of withdrawal remain part of 
the study. If the participant wishes to have their data removed and/or samples destroyed, they must 
make a written request to the investigator at their clinical site. The intention is to follow all randomized 
participants for safety and vital status even if they desire to withdraw from study participation. 
If a participant withdraws from the study, the reason for withdrawal will be recorded on the eCRF and 
the final visit will be completed at that time. If obtaining vital status via direct contact with the 
participant is not possible, vital status may be obtained at study end through the participant’s physician, 
medical claims or public information according to local guidelines and as allowed by local regulations. 
In Phase 2b, participants who sign the informed consent form (ICF) and are randomized but do not 
receive the study intervention may be replaced. Participants who sign the ICF, are randomized and 
receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the 
study, will not be replaced. Phase 3 is event driven, so replacement of participants is not an issue. 
 
 


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7.3 
LOST TO FOLLOW-UP 
All randomized participants will be followed for outcomes until Day 30 whether study medication has 
been continued or discontinued. Only if a participant withdraws consent for all follow-up (active and 
passive) will they be considered to have withdrawn consent. If a participant cannot be contacted or has 
requested no contact, site staff will ascertain clinical endpoint events through the patient’s physician or 
electronic medical record. A participant will be considered lost to follow-up if he or she is unable to be 
reached by the study site staff and no information from external sources (e.g. treating physicians, 
electronic medical record, family, registries) can be obtained. Only participants for whom no information 
can be ascertained, will be considered lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
STUDY PROCEDURES 
 
 


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8.1.1 SCHEDULE OF ACTIVITIES 
Table 2a. Schedule of Activities (SoA) 
 
 
Activity 
Screen 
Day -7 to 
 1 
Baseline 
Day 1 
Day 2 
(24h 
post-
dose 
+2h) 
Day 
3+1d 
Day 
5+1d 
Day 
8+1d 
Day of 
Hospital 
Discharge 
Day 30+3d 
Informed consent 
x 
 
 
 
 
 
 
 
Assess eligibility 
x 
x 
 
 
 
 
 
 
Randomize 
 
x 
 
 
 
 
 
 
Medical history (COVID-19, 
cardiovascular, medical/ 
surgical history) b 
 
x 
 
 
 
 
 
 
Concomitant medicationb 
 
x 
x 
x 
x 
x 
x 
xd 
Baseline demographicsb 
x 
 
 
 
 
 
 
 
Focused physical 
examination, vital signs, 
weight, heightb 
 
x 
 
 
 
 
 
 
Study medication c 
rNAPc2 7.5 μg/kg SC on Day 1 and 5μg/kg SC on Days 3 and 5  
or 
rNAPc2 5 μg/kg SC on Day 1 and 3 μg/kg SC on Days 3 and 5  
or  
heparin per SoC 
Local laboratory values 
xa 
 
Record values of interest performed in the hospital clinical laboratory until hospital 
discharge or day 30 visit (whichever is first). In the case where a lab test is measured 
multiple times per day, the first scheduled values as well as any additional values 
that represent a clinically significant change should be reported. 
Assess need for inpatient 
medical services  & complete 
ACTT 
 
Daily until discharged to outpatient status or death or Day 30 reached 
Clinical & adverse eventsg 
x 
x 
x 
x 
x 
x 
x 
xd 
Post-COVID functional status 
(PCFS) scale 
 
 
 
 
 
 
xh 
xd 
Vital status 
 
 
 
 
 
 
 
xd 
Healthcare utilization 
 
 
 
 
 
 
x 
xd 
Central Laboratory 
assessments (see Table 2b) 
 
x 
x 
xe 
 
xf 
xf 
xe 
 
a Local lab D-dimer drawn during hospitalization and prior to randomization will be used for eligibility and randomization 
stratification  
b May be obtained/extracted from medical record to minimize staff exposure to COVID-19 
c rNAPc2 must be dosed on Days 1, 3 and 5; only one rNAPc2 dose regimen is anticipated in Phase 3; Participants randomized to 
receive heparin will have doses administered per standard of care (SoC) 


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d Participants who are discharged prior to Day 30 may have these activities performed remotely  
e For phase 2b only 
f If participant is discharged prior to Day 8, central laboratory assessments should be performed at hospital discharge 
g Participants will be assessed at minimum daily, while hospitalized, for the occurrence of any clinical and adverse events (See 
Section 8.2 Efficacy Assessments and  Section 8.4 Adverse Events and Serious Adverse Events) by the clinical care team as a part 
of standard of care. The clinical care team should inform the study team of any potential events. Additionally, the study team is 
expected to assess for the occurrence of potential events during scheduled study visits.  
h If hospital discharge occurs before Day 30, the PCFS should be performed the day after hospital discharge (up to 3 days after 
discharge allowed).  A retrospective assessment of PCFS pre-COVID-19, which reflects functional status during the month 
preceding COVID-19 infection, should be performed after current PCFS assessment at hospital discharge. 
Following hospital discharge, study activities may be performed remotely except for central laboratory 
blood collection.  
8.1.2 LABORATORY SAMPLES AND VALUES 
Participants will have laboratory samples collected and analyzed both locally and centrally in accordance 
with the SoA.  
Local Laboratory Values 
Laboratory tests of interest listed below, obtained via the local laboratory that are used to assess 
eligibility*, or are collected during the participant’s enrollment until hospital discharge or Day 30 visit 
(whichever is first) should be reported via the eCRF. In the case of D-dimer, initial value (eligibility) is 
preferred as collected at the time of hospital admission, prior to initiation of heparin treatment. In the 
case where a lab test is measured multiple times per day, the first scheduled values as well as any 
additional values that represent a clinically significant change should be reported.   
• 
Hemoglobin 
• 
D-dimer*  
• 
White blood cell count (WBC) 
• 
Platelet count* 
• 
Estimated glomerular filtration rate (eGFR)* 
• 
Aspartate aminotransferase (AST) 
• 
Alanine aminotransferase (ALT) 
• 
Total bilirubin 
• 
Prothrombin time (PT) 
• 
Partial thromboplastin time (PTT)  
• 
Troponin 
• 
Brain natriuretic peptide (BNP) 
Central Laboratory Sample(s) 
Central laboratory samples should be collected and shipped to the central laboratory as described in the 
Laboratory Manual.  The following table outlines the samples that will be collected and analyzed via the 
central laboratory. 


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Table 2b. Central Laboratory Blood Collection 
Day 1a 
Day 2 (24h 
post-dose) 
Day 3 
Phase 2b only 
Day 8b, or Day of Hospital 
Discharge (if prior to Day 8) 
Day 30 
Phase 2b only 
Samples for clinical laboratory tests 
IL-6, hsCRP 
 
 
IL-6, hsCRP  
 
D-dimer, PT, PTT, 
factor Xa 
tissue factor, 
antiphospholipid 
antibody  
D-dimer, PT, 
PTT 
D-dimer, PT, PTT 
 
D-dimer, PT, PTT, factor Xa 
tissue factor, antiphospholipid 
antibody 
antiphospholipid 
antibody 
ADA for rNAPc2 
subjects 
(Phase 2b only) 
PK sample for 
rNAPc2 
subjects 
(Phase 2b 
only) 
 
PK sample for rNAPc2 subjects 
(Phase 2b only) 
ADA for rNAPc2 
subjects 
Samples for future research usec 
Future use serum 
and plasma 
aliquots and buffy 
coat 
 
 
Future use serum and plasma 
aliquots  
 
a Baseline Central Laboratory sample should be collected before administration of study medication (rNAPc2 or heparin). A 
sample up to 1-hour post-administration is acceptable. 
b For rNAPc2-allocated participants, Day 8 Central Laboratory samples should be collected before that day’s dose of SoC 
thromboprophylaxis, if prescribed. 
c Note, samples for future research use should only be collected for those participants that consent for optional sample banking 
for future research. 
ADA = anti-drug antibodies, hsCRP = high sensitivity C-reactive protein, IL-6 = interleukin-6, PT = prothrombin time, PTT = partial 
thromboplastin time 
 
The central laboratory will extract deoxyribonucleic acid (DNA) from buffy coat of participants 
consenting to genetic research, aliquot, store and batch ship DNA and future use serum and plasma 
samples to biobank, if applicable. 
  
Central laboratory results will not be provided to clinical sites but will be reviewed by the Data Safety 
Monitoring Committee.  
 
For females of child-bearing potential, a negative urine pregnancy test is required prior to initiation of 
study drug treatment at the Baseline/Day 1 visit, and additionally as required by local regulatory 
requirements. 
 
8.1.3 VISIT DESCRIPTION 
Screening Visit (Day -7 to 1) 
The screening visit may occur up to 7 days prior to the Baseline visit. The Screening and Baseline Visit 
may be performed on the same day, if appropriate.  
The following procedures will occur during the screening visit: 
• 
Informed consent 
o Informed consent must be obtained prior to any other research procedures. 


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• 
Assess eligibility 
• 
Local laboratory values, as applicable 
• 
Baseline demographics 
o Age 
o Sex 
o Childbearing Potential 
o Ethnicity 
o 
Race 
• 
Adverse events assessment 
o Assess for the occurrence of any serious adverse events and report via the eCRF as 
appropriate. See Section 8.4 Adverse Events and Serious Adverse Events for more 
information about adverse events. 
Baseline Visit (Day 1) 
The Baseline visit will be considered Day 1 and may be performed on the same day as the Screening 
Visit, if appropriate.  
The following procedures will occur during the Baseline visit: 
• 
Assess eligibility 
• 
Medical history (may be obtained/extracted from the medical record to minimize staff exposure 
to COVID-19) 
o COVID-19 symptoms 
o Cardiovascular history 
o Medical/surgical history 
• 
Concomitant medication (may be obtained/extracted from the medical record to minimize staff 
exposure to COVID-19) 
• 
Focused physical examination  
• 
Vital signs   
o Height 
o Weight 
o Temperature 
o Blood pressure 
o Respiratory rate 
o Heart rate 
o Oxygen saturation 
• 
Local laboratory values, if applicable 
• 
Central laboratory samples  
o The baseline samples should be collected before administration of study medication 
(rNAPc2 or heparin). A sample up to 1-hour post-administration is acceptable. 
o For females of child-bearing potential a negative urine pregnancy test is required prior 
to initiation of study drug  


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o An additional central laboratory sample must be collected 24h after the first dose of 
study drug (±2hours) 
• 
Randomization 
• 
Study medication administration 
• 
Clinical events and adverse events assessment 
o Assess for the occurrence of any adverse events and report via the eCRF as appropriate. 
See Section 8.4 Adverse Events and Serious Adverse Events for more information about 
adverse events. 
o Assess for the occurrence of any clinical event that suggests the possibility that an 
efficacy outcome event has occurred. See Section 8.2 Efficacy Assessments for more 
information about clinical events of interest. 
Day 2 (24 hours post dose +/- 2 hours) 
The following procedures will occur during the Day 2 visit: 
• 
Central laboratory samples must be collected 24h after the first dose of study drug (+/- 2hours) 
• 
Concomitant medication (may be obtained/extracted from the medical record to minimize staff 
exposure to COVID-19) 
• 
Assess need for inpatient medical services and complete ACTT 
o The need for inpatient medical services should be assessed daily after randomization 
until the participant is discharged from the hospital, deceased, or Day 30 visit is reached. 
o Documentation pertaining to this assessment must be provided to the CEC as outlined in 
the Site Manual.  
• 
Clinical events and adverse events assessment 
o Assess for the occurrence of any adverse events and report via the eCRF as appropriate. 
See Section 8.4 Adverse Events and Serious Adverse Events for more information about 
adverse events. 
o Assess for the occurrence of any clinical event that suggests the possibility that an 
efficacy outcome event has occurred. See Section 8.2 Efficacy Assessments for more 
information about clinical events of interest. 
Day 3 Visit (+/- 1 Day) 
The following procedures will occur during the Day 3 visit: 
• 
Concomitant medication (may be obtained/extracted from the medical record to minimize staff 
exposure to COVID-19) 
• 
Study medication administration 
o If an rNAPc2-allocated participant is discharged from the hospital before receiving the 
Day 3 dose, the dose(s) should be recorded in the electronic Case Report Form (eCRF) as 
not administered.  
• 
Local laboratory values, if applicable 


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• 
Assess need for inpatient medical services and complete ACTT 
o The need for inpatient medical services should be assessed daily after randomization 
until the participant is discharged from the hospital, deceased, or Day 30 visit is reached. 
o Documentation pertaining to this assessment must be provided to the CEC as outlined in 
the Site Manual.  
• 
Clinical events and adverse events assessment 
o Assess for the occurrence of any adverse events and report via the eCRF as appropriate. 
See Section 8.4 Adverse Events and Serious Adverse Events for more information about 
adverse events. 
o Assess for the occurrence of any clinical event that suggests the possibility that an 
efficacy outcome event has occurred. See Section 8.2 Efficacy Assessments for more 
information about clinical events of interest. 
• 
Central laboratory samples (Phase 2b only) 
Day 5 Visit (+/- 1 Day) 
The following procedures will occur during the Day 5 visit: 
• 
Concomitant medication (may be obtained/extracted from the medical record to minimize staff 
exposure to COVID-19) 
• 
Study medication administration 
o If an rNAPc2-allocated participant is discharged from the hospital before receiving the 
Day 5 dose, the dose(s) should be recorded in the electronic Case Report Form (eCRF) as 
not administered.  
• 
Local laboratory values, if applicable 
• 
Assess the need for inpatient medical services and complete ACTT 
o The need for inpatient medical services should be assessed daily after randomization 
until the participant is discharged from the hospital, deceased, or Day 30 visit is reached. 
o Documentation pertaining to this assessment must be provided to the CEC as outlined in 
the Site Manual.  
• 
Clinical events and adverse events assessment 
o Assess for the occurrence of any adverse events and report via the eCRF as appropriate. 
See Section 8.4 Adverse Events and Serious Adverse Events for more information about 
adverse events. 
o Assess for the occurrence of any clinical event that suggests the possibility that an 
efficacy outcome event has occurred. See Section 8.2 Efficacy Assessments for more 
information about clinical events of interest.  
Day 8 Visit (+/- 1 Day) 
The following procedures will occur during the Day 8 visit: 


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• 
Concomitant medication (may be obtained/extracted from the medical record to minimize staff 
exposure to COVID-19) 
• 
Study medication administration, if randomized to heparin and still hospitalized 
• 
Local laboratory values, if applicable 
• 
Assess need for inpatient medical services and complete ACTT 
o The need for inpatient medical services should be assessed daily after randomization 
until the participant is discharged from the hospital, deceased, or Day 30 visit is reached. 
o Documentation pertaining to this assessment must be provided to the CEC as outlined in 
the Site Manual.  
• 
Clinical events and adverse events assessment  
o Assess for the occurrence of any adverse events and report via the eCRF as appropriate. 
See Section 8.4 Adverse Events and Serious Adverse Events for more information about 
adverse events. 
o Assess for the occurrence of any clinical event that suggests the possibility that an 
efficacy outcome event has occurred. See Section 8.2 Efficacy Assessments for more 
information about clinical events of interest.  
• 
Central laboratory samples, if not already collected at Day of Hospital Discharge 
Day of Hospital Discharge 
The following procedures will occur on the Day of Hospital Discharge: 
• 
Concomitant medication (may be obtained/extracted from the medical record to minimize staff 
exposure to COVID-19) 
• 
Study medication administration, if applicable 
• 
Local laboratory values, if applicable 
• 
Assess need for inpatient medical services and complete ACTT 
o The need for inpatient medical services should be assessed daily after randomization 
until the participant is discharged from the hospital, deceased, or Day 30 visit is reached. 
o Documentation pertaining to this assessment must be provided to the CEC as outlined in 
the Site Manual.  
• 
Clinical events and adverse events assessment  
o Assess for the occurrence of any adverse events and report via the eCRF as appropriate. 
See Section 8.4 Adverse Events and Serious Adverse Events for more information about 
adverse events. 
o Assess for the occurrence of any clinical event that suggests the possibility that an 
efficacy outcome event has occurred. See Section 8.2 Efficacy Assessments for more 
information about clinical events of interest.  
• 
Post-COVID functional status (PCFS) scale 
o If hospital discharge occurs before Day 30, PCFS assessment should be performed the 
day after hospital discharge (up to 3 days after discharge allowed).  
o PCFS scale may be performed remotely e.g. by telephone.   


