Clinical-trial of COVID-19 Convalescent Plasma in Outpatients
Phase: PHASE3
Conditions: Covid19
Sponsor: Stanford University

 
 
 
Clinical-trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) 
Study Protocol and Statistical Analysis Plan 
NCT04355767 
 February 16, 2021 

 
 
1 
 
STUDY PROTOCOL 
Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO)  
 
A multicenter, two arm, randomized, single-blind clinical trial to determine if 
receiving one dose of convalescent plasma (CP) for mild COVID-19 illness 
prevents illness progression. 
 
 
 
Protocol Signature Page 
 
Principal Investigators: 
Clifton W Callaway, MD, PhD; Valerie Durkalski-Mauldin, Ph.D.; Frederick Korley, MD, PhD,  
Sharon Yeatts, Ph.D. 
 
Study Biostatisticians:   
Valerie Durkalski-Mauldin, Ph.D.;  Sharon Yeatts, Ph.D. 
 
Supported by grants: 
U24NS100659, U24NS100655 from  
The National Heart, Lung and Blood Institute (NHLBI) 
The National Institute of Neurological Disorders and Stroke (NINDS) 
Sponsor of FDA Investigational New Drug: Kevin Schulman, MD 
 
Clinicaltrials.gov: 
 

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I have reviewed and approved this protocol. My signature assures that this study will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality. 
  
 
02/16/2021 
Investigator-Sponsor’s Signature                               
Date of Signature (DD MMM YYYY) 
 
 
I have read this protocol and agree that it contains all the necessary details for carrying out the 
study as described. I will conduct this protocol as outlined herein, including all statements 
regarding confidentiality. I will make a reasonable effort to complete the study within the time 
designated. I will provide copies of the protocol and access to all information furnished by the 
Sponsor to study personnel under my supervision. I will discuss this material with them to 
ensure that they are fully informed about the drug and the study. I understand that the study 
may be terminated or enrollment suspended at any time by the Sponsor, with or without cause, 
or by me if it becomes necessary to protect the interests of the study subjects. 
I agree to conduct this study in full accordance with all applicable regulations and Good Clinical 
Practices (GCP). 
 
 
 
Site Principal Investigator’s Signature                    Date of Signature (DD MMM YYYY) 
  
 
 

 Protocol 5.0 
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Contact Information 
For updated contact information, including the Emergency 24/7 Toll Free Contact Number, 
please refer to the study website or the study Manual of Procedures. 
Clifton W Callaway, MD, PhD 
Contact Principal Investigator 
University of Pittsburgh 
Emergency Medicine 
callawaycw@upmc.edu 
Valerie Durkalski-Mauldin, Ph.D 
Contact Principal Investigator, DCC 
Medical University of South Carolina 
Biostatistics 
durkalsv@musc.edu 
Frederick Korley, MD, PhD 
Multiple Principal Investigator 
University of Michigan 
Emergency Medicine 
korley@med.umich.edu 
Sharon Yeatts, PhD 
Multiple Principal Investigator, DCC 
Medical University of South Carolina 
Biostatistics 
yeatts@musc.edu 
Robert Silbergleit, MD. 
SIREN CCC Principal Investigator 
University of Michigan 
Emergency Medicine 
robert.silbergleit@umich.edu  
William Barsan, MD 
SIREN CCC Principal Investigator 
University of Michigan 
Emergency Medicine 
wbarsan@umich.edu 
Robert Davenport, MD 
Co-Investigator 
University of Michigan 
Transfusion Medicine 
rddvnprt@med.umich.edu 
Alesia Kaplan, MD 
Co-Investigator 
University of Pittsburgh 

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Transfusion Medicine 
AKaplan@itxm.org 
John McDyer, MD 
Co-Investigator 
University of Pittsburgh 
Pulmonary and Critical Care Medicine 
mcdyerjf@upmc.edu 
Kevin Schulman, MD, MBA 
Co-Investigator 
Stanford University 
Hospital Medicine 
kevin.schulman@stanford.edu 
James Quinn, MD 
Co-Investigator 
Stanford University 
Emergency Medicine 
quinnj@stanford.edu 
Manesha Desai, PhD 
Co-Investigator  
Stanford University 
Biostatistics 
manisha.desai@stanford.edu 
SIREN Emergency Clinical Trials Network 
Clinical Coordinating Center 
University of Michigan 
24 Frank Lloyd Wright Dr. 
Suite H3100 
Ann Arbor, MI  48106 
734-232-2142 
 
 

 Protocol 5.0 
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Table of Abbreviations 
AE 
 
Adverse Event 
ADE 
 
Antibody-dependent enhancement  
ARDS  
Acute respiratory distress syndrome  
BARDA 
Biomedical Advance Research and Development Authority  
C3PO  
Clinical-trial of COVID-19 Convalescent Plasma in Outpatients 
CCC 
 
Clinical Coordinating Center 
CDC 
 
Centers for Disease Control and Prevention 
CFR 
 
Code of Federal Regulations 
CIRB  
Central Institutional Review Board 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 2019 
CP 
 
Convalescent Plasma 
CRF 
 
Case Report Form 
DCC 
 
Data Coordinating Center 
DM 
 
Data Manager 
DNR 
 
Do Not Resuscitate 
DSMB  
Data and Safety Monitoring Board 
EC 
 
Executive Committee 
ED 
 
Emergency Department 
eConsent  
Electronic Consent 
ESC 
 
External Steering Committee 
FDA 
 
Food and Drug Administration 
FM 
 
Financial manager 
GCP 
 
Good Clinical Practices 
HIPAA  
Health Information Portability and Accountability Act 
IDE 
 
Investigational device exemption 
IMSM  
Independent medical safety monitor 
IND 
 
Investigational new drug 
IQR 
 
Internal quality reviewer 
ITT 
 
Intention to treat 
LAR 
 
Legally authorized representative 
NCATS 
National Center for Advancing Translational Science 
NHLBI  
National Heart, Lung, and Blood Institute 
NIH 
 
National Institutes of Health 
NINDS  
National Institute of Neurological Disorders and Stroke 
PI 
 
Principal Investigator 
SAE 
 
Serious adverse event 
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2  
SC 
 
Study Coordinators 
SCG 
 
Scientific Coordinating Group 
SIREN  
Strategies to Innovate Emergency Care Clinical Trials Network 
TACO  
Transfusion Associated Circulatory Overload  
TRALI   
Transfusion-related acute lung injury 
WHO  
World Health Organization 
Table of Contents 
1. Protocol Summary 
8 

 Protocol 5.0 
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1.1 Brief Synopsis 
8 
1.2 Synopsis 
10 
Overview 
10 
Objectives 
11 
Study Design 
11 
Primary Endpoint 
11 
Secondary Endpoints 
11 
Study Population 
12 
Randomization 
12 
Consent 
12 
Intervention 
13 
1.3 Schema 
13 
1.4 Schedule of Activities 
13 
1.5 Study Flow and Daily Data Collection 
14 
2. Introduction 
17 
2.1 Study Rationale 
17 
2.2 Background 
18 
2.3 Risk/Benefit Assessment 
20 
3. Objectives and Endpoints 
21 
3.1 Primary Endpoint 
23 
3.2 Secondary Endpoints 
24 
3.3 Exploratory Endpoints 
24 
4. Study Design 
25 
4.1 Overall Design 
25 

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4.2 Scientific Rationale for Study Design 
25 
4.3 Definitions of Enrolled, Discontinued and Completed 
26 
5. Study Population 
27 
5.1 Inclusion Criteria 
27 
5.2 Exclusion Criteria 
29 
5.3 Screen Failures 
30 
5.4 Strategies for Recruitment and Retention 
30 
5.5  45 CFR 46 Subpart B Determination 
31 
6. Study Intervention 
32 
6.1 Study Intervention Administration 
32 
6.2 Preparation/Handling/Storage/Accountability 
33 
6.3 Measures to Minimize Bias: Randomization and Blinding 
35 
6.4 Concomitant Therapy and Hospitalization 
35 
7. Participant Discontinuation/Withdrawal 
35 
7.1 Participant Discontinuation/Withdrawal from the Study 
35 
7.2 Loss to Follow-Up 
35 
8. Study Assessments and Procedures 
36 
8.1 Efficacy Assessments 
36 
8.1.1 Primary Endpoint 
36 
8.1.2 Secondary Endpoints (clinical) 
36 
8.1.3 Secondary Endpoints (immunological): 
38 
8.1.4 Blood Sample Storage, Processing and Shipping for Antibody Titer Testing 
39 
8.1.5 Assessment of Blinding 
39 
8.1.6 Clinical and Demographic Data 
39 

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8.2 Safety and Other Assessments 
40 
8.2.1 Safety Assessment 
40 
8.3 Adverse Events and Serious Adverse Events 
40 
8.3.1 Definition of Adverse Events (AE) 
40 
8.3.2  Definition of Serious Adverse Event (SAE) 
40 
8.3.3 Classification of an Adverse Event 
41 
8.3.4 Relationship to Study Intervention 
41 
8.4 Unanticipated Problems 
43 
9. Statistical Considerations 
43 
9.1 Sample Size 
44 
9.2 Analysis Plan 
44 
10. Supporting Documentation and Operational Considerations 
46 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
46 
10.2 Key Roles and Study Governance 
47 
10.3 Safety Oversight 
48 
10.4 Site  Monitoring, Quality Assurance, and Quality Control 
49 
10.5 Study Records Retention 
50 
10.6 Protocol Deviations 
50 
10.7 Publication and Data Sharing Policy 
50 
11. Protocol Amendment History 
51 
12. References 
69 
 
 
 

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1. Protocol Summary 
1.1 Brief Synopsis 
Title 
Clinical-trial of COVID-19 Convalescent Plasma in Outpatients 
(C3PO)  
Protocol Number 
Pro00044489  
Phase 
Phase III 
Methodology 
Multi-center, randomized, single-blind, two-arm, placebo-controlled 
trial with blinded outcome assessment.  
Study Duration 
June 2020 to July 2021 
Study Center(s) 
SIREN Trial Network 
Objectives 
Primary: To determine the efficacy and safety of a single dose of 
convalescent plasma (CP) for preventing the progression from mild 
to severe COVID-19 illness.  
Secondary: Characterize the immunologic response to CP 
administration. 
Endpoints 
Primary:  
Disease progression defined as death or hospital admission or 
seeking emergency or urgent care within 15 days of randomization. 
Secondary: 
● Worst severity rating on the WHO's COVID Ordinal Scale 
for Clinical Improvement during the 30 days following 
randomization 
● Time to disease progression on the COVID Outpatient 
Ordinal Outcome Scale censored at 15 days after 
randomization. 
● Hospital-free days during the 30 days following 
randomization 
● All-cause mortality at 30 days 

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● Symptom inventory measured using the CDC list of COVID-
19 symptoms on days 2, 4, 6, 8, 10, 14, 15, 30 
● Neutralizing antibody titers at days 0 (pre-intervention and 
post-intervention), 15, and 30 
● Spike protein IgG antibody titers pre and post CP 
administration 
Number of Subjects 
Original planned maximum sample size: 600 (300 per arm) 
Revised maximum sample size based on planned re-estimation: 
900 (450 per arm) 
IND Sponsor 
Kevin Schulman, MD, MBA 
Main Inclusion 
Criteria 
● One or more symptoms of COVID-19 illness and laboratory-
confirmed SARS-CoV-2 infection. 
● Has at least one study defined risk factor for severe COVID-
19 illness 
● Clinical team deems stable for outpatient management 
without new supplemental oxygen 
● CP available at the site at the time of enrollment  
● Duration of symptoms ≤ 7 days at ED presentation and 
randomization 
● Informed consent from subject  
Major Exclusion 
Criteria 
● Age less than 18 years 
● Prisoner or ward of the state  
● Presumed unable to complete follow-up assessments  
● Prior adverse reaction(s) from blood product transfusion  
● Receipt of any blood product within the past 120 days  
● Treating clinical team unwilling to administer up to 250 ml 
fluid 
● Enrollment in another interventional trial for COVID-19 
illness or receipt of other active or passive immunization 
against SARS-CoV2. 
Study Product(s), 
Dose, Route, 
Regimen 
One unit (~200 ml) dose of ABO group compatible SARS-CoV-2 
convalescent plasma (CP) or placebo (250 ml) of normal saline 
with multivitamin. 
Duration of 
administration 
One time 

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Statistical 
Methodology 
Outcomes will be analyzed using the intent-to-treat principle (ITT).  
The primary analysis is to test the hypothesis of superiority of CP 
as compared to placebo. The posterior probability that the 
proportion of primary outcome events at 15-days post 
randomization is higher in the saline arm as compared to the CP 
arm will be calculated. The primary null hypothesis will be rejected 
if the posterior probability is greater than or equal to 0.975 
(selected to coincide with a one-sided alpha level of 0.025 under a 
frequentist design). Interim monitoring for stopping early due to 
overwhelming efficacy or futility will be conducted. We will conduct 
the first interim analysis after approximately 33% of  consecutively 
randomized ITT subjects complete the primary outcome 
assessment. Safety will be closely monitored and reported to the 
independent DSMB.  
  
1.2 Synopsis 
Overview 
A multi-center randomized, single blind, two arm, placebo controlled phase III trial with blinded 
outcome assessment to establish the safety and efficacy of a single dose of convalescent 
plasma (CP) for preventing the progression from mild to severe COVID-19 illness.  
COVID-19 is a respiratory illness caused by the Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2). As of May 1, 2020, over 3 million persons worldwide have been 
diagnosed with COVID-19 and approximately 250,000 persons have died from this disease. The 
majority (80%) of cases are categorized as mild, while approximately 15-20% of cases are 
categorized as severe, with about 5% of all cases progressing into critical illness, characterized 
by hypoxemic respiratory failure, shock, and end-organ failure.1,2 Among the 5% who develop 
severe disease, as many as 50% die.3 At present there is no specific therapy for preventing the 
progression of COVID-19 from mild to severe disease.  
Passive antibody therapy using plasma from donors who have been infected and then 
recovered (convalescent plasma, CP) contains neutralizing antibodies against the infectious 
agent.  Specifically, CP has been used in different respiratory illness epidemics, including the 
1918 influenza pandemic, the 2003 SARS-CoV-1 outbreak, and the 2009 H1N1 influenza 
pandemic. Use of CP for emerging infections has persisted because of strong mechanistic and 
observational data, but efficacy has yet to be well tested or demonstrated in clinical trials.  At 
this moment, there is no high quality evidence to support the efficacy of CP for treating COVID-
19 illness. Conceptually, CP has the highest chance of showing efficacy if used for early 
treatment of patients at the highest risk for severe disease and mortality.   
Objectives 
The overarching goal of this project is to confirm or refute the role of passive immunization as a 
safe and efficacious therapy in preventing the progression from mild to severe/critical COVID-19 
illness and to understand the immunologic kinetics of anti-SARS-CoV-2 antibodies after passive 
immunization.  
Primary Objective:  

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To establish the safety and efficacy of a single dose of convalescent plasma (CP) for preventing 
the progression from mild to severe/critical COVID-19 illness.   
Secondary Objectives:  
Characterize the immunologic response to CP administration. 
Study Design 
This is a multi-center randomized, two-arm, single-blind placebo-controlled phase III trial with 
blinded outcome assessment.  
Sample size: Original planned maximum sample size: 600 (300 per arm) 
Revised maximum sample size based on planned re-estimation: 900 (450 per arm) 
Study Duration: 12 months 
Study Duration for individual subjects: 30 days 
Age range: 18 years of age or greater 
Primary Endpoint 
Disease progression defined as hospital admission, death or seeking emergency or urgent care 
within 15 days of randomization 
Secondary Endpoints 
● Worst severity rating on the WHO's COVID Ordinal Scale for Clinical Improvement 
during the 30 days following randomization 
○ Death 
○ Hospitalized on invasive mechanical ventilation or ECMO 
○ Hospitalized on non-invasive ventilation or high flow nasal cannula  
○ Hospitalized on supplemental oxygen 
○ Hospitalized not on supplemental oxygen 
○ Not hospitalized with limitation in activity (continued symptoms) 
○ Not hospitalized without limitation in activity (no symptoms) 
● Time to disease progression on the COVID Outpatient Ordinal Outcome Scale censored 
at 15 days after randomization 
○ Patient requires care in the hospital 
○ Patient requires care in the ED or urgent care 
○ Patient at home with symptoms rated as moderate (defined as fever, shortness 
of breath, abdominal pain) 
○ Patient at home with symptoms rated as mild (defined as afebrile, constitutional 
symptoms (flu-like illness) without shortness of breath) 
○ Patient in their usual state of health 
● Hospital-free days during the 30 days following randomization 
● All-cause mortality at 30 days 
Exploratory Endpoints 
● Symptom inventory measured using the CDC list of COVID-19 symptoms on days 2, 4, 
6, 8, 10, 14, 15, 30 
● Neutralizing antibody titers at days 0 (pre-intervention and post-intervention), 15, and 30  
● Spike protein IgG antibody titers pre and post CP administration  

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Study Population 
Adults presenting to the emergency department (ED) with their first episode of symptomatic, 
laboratory-confirmed COVID-19 illness, who are at high risk for progression to severe/critical 
illness, but who are clinically stable for outpatient management at randomization.   
Inclusion Criteria  
● 
One or more symptoms of COVID-19 illness and laboratory-confirmed SARS-CoV-2 
infection 
● 
Has at least one study defined risk factor for severe COVID-19 illness   
● 
ED team deems stable for outpatient management without new supplemental oxygen 
requirement 
● 
Informed consent from subject 
● 
ABO-compatible CP available at the site at the time of enrollment  
● 
Duration of symptoms ≤ 7 days at ED presentation and randomization 
Exclusion Criteria   
● 
Age < 18 years 
● 
Prisoner or ward of the state.  
● 
Presumed unable to complete follow-up assessments  
● 
Prior adverse reaction(s) from blood product transfusion  
● 
Religious, social or other contraindications to receiving blood products 
● 
Receipt of any blood product within the past 120 days  
● 
Inability to tolerate up to 250 ml of intravenous fluid  
● 
Enrollment in another interventional trial for COVID-19 illness or receipt of other 
active or passive immunization against SARS-CoV2. 
Randomization 
A web-based central randomization system will assign treatment using a fixed 1:1 allocation 
ratio. The randomization algorithm will prevent possible selection bias by providing random 
treatment assignment to each subject and prevent accidental treatment imbalances in age and 
site. 
Consent 
Patients who are eligible for this trial will provide written informed consent. The COVID-19 
pandemic has created a need for novel consent and recruitment procedures.  We have 
developed entirely electronic consent forms, which will be used in this trial.  REDCap software 
can serve these forms to any internet connected device.  Coordinators, working from remote 
locations, may communicate with potential subjects in any ED using telephone or video 
connection (e.g. Zoom, FaceTime, Skype or other methods). We have several years experience 
with electronic consent in emergency patients. 
Intervention 
Subjects will be randomized in a 1:1 ratio to receive either one unit (~200 ml) dose of ABO 
group compatible SARS-CoV-2 convalescent plasma (CP) with neutralizing SARS-CoV2 
antibodies titers of ≥1:160 or placebo infusion of 250 ml of normal saline with 1-5 ml parenteral 
multivitamin concentrate. 
 