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o A retrospective assessment of PCFS pre-COVID-19, which reflects functional status 
during the month preceding COVID-19 infection, should be performed after current 
PCFS assessment at hospital discharge.  
• 
Healthcare Resource Utilization Assessment 
• 
Central laboratory samples, if Day of Hospital Discharge is prior to Day 8 
Day 30 Visit (+/- 3 Days) 
The following procedures will occur at the Day 30 visit: 
• 
Visit procedures other than central lab assessment may be performed remotely for participants 
who have already been discharged from the hospital 
• 
Concomitant medication (may be obtained/extracted from the medical record to minimize staff 
exposure to COVID-19) 
• 
Study medication administration, if randomized to heparin and still hospitalized 
• 
Local laboratory values, if applicable 
• 
Assess need for inpatient medical services and complete ACTT 
o The need for inpatient medical services should be assessed daily after randomization 
until the participant is discharged from the hospital, deceased, or Day 30 visit is reached. 
o Documentation pertaining to this assessment must be provided to the CEC as outlined in 
the Site Manual.  
• 
Clinical events and adverse events assessment  
o Assess for the occurrence of any adverse events and report via the eCRF as appropriate. 
See Section 8.4 Adverse Events and Serious Adverse Events for more information about 
adverse events. 
o Assess for the occurrence of any clinical event that suggests the possibility that an 
efficacy outcome event has occurred. See Section 8.2 Efficacy Assessments for more 
information about clinical events of interest.  
• 
Post-COVID functional status (PCFS) scale 
o PCFS scale may be performed remotely e.g. by telephone.   
o For patients discharged on Day 30, a retrospective assessment of PCFS pre-COVID-19, 
which reflects functional status during the month preceding COVID-19 infection, should 
be performed after current PCFS assessment.  
o PCFS scale assessments should be omitted if the patient remains hospitalized through 
Day 30 as the instrument is intended to assess outpatient recovery. 
• 
Vital Status (alive or deceased) 
• 
Healthcare Resource Utilization Assessment 
• 
Central laboratory samples (Phase 2b only) 
 
 


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8.2 
EFFICACY ASSESSMENTS  
Efficacy assessments include clinical outcomes, functional outcomes, and biomarker laboratory values. 
Refer to Section 3 OBJECTIVES AND ENDPOINTS for detailed information on study objectives and 
endpoints. 
Adjudication of clinical outcomes will be performed centrally by the CEC operating under the CEC 
charter through review of redacted medical records. If the patient received care in a different health 
system, the clinical site will be responsible for obtaining medical records for review by the CEC and for 
archiving those records. Adjudication results will be recorded in the adjudication eCRF.  
Clinical and functional outcomes will be assessed and documented by study site staff at the timepoints 
outlined in the SoA. Assessment may occur via telephone/web contact, review of the eCRF, electronic 
medical records (EMR), claims databases, Social Security Death Index, or other source documents. Study 
site staff should provide all information/documentation necessary for evaluation of the efficacy 
endpoints. 
Clinical outcomes: Clinical outcomes of interest as efficacy endpoints include: 
• 
Venous thromboembolic event (VTE) 
• 
Myocardial infarction (MI) 
• 
Stroke (ischemic, hemorrhagic, unknown etiology) 
• 
Acute limb ischemia (ALI) 
• 
Other arterial and venous thromboembolic events 
• 
All-cause mortality (and cause of death if known) 
• 
COVID digit 
• 
Time to recovery (as measured by the ACTT ordinal scale)  
• 
Re-hospitalization to an acute care facility* 
Any event that suggests the possibility that a clinical outcome has occurred (including acute coronary 
syndrome and transient ischemic attack) should be recorded in the eCRF and will be assessed by the CEC 
(*with the exception of re-hospitalization which will be investigator-reported). The Coordinating Center 
will also review serious adverse events (SAEs) to identify potential clinical thrombotic events. COVID-19 
has been associated with emboli in a variety of locations, including internal organs (e.g. mesenteric 
artery, renal artery). These should all be included in the event of “systemic embolization.” Unusual 
locations for VTE have also been reported in association with COVID-19 such as thrombosis of the 
cerebral veins or sinuses, gonadal or splanchnic veins. These should be recorded in the eCRF as VTE.  
Functional outcomes: 
• 
PCFS 
Biomarker laboratory values: 
• 
Biomarkers associated with outcomes including those related to coagulation and inflammation 
(e.g., D-dimer, PT, PTT, Tissue Factor, factor Xa, antiphospholipid antibodies, IL-6, hsCRP). 
ACTT ordinal scale: Study-site personnel will record ACTT information on the eCRF. Additionally, source 
documentation will be reviewed by the CEC which will adjudicate the ACTT and record the results in the 


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adjudication eCRF. The CEC will leverage the committee structure and collective experience to align on 
consistent criteria to distinguish between scores 5 and 6.  
1. Death 
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 
related or otherwise) 
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care 
7. Not hospitalized, limitation on activities and/or requiring home oxygen 
8. Not hospitalized, no limitations on activities 
Post-COVID-19 Functional Status Scale: The PCFS31 will be used to evaluate patient-reported functional 
status at hospital discharge, and 30-days post-randomization (if the patient has been discharged) (Figure 
7). Retrospective assessment of pre-COVID-19 functional status will also be recorded. Instructions for 
using the scale are provided in Section 10.4. 
 
 
Figure 7. Post-COVID Functional Status Scale 
8.3 
SAFETY AND OTHER ASSESSMENTS 
 
Safety assessments will include monitoring of serious and non-serious AEs and study endpoints. Efficacy 
and safety endpoints, including all bleeding events, will not be considered as AEs or SAEs (see Section 
8.4 Adverse Events and Serious Adverse Events). Safety evaluations will be assessed by the investigator 
per the SoA via EMR review, telephone or web contact with the participant or their health care provider. 
 
Safety Events: 
Bleeding events are considered safety endpoints for the study. 
 


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The study will classify bleeding events as major, non-major clinically relevant or non-major non-clinically 
relevant. Safety endpoints for this study include major, critical site and fatal bleeding and non-major 
clinically relevant bleeding using modified International Society on Thrombosis and Haemostasis (ISTH) 
bleeding criteria. All bleeding events will be assessed, classified and reported by the investigator in the 
eCRF. Major bleeding events will be adjudicated by the CEC. 
 
An ISTH major bleeding event is defined as overt bleeding that is associated with: 
• 
A fall in hemoglobin of 2 g/dL (1.24 mmol/L) or more, or 
• 
A transfusion of 2 or more units of packed red blood cells or whole blood, or 
• 
A critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with 
compartment syndrome, retroperitoneal, or 
• 
A fatal outcome. 
 
Non-major clinically relevant bleeding is defined as overt bleeding not meeting the criteria for 
major bleeding but associated with medical intervention, unscheduled visit or telephone call with a 
healthcare provider or temporary or permanent cessation of study treatment or associated with 
discomfort for the participant such as pain or impairment of activities of daily life. 
 
Bleeding events not meeting the definition of major or non-major clinically relevant bleeding will be 
classified as non-major, non-clinically relevant. 
   
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.4.1 DEFINITION OF ADVERSE EVENTS  
An AE is any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related. 
COVID-19 Related Events 
 
The following are considered COVID-19-related symptoms: 
 
World Health Organization-specified COVID-19 symptoms32 
Most Common Symptoms 
Fever, dry cough, tiredness 
Less Common Symptoms 
 
aches and pains, sore throat, diarrhea, conjunctivitis, headache, loss of 
taste or smell, a rash on skin, or discoloration of fingers or toes 
Serious Symptoms 
 
difficulty breathing or shortness of breath, chest pain or pressure, loss 
of speech or movement 
 
Other COVID-19 related events include: adult respiratory distress syndrome (ARDS), and disseminated 
intravascular coagulation (DIC). 
 
Symptoms and events that are known to be associated with COVID-19 will be reported by the 
investigator in the eCRF when they meet criteria as AEs or SAEs. Safety evaluations will be assessed by 
the investigator per the SoA via EMR review, telephone or web contact with the participant or their 
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8.4.2 DEFINITION OF SERIOUS ADVERSE EVENTS  
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes:  
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
• 
A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the participant and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
8.4.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.4.3.1 SEVERITY OF EVENT 
The investigator will classify AE severity according to the following scale. 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious.” 
8.4.3.2 RELATIONSHIP TO STUDY INTERVENTION 
The investigator will assess the relationship of AEs to study intervention using the categories below.  
 
• 
Related – The AE is known to occur with the study intervention or there is evidence to suggest a 
causal relationship between the study intervention and the AE. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of study medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events).  
• 
Not Related – There is not evidence to suggest a causal relationship with study intervention or 
an alternate etiology has been established. 
 
 


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8.4.3.3 EXPECTEDNESS  
For rNAPc2, expectedness of an AE will be determined by whether it is listed in the Investigator 
Brochure, section on Risks, Side Effects and Precautions. 
8.4.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Adverse Events and SAEs will be identified as per the SoA. All AEs will be collected from the time of 
randomization until the participant completes their Day 30 visit or final contact.  
All SAEs from the time of consent until the participant completes their Day 30 visit or final contact, 
whichever is longer, must be reported. All SAEs will be followed until satisfactory resolution or until the 
site investigator deems the event to be chronic or the participant is stable. Follow up may be conducted 
by EMR review or communication with the participant’s health care provider.   
 
8.4.5 SERIOUS ADVERSE EVENT REPORTING  
All SAEs occurring during the study must be reported to the appropriate sponsor contact person by 
study-site personnel within twenty-four (24) hours of their knowledge of the event. 
 
Regulatory Reporting Requirements for Serious Adverse Events 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. The 
sponsor or delegate will also report all suspected unexpected serious adverse reactions (SUSARs) to 
clinical site investigators. The investigator (or sponsor where required) must report SUSARs to the 
appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the 
protocol unless otherwise required and documented by the IEC/IRB. 
 
To protect the integrity of the study, thromboembolic and bleeding endpoints will not be unblinded for 
reporting to Health Authorities or investigators as safety reports unless otherwise requested by Health 
Authorities or IEC/IRB.  
 
After study completion, these events will be included in the final analysis which will be unblinded and 
submitted to Health Authorities with the study report.  
 
Expedited Reporting Requirements 
The Sponsor will promptly evaluate all SAEs against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to Investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. Certain events are anticipated to occur in the study 
population at some frequency independent of study drug exposure and will be excluded from expedited 
reporting, as noted below in Table 3: 
 
 
 


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Table 3: Reporting of Suspected Unexpected Serious Advers Reactions (SUSARs; Unless Otherwise 
Requested by Health Authorities or Ethics Committees) 
Event type 
Expedited report to health 
authorities and investigators 
Unblinded to 
health authorities 
Unblinded to 
investigators 
Study endpoint events, including 
bleeding endpoints 
N 
N 
N 
Non-endpoint SAEs determined to be 
related to study drug 
Y 
Y 
N 
Non-endpoint SAEs determined to un-
related to study-drug (e.g., COVID-19 
related events) 
N 
N 
N 
 
Data Safety Monitoring Committee oversight is described in Section 10.1.6 Safety Oversight. 
 
8.4.6 REPORTING EVENTS TO PARTICIPANTS  
After study completion, a summary of study results will be provided to clinical sites for transmission to 
study participants. 
8.4.7 EVENTS OF SPECIAL INTEREST  
Safety events of interest that may require expedited reporting and/or safety evaluation include, but are 
not limited to: 
• 
Overdose of a sponsor study drug 
• 
Suspected abuse/misuse of a sponsor study drug 
• 
Inadvertent or accidental exposure to a sponsor study drug 
• 
Medication error involving a sponsor product (with or without participant/patient exposure to 
the sponsor study drug, e.g. administration to the wrong patient) 
Special reporting situations should be recorded in the eCRF and source documents. Any special 
reporting situation that meets the criteria of an SAE should be recorded on the SAE page of the eCRF. 
 
8.4.8 REPORTING OF PREGNANCY  
All initial reports of pregnancy in female participants or partners of male participants must be reported 
to the sponsor by the study-site personnel within twenty-four (24) hours of their knowledge of the 
event using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (e.g. 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered 
SAEs and must be reported on the SAE page of the eCRF. Participants who become pregnant should 
permanently discontinue treatment with rNAPc2. Management of heparin-allocated participants should 
be deferred to the participant’s treating physician for thrombotic risk assessment.  
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant 
will be required. 
 
 


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9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
During Phase 2b, the null hypothesis for the primary endpoint is that treatment with rNAPc2 and 
heparin will similarly reduce D-dimer at Day 8; the alternative hypothesis is that rNAPc2 is superior to 
heparin in reducing D-dimer.  
During Phase 3, the null hypothesis for the primary endpoint is that time to recovery within 30 days of 
randomization is similar for treatment with rNAPc2 and heparin; the alternative hypothesis is that 
rNAPc2 is superior to heparin by promoting shorter time to recovery. 
9.2 
SAMPLE SIZE DETERMINATION 
During Phase 2b, approximately 160 participants will be enrolled and randomized 1:1:2 to rNAPc2 
dose regimen 1, rNAPc2 dose regimen 2, and heparin standard of care, respectively. Assuming 
approximately 20% of participants may not be evaluable for any reason, 160 randomized participants 
will provide for approximately 130 evaluable participants. At a sample size of 160 or greater, the study 
will have adequate power across a range of effect sizes. This sample size was selected to ensure 
inferences for the primary endpoint analysis will be robust, given certain potential confounding factors 
such as missing data (random or non-random), heterogeneous application of heparin (low molecular 
weight and unfractionated; prophylactic and therapeutic), effects of subject-level covariates (e.g., 
cormorbidities), and effects of site-level covariates (e.g., country). 


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During Phase 3, 450 patients yielding 360 recovery events randomized 1:1 into the two treatment 
groups have approximately 80% power with 5%, two-sided type 1 error assuming median recovery times 
of 11 and 15 days for the rNAPc2 and heparin groups, respectively (i.e., treatment hazard ratio 
(HR)=1.36). As described in Section 9.4.6 Planned Interim Analyses, at the second Phase 3 interim 
analysis (67% of the initial target number of events), if conditional power, based on the estimated 
interim hazard ratio, falls within 30% and 80%, the sample size and target number of events will be 
increased to target 90% conditional power for the final analysis. 
9.3 
POPULATIONS FOR ANALYSES 
Randomized participants consist of all screened participants with randomization assignment, regardless 
of whether or not study intervention was administered. Participants treated without being randomized 
or treated before randomization will not be considered as randomized and will not be included in any 
analysis population. The safety experience of these participants will be reported separately, and they 
will not be included in the safety population. 
The efficacy analysis population will be the intent-to-treat (ITT) population, consisting of all randomized 
participants as defined above. Participants in the ITT population will be analyzed according to the 
treatment group allocated by randomization. 
An additional efficacy analysis population for sensitivity analyses of the primary efficacy endpoints will 
be the modified intent-to-treat (mITT) population, consisting of the subset of the ITT population that 
received at least one dose of study drug.  Participants in the mITT population will be analyzed according 
to the treatment group allocated by randomization.   
Power, Primary Endpoint 
  
 
 
Effect Size (Proportional Reduction) 
  
Enrolled 
Subjects 
Evaluable 
Subjects 
20% 
25% 
30% 
35% 
40% 
Sample 
Size 
80 
64 
55.8% 
67.4% 
75.6% 
81.0% 
84.5% 
100 
80 
60.5% 
72.7% 
80.1% 
84.9% 
87.8% 
110 
88 
63.6% 
76.2% 
80.7% 
86.6% 
89.2% 
120 
96 
65.2% 
78.0% 
82.8% 
86.9% 
91.0% 
130 
104 
68.2% 
79.3% 
84.8% 
88.7% 
91.7% 
140 
112 
68.9% 
80.7% 
86.6% 
89.3% 
92.5% 
160 
128 
71.3% 
83.1% 
88.3% 
91.3% 
94.1% 
180 
144 
74.9% 
84.5% 
89.5% 
92.5% 
94.6% 
200 
160 
77.2% 
86.5% 
91.0% 
93.8% 
95.8% 
*Significance via α = 0.05 
†Simulated with 20% Missing Data  
‡Percentages as Averages Across Other Simulation Conditions 


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A per protocol population will include all participants who are randomized and receive all three doses of 
study drug post-randomization. Participants will be analyzed according to the treatment actually 
received. 
The safety analysis population will be the safety population, consisting of the randomized population 
who received at least one dose or part of a dose of study treatment. Participants will be analyzed 
according to the treatment received (rNAPc2 or heparin). 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
The statistical analyses described in this section will be performed as further detailed in a separate 
statistical analysis plan. The statistical analysis plan will supersede the protocol in the event of any 
differences between the two documents in the plans for data analysis, and the protocol will be amended 
if appropriate. The statistical analysis plan will be included as an appendix in the clinical study report for 
this protocol.  
 
Descriptive statistics for continuous variables will include the number of participants, mean and 
standard deviation, median, first and third quartiles, and minimum and maximum values. Descriptive 
statistics for categorical variables will contain count and percentage. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Phase 2b:  Primary efficacy endpoint is change in D-dimer level from Baseline to Day 8, or day of 
discharge if prior to Day 8. The change in D-dimer will be calculated using proportional change in 
D-dimer level from the level at baseline to the level at either Day 8 or discharge if discharge occurs 
before Day 8. A Wilcoxon rank sum test will be performed to compare baseline and Day 8 (or early 
discharge) D-dimer levels within each treatment group. A second Wilcoxon rank sum test will be used to 
compare proportional change from baseline to Day 8 (or early discharge) between treatment groups. 
The primary analysis will involve a comparison of the pooled rNAPc2 treatment groups against the 
heparin treatment group. Secondary and sensitivity analyses of the primary endpoint will be conducted 
as described in the statistical analysis plan. 
Because the optimal dose rNAPc2 is unknown and its determination is a key objective of the Phase 2b 
study, the assumption that both doses will be effective and thus can be pooled for statistical analysis 
may not be correct. Therefore, a series of secondary analyses will be conducted, consisting of analysis 
for dose response, effectiveness in a single dose group, effectiveness that is related to the extent of 
baseline D-dimer elevation, and the subgroup analyses described in Section 9.4.7 SubGroup Analyses. 
Missingness within the data is to be expected. Subject profile, mortality, or early discharge give rise to 
the possibility that nonrandom attrition may bias the point estimate for the treatment effect for the 
primary endpoint. Therefore, missingness will be handled by multiple imputation during a sensitivity 
analysis as described in the Statistical Analysis Plan (SAP).  
Phase 3: The primary efficacy endpoint is time to recovery by Day 30, with day 1 being the date of 
randomization. Recovery is defined as the first day a participant meets criteria for category 6, 7 or 8 of 
the ACTT ordinal scale. The analysis of the primary efficacy endpoint will be a comparison of the two 
treatment groups by a stratified log-rank test, where stratification is according to local laboratory 
screening D-dimer level > or ≤ 2X  local laboratory ULN. Cumulative incidence by treatment group will be 


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summarized by Kaplan-Meier estimates. Additionally, a treatment hazard ratio and corresponding 95% 
confidence interval will be estimated by a Cox proportional hazard model stratified by local laboratory 
D-dimer level at screening. 
In the analysis of the primary efficacy endpoint, participants who die within 30 days of randomization 
will be censored at Day 30. In addition, participants surviving to Day 30 who have not met the criteria for 
recovery by the time of their last ACTT scale assessment on or prior to Day 30 will be censored on the 
day of their last assessment. There will be no censoring prior to Day 30 due to study treatment 
discontinuation, initiation of non-study treatment, or intermittently missed ACTT scale assessments.  
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Phase 2b: Proportional change in D-dimer level from Baseline to 24 hours post-dose (Day 2) and Day 3 
and change in the additional biomarkers associated with outcomes, including those related to 
coagulation and inflammation from baseline through Day 8, will be analyzed by the same methods as 
described for the primary efficacy endpoint. Time-to-event outcomes will be analyzed by the same 
methods as described for Phase 3. 
Phase 3: Time to first occurrence of a composite of thrombotic events and all-cause mortality within 30 
days of randomization and time to all-cause mortality within 30 days of randomization will be analyzed 
by the same methods as described for the primary efficacy endpoint, with the exception that deaths will 
be counted as an event. Events included in these analyses will be those as adjudicated by the CEC. 
Participants without an adjudicated event by Day 30 will be censored on the study day of last contact or 
Day 30, whichever is earlier. Similar to the primary endpoint, there will be no censoring prior to Day 30 
due to study treatment discontinuation or initiation of non-study treatment. The analysis method for 
the proportion of participants alive and out of the hospital at 30 days post-randomization will be 
specified in the Statistical Analysis Plan (SAP) which will also include a multiplicity plan for alpha 
allocation within the secondary endpoints. 
Change in the biomarkers associated with outcomes including those related to coagulation and 
inflammation will be analyzed by the same methods as described for Phase 2b.  
Days in intensive care unit, on ventilator, vasopressors, renal replacement therapy, and circulatory 
support will be summarized with descriptive statistics. 
9.4.4 SAFETY ANALYSES 
Incidence rates of AEs including adjudicated bleeding events, all, serious, fatal, severe and treatment-
related AEs reported throughout the conduct of the study will be tabulated by preferred term and 
system organ class. 
Changes in laboratory values and vital signs will be summarized with descriptive statistics. The incidence 
of concomitant medications will also be summarized. 
Drop in hemoglobin level as reported per local laboratory data will be used as an indicator of potential 
bleeding risk. 
 
 


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9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline demographic information and patient characteristics including, but not limited to, gender, race, 
age, COVID-19 symptoms, ACTT ordinal scale category, study entry D-dimer median value , remdesivir or 
other antiviral therapy, concomitant medications, vital signs, and laboratory parameters will be 
summarized by treatment group for the ITT population.  
9.4.6 PLANNED INTERIM ANALYSES  
Additional details of the planned interim analyses will be provided in interim analysis plans, 1 plan each 
for Phase 2b and Phase 3, respectively. 
Phase 2b: An interim efficacy analysis will be conducted when 120 participants have completed Day 8 
assessments or Day of Discharge assessments if the participant is discharged prior to Day 8. To account 
for early recovery, deaths, and lab errors which may lead to lack of Day 8 D-dimer in approximately 20% 
of patients, 120 participants will provide for approximately 100 participants to be evaluated in the 
interim efficacy analysis. The interim efficacy analysis will test for futility based on the primary study 
hypothesis. Additionally, at the interim efficacy analysis, the Data Safety Monitoring Committee will be 
empowered to adjust sample size as pre-specified in the Phase 2b interim analysis plan. An interim 
safety analysis will occur after approximately one third of the total target enrollment (i.e., 30-40 
participants) completes the Day 8 assessments. Outcomes of the interim analyses may include changes 
to dose regimens, or other adjustments related to safety or trial logistics. No spending of type 1 error 
will occur during the interim analysis.  
Phase 3: Interim analyses on time to recovery will occur when approximately 33% and 67% of the initial 
target number of events (i.e., 120 and 240) have occurred. The following is an outline of the interim 
analysis plan: 
• 
Both interim analyses will include a non-binding assessment for futility; no formal boundary will 
be used in the first interim analysis, while the second will use a boundary corresponding to 10% 
conditional power.  
• 
Both interim analyses will have a specified boundary for unequivocal efficacy corresponding to a 
p-value of 0.0001, 1-sided solely for the purposes of a sample size re-estimation at the second 
interim analysis; the study will not be stopped for unequivocal efficacy even if this boundary is 
crossed at one of the interim analyses.  
• 
The interim analysis at 67% of the initial target number of recovery events will include a 
"promising zone" analysis of conditional power, whereby sample size may be increased by up to 
150 additional participants (e.g., 600 total participants) and 120 additional events (i.e., 480 total 
events) to target 90% conditional power for the final analysis if conditional power, based on the 
estimated interim HR, is within 30% and 80%. 
In addition to the unblinded interim analyses described above, given that the Phase 3 is event-driven 
and participants are followed for the primary endpoint for a fixed period of time (30 days), the event 
rate will be monitored in a blinded fashion throughout the study. If the blinded (noncomparative) event 
rate indicates that less than 360 primary events are unlikely to be observed among 450 randomized 
participants – or the upsized number of events and participants based on the conditional power analysis 


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at the second interim analysis described above – the number of randomized participants will be 
increased to ensure the target number of events is achieved. 
The alpha level for the final analysis will be 0.05 − 0.0001, or 0.0499.  
9.4.7 SUBGROUP ANALYSES 
For the primary efficacy endpoint for each Phase, the treatment effects across the following subgroup 
factors will be examined: 
• 
D-dimer  
• 
Gender 
• 
Age group (<65, >65 years) 
• 
Race/ethnicity 
• 
Planned or ongoing therapy with an agent with demonstrated efficacy in patients with COVID-19 
(yes, no) 
• 
Baseline ACTT ordinal scale category  
• 
Background antiplatelet therapy at baseline 
 
For the Phase 2b primary efficacy endpoint, possible heterogeneity in the treatment effect for 
subgroups within each factor will be assessed by including the factor and the interaction between the 
factor and treatment in the analysis of covariance (ANCOVA) model.  
Additionally, the heterogeneous application of heparin dichotomized by therapeutic vs. prophylactic 
uses, as well as the different standards of use across site, pose the need for sensitivity analyses to 
determine the degree to which the primary endpoint finding generalizes across sites.  
Similarly, for the Phase 3 primary efficacy endpoint, possible heterogeneity in the treatment effect for 
subgroups within each factor will be assessed by including the factor and the interaction between the 
factor and treatment in the Cox proportional hazards model. 
9.4.8 PHASE 2B TO 3 TRANSITION 
At the end of the Phase 2b study, data will be analyzed, and a dose and comparator arm will be 
identified. The Phase 3 study will then resume once appropriate regulatory authority communications 
have been conducted and concluded.  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
Each participant or their Legally Authorized Representative (LAR) must provide electronic or written 
informed consent according to local requirements after the nature of the study has been fully explained. 


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A LAR is defined by the US Department of Health and Human Services as “any individual person, judicial 
body or other body of individuals who are legally authorized under state and federal law to consent to 
research participation on behalf of a designated person.” The LAR may be a parent, grandparent, or 
caregiver who has the legal authority to grant consent on behalf of another who has been invited to 
participate in research. 
The ICF must be signed before performance of any study-related activity. The ICF and any other written 
information provided to participants must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the participant can read and understand. The consent should be in 
accordance with principles that originated in the Declaration of Helsinki, current International 
Conference on Harmonisation (ICH) and GCP guidelines, applicable regulatory requirements, and 
sponsor policy. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Before enrollment in the study, the investigator or an authorized member of the study-site personnel 
must explain (in a language the participant understands) to potential participants or their LAR the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Participants will be informed that their participation is voluntary 
and that they may withdraw consent to participate at any time. They will be informed that choosing not 
to participate will not affect the care the participant will receive. Participants will be told that refusal to 
take part in the study will not prejudice future treatment. Finally, they will be told that the investigator 
will maintain a participant identification register for the purposes of long-term follow-up if needed and 
that their records may be accessed by health authorities and authorized sponsor personnel without 
violating the confidentiality of the participant, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF, the participant or LAR is authorizing such access, which includes 
permission to obtain information about his or her survival status.  
The participant or LAR will be given sufficient time to read the electronic ICF and the opportunity to ask 
questions. Once the participant or LAR understands all aspects of the ICF, consent should be 
appropriately recorded by means of the participant’s or LAR’s signature. After having obtained the 
consent, the participant will receive a signed/dated copy for their records. 
If the participant or LAR is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and should 
personally date and sign the ICF after the oral consent of the participant [or LAR] is obtained. 
The ICF and any other written information provided to participants will be revised whenever important 
new information becomes available that may be relevant to their consent, or there is an amendment to 
the protocol that necessitates a change to the content of the patient information and/or ICF. The 
investigator will inform the participant or their LAR of changes in a timely manner and will ask the 
participant or their LAR to confirm his/her participation in the study by signing the revised ICF. Any 
revised written ICF and written information must receive the IEC/IRB`s approval/favorable opinion in 
advance of use. 
Informed consent for study participation includes collection and storage of plasma and serum samples 
for future research on sequelae of COVID-19. Separate consent will be requested for collection and 
analysis of Deoxyribonucleic acid (DNA) for future research on genetics of COVID-19 sequelae and 


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response to treatment. Participants may join the study without agreeing to collection and analysis of 
DNA. 
10.1.2 STUDY CLOSURE 
The sponsor may temporarily or permanently stop the study for any reason. If the study is prematurely 
terminated or suspended, the sponsor will notify clinical site investigators who must promptly inform 
their IEC/IRB and study participants. The sponsor will provide instructions for interim or closeout 
procedures. 
10.1.3 CONFIDENTIALITY AND PRIVACY  
The electronic enrollment log at each clinical site which links participant identifiers to their screening 
identification number will be treated as confidential and filed by the investigator in the study file. To 
ensure participant confidentiality, no copy will be made. All reports and communications relating to the 
study will identify participants by identification number. 
Privacy of Personal Data 
The collection and processing of personal data from participants enrolled in this study will be limited to 
those data that are necessary to fulfill the objectives of the study. These data must be collected and 
processed with adequate precautions to ensure confidentiality and compliance with applicable data 
privacy protection laws and regulations. Appropriate technical and organizational measures to protect 
the personal data against unauthorized disclosures or access, accidental or unlawful destruction, or 
accidental loss or alteration must be put in place. Sponsor personnel whose responsibilities require 
access to personal data agree to keep the identity of participants confidential. The informed consent 
obtained from the participant (or his or her LAR) includes explicit consent for the processing of personal 
data and for the investigator/institution to allow direct access to his or her original medical records 
(source data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. 
This consent also addresses the transfer of the data to other study-related entities and to other 
countries. 
The participant has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps will be 
taken to respond to such a request, taking into consideration the nature of the request, the conditions 
of the study, and the applicable laws and regulations. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Plasma, serum and samples for DNA extraction will be processed and stored at the clinical sites for batch 
shipping to the study biobank, consistent with local regulatory requirements. The site investigator will 
maintain full traceability of collected biological sample shipment or disposal (where appropriate) and 
documentation of receipt of arrival. The sample receiver keeps full traceability of samples arrival, 
storage and use until used or disposed of or until further shipment. 
 