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1.3 Schema 
Timeline for study events.  Enrollment and intervention (CP or Placebo) occurs in the 
emergency department (or adjacent care clinic). Blood samples 1 and 2 are collected during 
that visit. Residual viral media samples from nasopharyngeal swabs and/or saliva samples will 
also be collected during the enrollment visit. Outpatient follow-up is conducted remotely by 
telephone or other contact.  Subjects have phlebotomy on Day 15 and Day 30 for blood 
samples 3 and 4.  In-person or remote contact on Day 15 and Day 30, and medical record 
review on Day 30, will confirm subject outcomes. We will collect information on participants’ 
SARS-CoV-2 viral genotype from the enrolling institution if available.  
1.4 Schedule of Activities 
 
Study Day 
 
0 
2 
4 
6 
8 
10 
12 
14 
15 
30 
Inclusion/Exclusion 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
Medical History 
Contact Information 
X 
X 
X 
 
 
 
 
 
 
 
 
 
ABO type 
X 
 
 
 
 
 
 
 
 
 
Randomization 
Pre-intervention research blood draw 
Administer CP or Placebo 
Post-intervention research blood draw 
X 
X 
 
X 
X 
  
 
 
 
 
 
 
 
 
Research Blood Draw 
 
 
 
 
 
 
 
 
X 
X 
Residual viral media / saliva sample 
X 
 
 
 
 
 
 
 
 
 
Assess for Hospitalization 
Vital Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom Inventory 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Adverse Event Assessment 
Review Electronic Medical Record / 
Death Index 
X    
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Day 0 is the same as the day of randomization. Day 0 starts from the time of 
randomization until 23:59 of that calendar day. Day 1 begins at 00:00 on the following day.    
 
1.5 Study Flow and Daily Data Collection 
The enrollment and follow-up process will be tailored to the particulars of each site, but will 
generally be as follows.   
● Units of SARS-CoV-2 convalescent plasma (CP) with neutralizing SARS-CoV2 
antibodies titers of ≥1:160 will be sent to sites for storage. 
● Site study teams will be notified whenever a COVID-19 test is ordered on an Emergency 
Department patient.   
● The site study team will then consult with the treating team and/or the electronic health 
record to screen for potential eligibility.   
● If the treating team anticipates discharge, the site study team will connect with the 
patient on the patient’s mobile device, by bedside telephone in the ED room, on a study 
provided tablet device, or in person using all appropriate personal protective equipment.  
They will verbally describe the trial and participation and complete the informed consent 
process.   
● Those wishing to participate will complete the electronic informed consent document and 
provide contact information.   
● When all eligibility criteria have been met, the site study team will enroll and randomize 
the subject in the study web-based clinical trial management system (WebDCU).   
● The site study team will complete Day 0 (Baseline) case report forms.   
● All subjects will have a pre-infusion blood draw.  Blood from consented subjects will be 
sent for blood type. Blood from all subjects will be processed and frozen for later 
analysis.   
● Residual viral media samples from nasopharyngeal swabs and/or saliva samples will 
also be collected during the enrollment visit. 
● If randomized to CP, an order will be placed by the study team to the blood bank for 1 
unit of study CP.   
● If randomized to placebo, an order will be placed to the pharmacy for 250 ml NS + 1-5 ml 
parenteral MVI (see MOP for details).   
● CP or placebo will then be infused in a fashion blinded to the participant over 30 minutes 
(or longer depending on subject’s cardiopulmonary status) with the infusion bag covered.   
● The participant will be observed in the emergency department for at least 1 hour after 
infusion.  At one hour, another blood sample will be drawn and frozen for later analysis.   
● The participant will then be discharged from the emergency department.   
● The central study team follow-up core will contact the participant by telephone or video 

 Protocol 5.0 
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chat every other day to assess disease progression and serious adverse events for 2 
weeks.  They will assess blinding to treatment on day 2. 
● The site study team will arrange collection of blood samples at days 15 and 30 to be 
frozen for later analysis.  Subjects may visit a clinic, phlebotomy site, or other site-
specific arrangement. 
● The site study team will also collect data from any hospitalizations and ED/Urgent Care 
visits occurring within the study period. In addition, the study team will collect a symptom 
inventory on days 15 and 30 and assess blinding to treatment on day 15. 
● Participation in the trial ends 30 days after enrollment.   
● Blood samples from participants will be shipped to the study core lab at the University of 
Pittsburgh for analysis. 
● Residual viral media and saliva samples will be shipped to a central lab for analysis. 
● If hospitalized, participants are permitted to receive non-study CP or other emergency 
use or investigational treatments if available. In the event a participant is hospitalized, 
they may contact the study team for information regarding their study group allotment.          
1.5.1 Day 0 Enrollment 
1.5.1.1 Screening, Informed Consent, and Randomization 
● Inclusion and Exclusion Criteria 
● Informed Consent 
● Random Assignment via WebDCU 
1.5.1.2 Data Collection 
● Demographics 
● Detailed Contact Information 
● Medical History 
● Concurrent Medications 
● Symptoms, including day of symptom onset 
● SARS-CoV-2 viral genotype, if available 
1.5.1.3 Intervention 
● Blood type 
● Blood sample for antibody titer 
● Infuse CP or saline placebo 
● Blood sample for antibody titer, 1 hour after infusion 
● Residual viral media and/or saliva sample 
1.5.2 Follow-up Assessments 
1.5.2.1 Day 2  Telephone or remote assessment of 
● Hospitalization, urgent medical visits, and vital status 
● Symptoms 
● Blinding to intervention arm 
1.5.2.2 Day 4  Telephone or remote assessment of 
● Hospitalization, urgent medical visits, and vital status 

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● Symptoms 
 
1.5.2.3 Day 6  Telephone or remote assessment of 
● Hospitalization, urgent medical visits, and vital status 
● Symptoms 
1.5.2.4 Day 8  Telephone or remote assessment of 
● Hospitalization, urgent medical visits, and vital status 
● Symptoms 
1.5.2.5 Day 10  Telephone or remote assessment of 
● Hospitalization, urgent medical visits, and vital status 
● Symptoms 
1.5.2.6 Day 12  Telephone or remote assessment of 
● Hospitalization, urgent medical visits, and vital status 
● Symptoms 
1.5.2.7 Day 14 Telephone or remote assessment of 
● Hospitalization, urgent medical visits, and vital status 
● Symptoms 
1.5.2.8 Day 15  
● Collect blood sample for antibody testing 
Telephone, remote, or in-person assessment of 
● Hospitalization, urgent medical visits, and vital status 
● Any adverse event 
● Symptoms 
● Blinding to intervention arm 
1.5.2.9 Day 30   
● Collect blood sample for antibody testing 
Telephone, remote, or in-person assessment of 
● Hospitalization, urgent medical visits, and vital status 
● Any serious adverse event 
● Symptoms 
1.5.3 Day  30   End of Study 
● Review electronic medical record for hospitalizations or serious adverse events 
● Review death notifications for any subjects lost to follow-up 

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2. Introduction 
This trial will test a therapy of strategic importance to the current and future worldwide response 
to COVID-19 (right therapy) in subjects most likely to benefit from the therapy (right patients) at 
the time during their illness when the therapy is most likely to show efficacy (right time).  This 
trial uses clinically important, objectively measured endpoints with low risk of missingness 
(rigorous).  The analysis of the trial data will describe the probability that the therapy has benefit 
in the most important manner for making decisions about further refinement or immediate 
adoption into clinical use (impact), including providing data on dose-effect relationship (right 
dose). 
2.1 Study Rationale 
Passive antibody therapy involves the administration of antibodies against a given agent to a 
susceptible individual for the purpose of preventing or treating an infectious disease due to that 
agent. In contrast, active vaccination requires the induction of an immune response that takes 
time to develop and varies depending on the vaccine recipient. Some immunocompromised 
patients fail to achieve an adequate immune response with active immunization, and some 
immunocompetent patients fail to generate protective antibodies in response to a given vaccine. 
Thus, passive antibody administration is the only means of providing immediate immunity to 
susceptible or non-immune persons and immunity of any measurable kind for highly 
immunocompromised patients. 
The only antibody type that is currently available for immediate use is that found in human 
convalescent plasma (CP). As more individuals contract COVID-19 and recover, the number of 
potential donors will continue to increase. CP can be collected and administered anywhere in 
the world that is affected by  COVID-19.   Thus, CP represents an immediately and universally 
available therapeutic strategy for treating a pandemic prior to development of effective vaccines 
and in the absence of other pharmacological tools.   
If CP is effective, it  will support subsequent development of hyperimmune antibody 
preparations that can be immediately available for future outbreaks, prophylaxis, or individual 
treatment.  This strategy has resulted in widely used products including hepatitis B-Ig, rabies-Ig, 
tetanus-Ig, and even respiratory pathogen products like respiratory syncytial virus-Ig. It is 
important to study CP now, because it is unknown if hyperimmune globulins (hyper-Ig) will be 
developed successfully, and it is also possible that hyper-Ig will be too expensive for all markets 
globally. However, CP can be made available even in resource-poor areas. In addition, this trial 
will inform decisions regarding the use of CP early on in future pandemics. The trial will also 
inform the design and justification for any future hyper-Ig trials.  
At this moment, no high quality evidence supports the efficacy of CP for treating COVID-19 
illness.  Therefore, this is a pivotal trial to test the ability of passive antibody therapy to prevent 
progression of COVID-19 illness.  This will provide an immediate treatment for the current global 
pandemic, a treatment for future patients who cannot benefit from active vaccination, and a 
scientific basis for development of strategically important hyperimmune globulins that could help 
mitigate future outbreaks. 
 
2.2 Background  
Importance of research question 

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19 
Passive antibody therapy has been used for various illnesses for over 120 years.  Plasma from 
donors who have been infected and then recovered (convalescent plasma, CP) from many 
illnesses contains neutralizing antibodies against the pathogen.  Specifically, CP has been used 
in different respiratory illness epidemics, including the 1918 influenza pandemic, the 2003 
SARS-CoV-1 outbreak, and the 2009 H1N1 influenza pandemic.1  Use of convalescent plasma 
for emerging infections has persisted because of strong mechanistic and observational data, but 
efficacy has yet to be well tested or demonstrated in clinical trials.  The challenges for CP 
therapy include identifying suitable donors, identifying adequately active antibodies, and 
learning who are the optimal patients and what is the optimal timing in the course of the disease 
for receiving CP.  However, there is a suggestion in the SARS outbreak that the administration 
of CP earlier is more likely to be effective.2   For this reason, this trial will test CP in early, mild 
COVID-19. 
COVID-19 is a respiratory disease caused by the Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2). As of May 1st, 2020, over 3 million persons worldwide have been 
diagnosed with COVID-19 and approximately 250,000 persons have died from this disease. In 
the United States alone, as of May 1, 2020, there are approximately 1 million cases and 55,000 
deaths. In the most current case series, the majority (80%) of cases were mild and were 
characterized by fever, myalgia, fatigue or dry cough. However, approximately 15-20% of cases 
were severe and were characterized by dyspnea and hypoxia, with about 5% of all cases 
progressing into critical illness, characterized by hypoxemic respiratory failure, shock, and end-
organ failure.1,2 Among the 5% who develop severe disease, as many as 50% die.3 Although the 
time between illness onset and progression to severe disease is variable, it has been estimated 
to be approximately 10 days.4 Older age and comorbidities such as hypertension, diabetes, and 
coronary heart disease increase the risk for developing severe COVID-19 illness and 
mortality.3,4 At present there is no specific therapy for preventing the progression of COVID-19 
from mild to severe disease.  Hundreds of clinical trials are examining the efficacy of novel and 
repurposed therapeutic agents for treating patients with severe disease. In addition, efforts are 
currently underway to develop a vaccine for SARS-CoV-2 infection. However, only a handful of 
trials are exploring therapeutic agents for preventing the progression of mild to severe/critical 
COVID-19 illness.  
Passive antibody therapy has been used since the 1890s, and it was the only means of treating 
certain infectious diseases prior to the development of antimicrobial therapy in the 1940s.3,4 
Experience from prior outbreaks with other coronaviruses, such as SARS-CoV-1 shows that 
such convalescent plasma contains neutralizing antibodies to the relevant virus.5  In the case of 
SARS-CoV-2, the anticipated mechanism of action by which passive antibody therapy would 
mediate protection is viral neutralization. However, other mechanisms may be possible, such as 
antibody dependent cellular cytotoxicity and/or phagocytosis. Convalescent serum was also 
used in the 2013 African Ebola epidemic. A small non-randomized study in Sierra Leone 
revealed a significant increase in survival for those treated with convalescent whole blood 
relative to those who received standard treatment. 
CP has the highest chance of showing efficacy if used for treatment of COVID-19 patients early 
in the course of disease.  A general principle of passive antibody therapy is that it is more 
effective when used for prophylaxis than for treatment of disease. When used for therapy, 
passive immunization is most effective when administered shortly after the onset of symptoms. 
The reason for temporal variation in efficacy could reflect that passive antibody works by 
neutralizing the initial inoculum, which is likely to be much smaller than that of established 
disease. The benefit of CP may be greatest during the time prior to the recipient developing 
their own antibodies.6  Another explanation is that antibody works by modifying the inflammatory 
response, which is also easier during the initial immune response, which may be 

 Protocol 5.0 
20 
asymptomatic.7 As an example, passive antibody therapy for pneumococcal pneumonia was 
most effective when administered shortly after the onset of symptoms and there was no benefit 
if antibody administration was delayed past the third day of disease.8 In the SARS outbreak, 
administration of CP early in the disease appeared to be more effective.  
For passive antibody therapy to be effective, a sufficient amount of antibody must be 
administered. When given to a susceptible person, this antibody will circulate in the blood, 
distribute into the total interstitial fluid in order to reach tissues, and provide protection against 
infection. As a rough estimate, one unit of donor CP (~250 ml) will be diluted into ~15 L of total 
extracellular fluid in an adult recipient, resulting in about 60-fold dilution of antibody 
concentration.  For this reason, it is recommended that CP contain at least 1:80 titer and 
preferred 1:160 titer of antibodies against the pathogenic agent*.  Depending on the antibody 
amount and composition, the protection conferred by the transferred immunoglobulin can last 
from weeks to months. 
*https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-
process-cber/recommendations-investigational-covid-19-convalescent-plasma   
Supporting Evidence 
Pre-clinical studies: 
In the 21st century, there were two other epidemics with coronaviruses that were associated 
with high mortality, SARS in 2003 and MERS in 2012. In a mouse model of SARS infection, 
animals receiving immune serum from infected mice were protected against lower airway 
disease after intranasal challenge with virus.9 Several groups have also identified monoclonal 
neutralizing antibodies that have shown efficacy in animal models of SARS.10 In a mouse model 
of MERS infection, transfusion of sera from MERS-infected camels was efficacious for both 
prophylaxis and treatment.11 Similar results for convalescent sera were obtained in a marmoset 
model of MERS.12  
Clinical studies: 
In both SARS and MERS outbreaks, the high mortality and absence of effective therapies led to 
the use of convalescent plasma in human studies. The largest study involved the treatment of 
80 patients in Hong Kong with SARS.13 Patients treated before day 14 had improved prognosis 
defined by discharge from hospital before day 22, consistent with the notion that earlier 
administration is more likely to be effective. In addition, those who were RT-PCR positive and 
seronegative for coronavirus at the time of therapy had improved prognosis. There is also some 
anecdotal information on the use of convalescent plasma in seriously ill individuals. Three 
patients with SARS in Taiwan were treated with 500 ml of convalescent plasma, resulting in a 
reduction in plasma virus titer and each survived.14 Three patients with MERS in South Korea 
were treated with convalescent plasma, but only two of the recipients had neutralizing antibody 
in their plasma.15  The latter study highlights a challenge in using convalescent plasma, namely, 
that some who recover from viral disease may not have high titers of neutralizing antibody.16 
Consistent with this point, an analysis of 99 samples of convalescent sera from patients with 
MERS showed that 87 had neutralizing antibody with a geometric mean titer of 1:61. This 
suggests that antibodies decline with time and/or that only some patients make high titer 
responses. It is also possible that other types of non-neutralizing antibodies are made that 
contribute to protection and recovery as described for other viral diseases.17  
Current Trials of CP in Severe COVID-19 