Withdrawal of informed consent for biological samples 
 
If a patient withdraws consent for the use of biological samples, the samples will be disposed 
of/destroyed, and the action documented. If samples are already analyzed, the sponsor is not obliged to 


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destroy the results of this research. When the site investigator receives notification of withdrawal of 
consent to the use of collected biological samples, he/she should: 
• 
document this notification in the participant’s record 
• 
Ensure that biological samples from that participant, if stored at the study site, are immediately 
identified, disposed of/destroyed, and the action documented 
• 
If the participant’s samples have been shipped to the study biobank, ensure the laboratory(ies) 
holding the samples is/are informed about the withdrawn consent immediately and that 
samples are disposed of/destroyed, the action documented and the signed documentation 
returned to the study site for archiving 
• 
Ensures that the participant and sponsor are informed of the sample disposal. 
For additional information on participant discontinuation or withdrawal, see Section 7 STUDY 
INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL. 
10.1.5 TRIAL COMMITTEES 
Executive Committee  
 
The Executive Committee (EC) consists of members of the academic leadership of the study and the 
sponsor. Ad hoc members may be appointed as necessary. The EC has overall responsibility for the 
design, conduct and reporting of the study. The EC will monitor overall safety during the study and will 
receive any recommendations from the DSMC regarding possible additional analyses or modifications to 
the study and decide whether to accept them. The EC will oversee the implementation of any 
modifications to the study and publication of the results. 
 
Clinical Endpoint Committee  
 
A CEC, comprised of physicians blinded to treatment assignment, will review source documentation and 
centrally adjudicate clinical and functional outcomes for the trial. The CEC will be responsible for 
adjudicator training, endpoint definitions and classification procedures for suspected thrombotic events 
and quality control procedures as described in the CEC charter.   
 
Data Safety Monitoring Committee   
 
A DSMC will be appointed by and provide its input to the EC to monitor safety and evidence of 
effectiveness and to recommend modifications to the adaptive trial design. Modifications to eligibility 
criteria could include enrollment in Phase 3 of participants 16-17 years of age, based on safety data with 
weight-based dosing of rNAPc2 in the target population. For safety, ISTH major bleeding, SAEs and all-
cause mortality will be monitored monthly by the DSMC Chairperson and at scheduled interim analyses 
by the full committee (Section 9.4.6 Planned Interim Analyses). Based on monthly reviews, the DSMC 
Chairperson may call additional undscheduled meetings at anytime during the study. In addition, the 
study team may advise the DSMC chair of severe safety events (e.g. fatal bleeding) in a blinded fashion 
in real time, enabling the chair to work with the DSMC statistician and committee as needed to ensure 
the safety of study participants. The DMSC will operate under the rules of a charter that will be reviewed 
at the organizational meeting of the DSMC and approved by the principal investigator and Sponsor.  
 
 


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10.1.6 SAFETY OVERSIGHT 
A DSMC will be appointed by and provide its input to the EC to monitor safety and evidence of 
effectiveness and to recommend modifications to the trial design.  
10.1.7 CLINICAL MONITORING 
The Sponsor or designee will review eCRF data for accuracy and completeness via centralized, remote, 
and/or on-site monitoring methods described in the Monitoring Plan. Representatives of the sponsor 
may visit the study site at any time during or after completion of the study to conduct an audit of the 
study in compliance with regulatory guidelines and company policy. These audits will require access to 
all study records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and available for 
consultation during routinely scheduled study-site audit visits conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part of a 
national GCP compliance program or to review the results of this study in support of a regulatory 
submission. The investigator should immediately notify the sponsor if he or she has been contacted by a 
regulatory agency concerning an upcoming inspection. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites and review of protocol procedures with the investigator and 
study-site personnel before the study. Guidelines for eCRF completion will be provided and reviewed 
with participating study-site personnel before the start of the study. The Sponsor, or designee will 
review eCRF data for accuracy and completeness via centralized, remote, and/or on-site monitoring 
methods; any discrepancies will be resolved with the investigator or designee, as appropriate. 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Study data will be recorded into the electronic data capture system. The data system includes password 
protection and internal quality checks to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from source documents.  
10.1.9.2 STUDY RECORDS RETENTION  
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and all 
source documents that support the data collected from each participant, as well as all study documents 
as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical Trial, and all study 
documents as specified by the applicable regulatory requirement(s). The investigator/institution will 
take measures to prevent accidental or premature destruction of these documents.  
Essential documents must be retained until at least two (2) years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least two (2) years have elapsed since the formal discontinuation of clinical 


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development of the investigational product. These documents will be retained for a longer period if 
required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility 
of keeping the study records, custody must be transferred to a person who will accept the responsibility. 
The sponsor must be notified in writing of the name and address of the new custodian. Under no 
circumstance shall the investigator relocate or dispose of any study documents before having obtained 
written approval from the sponsor. If it becomes necessary for the sponsor or the appropriate 
regulatory authority to review any documentation relating to this study, the investigator/institution 
must permit access to such reports. 
10.1.10 
PROTOCOL DEVIATIONS  
Protocol deviations will be identified manually and programmatically prior to unblinding. However, as 
the primary analysis is ITT, protocol deviations will not imply exclusion from analysis. A summary of 
major protocol deviations will be given by frequency tables showing the number of participants with 
major protocol deviations overall and by deviation.  
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
All information, including but not limited to information regarding rNAPc2 or the sponsor's operations 
(e.g., patent application, formulas, manufacturing processes, basic scientific data, prior clinical data, 
formulation information) supplied by the sponsor to the investigator and not previously published, and 
any data, including research data, generated as a result of this study, are considered confidential and 
remain the sole property of the sponsor. The investigator agrees to maintain this information in 
confidence and use this information only to accomplish this study and will not use it for other purposes 
without the sponsor's prior written consent. 
The investigator understands that the information developed in the study will be used by the sponsor in 
connection with the continued development of rNAPc2, and thus may be disclosed as required to other 
clinical investigators or regulatory agencies. To permit the information derived from the clinical studies 
to be used, the investigator is obligated to provide the sponsor with all data obtained in the study. The 
results of the study will be reported in a Clinical Study Report generated by the sponsor and will contain 
data from all study sites that participated in the study as per protocol. Study participant identifiers will 
not be used in publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work.  
Consistent with Good Publication Practices and International Committee of Medical Journal Editors 
(ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) data and 
information without approval from the investigator. The investigator has the right to publish study-site-
specific data after the primary data are published. If an investigator wishes to publish information from 
the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before 
submission for publication or presentation. Expedited reviews will be arranged for abstracts, poster 
presentations, or other materials. If requested by the sponsor in writing, the investigator will withhold 
such publication for up to an additional 60 days to allow for filing of a patent application. In the event 


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that issues arise regarding scientific integrity or regulatory compliance, the sponsor will review these 
issues with the investigator. The sponsor will not mandate modifications to scientific content and does 
not have the right to suppress information.  
For multicenter study designs and sub-study approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators will 
recognize the integrity of a multicenter study by not submitting for publication data derived from the 
individual study site until the combined results from the completed study have been submitted for 
publication, within 18 months after the study end date, or the sponsor confirms there will be no 
multicenter study publication. Authorship of publications resulting from this study will be based on the 
guidelines on authorship, such as those described in the ICMJE Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals, which state that the named 
authors must have made a significant contribution to the conception or design of the work; or the 
acquisition, analysis, or interpretation of the data for the work; and drafted the work or revised it  
critically for important intellectual content; and given final approval of the version to be published; and 
agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy 
or integrity of any part of the work are appropriately investigated and resolved. 
10.1.12 
CONFLICT OF INTEREST POLICY 
The Sponsor will register and disclose the existence and results of clinical studies as required by law. The 
disclosure of the final study results will be performed after the end of study. 
10.2 ACRONYMS 
 
ACTT 
Adaptive COVID-19 Treatment Trial 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALI 
Acute limb ischemia 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
CEC 
Clinical endpoint committee 
CRA 
Clinical Research Associate 
DIC 
Disseminated intravascular coagulation 
DSMC 
Data Safety Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DVT 
Deep vein thrombosis 
EC 
Executive Committee 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EMR 
Electronic medical record 
fVIIa 
Activated factor VII 
fXa 
Activated factor X 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
HITT 
Heparin-induced thrombocytopenia and thrombosis 


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HR 
Hazard ratio 
HS 
Healthy subjects 
hsCRP 
High sensitivity C reactive protein 
HSV1 
Herpes simplex virus 1 
ICF 
Informed consent form 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IL-6 
Interleukin-6 
IND 
Investigational New Drug Application 
IEC/IRB 
Independent Ethics Committee/Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
ITT 
Intention-To-Treat 
IV 
Intravenous 
LAR 
Legally authorized representative 
LMWH 
Low molecular weight heparin 
MAD 
Multiple ascending dose 
mITT 
Modified intention-to-treat 
NSTE-ACS 
Non-ST elevation acute coronary syndrome 
PAR 
Protease activated receptor 
PCI 
Percutaneous coronary intervention 
PCR 
Polymerase chain reaction 
PCFS 
Post COVID-19 Functional Status 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
rfVIIa 
Recombinant activated factor VII 
rNAPc2 
Recombinant nematode anticoagulant protein c2 
SAD 
Single ascending dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous 
SoA 
Schedule of Activities 
SoC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reactions 
TF 
Tissue factor 
UFH 
Unfractionated heparin 
ULN 
Upper limit of normal 
UP 
Unanticipated Problem 
VTE 
Venous thromboembolic event 
WBC 
White blood cell count 
 
 
 


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10.3 HEPARIN GUIDANCE 
 
Population 
Guidance 
VTE prophylaxis in non-ICU 
hospitalized COVID-19 
patients 
1. A universal strategy of routine thromboprophylaxis with standard-
dose UFH or LMWH should be used after careful assessment of 
bleed risk, with LMWH as the preferred agent. Intermediate dose 
LMWH may also be considered.  
 
2. VTE prophylaxis recommendations should be modified based on 
extremes of body weight, severe thrombocytopenia (i.e. platelet 
counts of 50 000 × 109 per liter or 25 000 × 109 per liter) or 
deteriorating renal function. 
VTE prophylaxis in sick ICU 
hospitalized COVID-19 
patients 
1. Routine thromboprophylaxis with prophylactic-dose UFH or 
LMWH should be used after careful assessment of bleed risk. 
Intermediate-dose LMWH (50% of respondents) can also be 
considered in high risk patients. Patients with obesity as defined by 
actual body weight or BMI should be considered for a 50% increase 
in the dose of thromboprophylaxis. Treatment-dose heparin should 
not be considered for primary prevention until the results of 
randomized controlled trials are available. 
 
2. Multi-modal thromboprophylaxis with mechanical methods (i.e. 
intermittent pneumonic compression devices) should be considered. 
 
Perioperative and Critical Care Thrombosis and Haemostasis of the Scientific, Standardization 
Committee of the International Society on Thrombosis and Haemostasis.30 
 
10.4 POST-COVID FUNCTIONAL STATUS SCALE 
 
The post-COVID-19 functional status (PCFS) scale31 focuses on relevant aspects of daily life during follow-
up after the infection. The scale is intended to help users becoming aware of current functional 
limitations in COVID-19 patients, whether or not as a result of the specific infection, and to objectively 
determine this degree of disability. This will aid in demarcating effective and ineffective COVID-19 
therapies on functional outcomes in an experimental setting, as well as pave the road for value-based 
healthcare.  
General description of each scale grade  
• 
Grade 0 reflects the absence of any functional limitation.  
• 
Grades 1 and 2 correspond to a condition for which usual duties/activities could be carried out, 
defined as any activity that patients undertake on a monthly basis or more frequently, either at 
home or at work/study. Importantly, this includes sports and social activities. Specifically, Grade 1 is 
reserved for patients with some symptoms, which however do not prohibit or limit doing any usual 
activities. Grade 2 is reserved for patients who are able to independently perform all usual activities 


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but at a lower intensity, sometimes combined with mild limitations in participation in usual social 
roles.  
• 
Grade 3 accounts for moderate functional limitations that force patients to structurally modify usual 
activities, reflecting the inability to perform certain activities which, therefore, need to be taken 
over by others. Those patients may require assistance in instrumental activities of daily living, e.g. 
managing basic household chores, community mobility, shopping for groceries or necessities, or 
participation in usual social roles is restricted.  
• 
Grade 4 describes those patients with severe functional limitations who require assistance with 
activities of daily living (ADL), not necessarily administered by a certified nurse. It should be 
indicated that assistance with some ADL activities, e.g. using the toilet, managing routine daily 
hygiene and functional mobility, is essential. Participation in usual social roles is likely restricted.   
Timing  
The PCFS is intended to be assessed 1) at the time of discharge from the hospital and 2) in the first 
weeks after discharge to monitor direct recovery. Providing a pre-COVID-19 reference value will allow to 
measure the change in status. To measure this pre-COVID-19 functional status, the functional status 
assessment should refer to the status 1 month prior to the infection. Assessment of the pre-COVID-19 
functional status should be performed after assessment of the current functional status.  
General Instructions  
Characteristics of the PCFS scale  
The scale is ordinal, has 6 steps ranging from 0 (no symptoms) to 5 (death, D), and covers the entire 
range of functional outcomes by focusing on limitations in usual duties/activities either at home or at 
work/study, as well as changes in lifestyle.  
Procedure  
The post-COVID-19 functional status scale can be assessed by either medical experts or trained 
interviewers during a short, structured interview. For any type of data collection, raters are encouraged 
to base their assessments on the ability of the patient to perform the activity rather than whether the 
patient actually performs the activity currently. This prevents overestimation of the severity of 
symptoms in patients who have chosen to abandon or who simply never performed certain activities.  
Information should be ideally obtained primarily from the patient and/or a close friend or caregiver 
(proxy) who is familiar with the daily routine of the patient. If the patient lacks insight into some 
questions or if responses are inconsistent, it may be helpful to interview a caregiver or relative 
independently. Limitations or symptoms may vary over time, the measurement concerns the average 
situation of the past week (except for when assessed at discharge, in that case it concerns the situation 
of the day of discharge). The standardized questions cover 5 sections corresponding to the separate 
levels of disability, see below table.. However, it is encouraged to ask questions beyond those stated to 
ensure that the patient has grasped the meaning of the question and to further clarify their responses. 
Additionally, it is recommended to adapt the interviewing strategy according to the patient’s status and 
his/her answers. Open questions can be a great way to start the interview, during which some key 
information will be obtained useful to score the patients. Later, more targeted or even closed questions 
can help to make a clear distinction between adjacent grades. The corresponding PCFS scale grade is 
provided in the column besides each specific response. In case two grades seem to be appropriate, the 


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patient will be assigned to the highest grade with the most limitations. 
Question 
PCFS scale 
grade if 
the answer 
is ‘YES’ 
1. SURVIVAL 
 
1.1 Has the patient died after the COVID-19 diagnosis? 
D 
2.   CONSTANT CARE Explanation: meaning someone else needs to be available at all times. Care may 
be provided by either trained or an untrained caregiver. The patient will usually be bedridden and may 
be incontinent.  
 