 Protocol 5.0 
21 
There are also recent reports of improvement from SARS-CoV-2 infection in hospitalized 
patients given convalescent plasma (http://www.xinhuanet.com/english/2020-
02/28/c_138828177.htm). In another report, 5 critically ill patients with COVID-19 were given 
high-titer convalescent plasma.18 All patients had improved viral loads, 4 had resolution of 
ARDS, and 3 were weaned from mechanical ventilation within 2 weeks of treatment. There were 
no reported adverse events in the treated patients. However, this study was uncontrolled and all 
5 patients also received other anti-viral treatments and corticosteroids, highlighting the need for 
a randomized controlled trial. In another case series, 10 patients with severe COVID-19 were 
administered convalescent plasma, and all improved clinically without any serious adverse 
events. In a historical control group matched to the 10 treated patients, only 1 out 10 patients 
showed similar improvements.19  
2.3 Risk/Benefit Assessment 
2.3.1 Known potential risks 
A theoretical risk of CP is antibody-dependent enhancement (ADE) of illness. ADE involves an 
enhancement of disease in the presence of cross-reacting antibodies that activate receptors 
that suppress immune response. For coronaviruses,  there is the theoretical concern that 
antibodies to one type of coronavirus could enhance infection to another viral strain.20 However,  
use of CP in the COVID-19 epidemic will rely on products with neutralizing antibody against the 
same virus, SARS2-CoV-2, which should make ADE unlikely. The available evidence from the 
use of CP in patients with SARS1 and MERS21 and anecdotal evidence of its use in patients 
with COVID-19 (http://www.xinhuanet.com/english/2020-02/28/c_138828177.htm and,18 suggest 
it is safe. Nevertheless, this trial will monitor illness severity over time for any evidence of 
enhanced infection. 
Another theoretical risk is that antibody administration to those exposed to SARS-CoV-2 may 
avoid disease but modify the immune response such that those individuals mount attenuated 
immune responses, which would leave them vulnerable to subsequent re-infection. In this 
regard, passive antibody administration before vaccination with respiratory syncytial virus was 
reported to attenuate humoral but not cellular immunity.22 This concern could be investigated as 
part of a clinical trial by measuring immune responses in those exposed and treated with 
convalescent plasma to prevent disease. If the concern proved real, these individuals could be 
vaccinated against COVID-19 when a vaccine becomes available. These concerns seem 
modest compared to the possibility of limiting the duration and severity of disease, and avoiding 
interventions like mechanical ventilation, ARDS and sepsis.  
Finally, there are risks associated with any transfusion of plasma including transmission of 
transfusion transmitted viruses (e.g. HIV, HBV, HCV, etc.), allergic transfusion reactions, 
anaphylaxis to transfusion, febrile transfusion reaction, transfusion related acute lung injury 
(TRALI), transfusion associated cardiac overload (TACO), and hemolysis should ABO 
incompatible plasma be administered.23   In addition, donors will fulfill donor requirements for 
whole blood donation and frequent apheresis plasma donation with the exception of recent 
illness, in this case COVID-19 infection. With current practice, transfusion transmission of 
infections is very rare. In addition, the risk of TRALI is also very rare because CP will be 
collected from populations with reduced risk for allo-antibodies such as: males, never pregnant 
females, and females who test negative for HLA antibodies. 
Preliminary safety results from the Expanded Access Program for CP in moderate-severe 
COVID-19 have been posted, but not yet peer-reviewed 
(https://www.medrxiv.org/content/10.1101/2020.05.12.20099879v1).  Among 5000 transfusions, 
there were 36 serious adverse events (0.7%) with 25 adjudicated as related (0.5%).  Related 

 Protocol 5.0 
22 
events included mortality (n=4, 0.08%), TACO (n=11,0.22%), TRALI (n=7,0.14%)  and allergic 
reaction (n=3,0.06%).  Another 11 deaths were reported but judged not to be related. 
2.3.2 Known potential benefits 
A key potential benefit is treatment for established infection.  Convalescent plasma would be 
administered to those with clinical disease in an effort to reduce their symptoms and mortality. 
Based on the historical experience with antibody administration, it can be anticipated that antibody 
administration relatively early in the course of disease would be more effective in preventing 
disease progression than in the treatment of established severe disease. 
Given that historical and current anecdotal data on use of CP suggest it is safe in coronavirus 
infection, the high mortality of COVID-19, particularly in elderly and vulnerable persons, suggests 
that the benefits of its use in those at high risk for or with early disease outweigh the risks. 
However, for all cases where convalescent plasma administration is considered, a risk-benefit 
assessment must be conducted to assess individual variables. 
 
3. Objectives and Endpoints  
Objectives 
Endpoints 
Justification for 
endpoints  
Primary 
To establish the efficacy 
of a single dose of 
convalescent plasma 
(CP) for preventing the 
progression from mild to 
severe COVID-19 
illness.   
Disease progression defined as death or 
hospital admission or seeking emergency 
or urgent care within 15 days of 
randomization 
This will allow 
quantification of 
disease progression 
from mild to 
moderate/severe/critical
.  
Secondary and Exploratory 
Determine the effect of 
CP on COVID-19 illness 
severity 
Worst severity rating on the WHO's 
COVID Ordinal Scale for Clinical 
Improvement during the 30 days following 
randomization 
○ Death 
○ Hospitalized, intubated, mechanically 
ventilated and requiring additional 
organ support (pressors, renal 
replacement therapy) 
○ Hospitalized on invasive mechanical 
ventilation or ECMO 
○ Hospitalized on non-invasive 
ventilation or high flow nasal cannula  
○ Hospitalized on supplemental oxygen 
This scale was 
developed by a special 
World Health 
Organization (WHO) 
committee for 
quantifying COVID-19 
illness severity 

 Protocol 5.0 
23 
○ Hospitalized not on supplemental 
oxygen 
○ Not hospitalized with limitation in 
activity (continued symptoms) 
○ Not hospitalized without limitation in 
activity (no symptoms) 
Determine the effect of 
CP on COVID-19 illness 
severity 
Time to disease progression on the 
COVID Outpatient Ordinal Outcome 
Scale censored at 15 days after 
randomization 
● Patient requires care in the 
hospital 
● Patient requires care in the ED or 
urgent care 
● Patient at home with symptoms 
rated as moderate (defined as 
fever, shortness of breath, 
abdominal pain) 
● Patient at home with symptoms 
rated as mild (defined as afebrile, 
constitutional symptoms (flu-like 
illness) without shortness of 
breath) 
● Patient in their usual state of 
health 
This scale was adapted 
for outpatient use from 
Harrell 2020 
(http://hbiostat.org/proj/
covid19/bayesplan.html
) to provide more 
granular detail for 
outpatients than the 
WHO scale. 
Determine the effect of 
CP on prevention of 
hospitalization 
Hospital-free days during the 30 days 
following randomization 
This is a more graded 
measurement of 
hospitalization than the 
binary primary outcome 
Determine the effect of 
CP on mortality 
All-cause mortality at 30 days 
Critical safety outcome 
Determine the effect of 
CP on the duration of 
symptoms 
Symptom inventory measured using the 
CDC list of COVID-19 symptoms on days 
2, 4, 6, 8, 10, 14, 15, 30 
Patient centered 
outcome relevant to 
patient experience of 
illness 
Characterize the 
immunological response 
to CP administration  
Neutralizing antibody titers at days 0 (pre-
intervention and post-intervention), 15, 
and 30 using different methods 
Determine if CP 
administration 
increases recipient 
antibody titers that can 
inhibit virus 

 Protocol 5.0 
24 
Measure change in 
spike protein IgG titers 
in CP recipient from 
pre- to post-CP   
Spike protein IgG antibody titers pre and 
post CP administration using different 
methods 
Determine distribution 
of CP antibodies into 
recipient 
3.1 Primary Endpoint 
 
Operational definition of Hospitalization Care in the primary endpoint: 
● The endpoint is determined based on the order to admit the patient to an inpatient 
hospital bed (including admission to observation status).  Patients may board in 
emergency departments or other outpatient areas awaiting inpatient beds for some time; 
therefore, the intent to place the patient in an inpatient bed is considered to be 
hospitalization. Observation in an emergency department observation unit would not 
count as hospitalization but only as emergency care.  In the event that a patient worsens 
in the emergency department shortly after administration of the intervention and requires 
admission during that same visit, we will consider that that patient has met this primary 
endpoint.  
 
Operational definition of Emergency Care in the primary endpoint: 
● This endpoint is determined based on any presentation to an emergency department or 
urgent clinic for care.  COVID-19 patients may be redirected to special areas adjacent to 
or outside of the usual emergency department for evaluation and treatment; therefore, 
the presentation for emergency or urgent care is considered the endpoint rather than 
physical entry into a specific area.  
 
Operational definition of Death in the primary endpoint: 
● Patients who die outside the hospital during the 15 days following randomization will 
meet this endpoint.  Death notice or public records can confirm death.   
Justification of the primary endpoint: 
Hospitalization is a hard metric of meaningful worsening of disease.   
● Hospitalization is a readily observable and objective outcome.  It does not depend 
on self assessment, does not depend on return to the enrollment site, and can be 
verified by self-report, proxy-report, or even limited source documents from any 
admitting hospital or clinic.  As such, it has low vulnerability to missing data or bias.   
● The endpoint is a marker for worsening of disease. Hospitalization is a marker for 
the need of more intensive treatment that cannot be managed as an outpatient and 
is similar to the criteria used to characterize an adverse event as serious. 
● The endpoint matters to patients. The need for hospitalization is a significant and 
meaningful event for patients. Hospitalization also removes patients from families 
and support systems further aggravating other symptoms of disease progression. 
● The endpoint matters to the healthcare system. The need for hospitalization is the 
primary indicator of demand and capacity of the healthcare and public health 
systems during pandemic illness.  This endpoint has direct implications for 
healthcare utilization in times of healthcare system stress. 
● Preventing treatment imbalances within site (while maintaining randomness in 
treatment assignment) minimizes the effect of variations in practice or hospital 
capacity on the primary endpoint. 

 Protocol 5.0 
25 
● Fifteen days is an appropriate time frame given the natural history of COVID-19. 
The median time to hospitalization from symptom onset is approximately 9-10 days. 
Longer time periods increase the risk of competing unrelated events.  
 
Seeking Emergency Care is a hard metric of meaningful worsening of disease.   
● Emergency and Urgent care is readily observable and objective.  Like 
hospitalization, this event can be captured with limited source documents or patient 
report, and thus has low vulnerability to missing data or bias. 
● Seeking medical care represents symptom progression that a patient cannot 
manage at home.  Therefore, this is an event of sufficient severity to require action. 
● The endpoint matters to the healthcare system. Emergency and urgent care 
represents health care utilization. 
● This endpoint captures moderate disease progression.  Patients treated in 
emergency departments or clinics but not admitted to the hospital have actionable 
disease progression that is less severe than those admitted to the hospital.  
 
 
Death is a the most profound worsening of disease 
● Subject death is readily ascertained and objective.  Death can be confirmed by 
multiple data sources.    
3.2 Secondary Endpoints 
These endpoints explore the trajectory of illness in greater detail.  These will provide additional 
information about CP effects on disease progression and maximal disease severity. 
● WHO's COVID Ordinal Scale for Clinical Improvement 
● COVID-19 Outpatient Ordinal Scale 
● Hospital-free days 
● All-cause mortality 
3.3 Exploratory Endpoints 
● Symptom inventory 
These endpoints will determine the ability of CP to increase the titers of neutralizing antibodies 
in recipients. 
● Antibody titers at pre-infusion, post-infusion and at 15 and 30 days in CP 
recipients and controls 
● Spike protein IgG antibody titers pre and post CP administration 
 
4. Study Design  
4.1 Overall Design  
This is a multi-center randomized, two-arm, single-blind, placebo-controlled phase III trial with 
blinded outcome assessment. We hypothesize that in patients with mild COVID-19 illness, the 
administration of convalescent plasma will decrease the need for hospital admission or 
emergency care for worsening, severe, or critical illness.  

 Protocol 5.0 
26 
4.2 Scientific Rationale for Study Design 
Rationale for using normal saline control group: 
We considered comparing CP to non-immune plasma collected either prior to the spread of the 
SARS-CoV-2 virus or from donors with no known COVID-2 illness. Non-immune plasma would 
have similar appearance, volume, protein content and non-specific factors.    
We believe there is some small risk to fresh frozen plasma (allergic, anaphylactic, and hemolytic 
reactions, and risk of transmission of infectious diseases) with no known benefit to the subject.  
This fact increases risk primarily in order to improve blinding.   In addition, there is possible 
prevalence of antibodies to other coronaviruses in non-immune plasma which may in fact 
modulate COVID-19 illness or even cross-react with SARS-CoV-2.  These antibodies, if present, 
might reduce the ability to detect an effect of CP.  Finally, the  trial must instruct future clinicians 
not whether to give CP versus non-immune plasma, but instead whether to give CP or not.  
Thus, a non-plasma control is a better placebo for a trial to guide clinical practice.    
Saline as Control Group 
Plasma as Control Group 
Advantages 
● No risk of reaction 
● Maximizes opportunity to see effect of 
CP, including any non-specific effects 
● Participants perceive as low-risk 
● ED providers perceive as no-risk 
Advantages 
● Preserves double-blind 
● Controls for non-specific or 
immunomodulatory effects of plasma 
Disadvantages 
● Risk that subject may be unblinded 
● ED staff will not be blinded 
● ED staff must receive CP intervention 
from blood bank and placebo 
intervention from pharmacy  
Disadvantages 
● 1-3% chance of mild reaction 
● Blood Bank must manage 
randomization  
● Non-specific antibodies that cross-
react with SARS-CoV-2 may reduce 
opportunity to see effect of CP 
● ED providers ambivalent about giving 
plasma without clear indication 
 
Rationale for single-blind design: 
We considered blinding ED providers by using fresh frozen plasma or other colloid fluid as a 
control.  This procedure would require overcoming a number of major logistical hurdles including 
securing supply of sham plasma, labeling and tracking of sham plasma, and creating 
mechanisms to unblind providers in the event a patient seemed eligible for subsequent 
compassionate use CP.   If a non-plasma control is used, it is unlikely that we can make it 
resemble plasma sufficiently to deceive experienced clinicians.   
We believe that the patient can be blinded well to the intervention. Most patients do not receive 
blood products often or ever and will have no comparison.  The bag and infusion line will be 
covered from patient view, removing clues from the appearance of the infusion.  Adding a 
multivitamin to the saline will make the placebo bag color similar to plasma. Other aspects of 
treatment will be identical. 

 Protocol 5.0 
27 
Because ED providers will not interact with the subject after the intervention is delivered, we 
believe that allowing these providers to know the intervention will not bias outcomes.   Follow-up 
coordinators who make telephone or remote assessments usually will not be at the same site 
and will not look at the medical record: therefore, their outcome assessments will be blinded.  
Site coordinators who review the medical record may become unblinded, but these coordinators 
will be collecting primarily very objective data on health care visits (yes/no), vital status 
(live/dead), and adverse events.  Those outcomes are easily audited and less prone to bias.  
For safety, if a patient presents to another healthcare facility during their follow-up, the single-
blind design allows the subsequent clinicians to easily discover what the patient has received 
prior using standard medical record data. 
Rationale for Dose (1 unit) of convalescent plasma 
We discussed weight-based dosing of CP.  However, the optimal titer of neutralizing antibodies 
in CP and the minimum effective dose of CP have not yet been established. Secondary 
analyses from this trial will provide information about dose-effect by examining the association 
between different titers and outcomes. In the absence of knowledge to be gained from this trial, 
we have no rationale to administer more than a single unit of CP.  Risks of volume overload or 
other side-effects may increase with administration of more units. 
4.3 Definitions of Enrolled, Discontinued and Completed 
Enrolled 
A subject will be considered enrolled at the time of randomization. Patients who provide 
electronic consent but are not randomized will be documented as a screen failure.   
Discontinued 
Subjects are considered discontinued when they meet 1 or more of the following criteria: 
● Subject withdraws consent after being dosed and prior to the completion of Day 30. 
● Subject is lost to follow-up. 
Completed 
Subjects are considered completed when they are followed through Study Day 30 and complete 
the final study follow-up visit scheduled for that time. 
5. Study Population 
5.1 Inclusion Criteria 
● One or more symptoms of COVID-19 illness  
● Laboratory-confirmed SARS-CoV-2 infection 
● Has at least one study defined risk factor for severe COVID-19 illness:   
○ Study defined risk factors initially include: age≥50 years; hypertension; diabetes; 
coronary artery disease; chronic lung disease; chronic kidney disease; 
immunosuppression; sickle cell disease, and obesity (body mass index [BMI]>30) 
and are updated as needed in the C3PO Manual of Procedures in response to 
changes in CDC guidance or other information. 
● Clinical team deems stable for outpatient management without new supplemental 
oxygen 

 Protocol 5.0 
28 
● ABO-compatible CP available at the site at the time of enrollment  
● Duration of symptoms ≤ 7 days at ED presentation and randomization. 
● Signed informed consent  
 
Criteria 
Metric 
Rationale 
One or more symptoms of 
COVID-19 illness  
Cough, shortness of breath or 
difficulty breathing, fevers, 
chills, repeated shaking with 
chills, muscle pain, 
headache, sore throat, new 
loss of taste or smell 
CDC has defined a list of 
symptoms that include cough, 
shortness of breath or 
difficulty breathing, fevers, 
chills, repeated shaking with 
chills, muscle pain, 
headache, sore throat, or 
new loss of taste or smell. 
For purposes of this trial 
symptoms include any 
symptoms of COVID-19 
illness listed by the CDC case 
definition guidance at the 
time of enrollment. 
Symptomatic COVID-19 
illness justifies therapy.  
Asymptomatic illness is 
unlikely to be present in the 
emergency department 
unless it is an incidental 
finding.   
Laboratory-confirmed SARS-
CoV-2 infection 
Local laboratory approved 
test for acute infection with 
SARS-CoV-2  
Target illness is present.  
Testing for the presence of 
virus continues to improve at 
different sites over time. 
Tests should be specific and 
results available prior to 
enrollment. This should be 
their first episode of COVID-
19 illness. See MOP for 
additional details.   
Has at least one study 
defined risk factor for severe 
COVID-19 illness:   
 