2.1 Do you require constant care? 
4 
2. BASIC ACTIVITIES OF DAILY LIVING Explanation: assistance includes physical assistance, verbal 
instruction, or supervision by another person. It may be considered essential when there is a need for 
physical help (by another person) with an activity or for supervision, or the patient needs prompting or 
reminding to do a task. The need for supervision for safety reasons should be due to objective danger 
that is posed, rather than ‘just in case’. 
 
3.1 Is assistance essential for eating? (Eating without assistance: food and implements may be 
provided by others)  
4 
3.2 Is assistance essential for using the toilet? (Using toilet without assistance: reach 
toilet/commode; undress sufficiently; clean self; dress and leave) 
4 
3.3 Is assistance essential for routine daily hygiene? (Routine hygiene includes only washing 
face, doing hair, cleaning teeth/fitting false teeth. Implements may be provided by others without 
considering this as assistance) 
4 
3.4 Is assistance essential for walking? (Walking without assistance: if absolutely necessary, able to 
walk indoors or around house or ward, may use any aid, however not requiring physical help or verbal 
instruction or supervision from another person) 
4 
4. INSTRUMENTAL ACTIVITIES OF DAILY LIVING Explanation: assistance includes physical 
assistance, verbal instruction, or supervision by another person. It may be considered essential when there 
is a need for physical help (by another person) with an activity or for supervision, or the patient needs 
prompting or reminding to do a task. The need for supervision for safety reasons should be due to objective 
danger that is posed, rather than ‘just in case’.  
 
4.1 Is assistance essential for basic household chores which are important for daily life?  
(E.g. preparing a simple meal, doing the dishes, take out the garbage; exclude chores that do not need to be 
done every day)  
4 
4.2 Is assistance essential for local travel? (Local travel without assistance: the patient may drive 
or use public transport to get around. Ability to use a taxi is sufficient, provided the patient can manage to 
call and instruct the driver)  
4 
4.3 Is assistance essential for local shopping? (The patient is not able to buy groceries or 
necessities by him or herself)  
3 
5. PARTICIPATION IN USUAL SOCIAL ROLES Explanation: this section concerns impairment in 
fulfilment of major social roles (not social or financial circumstances). 
 
5.1 Is adjustment essential for duties/activities at home or at work/study because you 
are unable to perform these yourself (e.g. resulting in a change in the level of 
responsibility, a change from full-time to part-time work or a change in education)? 
(Work refers to both paid employment and voluntary work. Special arrangements which allow someone to 
return to work, even though normally he/she wouldn’t be able to work, should be considered as 
adjustment of work.)  
3 
5.2 Do you occasionally need to avoid or reduce duties/activities at home or at 
work/study or do you need to spread these over time (while you are basically able to 
perform all those activities)?  
2 


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5.3 Can you no longer take good care of loved ones as before? (Taking good care includes 
babysitting, looking after your partner, parents, grandchildren or dependent others.)  
3 
5.4 Since the COVID-19 diagnosis, have there been problems with relationships or have 
you become isolated? (These problems include communication problems, difficulties in relationships 
with people at home or at work/study, loss of friendships (increase in) isolation, etc.)  
3 
5.5 Are you restricted in participating in social and leisure activities? (Comprising hobbies 
and interests, including going to a restaurant, bar, cinema, going for walks, playing games, reading books, 
etc.)  
2 
6. SYMPTOM CHECKLIST Explanation: these can be any symptoms or problems reported by the 
patients or found on physical examination. Symptoms include but are not limited to: dyspnea, pain, fatigue, 
muscle weakness, memory loss, depression and anxiety.  
 
6.1 Do you report symptoms through which usual duties/activities need to be avoided, 
reduced or spread over time?  
2 
6.2 Do you report any symptoms, resulting from COVID-19, without experiencing 
functional limitations?  
1 
6.3 Do you have problems with relaxing or do you experience COVID-19 as a trauma? 
(‘Trauma’ is defined as: suffering from intrusive memories, flashbacks or avoidance responses, associated 
with having experienced COVID-19.)  
1 
 
Assigning a grade on the post-COVID-19 functional status scale  
The overall rating is simply the poorest functional status indicated by the patient’s answers (the highest 
grade corresponds with the most limitations). If a respondent has no limitations or symptoms, then the 
appropriate scale grade is 0. 
 
 


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Anticoagulant Protein c2 following subcutaneous administration in man. Dependence on the 
stoichiometric binding to circulating factor X. Thromb Haemost 2003;90(5):803-12. 
23. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for 
thromboprophylaxis after knee replacement (ADVANCE-2): a randomized double-blind trial. Lancet 
2010; 375: 807–15. 
24. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or Enoxaparin for 
Thromboprophylaxis after Knee Replacement. N Engl J Med 2009;361:594-604. 
25. Eriksson BI, Dahl OE, Rosencher N, Kurth A, van Kiijk CN, Frostick SP, Kalebo P, Christiansen AV, 
Hantel S, Hettiarachchi R, Schnee J, Buller HR. Oral dabigatran etexilate vs. subcutaneous enoxaparin 
for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL 
randomized trial. J Thromb Haemost 2007;5:2178–2185. 
26. Freiderich PW, Levi M, Bauer KA, Vlasuk GP, Rote WE, Breederveld D, Keller T, Spataro M, Barzegar 
S, Buller HR. Ability of Recombinant Factor VIIA to Generate Thrombin During Inhibition of Tissue 
Factor in Human Subjects. Circulation 2001;103:2555-9. 
27. Hannsson L, Hedner T, Dahlof B. Prospective Randomized Open Blinded End-point (PROBE) Study. A 
novel design for intervention trials. Blood Pressure 1992; 1: 113-119 
28. Kohro T, Tsutomu Y. Cardiovascular clinical trials in Japan and controversies regarding prospective 
ransomized open-label blinded end-point design. Hypertension Research 2009; 32: 109-114 
29. Preliminary estimates of the prevalence of selected underlying health conditions among patients 
with coronavirus disease. MMWR 2020;69(13):382-386.  
30. Spyropoulos AC, Connors J, Hunt B et al. Scientific and Standardization Committee Communication: 
Clinical Guidance on the Diagnosis, Prevention and Treatment of Venous Thromboembolism in 
Hospitalized Patients with COVID-19. J Thromb Haemost 2020; 2020; 18: 1859–65.  
31. Klok FA, Boon GJAM, Barco S, Endres M, Geelhoed JJM, Knauss S, Rezek SA, Spruit A, Vehreschild J, 
Sigerink B. The Post-COVID-19 Functional Status (PCFS) Scale: a tool to measure functional status 
over time after COVID-19. Eur Respir J 2020. doi.org/10.1183/13993003.01494-2020. 
32. https://www.who.int/health-topics/coronavirus#tab=tab_3 (accessed 1/28/2021) 

SAP_001.pdf: 
 
 
 
  
  
  
  
  
  
Statistical Analysis Plan 
ASPEN-COVID-19 Phase 2b 
  
  
  
Study Title:  
Assessing Safety, Hospitalization and Efficacy of rNAPc2 in 
COVID-19 (ASPEN-COVID-19) 
Sponsor:  
ARCA biopharma, Inc.  
10170 Church Ranch Way, Suite 100  
Westminster, Colorado 80021  
Phone: 720-940-2100 
Protocol Number 
NAPc-201/301 
ClinicalTrials.gov Identifier 
NCT04655586 
Study Drug:  
rNAPc2 
Comparator:   
Heparin 
Analysis Plan Version  
3.0 
Date:   
February 24, 2022 
  
  
  


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Table of Contents 
1 
Introduction............................................................................................................................. 8 
2 
Study Design and Plan ............................................................................................................ 8 
2.1 
Design and Primary Objectives ........................................................................................ 8 
2.2 
Sample Size Determination .............................................................................................. 8 
2.3 
Participant Selection, Randomization, and Blinding/Unblinding .................................... 9 
2.4 
Primary Endpoints .......................................................................................................... 10 
2.4.1 
Efficacy ................................................................................................................... 10 
2.4.2 
Safety ...................................................................................................................... 10 
2.5 
Secondary Endpoints ...................................................................................................... 10 
2.5.1 
Efficacy ................................................................................................................... 10 
2.5.2 
Safety ...................................................................................................................... 10 
3 
Data Set Specifications ......................................................................................................... 11 
3.1 
Database Description...................................................................................................... 11 
3.2 
Creating Analysis Data Sets ........................................................................................... 11 
3.3 
Generation and Validation of Data Analysis Programs and Output .............................. 11 
3.4 
Archiving Data and SAS Files ....................................................................................... 11 
4 
Considerations and Methodology ......................................................................................... 11 
4.1 
Reporting Timeframes.................................................................................................... 12 
4.2 
Analysis Display Conventions ....................................................................................... 12 
4.3 
Determination of Study Day .......................................................................................... 13 
4.4 
Definition of Phases, Visit, or Windows ........................................................................ 13 
4.5 
Display of Treatment Groups ......................................................................................... 13 
4.6 
Protocol Deviations or Violations .................................................................................. 14 
5 
Statistical Methods................................................................................................................ 14 
5.1 
Missing Data .................................................................................................................. 14 
5.1.1 
Missing Values........................................................................................................ 14 
5.1.2 
Undetectable Values ............................................................................................... 15 
5.2 
Analysis Populations and Scopes ................................................................................... 15 
5.3 
Subgroups ....................................................................................................................... 15 
5.4 
Adjustments for Covariates ............................................................................................ 16 
5.5 
Multi-center Studies ....................................................................................................... 16 
5.6 
Pooling of Dose Groups ................................................................................................. 16 
5.7 
Multiplicity Issues .......................................................................................................... 16 
5.8 
Transformations and Normality ..................................................................................... 16 
6 
Baseline Characteristics and Subject Disposition ................................................................ 17 
6.1 
Subject Disposition ........................................................................................................ 17 
6.2 
Demographics and Baseline Characteristics .................................................................. 17 
6.2.1 
Baseline (pre-randomization) & Concomitant (post-randomization) Medications 17 
6.2.2 
Medical History ...................................................................................................... 18 
6.2.3 
Vital Signs ............................................................................................................... 18 
6.2.4 
Physical Examination.............................................................................................. 18 
6.3 
Treatment Exposure and Adherence .............................................................................. 18 
7 
Efficacy Analysis .................................................................................................................. 18 


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7.1 
Primary Efficacy Endpoint ............................................................................................. 18 
7.1.1 
Primary Analysis of the Primary Efficacy Endpoint .............................................. 18 
7.1.2 
Secondary Analysis of the Primary Efficacy Endpoint .......................................... 19 
7.2 
Secondary Efficacy Endpoints ....................................................................................... 19 
7.2.1 
Analysis of Secondary Efficacy Endpoints............................................................. 19 
7.2.2 
Time to Recovery .................................................................................................... 19 
7.3 
Exploratory Efficacy Endpoints ..................................................................................... 21 
7.3.1 
Composite of All-Cause Mortality and Thrombotic Events ................................... 21 
7.3.2 
Healthcare Resource Utilization ............................................................................. 21 
7.3.3 
Post-COVID Functional Status ............................................................................... 21 
7.4 
Significance .................................................................................................................... 21 
8 
Safety Analysis ..................................................................................................................... 21 
8.1 
Primary Safety Endpoint ................................................................................................ 21 
8.2 
Secondary Safety Endpoints........................................................................................... 22 
8.2.1 
Major or non-major clinically relevant bleeding through Day 30 .......................... 22 
8.2.2 
Any bleeding through Day 8 and through Day 30 .................................................. 22 
8.2.3 
Other Adverse Events ............................................................................................. 22 
8.3 
Laboratory Data.............................................................................................................. 23 
9 
Interim Analyses ................................................................................................................... 23 
10 Composite and Net Endpoints .............................................................................................. 23 
11 Subgroup and Sensitivity Analyses ...................................................................................... 23 
11.1 
Primary Efficacy Endpoint Sensitivity Analysis ........................................................ 23 
11.2 
Primary Efficacy Endpoint Subgroup Analyses ......................................................... 23 
11.3 
Secondary Efficacy Endpoint Subgroup and Sensitivity Analyses ............................ 24 
11.4 
Additional Safety Analyses ........................................................................................ 24 
12 Changes from Methods Planned in the Protocol .................................................................. 24 
13 References............................................................................................................................. 24 
14 Appendix............................................................................................................................... 25 
14.1 
COVID Severity Definitions ...................................................................................... 25 
14.2 
Descriptions of the Models and Methods Used .......................................................... 25 
14.2.1 Bayesian Description .............................................................................................. 25 
14.2.2 MI Description ........................................................................................................ 25 
14.2.3 Power Description ................................................................................................... 25 
 
  
 


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Approvals 
Signatures 
 
 
 
 
 
 
 
Biostatistician (ARCA)  
 
 
 
 
 