Age is biological age. 
Hypertension must be treated 
with medications. 
Diabetes must be treated with 
medications. 
Chronic lung disease, 
coronary artery disease, 
chronic  kidney  disease23 per 
medical record. 
Immunosuppression with 
Age, hypertension, diabetes, 
coronary heart disease, 
chronic lung disease and 
chronic kidney disease are 
associated with higher 
COVID-19 morbidity and 
mortality.22,23   
Hypertension and diabetes 
are on a continuum and 
sometimes controlled without 

 Protocol 5.0 
29 
medications. 
Obesity is defined as BMI>30 
Sickle cell disease is based 
on past medical history 
medications.  We will restrict 
to medication-treated 
conditions in order to clearly 
define comorbidities that 
have prompted medical 
treatment.  Patients on 
immunosuppression for solid 
organ transplants are more 
often hospitalized for severe 
COVID-19 illness.25 Emerging 
data suggests that sickle cell 
disease and obesity are risk 
factors for severe disease. 
ED team deems stable for 
outpatient management 
without new supplemental 
oxygen requirement 
Plan is to not place patient in 
inpatient bed, but to 
discharge from emergency 
department without 
supplemental oxygen 
(patients intended for 
observation for <24 hours or 
<2 midnights in an outpatient 
observation unit without 
oxygen supplementation 
would be eligible).  Patients 
discharged from the ED may 
be brought back for 
randomization and treatment 
so long as they meet study 
inclusion criteria at the time of 
randomization.  
Illness is mild, which allows 
potential to observe 
progression. Supplemental 
oxygen use would imply that 
the patient has little 
physiological reserve and 
already is at the verge of 
primary outcome.  
ABO-compatible CP available 
at the site at the time of 
enrollment  
Blood bank to check blood 
type  
Must be able to deliver 
intervention. 
Duration of symptoms ≤ 7 
days at ED presentation and 
randomization 
Subject report of symptom 
onset 
CP therapy is most likely to 
have benefits early in the 
course of illness. 
Signed informed consent  
Informed consent document 
Subject understands the risk 
and details of the trial 
Immunocompromised: Any condition that causes reduced ability to fight infections. This may be 
caused by certain diseases (eg: cancer, diabetes); genetic disorders (eg: severe combined 
immune deficiency); or medications (eg: steroids, chemotherapy) 
5.2 Exclusion Criteria 
● Age less than 18 years 
● Prisoner or ward of the state 

 Protocol 5.0 
30 
● Presumed unable to complete follow-up assessments 
● Prior adverse reaction(s) from blood product transfusion 
● Receipt of any blood product within the past 120 days 
● Treating clinical team unwilling to administer up to 250 ml fluid 
● Enrollment in another interventional trial for COVID-19 illness or receipt of other active or 
passive immunization against SARS-CoV2. 
 
Criteria 
Metric 
Rationale 
Age less than 18 years 
Biological age 
Persons <18 years of age are 
less likely to develop 
severe/critical illness, and 
remote consent via parent or 
guardian will be more 
complex 
Prisoner or ward of the state  
Documentation of the same 
A vulnerable population 
Presumed unable to 
complete follow-up 
assessments 
Multifactorial determination 
(clinical, psychosocial, 
subject self-report) 
Difficulties with ascertaining 
outcome 
Prior adverse reaction(s) from 
blood product transfusion 
Subject self-report 
Decrease the risk research 
presents to subjects 
Receipt of any blood product 
within the past 120 days  
Subject self-report 
Minimize the risk of 
confounding 
Treating clinical team 
unwilling to administer up to 
250  ml fluid 
Clinical team’s assessment of 
whether patient will tolerate 
fluid, based on history and 
exam 
To avoid iatrogenic fluid 
overload resulting from  the 
administration of intervention 
Enrollment in another 
interventional trial for COVID-
19 illness or receipt of other 
active or passive 
immunization against SARS-
CoV2. 
Subject self-report 
Minimize the risk of 
confounding 
5.3 Screen Failures 
We will track screen failures to characterize the population of COVID-19 patients that are not 
enrolled in the study at participating institutions. We will utilize total counts of all COVID-19 
patients who are evaluated in the emergency department of a participating institution, and are 
discharged home from the emergency department, but are not enrolled in the study.  A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demographics and reason(s) for exclusion. 

 Protocol 5.0 
31 
5.4 Strategies for Recruitment and Retention 
Target study sample size: Maximum of 900 
Anticipated accrual rate: Accrual will vary by month depending on the progression or 
resolution of the pandemic.   
Anticipated number of sites: The C3PO trial will be conducted in the Strategies to Innovate 
EmeRgENcy Care Clinical Trials Network (SIREN) network. The network is composed of the 
Clinical Coordinating Center (CCC) at the University of Michigan, which provides overall project 
management for the trial, the SIREN Data Coordinating Center (DCC) at the Medical University 
of South Carolina, which provides data management and statistical support, and 11 SIREN 
Hubs located in tertiary care facilities across the US. Subjects will be enrolled from at least 30 
sites that are hub and spoke hospitals within the SIREN network who anticipate being able to 
enroll at least 4 cases per month.  
Source of participants: Hospital emergency departments   
Identifying and Recruiting Candidates.  Potential subjects for this trial will be recruited from 
emergency department patients who have their first episode of symptomatic laboratory-
confirmed SARS-CoV-2 infection and are being considered for outpatient management. All 
participating clinical sites are staffed by trained research personnel capable of performing 
careful screening of each potential subject according to the inclusion/exclusion criteria 
described above.  
Recruitment of a diverse study population: COVID-19 disproportionately affects ethnic 
minorities with African-Americans accounting for up to 50% of cases and up to 70% of deaths in 
some cities.25 We also believe that sex may be an important biological variable that may affect 
treatment outcomes for COVID-19. Therefore, we will enroll a racially diverse study population 
that is representative of the at-risk target population. In addition we will do our best to ensure 
that the proportions of males and females in the study population is balanced. Given the 
diversity in the geographical location, practice type (urban and non-urban academic medical 
centers and community hospitals) and racial composition of SIREN hub and spoke hospitals, 
our network is well positioned to recruit a study population that adequately represents the target 
population.  Since 2006, we have completed 7 clinical trials in the NETT, and the enrollment of 
African American and Hispanic subjects reflects the disease population most affected, rather 
than the percentage of the US population.  We accomplished this by having geographically 
representative sites with a good mix of large urban teaching hospitals, academic medical 
centers and community hospitals. Below is a table of the percentage of African-Americans and 
Hispanics enrolled in previously completed trials:  
Study 
Synopsis 
% African- 
American 
%Hispanic 
Rampart 
Treatment of status epilepticus in the prehospital 
setting comparing IM midazolam with IV lorazepam 
51 
12 
ProTECT Treatment of moderate-severe TBI with progesterone 
vs placebo 
15 
14 
ESETT 
Comparative effectiveness study of 3 anticonvulsants 
for benzodiazepine refractory status epilepticus 
43 
16 
SHINE 
Comparison of intensive treatment of blood glucose to 
30 
16 

 Protocol 5.0 
32 
usual care in Type 2 diabetic subjects with acute stroke 
POINT 
Treatment with clopidogrel and aspirin vs aspirin alone 
after TIA or minor stroke 
20 
6 
ALIAS2 
Treatment of acute stroke with albumin vs usual care 
19 
6 
ATACH2 
Comparison of intensive blood pressure control vs 
usual care in acute intracerebral hemorrhage 
28 
15 
 
For each DSMB report we will provide a summary table of the age, sex and racial composition 
of the subjects enrolled in this trial. We will monitor these distributions in real-time to ensure that 
the final study is representative of the target population.  
How potential participants will be identified and approached: Trained research coordinators 
will monitor all emergency department presentations for eligible subjects. They will ask the 
treating team for permission and introduction to approach potentially eligible participants for 
informed consent. See section 10.1.1 for information on informed consent procedures.  
Contact information at enrollment:  Separate from the clinical data in case report forms, we 
will collect multiple methods of contacting subjects while they are still in the emergency 
department.  At a minimum, this includes phone number, address and email for the subject, but 
also should include the phone numbers for an informant.  The informant may be a family 
member, caregiver, or close contact who will be able to report important information on the 
status of the subject in the event that the subject does not respond (e.g. whether the subject is 
hospitalized, at an emergency visit, or deceased).   
Remuneration of Subjects:  Subjects may be eligible for compensation for travel/parking at 
any of their visits based on local institution practices. 
5.5  45 CFR 46 Subpart B Determination 
Pregnant women are not systematically excluded from enrollment in the C3PO clinical trial, 
which therefore requires a 45 CFR 46 Subpart B determination by the IRB.  This research study 
does not, by design, target enrollment of pregnant women.  In fact, the risk factors necessary for 
inclusion markedly reduce the likelihood of pregnancy among eligible subjects.  However, the 
potential to enroll pregnant participants exists.  Pregnant patients are not systematically 
excluded from eligibility because pregnancy is not a contraindication to plasma infusion in any 
clinical setting.  Specifically, convalescent plasma is not contraindicated in pregnant patients 
with COVID-19 infection in clinical practice.  There are neither data to indicate, nor rationale to 
presuppose, any increased risk to pregnant participants or their pregnancies attributable to 
randomization to convalescent plasma or placebo in this trial.   
 
Not excluding pregnant women from this trial is consistent with current FDA draft guidance on 
the inclusion of pregnant women in clinical trials of drugs and biologics.  It is also consistent with 
the intent of the revised common rule, in which pregnant women are no longer examples of 
inherently vulnerable populations. 
 

 Protocol 5.0 
33 
6. Study Intervention 
6.1 Study Intervention Administration 
6.1.1 Study Intervention Description 
Subjects will be randomized in a 1:1 ratio to receive either ABO group compatible SARS-CoV-2 
convalescent plasma (CP) or normal saline with multivitamins.  
6.1.2 Dosing and Administration 
● Subjects will receive either one unit (~200 ml) of CP or 250 ml of normal saline with 
multivitamins.  
○ Volume of the CP unit actually administered will be recorded to account for 
variable volumes of units and any instances when infusion stopped because of 
reaction or other event 
● Study intervention will be administered after randomization and prior to discharge from 
the emergency department.   
● Infusion rate: 500 mL/hour or slower depending on subject’s cardiopulmonary status 
● Pretreatment to minimize transfusion reactions (e.g. acetaminophen, diphenhydramine) 
may be given  
● If an AE develops during infusion, the infusion may be slowed or stopped as per the 
treating team’s decision.  
● Most reactions to plasma are relatively minor and the infusion can generally be 
continued. Infusion site burning and non-allergic systemic effects can generally be 
managed with slowing of the infusion. Infusion is generally stopped in cases of itching or 
hives. Participants may be treated and then infusion re-started. 
● Allergic reactions, such as bronchospasm and hypotension, generally require 
discontinuation of the infusion.  
6.1.3 Blinding of Subjects 
To facilitate the blinding of participants to the intervention, the control arm will receive normal 
saline infused with 1-5 ml parenteral multivitamin. Blinding of the participant is supplemented by 
IV bag light shield bag covers. Placebo is intended to contribute to the single blind of the 
participant but not the care team.  
 

 Protocol 5.0 
34 
 
Figure: Placebo (saline with MVI) infusion on the left, Active intervention (plasma) infusion on 
the right.  Placebo is intended to contribute to the single blind of the participant but not the care 
team. Blinding of the participant is supplemented by IV bag light shield bag covers. 
 
6.2 Preparation/Handling/Storage/Accountability 
NHLBI is collaborating with BARDA who will contract with Vitalant to provide up to 500 units of 
CP with known titers of neutralizing SARS-CoV2 antibodies of 1:160 or higher for this trial. The 
supplier (Vitalant) has already collected many units of CP.  Donors will meet current FDA 
eligibility requirements for COVID-19 Convalescent Plasma (https://www.fda.gov/vaccines-
blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-
cber/recommendations-investigational-covid-19-convalescent-plasma) 
1. COVID-19 convalescent plasma will be collected from individuals who meet all donor 
eligibility requirements. 
2. COVID-19 convalescent plasma is collected from individuals who meet all of the 
following qualifications: 
a.    
A positive serological test for SARS-CoV-2 antibodies after recovery. 
b.    
Complete resolution of symptoms at least 14 days before the donation. A 
negative result for COVID-19 by a diagnostic test is not necessary to qualify the 
donor. 
c.    
Male donors, or female donors who have not been pregnant, or female 
donors who have been tested since their most recent pregnancy and results 
interpreted as negative for HLA antibodies. 
Serologic testing will be performed using state-of-the-art research methods. Specifically, CP will 
be tested using a chemiluminescent test for IgG and IgM against spike protein (Ortho VITROS 
Anti-SARS-CoV2 Total) or equivalent assay. This assay has been granted FDA Emergency Use 
Authorization (EUA). If this qualitative test is positive, then the CP is also tested with the Vitalant 
Research Institute SARS-CoV2 Reporter Viral Particle Neutralization (RVPN) test or equivalent 
assay. The presence of antibodies  are generally confirmed within 48 hours of donor collection. 
Assays will be conducted by a central laboratory and assays will also be made available to 

 Protocol 5.0 
35 
study investigators.The CP is labeled with the titer from the RVPN test as: negative, <1:40, 
positive 1:40, 1:160; 1:640, 1:2560, 1:10240, >1:10240.  We do not intend to use CP with 1:40 
or <1:40 titer. 
Plasma will be distributed from the central supplier to local blood banks at study sites and 
replenished as it is used. Each site will receive 4 or more units of CP at a time, and units will be 
replenished from the central supplier as they are used.  Over the trial, each of the 30 or more 
SIREN sites will receive an average of 10-12 units of CP. We will ensure that, at all times, 
approximately half of the units of CP at each site will be of the group O-type and the remaining 
half will be group A units. Given the low prevalence of the AB group in the population, we expect 
very few CP donors will be of the AB-group.   CP will be stored using usual storage for blood 
products, and ABO-type compatible CP dispensed to subjects, using local standard care for 
ABO compatibility. Vitalant will send samples from each CP unit to the study core laboratory at 
the University of Pittsburgh for antibody characterization.    
In order to increase the rigor and reproducibility of antibody characterization in the CP units, we 
will determine the total titers to SARS CoV-2 S (Spike) protein (BSL-2+) using at least one other 
assay (e.g. EuroImmun ELISA). We will measure neutralization antibody titer in CP using a viral 
plaque assay at University of Pittsburgh (inhibition of SARS-CoV-2 infection of cells in vitro - the 
Gold Standard), thereby providing information about whether high titer CP has superior 
neutralization capacity for SARS-CoV-2. These data will inform large-scale screening of donors 
for CP in regions and settings where it is impossible to work directly with live viral inhibition 
assays (BSL-3).   
A blood type will be performed in all potential subjects after the informed consent form is signed. 
If a subject is randomized to the CP arm, an order will be sent to the blood-bank for one unit of 
ABO-compatible CP. Upon receiving the order, the local blood bank will thaw ABO-compatible 
plasma at 30 - 37°C in an FDA cleared thawing device. If thawed in a water bath, a protective 
wrap will be used to prevent contamination of the ports on the unit. Thawed CP will be sent to 
the emergency department for infusion. 
If a subject is randomized to the control (saline) arm, an order will be sent to the pharmacy or 
investigational drug service for a 250 ml bag of isotonic saline with 1-5 ml of parenteral 
multivitamin (to provide color similar to plasma).  This bag will be sent to the emergency 
department for infusion.  When administering the saline, nurses will place a light cover over the 
bag to hide its contents from the subject.  
A study PI and/or study investigators who are transfusion medicine specialists will be available 
24/7 to answer questions related to the study intervention in real time. Sites will be able to reach 
these investigators via the study hotline.   
One threat to this trial is that the national demand for CP in severe COVID illness may compete 
with the supply of CP for this study.  However, Vitalant has already secured many units of CP 
and anticipates no problem with supply.  Vitalant also is a separate supplier from the sources 
being used in the expanded use authorization for severe COVID-19 (e.g. American Red Cross), 
and will not deplete that supply.   Many of the SIREN sites who will conduct this trial are 
developing local plans to create a CP pool using local donors.  For example, Stanford University 
has recruited enough donors at present that it could supply some other sites.  Similarly, the 
University of Pittsburgh has developed its own CP inventory. In the event that the NHLBI and 
BARDA national suppliers cannot match demands from trial recruitment, the Transfusion 
Medicine core of our Scientific Core Group will work with the blood bank for each individual 
SIREN site to develop local CP supplies.  This ability will also become important in the event 
that any sample size re-estimation concludes that more CP units would be desirable. 

 Protocol 5.0 
36 
6.3 Measures to Minimize Bias: Randomization and Blinding 
A web-based central randomization system will be developed by the SIREN DCC and installed 
on the WebDCU™ study website.  Allocation will be fixed using a 1:1 allocation ratio. The 
objective of randomization is to prevent possible selection bias by providing random treatment 
assignment to each subject and to prevent accidental treatment imbalances for known 
prognostic variables. Variables that will be included in the randomization scheme are: age 
(treated as a continuous variable) and site. Site is included in the randomization scheme to 
avoid severe treatment imbalances within each site. Randomization will occur via the study-
specific password-protected website accessed by an authorized research coordinator or 
investigator at the clinical site.  If, in rare circumstances, the web system is not available, the 
coordinator or investigator will have access to emergency randomization procedures that will 
allow the site to randomize the subject.  Subjects will be considered randomized in this trial at 
the time of randomization, regardless of whether or not they receive the assigned study 
treatment. 
The primary outcome assessment in this trial will be performed by study team members who are 
blinded to study group allotment. To test the effectiveness of blinding procedures, subjects will 
be asked at the Day 2 and Day 15 follow-up assessment to which treatment arm they believe 
they were assigned and how confident they are in their response. If the subject becomes 
knowledgeable of their treatment assignment at any point during study participation, this will be 
documented in the study database. Regardless of unblinding, the subject will remain in the 
study and be part of the analysis population. 
6.4 Concomitant Therapy and Hospitalization 
Concomitant medications will be documented on the CRF. We will not enroll patients already in 
another clinical trial. Subjects should not enroll in another interventional trial as an outpatient 
while in this clinical trial. 
In the event that a subject worsens and is admitted to a hospital, that subject will have met the 
primary endpoint of this trial.  We will not restrict that subject from enrolling in another trial if 
eligible, especially because other trials may be the only access for potential COVID-19 
therapies.  In particular, control subjects should be eligible for compassionate use CP, though 
this trial cannot guarantee CP will be available at a site precisely when the subject is 
hospitalized.   Patients in either arm who develop severe/critical disease are not precluded from 
receiving compassionate use CP after meeting the primary endpoint, if this therapy is available 
for routine clinical care at the institution where they receive care.  
7. Participant Discontinuation/Withdrawal 
7.1 Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. The 
reason for participant discontinuation from the study will be recorded on the Case Report Form 
(CRF). Subjects who are randomized and subsequently withdraw informed consent will not be 
replaced. 
7.2 Loss to Follow-Up 
To attain a high rate of follow up (>90%), the study team will request multiple phone numbers 
(home, cell phones, pagers, etc) and addresses from the subject and his/her relatives, friends, 
primary doctor (if available), clergy and clinics. At the time of consent and enrollment, subjects 

 Protocol 5.0 
37 
will be asked to provide the address and telephone number of the place where the subject will 
likely reside following discharge.  
Following ED discharge, a blinded research coordinator will telephone subjects every other day 
for a health status inquiry and to maintain and update tracking information. During follow-up 
phone calls, if medical concerns are raised, subjects will be referred to their usual care provider 
or to emergency care if urgent. In the event that the research coordinator cannot reach a subject 
or an informant, the coordinator will continue to call frequently for up to 2 weeks after the last 
scheduled contact before considering a subject lost to follow-up.   Subjects cannot be deemed 
“Lost to Follow-up” without the C3PO Operations Committee approval. The site PI must present 
a case to the C3PO Operations Committee that includes the efforts exerted to locate the study 
subject. The Site PI may be asked to continue their efforts prior to approval. 
8. Study Assessments and Procedures 
8.1 Efficacy Assessments 
Trained study personnel who are blinded to study group allotment will interview participants via 
telephone every other day during the first 14 days of the study and on day 15 (window: days 
14,15 and 16) and 30 (window: days 29, 30, 31, 32, 33) to ascertain efficacy and safety 
endpoints. Assessments will be performed either by study personnel at local sites or by a 
centralized pool of trained personnel. Data will be documented in WebDCU.  
Central caller assessments completed within 1 day of the time point will be counted as 
qualifying and not considered missing.  
On study days 15 (window: days 14, 15, 16) and 30 (window: 29, 30, 31, 32, 33), participants 
will be asked to return for research blood draws. If there is no follow-up due to lack of patient 
response, the patient will be considered lost to follow-up.  
8.1.1 Primary Endpoint  
These events can be ascertained from the subject or informant report during follow-up calls, 
electronic health record review, death notices, or direct contact with the subject during follow-up 
visits.  Thus, we have multiple opportunities to collect and confirm the primary endpoint, 
minimizing risk of missing data.   
Subjects will meet the primary endpoint of the study (1) if they are admitted to a hospital as an 
inpatient/observation status for any reason during the 15 days following randomization, (2) if 
they have an emergency department or urgent clinic visit during the 15 days following 
randomization, or (3) die outside the hospital during the 15 days following randomization.  
Scheduled medical follow-up visits or rechecks will not meet the definition of emergency care.   
8.1.2 Secondary Endpoints (clinical) 
These endpoints can be ascertained from the subject or informant report during follow-up calls, 
supplemented by review of health records.  Surveys and assessments from day 0-14 that are 
completed within 1 day of the time point will be counted as qualifying and not considered 
missing (for example day 4 assessment may be done on day 4 or 5).  
COVID-19 illness severity: We will quantify COVID-19 illness severity using a 8-point ordinal 
scale developed by a World Health Organization (WHO) committee. We will record the worst 
illness severity rating observed during the 30 days following randomization: 
WHO's COVID Ordinal Scale for Clinical Improvement 

 Protocol 5.0 
38 
● 8 = Death 
● 7 = Hospitalized, intubated, mechanically ventilated and requiring additional organ 
support (pressors, renal replacement therapy) 
● 6 = Hospitalized, intubated and mechanically ventilated 
● 5 = Hospitalized on non-invasive ventilation or high flow nasal cannula  
● 4 = Hospitalized on supplemental oxygen by mask or nasal prongs 
● 3 = Hospitalized not on supplemental oxygen 
● 2 = Not hospitalized with limitation in activity (continued symptoms) 
● 1 = Not hospitalized without limitation in activity (no symptoms) 
COVID-19 illness severity (outpatient): An adaptation of the WHO scale, based on the quality of 
symptoms reported by the subject, can quantify outpatient disease severity among patients at 
home (scores 1-2 on the WHO scale). This 5-point COVID Outpatient Ordinal Outcomes scale 
was adapted for outpatient use from Harrell 2020 
(http://hbiostat.org/proj/covid19/bayesplan.html). This scale is hierarchical where 1 is the highest 
severity (hospitalization) and 5 is the lowest severity.   
COVID Outpatient Ordinal Outcomes Scale 
● 1 = patient requires care in the hospital 
● 2 = patient requires care in the ED or urgent care 
● 3 = patient at home with symptoms rated as moderate (defined as fever, shortness of 
breath, abdominal pain) 
● 4 = patient at home with symptoms rated as mild (defined as afebrile, constitutional 
symptoms (flu-like illness) without shortness of breath) 
● 5 = patient in their usual state of health 
Worsening of symptoms is defined as any subject admitted to the hospital (level 1), seen in the 
emergency room (level 2), a patient who reports increased symptoms of 2 levels on the scale 
over a 24 hour period, or a patient who reports increased symptoms of 1 level observed for a 48 
hour period. 
Symptom inventory: On study days 2, 4, 6, 8, 10, 12, 14, 15 and 30, we will record the burden of 
symptoms listed by the Centers for Disease Control and Prevention (CDC) as typical of COVID-
19 illness. For purposes of this trial symptoms include any symptoms of COVID-19 illness listed 
by the CDC case definition guidance at the time of enrollment. These include but are not limited 
to the following: . 
● Fever or chills 
● Cough 
● Shortness of breath or difficulty breathing 
● Fatigue 
● Muscle or body aches 
● Headache 
● New loss of taste or smell 
● Sore throat 
● Congestion or runny nose 
● Nausea or vomiting 
● Diarrhea 
● Abdominal pain 
● Limitations of activities because of COVID-19 symptoms 
Refer to the Manual of Procedures for the latest CDC list of COVID-19 symptoms. 

 Protocol 5.0 
39 
Hospital-free days: We will record the number of days a subject was not admitted to a hospital 
during the first 30 days following randomization.  
All-cause mortality: We will record death from any cause that occurred during the first 30 days 
following randomization.  
8.1.3 Secondary Endpoints (immunological):  
These endpoints will be measured using 4 blood samples collected pre-intervention in the 
emergency department, post-intervention in the emergency department, and at days 15 and 30 
(as outpatients).   At days 15 and 30, subjects will return to a clinic, phlebotomy site, or have 
outpatient phlebotomy to measure circulating antibodies.  Each site will need to determine a 
blood sampling site that is qualified and safe for phlebotomy in persons with recent COVID-19 
illness according to current CDC guidance.  While guidance continues to evolve, patients are 
thought to be safe to leave isolation when symptoms have resolved for 3 days or at least 10 
days have passed since COVID-19 diagnosis (https://www.cdc.gov/coronavirus/2019-ncov/if-
you-are-sick/steps-when-sick.html), which will be prior to any of the in-person evaluations. 
No more than 50 mL of blood will be drawn per day: 15 ml (one tablespoon) of whole blood will 
be collected from subjects at the following timepoints: 
● After consent  but before the administration of study intervention 
● 1 (+/- 30 minutes) hours following the end of the administration of study intervention, and 
● During study visits occurring on study days 15 and 30. 
Whole blood will be processed into serum and plasma, and stored in a -70ºC freezer or colder 
within 2 hours of sample collection. Samples will be shipped periodically to the study 
biorepository housed at the University of Pittsburgh. 
Our exploratory aim is to characterize the agreement between or differences between the 
multiple assays for antibodies.  This is important to inform future investigations about how to 
interpret titers reported by one platform or another. This will also inform about the development 
of innate immunity in control subjects.  Increase in antibodies over time in CP recipients, if it 
occurs, will also inform about development of innate immunity after passive immunization.  
Therefore, we plan to perform multiple assays on any available sample from the donor unit, and 
also on the blood obtained from recipients of the intervention. Specifically, we plan to measure 
at least the following well characterized tests: 
● Quantitate Anti-spike (S1) protein IgG, IgA titers (e.g. EUROIMMUN) on CP units 
● Correlation of ELISA titers with Vitalant RVPN titers (neutralizing antibodies) on CP units  
● Assessment of S1 titers in CP recipients and controls pre-CP, 1 hr post, 15 and 30 days 
post to assess the impact of CP and determine whether titers rise with time (showing 
endogenous response not negatively impacted by CP) 
● Use Lentiviral pseudovirus reporter assay to quantitate neutralization Ab titers in 
recipients of CP units at pre- post-CP. 
● Neutralization of SARS CoV-2 Plaque Formation (gold standard) in a subset of CP to 
correlate with other assays. 
 
In addition to the blood samples collection outlined above, for subjects who consent to 
participating in an optional study evaluating the evolution of the adaptive immune response in 
CP recipients, an additional 20 ml of whole blood will be collected on the day of enrollment and 

 Protocol 5.0 
40 
on study days 15 and 30. These samples will be shipped within 1 day of collection to a central 
laboratory for processing.  
Residual viral media and saliva specimens collected will be analyzed for SARS-CoV-2 viral 
genotype 
8.1.4 Blood Sample Storage, Processing and Shipping for Antibody Titer Testing 
Each site will ship the 4 blood samples from each participant to the central testing laboratory 
(University of Pittsburgh).  The site can ship all of the samples for one participant together in a 
single package.  Labels for samples with barcodes will be provided to sites in advance in order 
to ensure accurate sample tracking.  Labeling samples with the subject ID from WebDCU can 
serve as a backup procedure.   
Antibody titres: To determine the immunologic response to CP administration, we will measure 
anti-SARS-CoV-2 IgG, IgM and neutralizing antibody titres pre-intervention, post-intervention 
and at days 15 and 30.   
Testing will be identical to the testing performed to determine the titer of the donor CP.  We will 
determine the IgG/IgM  titers to SARS CoV-2 S (Spike) protein using enzyme linked 
immunoassays (BSL-2+).  There are multiple assays available and in development.  We will 
compare titres from the Vitalant (Ortho VITROS Anti-SARS-CoV2 Total) assay to titres from 
other assays (e.g. EuroImmun ELISA) whenever possible to determine the concordance. In a 
subset of these samples, we will measure antibody neutralization titers using the gold standard 
assay, a viral plaque assay performed in a BSL-3 facility at University of Pittsburgh. This will 
allow us to determine whether high titers in binding assays actually represent superior 
neutralization capacity for inhibiting SARS-CoV-2 infection. 
8.1.5 Assessment of Blinding 
As part of follow-up assessments on Days 2 and 15, investigators will ask subjects to indicate 
which  intervention (CP or placebo) they believe that they received, and how confident they are 
in their response.  If blinding is successful, subjects will be no more accurate than chance.  We 
will also examine the rate of successful follow-up contacts between groups.  If blinding is 
successful, missingness will not differ between groups.  We will have local site investigators 
review emergency department practice and communication, potentially to create a corrective 
action plan, in the event we see a pattern at a site that suggests a high rate of subject 
unblinding. 
If the subject becomes knowledgeable of their treatment assignment at any point during study 
participation, this will be documented in the study database. Regardless of unblinding, the 
subject will remain in the study and be part of the analysis population. 
8.1.6 Clinical and Demographic Data 
At enrollment, we will collect data from the subject and the medical record to validate eligibility 
for enrollment into the trial and to assess risk factors for developing severe/critical COVID-19 
illness. This data includes but is not limited to: inclusion and exclusion criteria, demographic 
information, vital signs, medical history, and medications.  We will collect time of COVID-19 
symptom onset by self-report from the subject.  

 Protocol 5.0 
41 
8.2 Safety and Other Assessments 
8.2.1 Safety Assessment 
All adverse events (AEs) will be recorded until ED discharge. All AEs occurring until discharge 
from the emergency department must be reported in WebDCUTM. After discharge from the 
emergency department and at each follow-up contact until the end of study, only serious 
adverse events will be reported in WebDCU and any event that leads to hospitalization or an ED 
or urgent care visit even if deemed non-serious. Investigators will also review medical records 
on Day 30 for any serious adverse events.   
Subjects will be monitored for the following plasma-specific AEs: 
● Transfusion reactions: fever, rash, itching 
● Serious allergic reactions (anaphylaxis or bronchospasm requiring treatment)  
● Transfusion Associated Acute Lung Injury (TRALI), as defined by 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850655/ (21). Given that these are 
patients with other risk factors for ARDS, a diagnosis of “possible TRALI” will require 
stable respiratory status in the 12 hours before transfusion. Because TRALI may mimic 
the natural progression of COVID-19, the demonstration of HLA antibodies in the donor 
product that matches the recipient’s HLA type will also be necessary to make the 
diagnosis of “possible TRALI”. 
● Transfusion Associated Circulatory Overload (TACO)  
8.3 Adverse Events and Serious Adverse Events 
8.3.1 Definition of Adverse Events (AE) 
An Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical 
treatment or procedure that may or may not be considered related to the medical treatment or 
procedure. An AE is a term that is a unique representation of a specific event used for medical 
documentation and scientific analyses. 
8.3.2  Definition of Serious Adverse Event (SAE) 
An adverse event (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 adverse event, or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions. Important 
medical events may also be considered serious when they require medical or surgical 
intervention to prevent death, risk of permanent injury or disability, or prolonged hospitalization. 
COVID-19 patients who require hospital admission are clinically expected to have adverse 
events related to their underlying condition and standard treatment, independent of any 
research intervention.  Examples of common medical events in this population include (but are 
not limited to): respiratory failure requiring oxygen supplementation and/or intubation, ventilator 
associated pneumonia, venous thromboembolic disease, or encephalopathy, cytokine storm, 
shock requiring vasopressors and renal failure requiring renal replacement therapy.  
Subjects may also incur AEs that could be expected to occur at higher rates because of the 
study intervention. These include medical events such as: serious allergic reactions 
(anaphylaxis or bronchospasm requiring treatment), transfusion related acute lung injury 

 Protocol 5.0 
42 
(TRALI), transfusion associated circulatory overload (TACO) and transmission of infectious 
agents.23  
Pre-existing medical conditions or unchanged, chronic medical conditions.  Pre-existing 
medical conditions or unchanged, chronic medical conditions are NOT considered AEs and 
should not be recorded on the AE case report form (CRF). These medical conditions should be 
adequately documented on the medical history and/or other source documents. In this trial, any 
medical conditions not present prior to randomization but that emerge after randomization are 
considered AEs.  
Exacerbation of Pre-existing medical conditions.  A pre-existing medical condition judged by 
the investigator to have worsened in severity or frequency or changed in character is considered 
an adverse event. 
8.3.3 Classification of an Adverse Event 
For adverse events (AEs) not included in the protocol defined grading system, the severity of 
adverse events will be determined referencing the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events Version 5.0 (CTCAE).  The CTCAE provides a grading 
(severity) scale for AEs with unique clinical descriptions of severity based on this general 
guidance: 
Grade 1: Mild AE 
Grade 2: Moderate AE 
Grade 3: Severe AE 
Grade 4: Life-Threatening or Disabling AE 
Grade 5: Death related to AE 
8.3.4 Relationship to Study Intervention 
Adverse reaction is different from an adverse event.  Suspected adverse reaction means any 
adverse event for which there is a reasonable possibility that the study intervention caused the 
adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is 
evidence to suggest a causal relationship between the study intervention and the adverse 
event. A suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means an adverse event is definitely caused by the study intervention. 
Per FDA guidance a suspected adverse reaction is one that is known to be strongly associated 
with the study intervention, or one that is very uncommon in the study population, or one shown 
in aggregate analysis to occur more frequently in the treatment group.  Generally anticipated 
adverse events are not suspected adverse reactions. 
Because ‘reasonable possibility’ can be difficult to determine, this trial uses an algorithmic 
approach to describing relatedness. 
Algorithm to Determine Relatedness of Adverse Event to Study Agent 

 Protocol 5.0 
43 
  
Not Related 
The temporal relationship between treatment exposure and the adverse 
event is unreasonable or incompatible and/or adverse event is clearly due 
to extraneous causes (e.g., underlying disease, environment) 
  
Unlikely 
Must have both of the following 2 conditions, but may have reasonable or 
only tenuous temporal relationship to intervention. 
● Could readily have been produced by the subject’s clinical state, or 
environmental or other interventions. 
● Does not follow a known pattern of response to intervention. 
  