_____________________________ 
Ian Carroll, PhD 
 
 
 
 
 
_____________  
Date 
 
 
 
 
 
 
Biostatistician (CPC) 
 
 
 
 
 
 
_____________________________
Karen Liu, MSc 
 
 
 
 
 
 
_____________  
Date 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
 
_____________________________
Marc Bonaca, MD, MPH 
 
 
 
 
 
 
_____________  
Date 
 
 
 
 
 
 
Chief Scientific Officer 
(ARCA) 
 
 
 
 
 
 
 
_____________________________ 
Michael Bristow, MD, PhD 
 
 
 
 
 
 
_____________  
Date 
 
 
 


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Revision History 
VERSION 
DESCRIPTION OF CHANGE 
1.0 
Original 
2.0 
• 
Inserted language submitted in IND 150187, Sequence 0015 on 29 Nov 2021 
containing Sponsor’s response to the Division’s review of Version 1.0 clarifying 
Wilcoxon Signed Rank will not be used in the primary efficacy endpoint analysis. 
• 
Added composite of clinical events as a secondary efficacy endpoint in Section 
2.5.1. 
• 
Moved probability of discharge as assessed by ACTT from exploratory efficacy 
endpoint to secondary endpoint in Section 2.5.1 
• 
Added multiplicity control description to Section 5.7 
• 
Added Section 5.8 Transformations and Normality 
• 
Added Section 7.1.2 Secondary Analysis of the Primary Efficacy Endpoint 
• 
Added Section 7.2.3 Composite of Clinical Events 
• 
Added Section 10 Composite and Net Endpoints 
• 
Added Section 11 Subgroup and Sensitivity Analyses to provide additional 
description of how types of missingness will be addressed via multiple imputation. 
• 
Added Section 14.2 Description of Models and Methods which include descriptions 
of the Bayesian models, methods for multiple imputation, and methods for power 
analysis used in this study. 
• 
Added Section 12 Changes from Methods Planned in the Protocol to describe the 
key changes in either endpoint or analysis methodology. 
3.0 
• 
Corrected the censoring date for death in Section 7.2.2 to "day x+1, where x denotes 
the longest observation window among all subjects in the analysis” from “day of 
death”. This brings censoring date for death into alignment with the NAPc-201 
clinical protocol language. 
• 
Added clarifying language to Section 7.2.3 regarding pre-existing organ support of 
any modality as an additional covariate, representing a special case arising from the 
specifications of the analysis. 
 
 
 


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List of Abbreviations 
Abbreviation 
Term 
ACTT 
Adaptive COVID-19 Treatment Trial 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CEC 
Clinical Endpoint Committee 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTMS 
Clinical Trial Management System 
DAPT 
Dual Antiplatelet Therapy 
DMP 
Data Management Plan 
DSMC 
eGFR 
Data Safety Monitoring Committee 
Estimated Glomerular Filtration Rate  
FDA 
Food and Drug Administration 
hsCRP 
High Sensitivity C-reactive Protein 
ICF 
Informed Consent Form 
IL-6 
Interleukin-6 
ITT 
Intent-to-Treat 
kg 
Kilogram 
LLN 
Lower Limit of Normal 
LMWH 
low molecular weight heparin 
MCAR 
Missing Completely At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/dl 
Milligram per deciliter 
mITT 
Modified Intent-to-Treat 
mmHg 
Millimeters of mercury 


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Abbreviation 
Term 
NSAIDS 
Non-Steroidal Anti-Inflammatory Drugs 
PCFS 
Post-COVID Functional Status 
PCR 
Polymerase Chain Reaction 
PT 
Prothrombin Time 
PTm 
Preferred Term 
PTT 
Partial Thromboplastin Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SoC 
Standard of Care 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Figures, and Listings 
UFH 
Unfractionated Heparin 
ULN 
Upper Limit of Normal 
URC 
Unblinded Review Committee 
WHO DDE 
World Health Organization Drug Dictionary (Enhanced) 
 
 


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1 Introduction 
The ASPEN-COVID-19 ("ASPEN") protocol comprises sequential Phase 2b and Phase 3 randomized, 
multicenter, active comparator studies evaluating the hypothesis that rNAPc2, a novel, potent and highly 
selective tissue factor inhibitor with anticoagulant, anti-inflammatory and potential antiviral properties, 
reduces elevated D-dimer levels (Phase 2b primary endpoint) and shortens time to recovery (Phase 3 
primary endpoint) compared to heparin in hospitalized patients with COVID-19 and elevated D-dimer 
levels. Study participants and Clinical Endpoint Committee (CEC) members assessing the clinical 
endpoints are blinded to treatment assignment. Analysis of Phase 2b data could lead to study 
discontinuation, adjustment of eligibility criteria or sample size, and will inform the rNAPc2 dose 
regimen to be studied in Phase 3. 
This statistical analysis plan (SAP) describes all study related details and statistical analyses and 
summaries to be generated on data collected from the Phase 2b ASPEN-COVID-19 study. 
The SAP is designed to assist in the analysis of clinical study data for final reporting of the Phase 2b 
study. This content includes, but is not limited to, statistical analysis and summary of all endpoints 
identified in the study protocol, heretofore referred to as ‘the study’ or ‘study.’ 
Details of reporting for the purpose of the Data Safety Monitoring Committee (DSMC) and other 
committees are documented elsewhere. Details of planned interim analyses are documented in the DSMC 
Charter and DSMC Reporting Plan. Reporting of the Phase 3 study will be documented in a separate 
analysis plan. 
2 Study Design and Plan 
2.1 
Design and Primary Objectives 
The primary objective of the Phase 2b study is to identify an rNAPc2 dosing regimen with an acceptable 
safety profile that reduces D-dimer levels compared to standard of care (SoC) heparin regimens. 
Secondary and exploratory objectives are to compare the treatment groups in terms of biomarkers 
associated with outcomes including those related to coagulation and inflammation, as well as for clinical 
and functional outcomes. 
2.2 
Sample Size Determination 
During Phase 2b, approximately 160 participants will be enrolled and randomized 1:1:2 to rNAPc2 dose 
regimen 1, rNAPc2 dose regimen 2, and heparin SoC, respectively. Assuming approximately 20% of 
participants may not be evaluable for any reason, 160 randomized participants will provide for 
approximately 130 evaluable participants. At a sample size of 160, the study will have adequate power 
across a range of clinically meaningful effect sizes, operationalized as proportional reductions in D-dimer 
(relative to heparin) from 20% to 40% in increments of 5% (see below). This sample size was selected, 
based on a statistical simulation using Wilcoxon rank sum and assuming a 20% missing/dropout rate, to 
ensure inferences for the primary endpoint analysis will be robust, given certain potential confounding 
factors such as missing data (random or non-random), heterogeneous application of heparin (low 
molecular weight and unfractionated; prophylactic and therapeutic), effects of subject-level covariates 
(e.g., comorbidities), and effects of site-level covariates (e.g., country). 
 
 


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2.3 
Participant Selection, Randomization, and Blinding/Unblinding 
Approximately 160 participants 18 to 90 years of age with COVID-19 documented by a validated test 
such as polymerase chain reaction (PCR) within 1 week of hospitalization or screening and D-dimer 
above the upper limit of normal will be eligible for the Phase 2b study. 
Participants will be randomly assigned 1:1:2 to receive rNAPc2 at one of 2 dose regimens, or a heparin 
regimen per site SoC (prophylactic or therapeutic). The higher rNAPc2 dose regimen will include a 
7.5 μg/kg subcutaneous (SC) loading dose on Day 1 followed by 5μg/kg SC on Days 3 and 5; the lower 
dose regimen will be administered as a 5 μg/kg SC loading dose on Day 1 followed by 3μg/kg SC on 
Days 3 and 5. Prophylactic or therapeutic doses of low molecular weight heparin (LMWH) or 
unfractionated heparin (UFH) will be prescribed in the control group as per local SoC. Participants will be 
stratified by local laboratory D-dimer level at screening (≤ or > 2 the assay’s upper limit of normal 
(ULN)). 
The NAPc-201/301 study utilizes a modified Prospective Randomized Open-Label, Blinded Endpoint 
(PROBE) design. In a traditional PROBE design, the participant and investigator are aware of treatment 
assignment, but endpoints are classified by blinded adjudicators. In the ASPEN trial, the site 
investigator(s) and research coordinator(s), as well as the treating clinical team are aware of treatment 


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assignment, but the randomized participants will not be told their treatment assignment and all efforts will 
be made at the site to keep them blinded in order to minimize bias in safety and clinical endpoint 
reporting. In addition, adjudicators of clinical events will be blinded to treatment assignment as well as 
other information relevant to unblinding in order to minimize any potential bias in event categorization. 
To support the integrity of study results, blinding of study management personnel (Sponsor, Contract 
Research Organization/Academic Research Organization, Oversight Committees, etc.) will be managed at 
the study role level as described in the Blinding Plan. Additionally, neither the study site, Sponsor, CEC, 
nor study participants will have access to the central laboratory results during the conduct of the trial with 
the exception of clinical safety alerts. The investigator will not be provided with randomization codes. 
The study site will know the treatment assignment; however, participants should not be made aware of 
their treatment assignment. 
2.4 
Primary Endpoints 
2.4.1 Efficacy 
The primary efficacy endpoint is proportional change, represented as percent change, in D-dimer level 
from baseline to Day 8 or Day of Discharge if prior to Day 8. 
Language pertaining to the primary efficacy endpoint in the ASPEN Protocol is operationalized as 
proportional change. 
2.4.2 Safety 
The primary safety endpoint is major or non-major clinically relevant bleeding within eight (8) days of 
randomization as compared to heparin. 
2.5 
Secondary Endpoints 
2.5.1 Efficacy 
Secondary efficacy endpoints are: 
• 
Change in D-dimer level from baseline to 24 hrs post the institution of study medication 
following randomization (Study Day 2), and 48 hours after institution of study medication (Study 
Day 3) 
• 
Probability of discharge as assessed by ACTT ≥ 6 by Day 8 and Day 30 post randomization 
• 
Composite of death, thrombosis, organ support, or rehospitalization within 30 days adjudicated as 
to its relatedness to COVID-19 
• 
Change in biomarkers associated with outcomes including those related to coagulation and 
inflammation from baseline through Day 8 
2.5.2 Safety 
Secondary safety endpoints are:  
• 
Major or non-major clinically relevant bleeding with rNAPc2 vs. heparin 
• 
Bleeding with higher vs. lower dose rNAPc2 through Day 30 
• 
Other adverse events (AEs) 


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3 Data Set Specifications 
3.1 
Database Description 
The following data sources will be used to create the final study tables, figures, and listings (TFLs). 
• 
Protocol Deviation database which will store protocol deviations  
• 
Clinical Endpoint Adjudication database which will store all adjudicated review fields and 
outcomes 
• 
Central laboratory data from PPD 
• 
Clinical database which will store all other data used for analysis 
These databases are hosted by the following systems: 
• 
Protocol Deviation database: DATATRAK UX CTMS 
• 
Adjudication database: AG Mednet 
• 
Central lab data from PPD transferred to CPC as SAS dataset 
• 
Clinical database: DATATRAK UX EDC™ 
Separate data management and adjudication plans will describe the set-up and management of these 
databases including preparing and selecting data for study analysis. The adjudication, laboratory and 
clinical databases will be reconciled to ensure within- and cross-form consistency. 
3.2 
Creating Analysis Data Sets 
To facilitate the analysis of study data, it will be necessary to extract and combine the relevant variables 
from the data sources described above. All analysis data sets will be generated using SAS software (SAS 
and all other SAS Institute Inc. products or service names are registered trademarks of SAS Institute Inc., 
Cary, NC, USA). 
3.3 
Generation and Validation of Data Analysis Programs and Output 
Programming and output developed prior to the database lock will be produced and displayed using 
dummy treatment codes to protect the integrity of the study and minimize any unintended bias in 
accordance with the Study Blinding Plan. 
3.4 
Archiving Data and SAS Files 
Following final database lock, the SAS® programs used to analyze data for the final Clinical Study Report 
(CSR) will be executed and archived. 
4 Considerations and Methodology 
The analysis of data for the study will be based on the objectives and endpoints outlined in the protocol. 
Final analysis will be produced on locked clinical study data using SAS version 9.4 or higher. 
Minor edits and additions which do not affect the content or meaning of either the text or mock shells 
(e.g., typos, spacing, etc.) will not constitute the need for an amendment to this plan. Major changes to 
this reporting plan will require an amendment and will require approval. All changes which are made to 
the reporting plan from the initial approval will be tracked on a Programming Changes Log. 


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4.1 
Reporting Timeframes 
This reporting plan describes the required output for final reporting for the Phase 2b study and will occur 
when all participants have completed the Phase 2b study and those data have been cleaned and locked 
according to the Data Management Plan (DMP). 
Interim reporting of efficacy and safety data to a DSMC, including planned interim analyses, will be 
described in the DSMC charter and a separate reporting plan. 
4.2 
Analysis Display Conventions 
General conventions for statistical analyses are pre-specified. Departures from these general conventions 
may be given in the specific detailed sections of this SAP. When this occurs, the rules set forth in the 
specific section take precedence over the general convention. 
• 
All tables will have the population sample size for each dosing group in the column heading. 
• 
Continuous variables will be summarized using the standard display of n, mean, standard 
deviation (SD) medians, minimum, and maximum, first and third quartiles for participants with 
non-missing data. 
• 
Ordinal or categorical variables will be summarized using the number and percentage of observed 
response in each category.   
• 
Summary statistics for discrete variables will consist of the number and percent of responses in 
each category. The count and percentage of responses will be presented in the form of 
XX (XX.X%), where the percentage is in parentheses. If the count is “0” then the percentage may 
not be presented. If the percentage is “100”, the decimal place may be dropped. In addition, the 
decimal place may also be dropped due to space constraints within a table where there is no 
impact on interpretation. Denominator for percent will be footnoted if not the population size in 
the column heading. 
• 
Leading zeros will be used for decimal values less than one. For example, use “0.05” rather than 
“.05.” 
• 
P values will be presented as 4 decimals (e.g., “0.0054”) or replacing the leading 0 with 
“< .0001” and “> .9999” if applicable. 
• 
A participant’s age will be calculated using birth date and informed consent date. Age will be 
reported in years and rounded to the lowest (floor) integer. 
• 
Body Mass Index (BMI) calculation is based on the formula below: 
BMI (kg/m2) = Weight (in kg) /Height2 (in meters) 
• 
All medical history and AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) as described in the DMP. 
• 
All medications will be coded using the World Health Organization Drug Dictionary [Enhanced] 
(WHO DDE) as described in the DMP. 