Reasonable 
Possibility 
Must have at least 2 of the following 3 conditions 
● Has a reasonable temporal relationship to intervention. 
● Could not readily have been produced by the subject’s clinical state 
or environmental or other interventions. 
● Follows a known pattern of response to intervention. 
  
Definitely 
Must have all 3 of the following conditions 
● Has a reasonable temporal relationship to intervention. 
● Could not possibly have been produced by the subject’s clinical state 
or have been due to environmental or other interventions. 
● Follows a known pattern of response to intervention. 
8.3.5 Time Period and Frequency for Event Assessment and Follow-up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by an independent medical safety monitor (section 10.4). 
Adverse events will be captured and reported in WebDCU™. Information to be collected 
includes time of onset, clinician’s assessment of severity, relatedness to study intervention, and 
time of resolution/stabilization of the event.  All SAES will also include a narrative of the event 
with additional testing results if conducted. All AEs occurring until discharge from the emergency 
department must be reported in WebDCUTM.  After discharge from the emergency department, 
only serious adverse events will be reported in WebDCUTM. All AEs will be followed to adequate 
resolution/stabilization or subject end of study. 
All non-serious AEs must be recorded on the electronic AE CRF within 5 days from the time it 
was discovered by the site study personnel. For SAEs, the data entry must take place within 24 
hours of discovery of the event. Upon submission of an SAE, the system will trigger an 
automatic email notification to the Independent Medical Safety Monitor (iMSM) stating that an 
SAE has occurred.  The iMSM will access the information via the password protected web 

 Protocol 5.0 
44 
based system and will review the SAE data within 2 business days of being notified for 
completeness of reporting, and will enter their assessment of relatedness and expectedness. 
Expedited reporting to the DSMB and regulatory parties will occur for all potentially related 
unexpected SAEs. The reporting timeline will follow FDA requirements: within 7 calendar days 
of the sponsor’s knowledge of an unexpected fatal or life-threatening event; within 15 calendar 
days for all other unexpected potentially related SAEs.  
8.4 Unanticipated Problems 
An Unanticipated Problem is any event, incident, experience, or outcome that is  
● unexpected in terms of nature, severity, or frequency in relation to  
○ the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents; 
○ the characteristics of the subject population being studied (persons with life 
threatening COVID-19); and 
● possibly, probably, or definitely related to participation in the research; and 
● places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized.  
Unanticipated Problems will be reported in WebDCU. Unanticipated problems may include 
problems with protocol implementation, participant safety, and/or concerns regarding informed 
consent.  Initial reports will be submitted within 7 calendar days of site awareness of the event. 
9. Statistical Considerations 
This trial is designed with sample size re-estimation to adapt to the evolving landscape of 
COVID-19 illness.  This trial design, as well as its implementation mechanics, can serve as a 
template for subsequent studies of how interventions delivered to patients presenting to the 
emergency department alter disease trajectory. 
 We believe that clinicians will change practice if CP can afford ~10% absolute risk reduction in 
disease progression, but the constrained sample size limits power to detect clinically significant 
changes if the control event rate for hospitalization, the most important sign of worsening, is too 
low.   
For this reason, we will look at a composite outcome that combines hospitalization, symptom 
progression that results in seeking medical evaluation or treatment (ED visit or urgent clinic 
visit), and death outside of the hospital.  The total event rate for this composite will be larger 
than hospitalization alone. 
In addition, we have selected a population with risk factors for more severe disease, based on 
the case series reported to date: older age and chronic end-organ disease or comorbidities.  
The event rate for the primary outcome is expected to be higher in this population than in all 
outpatients with COVID-19.  Further, this population is the one with most potential to benefit 
from CP therapy and is the most likely outpatient population in whom clinicians may choose to 
use a blood product. 
We considered comparing time to event as an alternative to comparing proportions of events 
between the treatment arms.  The gain in power from time to event analysis is offset by the 
concern that the time to event is affected more by the time course of the illness than by initiation 
of treatment, and that patient self-report of the day of symptom onset will not be sufficiently 
accurate to adjust. For example, a patient who presents to the ED and is enrolled on day 7 of 

 Protocol 5.0 
45 
COVID-19 illness may progress to hospitalization more quickly than a patient who presents to 
the ED and is enrolled on day 2 of COVID-19 illness.  In our chosen analysis, the similar 
worsening of illness in both patients is accurately captured by counting the presence of the 
primary endpoint by Day 15. Moreover, a delay in disease progression is not clinically important 
if the proportion of subjects who progress is not different.  
9.1 Sample Size 
Sample size is restricted by the availability of CP for the participating sites. Based on 
discussions with the NHLBI, we are assured to have sufficient CP available for roughly 300 
patients at the time of study initiation. 
Therefore, we provide power estimations 
based on our primary outcome, assuming a 
maximum of 600 randomizations (300 per 
group).  
Figure 1 provides a range of risk differences 
(control minus treatment) based on potential 
event rates for our control population. For 
example, if the primary outcome event 
proportion within 15 days from randomization is 
20% in the control population, then we have 
85% power to detect an absolute decrease of 
at least 10% in this proportion for those treated 
with CP. If the control proportion is less than 
20% then we can detect differences of roughly 8% while maintaining more than 80% power. 
Alternatively, if the control rate is closer to 30%, then our power begins to drop for detecting risk 
differences less than 10%. Based on the current information on hospitalizations in this COVID 
population, we do not expect the proportion in the standard of care arm to vary greatly from 
20%. Clinicians are unlikely to discharge patients whose risk for the primary outcome is 
significantly greater than 30%.. 
  
Sample Size Re-Estimation 
We recognize that sample size estimation is based on assumptions and, if our control proportion 
greatly varies from what we assumed, then we may begin to see a decrease in power. To 
reduce the likelihood of an underpowered study due to an incorrect assumption, we propose to 
conduct a sample size re-estimation at the time of the first interim analysis . The overall primary 
outcome proportion of the population will be estimated using the interim data for the sole 
purpose of sample size re-estimation (not for interim testing of a treatment effect).  If the 
observed overall event rate is greater than the assumed, then we may require additional 
subjects to maintain adequate power. Ultimately it is the DSMB’s decision to recommend an 
increase in the total sample size and this decision should take into account the safety profile, 
which will be provided to the DSMB at the time of analysis.  Based upon the DSMB’s 
recommendation, the study team in conjunction with NHLBI will need to determine the feasibility 
of an increase to the sample size in terms of the availability of additional units of CP and impact 
on funding.  We do not plan to decrease the sample size based on the re-estimation plan. 
9.2 Analysis Plan  
9.2.1 Primary Analysis 
Outcomes will be analyzed using the intent-to-treat principle (ITT).  The primary analysis for this 
trial is to test the hypothesis of superiority of CP as compared to saline in the ITT population. To 

 Protocol 5.0 
46 
test this hypothesis, the posterior probability that the proportion of primary outcome events at 
15-days post randomization is higher in the saline arm as compared to the CP arm will be 
calculated.  Because little is known about the impact of CP, we assume a non-informative beta 
distribution for the prior probability. The primary null hypothesis (that the CP proportion is 
greater than or equal to saline) will be rejected if the posterior probability is greater than or 
equal to 0.975 (selected to coincide with a one-sided alpha level of 0.025 under a frequentist 
design).  The treatment effect and corresponding credible interval will be constructed.   
If the trial fails to enroll the planned sample size due to a significant decrease in the number of 
COVID-19 patients, then Bayesian posterior and predictive probabilities will be used to assist in 
the interpretation of the observed data. 
Secondary analyses of the primary outcome will explore the impact of potential prognostic 
variables including age, sex, onset of symptoms duration and site.  A logistic regression model 
will be used for these additional analyses. We will also examine whether participants’ pre-
treatment antibody levels and/or the genotype of the SARS-CoV2 virus that they carry modify 
the association between CP and outcome.  
The inherent variability in antibody titer among CP units will provide an important opportunity to 
explore the dose-effect relationship for CP.  We envision performing a similar regression of the 
primary outcome using CP titer categories.   
  
9.2.2 Interim Analysis Plan 
The study design will include frequent monitoring of the primary outcome with planned looks for 
both overwhelming efficacy and futility after 33%, 50% and 75% of  consecutive enrollments 
complete 15 day follow-up. For efficacy, we will calculate the posterior probability that the 
primary outcome event proportion is higher in the saline arm as compared to the CP arm.  If this 
probability is greater than 0.999, then the trial could stop for overwhelming superiority of the CP. 
This threshold is based on a Haybittle-Peto type boundary, where the stopping threshold is 
constant across interim looks and the threshold at the final look approximates a design with no 
interim analyses. For futility, we will calculate a predictive probability (probability of success if 
the trial were to achieve the predefined maximum sample size).  If the probability is less than 
0.20 then the trial may stop for futility. Since several factors need to be taken into consideration 
before stopping a study, a complete report of overall study progress, data quality, and safety will 
be provided to the DSMB at each interim analysis. If a boundary is crossed, the report will also 
include secondary outcomes. This information will be taken into consideration by the DSMB in 
the decision to recommend stopping the study if an efficacy or futility boundary is crossed.  The 
ITT population, defined as all randomized subjects, will be used for the interim analyses.  
 
9.2.3 Missing Data 
Although every attempt will be made to prevent incomplete data, a certain amount of missing 
data is inevitable due to losses to follow-up or withdrawn consents. For the primary outcome 
data, subjects who do not complete the follow up because of withdrawal of consent will be 
considered missing. In the case of loss to follow-up, we would expect that the sites will be able 
to obtain information on the event within 15 days from randomization from the medical record; if 
the site cannot obtain information, the outcome will be considered missing. At the time of the 
planned analyses, the unblinded statistician will conduct a thorough analysis of outcome 
variables, reasons, and patterns of missing data, and provide this information in the DSMB 
report. Sensitivity to missing data will be assessed. If the outcome is insensitive to missing 
data, defined as no change in the conclusion regardless of the set of imputed values, each 
missing observation will be imputed an unfavorable outcome (i.e., event occured). If the 

 Protocol 5.0 
47 
outcome is sensitive to missing data, each observation will be imputed using a Bayesian 
imputation model.  
  
9.2.4 Analysis of Secondary and Exploratory Outcomes 
This study is designed to test the primary hypothesis; however, it also offers the opportunity to 
evaluate important additional secondary and exploratory outcomes. Continuous secondary 
endpoints will be summarized by the mean and standard deviation with corresponding 95% 
confidence intervals. Categorical endpoints will be summarized by the sample proportions with 
exact or asymptotic confidence intervals. For time to event analyses, we will construct Kaplan 
Meier curves.  Our analyses will consider sex as a biological variable that may affect treatment 
outcomes for COVID-19. 
10. Supporting Documentation and Operational 
Considerations 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Informed Consent Process 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the Central IRB (Advarra). A signed consent form will be obtained for 
every subject. The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation.  
10.1.1.1 Provision of Consent Form to Participants 
A copy of the consent form will be given to the subject, and this fact will be documented in the 
subject’s record. 
10.1.1.2 Consent Procedures and Documentation 
Consent is obtained by either the clinical site PI or by individuals to whom the clinical site PI has 
delegated authority to obtain informed consent.  The delegation of authority is documented and 
maintained in WebDCUTM. As with most clinical trial responsibilities delegated by the clinical site 
PI, it is his/her responsibility to ensure that the delegation is made only to those individuals who 
are qualified to undertake the delegated tasks, and that there is adherence to all applicable 
regulatory requirements and Good Clinical Practices (GCP) Guidelines. Additionally, it is the 
investigator’s responsibility to ensure that the subject has been given an adequate explanation 
of the purpose, methods, risks, potential benefits and subject responsibilities of the study. The 
consent form must be an up-to-date document that has been approved by the Central 
institutional review board (CIRB). A signed and dated informed consent is required prior to 
randomization. We anticipate that the electronic consent platform (eConsent) will be utilized for 
almost all subjects in this trial.  
Rationale for the use of e-consent: We have chosen this method of consent in order to minimize 
risk to the research team and healthcare providers and to decrease community spread of the 
disease. We have prior experience using telemedicine and phone consent coupled with 
electronic consent form review for time-sensitive clinical trials of traumatic brain injury and 
cardiac arrest. While the rationale for eConsent is different in this case (minimization of disease 
spread during a pandemic), we believe it is appropriate for the disease and intervention being 
studied. The low risk of adverse effects from CP, combined with the close remote follow-up 
methods proposed in this study make the risk: benefit ratio for the alteration of traditional 

 Protocol 5.0 
48 
consent process acceptable for participants, providers, and the public.  
10.1.2 Study Discontinuation and Closure 
The study may be modified or discontinued at any time by the NHLBI, the FDA, or other 
government agencies as part of their duties to ensure that research subjects are protected.  
10.1.3 Confidentiality and Privacy 
The subject’s identity will be kept as confidential as possible as required by law. Upon 
enrollment, WebDCUTM assigns a unique subject ID to each subject.  The link between the 
subject ID and the subject’s name will be confidentially maintained at the enrolling sites. In 
compliance with Health Information Portability and Accountability Act (HIPAA), collection, 
storage, display, and transfer of study subject personal identifiers in the WebDCUTM are 
carefully controlled.  Prior to creating the Public Use Dataset any personal identifiers, such as 
date of enrollment, will be de-identified. 
10.2 Key Roles and Study Governance 
Demonstrated ability of the group or history of the investigators in conducting clinical 
research: The C3PO trial will be conducted in the Strategies to Innovate EmeRgENcy Care 
Clinical Trials Network (SIREN) network. The network is composed of the Clinical Coordinating 
Center (CCC) at the University of Michigan, which provides overall project management for the 
trial, the SIREN Data Coordinating Center (DCC) at the Medical University of South Carolina, 
which provides data management and statistical support, and 11 SIREN Hubs located in tertiary 
care facilities across the US. Funded by the National Institute for Neurological Disorders and 
Stroke (NINDS), the National Heart Lung and Blood Institute (NHLBI) and the National Center 
for Advancing Translational Science (NCATS), the goal of SIREN is to improve the outcomes of 
patients with neurologic, cardiac, respiratory and hematologic emergencies by identifying 
effective treatments given in the earliest stages of care.  Regional hubs, with an average of five 
regional spokes, were chosen through a competitive funding mechanism of the NIH and provide 
training and clinical infrastructure for nearby spokes, comprising both academic and community 
hospitals with investigators but perhaps without fewer research staff.  This improves access to 
patients receiving advanced care capabilities at sites that might not normally compete for NIH 
grants.   
SIREN currently provides trial management for three NIH funded clinical trials. SIREN builds 
upon the success of the previous Neurologic Emergency Treatment Trials (NETT) network and 
incorporates expertise and experiences from the Resuscitation Outcome Consortium (ROC). 
Our previous experience as a clinical trial network has allowed NETT/SIREN to continuously 
hone our ability to recruit efficiently in the Emergency Department and to retain subjects through 
to their planned subject end of study. Consequently we have a strong track record of recruiting 
ahead of projections in 4 of our previously completed 7 trials, and we were on or close to 
projections for the others, with only one of 7 requesting supplemental funds to assist 
completion. We also have very low rates of loss to follow-up and subject withdrawal.   
The Clinical Coordinating Center (CCC) for the C3PO trial will be the SIREN CCC at the 
University of Michigan and the Data Coordinating Center (DCC) will be the SIREN DCC at the 
Medical University of South Carolina.  The Scientific Coordinating Group includes investigators 
from Stanford University, University of Michigan, and University of Pittsburgh. 
Clinical Coordinating Center (CCC).  The CCC is responsible for coordinating the Network 
and C3PO enrolling site leadership and for overall organization, administration, and 
communication.  These responsibilities include site management (regulatory management, 

 Protocol 5.0 
49 
enrollment performance, data monitoring, etc.), trial management (coordination of trial 
recruitment, publications, clinical translation), and management of study operations (protection 
of human subjects, outcomes assessment, training and education, etc.).  The SIREN CCC has 
a Financial Specialist who will provide management and reconciliation of the C3PO financial 
activities within the SIREN CCC, including review and processing of invoices for C3PO funded 
activity and enrollment at the clinical sites. 
Data Coordinating Center (DCC).  The main responsibilities of the DCC are to collaborate with 
the CCC on trial management/operations and to provide the clinical trials management system 
and statistical activities for the C3PO trial.  The DCC will be responsible for development and 
maintenance of the study database including the central randomization module, data processing 
and management of data obtained at all study sites and generation and distribution of progress 
reports as well as reports to the Data and Safety MonitoringBoard (DSMB).  The DCC will also 
implement any adaptive design procedures, such as sample size reestimation, interim analyses 
and will provide statistical support throughout the trial and participate in manuscript preparation 
and dissemination of study information at the end of the trial.  
Scientific Coordinating Group (SCG).  The SCG includes scientific experts in Transfusion 
Medicine, Immunology, Pulmonology and Emergency Medicine.  This group is responsible for 
scientific integrity of the study, interpretation of data, and review of study progress. Together 
with the DCC and CCC, the SCG will lead preparation of publications resulting from  this trial, 
including the primary manuscript.  The SCG will review and approve requests for trial data from 
outside investigators, proposals for ancillary trials or secondary analyses.  Unique to this trial, 
the SCG experts in Transfusion Medicine will lead implementation of CP acquisition, tracking, 
banking and release from the many blood banks across the network.    
Executive Committee (EC).  The EC consists of the leadership of the SCG, the CCC, the DCC, 
NIH Liaisons for the SIREN network, and the NHLBI program officer.  The EC is a working 
group responsible for the development and amendment of the study documents (e.g., protocol, 
case report forms and manual of procedures), collection, review, and oversight of dissemination 
of SAEs (occurrences and other important events pertinent to the study), and communication 
among all components of the study participants (e.g., CCC, DCC, SCG, clinical sites, and the 
NHLBI).  
Independent Medical Safety Monitor (IMSM).  The IMSM will have expertise in evaluating 
transfusion-related complications. The IMSM will  review all SAEs and determine whether they 
are serious, possibly related to CP administration, and unexpected.  If all three criteria are met, 
expedited reporting to the FDA and cIRB will be initiated.  
Data and Safety Monitoring Board (DSMB).  A Data and Safety Monitoring Board (DSMB) will 
be appointed by NHLBI. The DCC will generate Open and Closed DSMB Reports at a 
frequency determined by the DSMB, but no less than semi-annually. They also will create 
reports for each planned interim analysis. The DSMB’s overarching responsibility is the 
oversight of safety of the trial participants. The DSMB will review reports on safety, data quality 
and recruitment and retention, request additional data/information if necessary, and will be 
cognizant of external new information regarding the safety of CP treatment.  They also will 
receive reports for the planned interim analyses.  Upon review of the interim data reports or any 
ongoing reporting, they will advise the study team and the NHLBI regarding continuation of the 
trial. 
10.3 Safety Oversight 
Data and Safety Monitoring Board (DSMB).  The DSMB is the COVID-19 trial board 
appointed by NHLBI. The DCC will generate safety and other reports as requested by this 
DSMB. 