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4.3 
Determination of Study Day 
The day the participant is randomized will be considered study “Day 1.” The day prior to randomization 
will be considered study “Day -1.” There will be no Day 0. If the start day is missing the first day of the 
month will be used. 
If the start year or stop year is missing it is assumed the medication was taken concomitantly with study 
drug. 
4.4 
Definition of Phases, Visit, or Windows 
Visit labels will be used for reporting. For listings ordered by assessment date, if unscheduled visits are 
associated with a date of assessment, these will be included in the listing by date with the visit described 
as ‘unscheduled.’ Otherwise, if no date of assessment is associated with the unscheduled visit data, 
listings will be ordered by visit with unscheduled visits presented last. Unscheduled visits associated with 
discharge from hospital will be used in lieu of Day 8 in participants for whom there is no Day 8 
assessment, and other unscheduled visits will not be reported in summaries. 
Visits will be displayed as follows: 
 
Visit Label 
Short Descriptor if needed to accommodate space restrictions 
Screen 
SCRN 
Baseline 
BSLN 
Day 2 (24h post-dose) 
D2 
Day 3 
D3 
Day 5 
D5 
Day 8 
D8 
Day 10 
D10 
Day 30 
D30 
Unscheduled 
UNSCH 
 
4.5 
Display of Treatment Groups 
Summaries will be displayed by treatment group. Summaries and listings based on the Safety population 
will be displayed by actual treatment received. 
Treatment groups will be displayed as follows with respect to labels and ordering. 
 


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Label 
Short Label if needed to 
accommodate space 
Definition 
All Heparin  
All HEP 
Prophylactic and therapeutic doses 
heparin groups combined 
Heparin Prophylactic  
HEP Pro 
Initial Heparin Dosing Strategy 
(Prophylactic Heparin) as recorded by the 
investigator in the Case Report Form 
(CRF) 
Heparin Therapeutic 
HEP Ther 
Initial Heparin Dosing Strategy 
(Therapeutic Heparin) as recorded by the 
investigator in the CRF 
rNAPc2 Lower 
 
Lower Dose rNAPc2 (5 μg/kg on Day 1 
followed by 3μg/kg on Days 3 and 5) 
rNAPc2 Higher 
 
Higher Dose rNAPc2 (7.5 μg/kg on Day 
1 followed by 5μg/kg on Days 3 and 5) 
ALL rNAPc2 
 
Lower and Higher rNAPc2 doses 
combined 
Overall 
 
All participants who receive any study 
treatment (Heparin or rNAPc2) 
 
4.6 
Protocol Deviations or Violations 
All protocol deviations will be collected in the clinical trial management system (CTMS) database. Major 
deviations will be identified manually and programmatically prior to unblinding. A summary of major 
protocol deviations will be given by frequency tables showing the number of participants with major 
protocol deviations overall and by deviation. Protocol deviations will be listed for all screened 
participants. 
5 Statistical Methods 
5.1 
Missing Data 
The primary analysis will be performed using all complete data and, for subjects who do not have 
completed primary endpoint data, values obtained in the ± 48-hour window around Day 8 or Day of 
Discharge, as described in Section 7.1.1, will be used. If no values are present from the ± 48-hour 
window, Last Observation Carried Forward (LOCF) will be used. All values measured after the 
administration of the final dose will be eligible for LOCF. 
5.1.1 Missing Values 
In cases where data are missing but an entry is expected (e.g., required study procedure not performed) 
numeric values will appear in the database as follows:  
• 
‘Unable to obtain’ response will be recorded in the database as a ‘-97’. 
• 
‘Not Known’ response will be recorded in the database as a ‘-98’. 


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• 
‘Not Applicable’ response will be recorded in the database as a ‘-99’ value. 
These will be translated to meaningful entries during listing and/or summarization of the data as 
appropriate. 
5.1.2 Undetectable Values 
If a measured value of D-dimer is reported from the central laboratory as below the detectible limit of the 
assay, the value will be entered as 1 unit below the detectible limit. For example, if the result is 
‘< 120 ng/mL’ the value will be entered as 119 ng/mL. 
5.2 
Analysis Populations and Scopes 
All analyses are based on 2 elements: 
• 
Analysis population, which specifies which participants will be included in an analysis; and 
• 
Data scope, which specifies the time window within which data will be included in an analysis 
Five analysis populations are defined for this study.  
The Intent-to-Treat (ITT) population will include all participants who are randomized. Participants will 
be analyzed according to the treatment group allocated by randomization. 
The modified Intent-to-Treat (mITT) population will include all participants who are randomized and 
received at least one dose of study drug. Participants will be analyzed according to the treatment group 
allocated by randomization. 
The Per Protocol population will include all participants who are randomized, receive all three doses of 
study drug post randomization or receive SoC drug through day 7, have no major deviations from the 
protocol that affect the primary endpoint, and complete all pre-specified study assessments/activities. 
Participants will be analyzed according to the treatment actually received. 
The Safety population will include all participants who are randomized and receive at least one dose or 
part of a dose of study treatment post-randomization. Participants will be analyzed according to the 
treatment actually received.  
The All Screened population will be defined as all participants with any data entered into the database.   
The analysis populations will be listed by participant. 
The ITT, mITT and Per Protocol data scope includes outcomes and events observed from a given 
participant’s date of randomization until either their final or Day 30 contact, determined by whichever 
occurs first. This will be applied mainly to the analyses of efficacy endpoints. 
The ITT, mITT and Per Protocol data scope will also be used for the secondary safety endpoints of major 
or non-major clinically relevant bleeding through Day 30 and any bleeding through Day 30. 
The on-treatment data scope will include all outcomes and events observed from randomization until 72 
hours following permanent discontinuation of the study drug. This on-treatment data scope will be 
applied mainly to the analyses of safety endpoints. 
5.3 
Subgroups 
For the primary efficacy endpoint, the treatment effects across the following subgroup factors will be 
examined: 


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• 
D-dimer randomization stratification factor (> vs. ≤ 2x local laboratory ULN) 
• 
Treatment with an agent with demonstrated efficacy in patients with COVID-19, as described in 
Section 6.2.1 (yes, no) 
• 
Background antiplatelet therapy at baseline, as described in Section 6.2.1 
• 
rNAPc2 dose regimen 
• 
Initial heparin dosing strategy (prophylactic vs. therapeutic; within regimen comparison only) 
• 
Severity of disease (as defined in Section 14.1) 
• 
Source of Laboratory Values used for primary endpoint determination (central vs. local) 
5.4 
Adjustments for Covariates 
Where indicated analyses will include a covariate for study stratification ‘D-dimer level at screening’ 
(> or ≤ 2X the assay's ULN). 
5.5 
Multi-center Studies 
Data from all centers will be pooled for analysis. 
5.6 
Pooling of Dose Groups 
The primary analysis will involve a comparison of the pooled rNAPc2 treatment groups against the 
heparin treatment group. Because the optimal dose of rNAPc2 is unknown and its determination is a key 
objective of Phase 2b, the assumption that both doses will be effective and thus can be pooled for 
statistical analysis may not be correct. Therefore, each rNAPc2 dose regimen will also be analyzed as 
separate groups. 
Although this variable is included as a pre-specified subgroup of interest, it is of higher inferential priority 
because it does not share the same characteristics of the other subgroups, attributable entirely to the fact 
that group membership is determined solely by the experimental manipulation (i.e., treatment assignment) 
rather than any subject- or clinically-derived characteristic. 
5.7 
Multiplicity Issues 
Multiplicity control will be implemented for non-primary endpoints as described in Gou et al (2014), 
which is an improvement uniformly over the stepwise Hochberg procedure and in most cases over the 
Hommel procedure. 
5.8 Transformations and Normality 
In circumstances where univariate or multivariate normality is assumed but violated (where violations are 
determined via Shapiro-Wilk test), featured in the present study primarily in the Bayesian Linear Mixed 
Effects models, variable transformation will be performed in order to satisfy normality assumptions. 
Candidate transformations include square root, logarithmic, and reciprocal transformation for incremental 
severity of distributional skewness. 
The expected circumstances where transformation may need to be applied are certain biomarkers like 
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6 Baseline Characteristics and Subject Disposition 
6.1 
Subject Disposition 
Subject disposition will be summarized by treatment group in a table for all screened participants, and 
analysis population (ITT, mITT, Per Protocol) will be reflected within the table. 
6.2 
Demographics and Baseline Characteristics 
Baseline demographic information and clinical characteristics including, but not limited to, sex, race, 
ethnicity, age, ACTT ordinal scale category, severity as identified by the WHO COVID severity 
definitions (Appendix 14.1), and study entry D-dimer value will be listed and summarized by treatment 
group for the ITT and Per Protocol populations and listed for all screened participants. 
6.2.1 Baseline (pre-randomization) & Concomitant (post-randomization) Medications 
Concomitant medications consist of any medication given during the observation window. Concomitant 
medications will be coded using WHODrug as described in the DMP. Medications will be listed and 
summarized by Anatomical Therapeutic Chemical (ATC) Class 2nd Level, medicinal product name, and 
treatment group. Selected relevant medication classes will be presented as shown below. Concomitant 
medications at screening will be listed by participant and summarized.  
Selected Relevant Concomitant Medication Classes: 
• 
Antiplatelet 
o Aspirin 
o P2Y12 inhibitor – e.g., clopidogrel, prasugrel, ticagrelor, ticlopidine  
o Other – e.g., dipyridamole; vorapaxar, cilostazol 
• 
Anticoagulants 
o Warfarin 
o Factor Xa inhibitors (apixaban, rivaroxaban) 
o Unfractionated heparin 
o Low molecular weight heparin 
• 
COVID therapies 
o Systemic (non-topical) corticosteroids 
o Remdesivir 
o Baracitinib 
o Tocilizumab 
o Convalescent and non-convalescent plasma 
o Monoclonal or polyclonal Abs directed against SARS-CoV-2 
o Anti-inflammatory agents 
• 
NSAIDS  


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• 
Vasopressors 
• 
Inotropes 
• 
SARS-CoV-2 vaccine (Vaccine received yes or no; manufacturer, if known) 
If medication start date and end date are blank, it is assumed the medication was taken concomitantly with 
study drug. If medication start date and end date are both prior to Day 1, the medication will be 
considered as taken ‘prior’ to study drug. If medication start date is prior to Day 1 and end date is blank, 
the medication will be considered ‘ongoing’ and as a concomitant medication. 
6.2.2 Medical History 
The incidence of medical/surgical history (including COVID-19 and cardiovascular specific medical 
history) will be listed and summarized by treatment group for the ITT and Per Protocol populations and 
listed for all screened participants. 
6.2.3 Vital Signs 
Vital Sign data will be listed and summarized by treatment group for the ITT and Per Protocol 
populations and listed for all screened participants. 
6.2.4 Physical Examination 
Vital Sign and Physical Examination data will be listed and summarized by treatment group for the ITT 
and Per Protocol populations and listed for all screened participants. 
6.3 
Treatment Exposure and Adherence 
Treatment exposure and adherence will be summarized by treatment group for the ITT, Per Protocol and 
Safety population and listed. 
7 Efficacy Analysis 
The following efficacy analyses will be based on the ITT population and data scope. Accompanying 
analyses pertaining to mITT and Per Protocol population, subgroup and sensitivity are discussed in 
Section 11. 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint of Phase 2b is proportional change in D-dimer level from baseline (Day 1 
visit where randomization occurs and central laboratory samples are drawn) to Day 8, or Day of 
Discharge if prior to Day 8 between treatment groups.  The primary analysis will involve a comparison of 
the pooled rNAPc2 treatment groups against the heparin treatment group. 
7.1.1 Primary Analysis of the Primary Efficacy Endpoint 
Proportional change, represented by percent change, will be calculated as 100 × (D-Dimer level at Day 8 
or Day of Discharge if prior to Day 8 - D-Dimer level at baseline)/ D-Dimer level at baseline and will be 
based on data provided by the central laboratory, or local laboratory paired samples if the central 
laboratory values are not available. The pairing process will be operationalized as outlined: 
For Day 1 (baseline) paired local-local or central-central laboratory values: 
1. Use any lab D-dimer drawn during the current admission and up to randomization 


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2. Use the laboratory sample closest to randomization if there are multiple D-dimer measurements. 
3. All samples obtained more than 1-hour post-initiation of study drug are ineligible. 
For Day 8 or Day of Discharge paired laboratory values: 
1. Use laboratory samples collected within ± 48 h of the Day 8 or Day of Discharge study visit 
(whichever occurs first). 
2. If there are multiple laboratory samples collected within that window, use the lab value on the 
target day; if not available, use the lab value immediately after the target visit day. 
A Wilcoxon rank sum test will be used to compare proportional change from baseline to Day 8, or Day of 
Discharge if prior to Day 8, between treatment groups. The between treatment group rank sum test is 
considered the primary analysis of the primary endpoint. 
7.1.2 Secondary Analysis of the Primary Efficacy Endpoint 
A within treatment analysis of the proportional change in D-dimer levels will be a secondary analysis, 
subject to multiplicity control as for secondary endpoints. Wilcoxon signed rank tests will be used to 
compare within treatment group baseline vs. Day 8 D-dimer values, or Day of Discharge if prior to Day 8, 
values within each treatment group (i.e., rNAPc2 pooled, Heparin), (i.e., rNAPc2 pooled vs. Heparin). 
7.2 
Secondary Efficacy Endpoints 
Secondary efficacy outcomes are proportional change in D-dimer level from baseline to 24 hours post-
dose (Day 2) and Day 3, probability of discharge accompanied by ACTT ≥ 6 by Day 8 and Day 30, the 
secondary efficacy clinical composite, and change in biomarkers associated with outcomes including 
those related to coagulation and inflammation from baseline to Day 8 (or Day of Discharge if prior to 
Day 8). Inflammatory biomarkers include interleukin-6 (IL-6) and high sensitivity C-reactive protein 
(hsCRP), while coagulation biomarkers include prothrombin time (PT), partial thromboplastin time 
(PTT), factor Xa, and tissue factor. 
7.2.1 Analysis of Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be subject to the same analysis, same sensitivity analyses, and same 
subgroup analyses as the primary efficacy endpoints.  
7.2.2 Time to Recovery 
Time to recovery by Day 30, with Day 1 being the date of randomization. Recovery is defined as the first 
day a participant meets criteria for category 6, 7, or 8 of the ACTT ordinal scale. The analysis of time to 
recovery will be a comparison of the combined rNAPC2 dose groups vs. SoC heparin by a stratified log-
rank test, where stratification is according to local laboratory screening D-dimer level ≤ or > 2 local 
laboratory ULN. Cumulative incidence by treatment group will be summarized by Kaplan-Meier 
estimates. Additionally, a treatment hazard ratio and corresponding 95% confidence interval will be 
estimated by a Cox proportional hazard model stratified by local laboratory D-dimer level at screening. In 
addition, the two rNAPc2 dose groups will be compared for time to recovery. 
Participants who die within 30 days of randomization will be censored at the day x+1, where x denotes 
the longest observation window among all subjects in the analysis. In addition, participants surviving to 
their Day 30 visit who have not met the criteria for recovery by the time of their last ACTT scale 
assessment on or prior to the Day 30 visit will be censored on the day of their last assessment on or prior 
to the Day 30 visit. There will be no censoring prior to Day 30 due to study treatment discontinuation, 