 Protocol 5.0 
50 
10.4 Site  Monitoring, Quality Assurance, and Quality Control 
We will perform monitoring consistent with SIREN Site Monitoring standard operating 
procedures. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, with applicable FDA regulations (21 CFR 312), and with the FDA’s “Guidance for Industry 
Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring.”  Monitoring for 
this study will be performed by the DCC/CCC centrally, on site, and remotely.  Per the study’s 
monitoring plan, monitoring will include a combination of on-site monitoring (to verify data 
entered into the WebDCU™ database against source documents and query inaccuracies 
between the source documents and WebDCU™ database), remote monitoring (source 
document verification, including verification of written consent, may be performed remotely by 
reviewing source documents that have been uploaded into WebDCU™ or via remote access to 
electronic medical records), and central monitoring (using web-based data validation rules, data 
manager review of entered data, statistical analysis, and on-going review of site metrics).  
Further details of clinical site monitoring are documented in the study’s Monitoring Plan.  
The EC, on a regular basis, will review a summary of the data entered in the C3PO WebDCUTM 
database by the participating clinical sites to identify deficiencies in data collection and/or entry. 
This summary will be the result of the ongoing review by the DCC Data Manager (DM) and 
IMSM of data entered by all participating clinical sites. 
The DCC’s goal is to provide high quality, efficient data management for the successful 
implementation of studies conducted within SIREN.  Proper clinical trial oversight requires the 
monitoring of both study data as well as trial operations.  Our clinical trials management system, 
WebDCU™, enables the collection and maintenance of study data as well as study operational 
data (e.g., regulatory documents, drug receipt/tracking, subject enrollment, randomization and 
retention), which has afforded the DCC and its collaborators (e.g., CCCs, Trial PIs, NIH) the 
opportunity to make significant advances in its procedures for clinical trial oversight and 
monitoring. We work closely with the CCC to provide a risk-based monitoring approach that is 
multifaceted, dynamic, and focused on preventing and correcting errors associated with critical 
data, protocol compliance, protection of subjects, and study integrity. Central monitoring is aimed 
at quickly and systematically identifying issues affecting subject safety, trial operation integrity 
and data accuracy, reducing the effort required by on-site monitors, and providing an accurate 
final study database.  
One of the strengths of WebDCU™ is that it is an integrated clinical trials management system 
(CTMS), housing both the eCRF data as well as the complete trial operations data.  This provides 
the appropriate stakeholders including DCC and CCC personnel, site monitors, protocol PIs, and 
cIRB with real-time, secure access to the information needed to carefully monitor the performance 
at each site (including central calling centers) and identify and manage critical issues.  Examples 
of trial operation aspects to monitor quality include but are not limited to: timeliness and 
completeness of AE reporting, timeliness and completeness of regulatory document submission, 
certification/training of investigators, rate of screening, subject enrollment and subject retention, 
frequency of protocol violations, frequency of randomization errors, frequency of staff turn-over, 
timeliness and completeness of data submission and query response, and rate of data 
corrections.  
Reports programmed in WebDCU™ or provided by the statistical team facilitate the sharing of 
this information within and across studies as well as by Hub/Spoke through the duration of each 

 Protocol 5.0 
51 
trial.  As errors are identified, data managers generate data clarification requests (DCRs) in 
WebDCU™.  Site personnel receive email alerts and are required to provide a response for each 
DCR and correct the eCRF data, if needed. Critical and/or systemic errors identified by central 
monitoring are shared with all study team members via weekly team meetings so that swift and 
appropriate action can be taken, and consideration of a remote or on-site monitoring visit can be 
determined. To facilitate this review, WebDCU™ houses a SIREN Network Dashboard that 
provides specific trial metrics within and across trials on enrollment, retention, adherence and 
data quality. 
10.5 Study Records Retention 
In June 2005, Federal law extended the statute of limitations to six years to bring forward an 
allegation of research misconduct. In response to this extension, research records must be 
retained for a sufficient period to investigate an allegation of research misconduct and in 
compliance with federal law (currently a minimum of six years)or longer if local regulations 
require. 
Records will be maintained in a  secure location to ensure confidentiality. 
10.6 Protocol Deviations 
At regular intervals, the EC will review the material and discuss, among other items, any 
concerns regarding the principles and intensity of the overall care and aggregations of protocol 
violations/deviations at particular sites.  The EC may recommend that individual sites be 
contacted to discuss the issues identified at those sites and potential remedial measures.  As a 
result of these reviews, the EC may make recommendations for protocol changes if serious 
safety concerns arise or there is an overarching issue with implementation of the protocol.     
10.7 Publication and Data Sharing Policy 
Because of the ongoing pandemic, we will rapidly disseminate study findings to the medical 
community via high impact, peer-reviewed scientific journals within 2 months of the completion 
of study enrollment, via ClinicalTrials.gov, websites such as  https://covid19.trialstracker.net, 
https://covid-19.cochrane.org, https://covid-evidence.org, and via presentations at SIREN 
network meetings, national and international meetings, clinical practice committees and think 
thanks. Publication of the results of this trial will be governed by the policies and procedures 
developed by the EC.  The Publication Policy will be fully compliant with the voluntary NIH 
Public Access Policy mandated by the Consolidated Appropriations Act of 2008 (Division G, 
Title II, Section 218 of PL 110-161). The EC will follow NIH policies on data-sharing (as 
described at the site: 
http://grants2.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm and any updates 
thereto). 
At the completion of the study, the DCC will generate de-identified public use data files and data 
documentation elements that will be shared with the NHLBI data repository that is managed by 
the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). The 
investigators at University of Pittsburgh will house biological specimens, and the investigators 
will make those available, quantities permitting, to legitimate members of the research 
community with appropriate approval and agreements.  Long-term, residual samples can be 
deposited with NHLBI in the BioLINCC.  

 Protocol 5.0 
52 
11. Protocol Amendment History 
 
Version 1 
Version 2 
Section 
Page 
Previous text 
Page 
New text 
Table of 
Abbrevi
ations 
5 
PROMISⓇ 
Patient-
Reported Outcomes 
Measurement Information 
System (PROMIS) 
5 
Removed 
1.1 
9 
Dyspnea measured by the 
PROMIS measure on days 
4, 10, 15, and 30 
9 
Removed 
1.1 
10 
Treating clinical team 
unwilling to administer 300 
ml fluid 
10 
Treating clinical team unwilling to 
administer up to 250 ml fluid 
1.1 
10 
One unit (~250 ml) 
10 
One unit (~200 ml) 
1.2 
12 
Dyspnea measured by the 
PROMISⓇ Pool V 1.0 
Dyspnea Characteristics 
Questionnaire measured on 
days 4, 10, 15 and 30 
 
Removed 
1.2 
12 
Age≥50 years; hypertension; 
diabetes; coronary artery 
disease; chronic lung 
disease; chronic kidney 
disease; 
immunocompromised state 
 
12 
Removed. 
1.2 
13 
Inability to tolerate 300 ml of 
intravenous fluid  
1 
Inability to tolerate up to 250 ml 
of intravenous fluid  
1.2 
13 
one unit (~250 ml)  
13 
one unit (~200 ml) 
1.2 
13 
5 ml multivitamin 
concentrate, see MOP (MVI-
Adult, Hospira). 
13 
1-5 ml multivitamin concentrate, 
see MOP (MVI-Adult). 
1.4 
14 
Symptom Inventory 
14 
Symptom Inventory 

 Protocol 5.0 
53 
PROMIS Dyspnea 
Characteristic Scale 
 
1.5 
15 
250 ml NS + 5 ml MVI.   
 
250 ml NS + 1-5 ml parenteral 
MVI (see MOP).   
1.5.2.1 
16 
PROMISⓇ Pool V 1.0 
Dyspnea Characteristics 
Questionnaire 
16 
Removed 
1.5.2.2 
16 
PROMISⓇ Pool V 1.0 
Dyspnea Characteristics 
Questionnaire 
16 
Removed 
3 
24 
Determine the effect of CP 
on the severity of symptoms 
 
Dyspnea measured by the 
PROMISⓇ Pool V 1.0 
Dyspnea Characteristics  on 
days 4, 10, 15, and 30 
 
Validated measures of 
dyspnea and function 
 
24 
Removed 
3.3 
26 
PROMIS Dyspnea 
Characteristics 
Questionnaire 
 
Removed 
5.1 
28 
Has at least one study 
defined risk factor for severe 
COVID-19 illness:   
Age≥50 years; hypertension; 
diabetes; coronary artery 
disease; chronic lung 
disease; chronic kidney 
disease;24,24  
immunosuppression25;   
28 
Has at least one study defined 
risk factor for severe COVID-19 
illness:   
Study defined risk factors initially 
include: age≥50 years; 
hypertension; diabetes; coronary 
artery disease; chronic lung 
disease; chronic kidney disease; 
immunosuppression; sickle cell 
disease, and obesity (body mass 
index [BMI]>30) and are updated 
as needed in the C3PO Manual 
of Procedures in response to 

 Protocol 5.0 
54 
changes in CDC guidance or 
other information.. 
 
5.1 
29 
Has at least one study 
defined risk factor for severe 
COVID-19 illness:   
Age≥50 years; hypertension; 
diabetes; coronary artery 
disease; chronic lung 
disease chronic kidney 
disease; immunosuppression 
29 
Has at least one study defined 
risk factor for severe COVID-19 
illness.   
 
5.1 
29 
Age is biological age. 
Hypertension must be 
treated with medications. 
Diabetes must be treated 
with medications. 
Chronic lung disease, 
coronary artery disease, 
chronic  kidney  disease23 
per medical record. 
Immunosuppression with 
medications. 
29 
Age is biological age. 
Hypertension must be treated 
with medications. 
Diabetes must be treated with 
medications. 
Chronic lung disease, coronary 
artery disease, chronic  kidney  
disease23 per medical record. 
Immunosuppression with 
medications. 
Obesity is defined as BMI>30 
Sickle cell disease is based on 
past medical history 
5.1 
29 
Age, hypertension, diabetes, 
coronary heart disease, 
chronic lung disease and 
chronic kidney disease are 
associated with higher 
COVID-19 morbidity and 
mortality.22,23   
Hypertension and diabetes 
are on a continuum and 
sometimes controlled without 
medications.  We will restrict 
to medication-treated 
conditions in order to clearly 
define comorbidities that 
have prompted medical 
treatment.  Patients on 
immunosuppression for solid 
organ transplants are more 
often hospitalized for severe 
COVID-19 illness.25 
29 
Age, hypertension, diabetes, 
coronary heart disease, chronic 
lung disease and chronic kidney 
disease are associated with 
higher COVID-19 morbidity and 
mortality.22,23   
Hypertension and diabetes are 
on a continuum and sometimes 
controlled without medications.  
We will restrict to medication-
treated conditions in order to 
clearly define comorbidities that 
have prompted medical 
treatment.  Patients on 
immunosuppression for solid 
organ transplants are more often 
hospitalized for severe COVID-19 
illness.25 Emerging data 
suggests that sickle cell 
disease and obesity are risk 

 Protocol 5.0 
55 
factors for severe disease. 
5.2 
30 
● Treating clinical team 
unwilling to 
administer 300 ml 
fluid 
30 
● Treating clinical team 
unwilling to administer up 
to 250 ml fluid 
5.2 
31 
Treating clinical team 
unwilling to administer 300 
ml fluid 
31 
Treating clinical team unwilling to 
administer up to 250 ml fluid 
6.1.2 
33 
one unit (~250 ml) of CP 
33 
one unit (~200 ml) of CP 
8.1.2 
39 
Symptom inventory: On 
study days 2, 4, 6, 8, 10, 12, 
14, 15 and 30, we will record 
the burden of symptoms 
listed by the Centers for 
Disease Control and 
Prevention (CDC) as typical 
of COVID-19 illness.  The 
presence or absence of each 
of the following symptoms 
will be ascertained. 
● Fever or chills 
● Cough 
● Shortness of breath 
or difficulty breathing 
● Fatigue 
● Muscle or body aches 
● Headache 
● New loss of taste or 
smell 
● Sore throat 
● Congestion or runny 
nose 
● Nausea or vomiting 
● Diarrhea 
 
39 
Symptom inventory: On study 
days 2, 4, 6, 8, 10, 12, 14, 15 and 
30, we will record the burden of 
symptoms listed by the Centers 
for Disease Control and 
Prevention (CDC) as typical of 
COVID-19 illness. For purposes 
of this trial symptoms include 
any symptoms of COVID-19 
illness listed by the CDC case 
definition guidance at the time 
of enrollment. These include 
but are not limited to the 
following: 
● Fever or chills 
● Cough 
● Shortness of breath or 
difficulty breathing 
● Fatigue 
● Muscle or body aches 
● Headache 
● New loss of taste or smell 
● Sore throat 
● Congestion or runny nose 
● Nausea or vomiting 
● Diarrhea 
Refer to the Manual of 
Procedures for the latest CDC 
list of COVID-19 symptoms. 
 
 
 
Version 2 
Version 3 

 Protocol 5.0 
56 
Section 
Page 
Previous text 
Page 
New text 
Header 
2-59 
Protocol 2.0 
2-59 
Protocol 3.0 
Protocol 
Signature 
Page 
2 
Date of Signature 7/2/2020 
2 
9/7/2020 
1.0 
9 
(blank) 
9 
Pro00044489 
1.1 
10 
 We will conduct the first interim 
analysis after approximately 150 
consecutively randomized ITT 
subjects complete the primary 
outcome assessment. 
10 
 We will conduct the 
first interim analysis 
after approximately 200 
consecutively 
randomized ITT 
subjects complete the 
primary outcome 
assessment. 
1.2 
12 
Adults presenting to the 
emergency department (ED) 
with mild, symptomatic, 
laboratory-confirmed COVID-19 
illness, who are at high risk for 
progression to severe/critical 
illness, but who are clinically 
stable for outpatient 
management at randomization 
12 
Adults presenting to the 
emergency department 
(ED) with symptomatic, 
laboratory-confirmed 
COVID-19 illness, who 
are at high risk for 
progression to 
severe/critical illness, 
but who are clinically 
stable for outpatient 
management at 
randomization 
1.4 
14 
Pre-intervention Blood Sample 
14 
Pre-intervention 
research blood draw 
1.4 
14 
Post-intervention Blood Sample 
  
14 
Post-intervention 
research blood draw 
  

 Protocol 5.0 
57 
1.5 
15 
All subjects will have a pre-
infusion blood draw.  Blood from 
consented subjects will be sent 
for type and screen. 
15 
All subjects will have a 
pre-infusion blood draw.  
Blood from consented 
subjects will be sent for 
blood type. 
1.5 
15 
A sample of the CP will be 
frozen for later analysis.  
15 
Removed  
1.5 
15 
At one hour, another blood 
sample will be drawn from the 
existing IV access and frozen for 
later analysis.  
15 
At one hour, another 
blood sample will be 
drawn and frozen for 
later analysis.  
1.5 
15 
The central study team follow-up 
core will contact the participant 
by telephone or video chat every 
other day to assess disease 
progression and serious 
adverse events for 2 weeks and 
at days 15 and 30. 
15 
The central study team 
follow-up core will 
contact the participant 
by telephone or video 
chat every other day to 
assess disease 
progression and serious 
adverse events for 2 
weeks. They will assess 
blinding to treatment on 
day 2. 
1.5 
15 
The site study team will also 
collect data from any 
hospitalizations and ED/Urgent 
Care visits occurring within the 
study period. 
15 
The site study team will 
also collect data from 
any hospitalizations and 
ED/Urgent Care visits 
occurring within the 
study period. In 
addition, the study team 
will collect a symptom 
inventory on days 15 
and 30 and assess 
blinding to treatment on 
day 15. 