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initiation of non-study treatment, or intermittently missed ACTT scale assessments. Patients lost to 
follow-up or otherwise of unknown status occurring prior to Day 30 will be censored based on, and at the 
day of, the last known status.  
The frequency and percentage of participants with each recovery category (ACTT equal to 6, 7, or 8) will 
be summarized. 
7.2.3 Composite of Clinical Events 
The secondary efficacy clinical composite will be measured and compared between treatment groups. 
This composite will consist of death (all-cause), thrombotic events (Stroke, MI, PE, peripheral arterial and 
clinically relevant deep vein thrombosis), organ support as defined in Section 7.3.2, and rehospitalizations 
adjudicated as to its relatedness to COVID-19. 
The primary formulation of the composite will limit the number of contributing events per component per 
patient to one, i.e., the aggregate will have values from 0 – 4 for each patient. The component-wise 
analysis will be performed using logistic regression, where the contribution of each component is 
necessarily a dichotomous variable. The aggregate will be analyzed using Poisson regression. 
The secondary formulation will differ from the primary in that no limitation on the component-wise 
contributions will be imposed. Thus, component-wise analysis will also be Poisson regression except in 
the case of death or any data-driven circumstance where the only available values are binary. 
Regression models will include treatment in the unadjusted formulation, and treatment, D-dimer stratum 
and pre-specified subgroups in the covariate-adjusted formulation. Pre-existing organ support of any 
modality is discussed below as an additional covariate, representing a special case arising from the 
specifications of the analysis. 
Assumptions inherent to any of these models, e.g., whether data manifest in accordance with a Poisson 
distribution (where λ, the rate, is both mean and variance) will be tested. In the case of Poisson, testing 
significant deviations from assumptions will use Likelihood Ratio tests on Zero-inflated and/or Negative 
Binomial operationalizations of the dependent variable distribution (these are not mutually exclusive). 
Both Logistic and Poisson regression models may remove variables that introduce issues in the model 
estimation process, e.g., a regressor with no variance, cell sparsity, or sufficient multicollinearity to 
induce rank deficiency of the model-implied design matrix will flatten the likelihood function, 
destabilizing point estimates and inflating confidence intervals by orders of magnitude. 
Events in these analyses must be treatment-emergent to be eligible for inclusion, and therefore subjects 
with pre-existing organ support will need adjustment in order to properly estimate effects related to 
initiation of new organ support. This will manifest as a binary covariate indicating pre-existing organ 
support of any modality. 
7.2.4 Coagulation and Inflammation Biomarkers 
The following laboratory parameters will be collected and analyzed by a central laboratory. Change from 
baseline to both Day 8 or discharge will be summarized for inflammatory biomarkers (IL-6, hsCRP) and 
coagulation biomarkers (PT, PTT, factor Xa and tissue factor). All data will be listed. Primary analyses 
will be by Wilcoxon-family tests as described above in the primary efficacy endpoint. For purposes of 
interpretation of outcomes, IL-6 and hsCRP are considered measures of systemic inflammation, PT, PTT 
and factor Xa are coagulation parameters, and tissue factor is the biologic target of rNAPc2. In addition, 


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in a subset of participants anti-phospholipid antibodies known to be generated in COVID-19 and inhibited 
by rNAPc2, are being measured at baseline, Day 8/discharge and on Day 30 at a specialty laboratory. 
7.3 
Exploratory Efficacy Endpoints 
7.3.1 Composite of All-Cause Mortality and Thrombotic Events 
Time to first occurrence of a composite of all-cause mortality and any adjudicated thrombotic event 
within 30 days of randomization and time to all-cause mortality within 30 days of randomization will be 
analyzed by the same methods as described for ACTT above, with the exception that deaths will be 
counted as an event. Participants without an adjudicated event by Day 30 will be censored on the study 
day of last contact or Day 30, whichever is earlier. There will be no censoring prior to Day 30 due to 
study treatment discontinuation or initiation of non-study treatment. 
7.3.2 Healthcare Resource Utilization 
Days in intensive care unit, on ventilator, vasopressors, renal replacement therapy, and circulatory support 
will be summarized with descriptive statistics.   
Organ support free days will be compared between the rNAPc2 and heparin arms via Wilcoxon Rank 
Sum testing, as in analysis of the Primary Efficacy Endpoint. Organ support free days is defined as total 
number of days without any of the following: placement on invasive mechanical ventilation, intravenous 
inotrope or vasopressor administration, renal dialysis, mechanical circulatory support, or death will be 
documented for each patient, and the number of total as well as individual interventions per patient will 
be compared by treatment group. Subjects who die are assigned a score of -1 for organ support free days. 
In the event that a large number of ties exist (e.g., a substantial proportion of subjects have the entire 
30 days free of organ support), then organ support free days will be categorized as 30, 0-29, and -1 
representing no organ support needed, some organ support needed, and death, respectively. An equivalent 
scenario involving every day requiring organ support for many subjects would yield 1-30, 0, -1 as 
categories. This tabulation with be analyzed subsequently using an Exact Wilcoxon test, such that 
ordinality across categories is maintained. In a circumstance where only two of the three categories are 
observed, this becomes an exact binomial test. 
7.3.3 Post-COVID Functional Status  
Post-COVID Functional Status (PCFS) score at discharge and Day 30 will be summarized with 
descriptive statistics. 
7.4 
Significance 
All statistical tests and confidence intervals will use a 2-sided analysis with a significance level of 
α = 0.05. 
8 Safety Analysis 
The following safety analyses will be based on the Safety population and on-treatment data scope. 
Additional safety analyses are detailed in Section 11.4. 
8.1 
Primary Safety Endpoint 
The primary safety endpoint is major or non-major clinically relevant bleeding through the earliest of 
Day 8 or two days after Day of Discharge if prior to Day 8. 


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The frequency and percentage of participants with major or non-major clinically relevant bleeding within 
8 days of randomization as adjudicated by the CEC will be presented by each rNAPc2 dose and any 
heparin dose. 
8.2 
Secondary Safety Endpoints 
8.2.1 Major or non-major clinically relevant bleeding through Day 30 
The frequency and percentage of participants with major or non-major clinically relevant bleeding 
through Day 30 as adjudicated by the CEC will be presented by each rNAPc2 dose and heparin dose 
(pooled and via characteristics, i.e., Prophylactic vs. Therapeutic, Unfractionated vs Low Molecular 
Weight). 
8.2.2 Any bleeding through Day 8 and through Day 30 
The frequency and percentage of participants with any bleeding major, non-major clinically relevant, non-
major and not clinically relevant as defined in the protocol) through Day 8 and through Day 30 will be 
presented by each rNAPc2 dose and heparin dose (pooled and via characteristics, i.e., Prophylactic vs 
Therapeutic, Unfractionated vs. Low Molecular Weight). 
8.2.3 Other Adverse Events 
Safety assessments will also include monitoring of serious adverse event(s) (SAE) and non-serious 
adverse event(s) (AE). Efficacy and safety endpoints that are adjudicated positively as study outcomes, 
including all bleeding events, will not be considered as AEs or SAEs. 
All AEs will be collected from the time of randomization until the participant completes Day 30 or final 
contact, whichever is longer. All SAEs will be collected from the time of consent until the participant 
completes Day 30 or final contact, whichever is longer. 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Participant counts will be summarized using frequencies and percentages. A participant will be counted 
only once per category of summarization (e.g., if a participant has multiple AEs, the participant will only 
be counted once in the overall ‘Any AE’ row and will be counted once in each row for the specific AE 
category reported). Where participants have more than one level of severity/relatedness recorded only the 
highest level of severity/relatedness will be summarized. 
Participant counts will be summarized by system, organ class and preferred term (PTm) by treatment 
group for treatment-emergent AEs (TEAEs) and by seriousness, relatedness. 
An AE identified by the investigator as ‘Related’ or ‘Potentially Related’ or where relationship is missing 
will be considered ‘related to study treatment.’ 
All AEs will be listed. Listings of SAEs, Related AEs, fatal and AEs of special interest (e.g., Overdose, 
misuse, or accidental exposure to study drug; medical error involving study drug), will also be listed. 
Additional details of SAEs and Deaths will also be listed. 
Treatment Emergent is defined as any SAE/AE that has a start date during or after administration of the 
investigational product (i.e., randomized rNAPc2 or heparin treatment), post-randomization up to Day 30 
or final contact. 
Data will be displayed as collected in the clinical database. Adverse Events with missing start dates will 
be considered as treatment emergent. 


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8.3 
Laboratory Data 
A summary of laboratory (Central Laboratory) values (e.g., AST, ALT and bilirubin) outside normal 
limits (i.e., either above the ULN or below the lower limit of normal (LLN) where limits are defined), as 
well as a summary of any participant potentially meeting the criteria for Hy’s law will be provided where 
Hy’s Law criteria will be defined as: AST or ALT > 3 ULN and total bilirubin > 2 ULN at any time 
during the study. 
9 Interim Analyses 
Additional details of these analyses will be described in the DSMC Charter. 
10 
Composite and Net Endpoints 
Composite endpoints will first be analyzed as an aggregate and then component-wise, as discussed in the 
context of modeling clinical events in Section 7.2.3. The primary approach to net outcomes will be to 
perform them in all randomized patients in the 30-day study period. 
Composite/net clinical outcomes include the combination of irreversible harm and efficacy outcomes, 
including: 
• 
All-cause mortality, thrombotic events, initiation of organ support, rehospitalization adjudicated 
as to its relatedness to COVID-19. 
11 Subgroup and Sensitivity Analyses 
The sensitivity analyses will be performed on the ITT, mITT, and Per Protocol populations. 
11.1 
Primary Efficacy Endpoint Sensitivity Analysis 
As a sensitivity analysis, all types of missingness will be addressed via multiple imputation, with a target 
of 100 multiply imputed datasets. These analyses will be created for findings obtained initially with all 
available data, with subsequent analysis and pooling performed to evaluate if missing data produces bias 
in model point estimates or otherwise influences the inferential process. 
Multiple imputation will be performed via PROC MI in SAS v9.4. The variables used in the imputation 
model are the six pre-specified sub-groups of interest, along with any relevant measurements for a subject 
that will better inform the imputation process (e.g., with missing Day 8 D-dimer, one would include 
baseline D-dimer in the model). The missing data mechanisms theoretically conferring unbiased 
estimation (given appropriate covariate selection in the imputation model) using this methodology are 
MCAR and MAR, although “modern” methodology (MI or FIML [full information maximum 
likelihood]) also demonstrates superior properties to listwise deletion et al in the MNAR case. Reference 
Appendices in Section 14.2 which contain descriptions of the Bayesian models, methods for multiple 
imputation, and methods for power analysis used in this study. 
11.2 
Primary Efficacy Endpoint Subgroup Analyses 
In order to test for subgroup sensitivities, a Bayesian generalized linear mixed effects model will be 
constructed. This model will evaluate the influence of pre-specified subgroups of interest, D-dimer 
stratum, and potential site-level heterogeneity in patient outcomes. 
A separate set of analyses for each rNAPc2 dosing instance will be constructed, such that the effect on D-
dimer of each incremental dose of rNAP2 is estimated.  These analyses will therefore be equivalent in 


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formulation to the Primary Efficacy Analysis as specified above, with estimates of instantaneous 
treatment effect at Days 3, 5, and 8 for subjects receiving 1, 2 or 3 doses of rNAPc2 or receiving SoC 
heparin through days 1, 3, and 7, respectively. 
11.3 
Secondary Efficacy Endpoint Subgroup and Sensitivity Analyses 
Secondary efficacy endpoints will be subject to the same sensitivity and subgroup analyses as the primary 
efficacy endpoints. 
The following laboratory parameters will be collected and analyzed by a central laboratory. Change from 
baseline to both Day 8 or discharge will be summarized for inflammatory biomarkers (IL-6, hsCRP) and 
coagulation biomarkers (PT, PTT, factor Xa and tissue factor). All data will be listed. Analyses will be by 
generalized linear mixed effects models as described above for sensitivity and subgroup in the primary 
efficacy endpoint. For purposes of interpretation of outcomes, IL-6 and hsCRP are considered measures 
of systemic inflammation, PT, PTT and factor Xa are coagulation parameters, and tissue factor is the 
biologic target of rNAPc2. In addition, in a subset of participants anti-phospholipid antibodies known to 
be generated in COVID-19 and inhibited by rNAPc2, are being measured at baseline, Day 8/discharge 
and on Day 30 at a specialty laboratory. 
11.4 
Additional Safety Analyses 
Decrease in hemoglobin level reported by local laboratories will be monitored to be used as an indicator 
of potential bleeding risk. As a variable, decrease will be dichotomized such that a decrease of more than 
3 g/dL will constitute an event, and any decrease of less than 3g/dL will constitute a non-event. To 
provide the broadest view of potential bleeding risk, heparin treated subjects will be considered together 
regardless of prophylactic or therapeutic regimens. The rNAPc2 subjects will be stratified with regard to 
regimen received. A Cochran Mantel Haenszel Test with stratification will be performed to examine the 
frequency of events and non-events across the two treatment groups. 
12 
Changes from Methods Planned in the Protocol  
Wilcoxon Signed Rank will not be used in the analysis of the primary efficacy endpoint. 
Probability of discharge as assessed by ACTT ≥ 6 by Day 8 and Day 30 post randomization is now a 
secondary efficacy endpoint. 
Composite of death, thrombosis, organ support, or rehospitalization within 30 days is now a secondary 
efficacy endpoint. 
Rehospitalizations and their relatedness to COVID-19 will be adjudicated. 
13 References 
Gou J, Tamhane AC, Xi D and Rom D. A class of improved hybrid Hochberg-Hommel type step-up 
multiple test procedures. Biometrika 2014;101(4):899–911. http://www.jstor.org/stable/43304695 
 
 


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14 Appendix 
14.1 
COVID Severity Definitions 
Subgroup analyses according to baseline severity of COVID-19 illness will be performed. The primary 
categorization will be adapted from the WHO Scale for Clinical Improvement (mild vs. severe) from the 
COVID-19 Therapeutic Trial Synopsis (see below). In addition, patients may be categorized according to 
critical illness at baseline (based on use of inotropes or vasopressors, intubation, CPAP/BiPAP, Venturi, 
and non-rebreather oxygen supplementation) as well as the combination of both approaches, further 
subgrouping the WHO Hospitalized Severe into those with and without critical illness at baseline. 
 
Severity 
Definition 
Hospitalized Mild 
No oxygen therapy 
Hospitalized Mild 
Oxygen by mask or nasal prongs 
Hospitalized Severe 
Non-invasive ventilation (inc. high-flow O2) 
Hospitalized Severe 
Intubation and mechanical ventilation 
Hospitalized Severe 
Ventilation and additional organ support 
(vasopressors, renal replacement therapy, ECMO) 
 
14.2 
Descriptions of the Models and Methods Used 
14.2.1 Bayesian Description 
14.2.2 MI Description 
14.2.3 Power Description