 Protocol 5.0 
58 
1.5 
16 
Blood samples from participants 
and a sample of each CP unit 
administered will be shipped to 
the study core lab at the 
University of Pittsburgh for 
analysis. 
16 
Blood samples from 
participants will be 
shipped to the study 
core lab at the 
University of Pittsburgh 
for analysis. 
1.5 
16 
If hospitalized, participants are 
permitted to receive non-study 
compassionate use of CP or 
other emergency use or 
investigational treatments if 
available. 
16 
If hospitalized, 
participants are 
permitted to receive 
non-study CP or other 
emergency use or 
investigational 
treatments if available. 
1.5.2.1 
16 
Type and Screen 
16 
Blood type 
1.5.2.1 
16 
Any adverse event 
16 
remove 
1.5.2.2 
16 
Any adverse event 
16 
remove 
1.5.2.3 
16 
Any adverse event 
16 
remove 
1.5.2.4 
17 
Any adverse event 
16 
remove 
1.5.2.5 
17 
Any adverse event 
17 
remove 
1.5.2.6 
17 
Any adverse event 
17 
remove 
1.5.2.7 
17 
Any adverse event 
17 
remove 
5.1 
28 
(body mass index [BMI]>30) 
28 
(body mass index 
[BMI]>30) 
5.1 
29 
BMI>30 
29 
BMI>30 

 Protocol 5.0 
59 
5.1 
30 
Blood bank to check type and 
screen 
30 
Blood bank to check 
blood type 
5.4 
31 
Average of 3 - 4 subjects per 
month at each study site over 6 
months (~100 subjects in the 
study per month) 
31 
Average of 6 subjects 
per month at each study 
site over 2 months 
(~300 subjects in the 
study per month) 
6.2 
34 
The supplier (Vitalant) has 
already collected over 1700 
units of CP. 
34 
The supplier (Vitalant) 
has already collected 
many units of CP. 
6.2 
35 
Specifically, CP will be tested 
using a chemiluminescent test 
for IgG and IgM against spike 
protein (Ortho VITROS Anti-
SARS-CoV2 Total). 
35 
Specifically, CP will be 
tested using a 
chemiluminescent test 
for IgG and IgM against 
spike protein (Ortho 
VITROS Anti-SARS-
CoV2 Total) or 
equivalent assay. 
6.2 
35 
If this qualitative test is positive, 
then the CP is also tested with 
the Vitalant Research Institute 
SARS-CoV2 Reporter Viral 
Particle Neutralization (RVPN) 
test. 
35 
If this qualitative test is 
positive, then the CP is 
also tested with the 
Vitalant Research 
Institute SARS-CoV2 
Reporter Viral Particle 
Neutralization (RVPN) 
test or equivalent 
assay. 
6.2 
35 
A positive Ortho VITROS test 
corresponds to at least a titer of 
1:160 in the RVPN test. 
35 
remove 

 Protocol 5.0 
60 
6.2 
35 
The presence of antibodies is 
confirmed within 24 hours of 
donor collection. 
35 
The presence of 
antibodies  are 
generally confirmed 
within 48 hours of donor 
collection. 
6.2 
35 
Each site will receive 4 units of 
CP at a time, and units will be 
replenished from the central 
supplier as they are used. 
35 
Each site will receive 4 
or more units of CP at a 
time, and units will be 
replenished from the 
central supplier as they 
are used. 
6.2 
35 
Over the trial, each of the 30 
SIREN sites will receive an 
average of 10-12 units of CP. 
35 
Over the trial, each of 
the 30 or more SIREN 
sites will receive an 
average of 10-12 units 
of CP. 
6.2 
35 
Samples from each CP unit will 
be sent to the study core 
laboratory at the University of 
Pittsburgh for antibody 
characterization. 
35 
Vitalant will send 
samples from each CP 
unit to the study core 
laboratory at the 
University of Pittsburgh 
for antibody 
characterization. 
6.2 
35 
A type and screen will be 
performed in all potential 
subjects after the informed 
consent form is signed. 
35 
A blood type will be 
performed in all 
potential subjects after 
the informed consent 
form is signed. 

 Protocol 5.0 
61 
6.2 
36 
If a subject is randomized to the 
control (saline) arm, an order 
will be sent to the pharmacy or 
investigational drug service for a 
250 ml bag of isotonic saline 
with an added ampule of 
multivitamin (to provide color 
similar to plasma). 
36 
If a subject is 
randomized to the 
control (saline) arm, an 
order will be sent to the 
pharmacy or 
investigational drug 
service for a 250 ml bag 
of isotonic saline with 1-
5 of parenteral 
multivitamin (to provide 
color similar to plasma). 
6.2 
36 
Vitalant has already secured 
over 1700 units of CP and 
anticipates no problem with 
supply. 
36 
Vitalant has already 
secured many units of 
CP and anticipates no 
problem with supply. 
8.1 
38 
Surveys and assessments 
completed within 2 days of the 
time point will be counted as 
qualifying and not considered 
missing. 
38 
Central caller 
assessments completed 
within 1 day of the time 
point will be counted as 
qualifying and not 
considered missing. 
8.1.2 
38 
Surveys and assessments from 
day 0-14 that are completed 
within 1 days of the time point 
38 
Surveys and 
assessments from day 
0-14 that are completed 
within 1 day of the time 
point 

 Protocol 5.0 
62 
8.1.2 
39 
·         Fever or chills 
·         Cough 
·         Shortness of breath 
or difficulty breathing 
·         Fatigue 
·         Muscle or body 
aches 
·         Headache 
·         New loss of taste or 
smell 
·         Sore throat 
·         Congestion or runny 
nose 
·         Nausea or vomiting 
·         Diarrhea 
  
39 
·         Fever or 
chills 
·         Cough 
·         Shortness of 
breath or 
difficulty 
breathing 
·         Fatigue 
·         Muscle or 
body aches 
·         Headache 
·         New loss of 
taste or smell 
·         Sore throat 
·         Congestion 
or runny nose 
·         Nausea or 
vomiting 
·         Diarrhea 
·         Abdominal 
pain 
·         Limitations 
of activities 
because of 
COVID-19 
symptoms 
  
8.1.3 
40 
Whole blood will be processed 
into serum and plasma, and 
stored in a -80ºC freezer within 
2 hours of sample collection. 
40 
Whole blood will be 
processed into serum 
and plasma, and stored 
in a -70ºC freezer or 
colder within 2 hours of 
sample collection. 
8.1.5 
41 
As part of follow-up 
assessments on Day 15, 
41 
As part of follow-up 
assessments on Days 2 
and 15, 

 Protocol 5.0 
63 
8.2.1 
41 
After discharge from the 
emergency department and at 
each follow-up contact, only 
serious adverse events will be 
reported in WebDCU. 
41-42 
After discharge from the 
emergency department 
and at each follow-up 
contact until the end of 
study, only serious 
adverse events will be 
reported in WebDCU 
and any event that 
leads to hospitalization 
or an ED or urgent care 
visit even if deemed 
non-serious. 
8.2.1 
42 
All serious adverse events 
(SAEs) will be recorded until the 
end of the study. 
42 
remove 
9.1 
46 
The DSMB will be closely 
monitoring this assumed control 
rate in order to adjust sample 
size prior to the first official 
interim analysis as needed. 
  
46 
remove 

 Protocol 5.0 
64 
9.2.3 
48 
A Bayesian imputation model 
will be used to impute the 
primary outcome using 
information from previous time 
periods. 
48 
Sensitivity to missing 
data will be assessed. If 
the outcome is 
insensitive to missing 
data, defined as no 
change in the 
conclusion regardless 
of the set of imputed 
values, each missing 
observation will be 
imputed an unfavorable 
outcome (i.e., event 
occurred). If the 
outcome is sensitive to 
missing data, each 
observation will be 
imputed using a 
Bayesian imputation 
model. 
10.1.1.2 
49 
(in those studies, eConsent is 
used for consent via legally 
authorized representatives 
(LAR) 
49 
remove 
 
 
 
Version 3 
 
Version 4 
1.2 
12 
Adults presenting to the 
emergency department (ED) 
with symptomatic, laboratory-
confirmed COVID-19 illness 
12 
Adults presenting to the 
emergency department (ED) 
with their first episode of 
symptomatic, laboratory-
confirmed COVID-19 illness 
5.1 
29 
 
29 
This should be their first 
episode of COVID-19 illness. 
See MOP for additional 
details 
5.4 
31 
Potential subjects for this trial 
will be recruited from emergency 
department patients who have  
31 
Potential subjects for this 
trial will be recruited from 
emergency department 

 Protocol 5.0 
65 
laboratory-confirmed SARS-
CoV-2 infection 
patients who have their first 
episode of symptomatic 
laboratory-confirmed SARS-
CoV-2 infection 
5.4 
33 
Subjects may be eligible for 
compensation for the Day 15 
and Day 30 blood draws based 
on local institution practices. 
33 
Subjects may be eligible for 
compensation for 
travel/parking at any of their 
visits based on local 
institution practices. 
8.1.3 
40 
No more than 30 mL of blood  
40 
No more than 50 mL of blood  
8.1.3 
40 
Shortly after randomization but 
before the administration of 
study intervention 
40 
After consent but before the 
administration of study 
intervention 
8.1.3 
40 
 
40 
In addition to the blood 
samples collection outlined 
above, for subjects who 
consent to participating in an 
optional study evaluating the 
evolution of the adaptive 
immune response in CP 
recipients, an additional 20 
ml of whole blood will be 
collected on the day of 
enrollment and on study 
days 15 and 30. These 
samples will be shipped 
within 1 day of collection to a 
central laboratory for 
processing.  
 
 
Version 4 
Version 5 
Section 
Page 
Previous text 
Page 
New text 
Header 
2-68 
Protocol 4.0 
2-73 
Protocol 5.0 
Protocol Signature 
Page 
2 
Date of Signature 
11/3/2020 
2 
Date of Signature 2/16/2021 

 Protocol 5.0 
66 
1.1 Study Duration 9 
June 2020 to May 2021 
9 
June 2020 to July 2021 
1.1 Number of 
Subjects 
9 
600 (300 per arm) 
9-10 
Original planned maximum 
sample size: 600 (300 per arm) 
Revised maximum sample size 
based on planned re-estimation: 
900 (450 per arm) 
1.1 Main Inclusion 
Criteria 
10 
Clinical team deems 
stable for outpatient 
management without 
supplemental oxygen 
10 
Clinical team deems stable for 
outpatient management without 
new supplemental oxygen 
1.1 Main Inclusion 
Criteria 
10 
Duration of symptoms ≤ 7 
days at ED presentation 
10 
Duration of symptoms ≤ 7 days 
at ED presentation and 
randomization 
1.1 Major 
Inclusion Criteria 
10 
Enrollment in another 
interventional trial for 
COVID-19 illness 
10 
Enrollment in another 
interventional trial for COVID-19 
illness or receipt of other active 
or passive immunization against 
SARS-CoV2. 
1.1 Statistical 
Methodology 
 
10 
We will conduct the first 
interim analysis after 
approximately 200 
consecutively randomized 
ITT subjects complete the 
primary outcome 
assessment. 
10 
We will conduct the first interim 
analysis after approximately 
33% of consecutively 
randomized ITT subjects 
complete the primary outcome 
assessment. 
1.2 Study Design 
11 
Sample size: 600 
subjects 
11 
Original planned maximum 
sample size: 600 (300 per arm) 
Revised maximum sample size 
based on planned re-estimation: 
900 (450 per arm) 
1.2 Study Design 
11 
Study Duration: 6-9 
months 
11 
Study Duration: 12 months 
1.2 Inclusion 
Criteria 
12 
Duration of symptoms ≤ 7 
days at ED presentation 
12 
Duration of symptoms ≤ 7 days 
at ED presentation and 
randomization 
1.2 Exclusion 
Criteria 
13 
Enrollment in another 
interventional trial for 
COVID-19 illness 
13 
Enrollment in another 
interventional trial for COVID-19 
illness or receipt of other active 
or passive immunization against 
SARS-CoV2. 

 Protocol 5.0 
67 
1.3 Schema 
13 
Timeline for study events.  
Enrollment and 
intervention (CP or 
Placebo) occurs in the 
emergency department 
(or adjacent care clinic). 
Blood samples 1 and 2 
are collected during that 
visit.  Outpatient follow-up 
is conducted remotely by 
telephone or other 
contact.  Subjects have 
phlebotomy on Day 15 
and Day 30 for blood 
samples 3 and 4.  In-
person or remote contact 
on Day 15 and Day 30, 
and medical record 
review on Day 30, will 
confirm subject 
outcomes. 
13 
Timeline for study events.  
Enrollment and intervention (CP 
or Placebo) occurs in the 
emergency department (or 
adjacent care clinic). Blood 
samples 1 and 2 are collected 
during that visit. Residual viral 
media samples from 
nasopharyngeal swabs and/or 
saliva samples will also be 
collected during the enrollment 
visit.  Outpatient follow-up is 
conducted remotely by 
telephone or other contact.  
Subjects have phlebotomy on 
Day 15 and Day 30 for blood 
samples 3 and 4.  In-person or 
remote contact on Day 15 and 
Day 30, and medical record 
review on Day 30, will confirm 
subject outcomes. We will 
collect information on 
participants’ SARS-CoV-2 viral 
genotype from the enrolling 
institution if available. 
1.4 Schedule of 
Activities 
14 
(No text) 
14 
Residual viral media / saliva 
sample 
Study Day 
0 
1.5 Study Flow 
and Daily Data 
Collection 
15 
(No text) 
15 
Residual viral media samples 
from nasopharyngeal swabs 
and/or saliva samples will also 
be collected during the 
enrollment visit. 
1.5 Study Flow 
and Daily Data 
Collection 
16 
(No text) 
16 
Residual viral media and saliva 
samples will be shipped to a 
central lab for analysis. 
1.5.2.1 Data 
Collection 
16 
1.5.2.1 Data Collection 
16 
1.5.1.2 Data Collection 

 Protocol 5.0 
68 
1.5.2.1 Data 
Collection 
16 
(No text) 
16 
SARS-CoV-2 viral genotype, if 
available 
1.5.2.1 
Intervention 
16 
1.5.2.1 Intervention 
16 
1.5.1.3 Intervention 
1.5.2.1 
Intervention 
16 
(No text) 
16 
Residual viral media and/or 
saliva sample 
5.1 Inclusion 
Criteria 
28 
Clinical team deems 
stable for outpatient 
management without 
supplemental oxygen 
28 
Clinical team deems stable for 
outpatient management without 
new supplemental oxygen 
5.1 Inclusion 
Criteria 
28 
Duration of symptoms ≤ 7 
days at ED presentation 
28 
Duration of symptoms ≤ 7 days 
at ED presentation and 
randomization. 
5.1 Inclusion 
Criteria 
Metric 
29 
observation unit without 
oxygen supplementation 
would be eligible) 
30 
observation unit without oxygen 
supplementation would be 
eligible).  Patients discharged 
from the ED may be brought 
back for randomization and 
treatment so long as they meet 
study inclusion criteria at the 
time of randomization.  
5.1 Inclusion 
Criteria 
Criteria 
30 
Duration of symptoms ≤ 7 
days at ED presentation 
30 
Duration of symptoms ≤ 7 days 
at ED presentation and 
randomization 
5.2 Exclusion 
Criteria 
30 
Enrollment in another 
interventional trial for 
COVID-19 illness 
30 
Enrollment in another 
interventional trial for COVID-19 
illness or receipt of other active 
or passive immunization against 
SARS-CoV2. 
5.2 Exclusion 
Criteria 
31 
Enrollment in another 
interventional trial for 
COVID-19 illness 
31 
Enrollment in another 
interventional trial for COVID-19 
illness or receipt of other active 
or passive immunization against 
SARS-CoV2. 

 Protocol 5.0 
69 
5.4 Strategies for 
Recruitment and 
Retention 
31 
Target study sample 
size: 600 
31 
Target study sample size: 900 
5.4 Strategies for 
Recruitment and 
Retention 
31 
Anticipated accrual 
rate: Average of 3 - 4 
subjects per month at 
each study site over 6 
months (~100 subjects in 
the study per month), with 
the expectation that 
accrual will vary by month 
depending on the 
progression or resolution 
of the pandemic.  It is 
expected that accrual will 
be higher at the onset of 
the trial and will slow with 
decreasing numbers of 
new cases. 
31 
Anticipated accrual rate: 
Accrual will vary by month 
depending on the progression or 
resolution of the pandemic. 
8.1.3 Secondary 
Endpoints 
(immunological) 
40 
(No text) 
 
41 
Residual viral media and saliva 
specimens collected will be 
analyzed for SARS-CoV-2 viral 
genotype 
9. Statistical 
Considerations 
45 
Design of this trial is 
initially constrained by the 
supply of CP to 300 total 
subjects. 
45 
(Previous text removed) 
9.2.1 Primary 
Analysis 
47 
Secondary analyses of 
the primary outcome will 
explore the impact of 
potential prognostic 
variables including age, 
sex, onset of symptoms 
duration and site.  A 
logistic regression model 
will be used for these 
additional analyses. 
47 
Secondary analyses of the 
primary outcome will explore 
the impact of potential 
prognostic variables including 
age, sex, onset of symptoms 
duration and site.  A logistic 
regression model will be used 
for these additional analyses. 
We will also examine whether 
participants’ pre-treatment 
antibody levels and/or the 
genotype of the SARS-CoV2 
virus that they carry modify the 
association between CP and 
outcome. 
 

 Protocol 5.0 
70 
12. References 
 
1. Guan, W. J., Ni, Z. Y., Hu, Y., Liang, W. H., Ou, C. Q., He, J. X., Liu, L., Shan, H., Lei, C. L., 
Hui, D. S. C., Du, B., Li, L. J., Zeng, G., Yuen, K. Y., Chen, R. C., Tang, C. L., Wang, T., Chen, 
P. Y., Xiang, J., Li, S. Y., Wang, J. L., Liang, Z. J., Peng, Y. X., Wei, L., Liu, Y., Hu, Y. H., Peng, 
P., Wang, J. M., Liu, J. Y., Chen, Z., Li, G., Zheng, Z. J., Qiu, S. Q., Luo, J., Ye, C. J., Zhu, S. 
Y., Zhong, N. S., and China Medical Treatment Expert Group for Covid-19. (2020). Clinical 
Characteristics of Coronavirus Disease 2019 in China. N Engl J Med  
2. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., 
Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H., 
Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J., and Cao, B. (2020). Clinical 
features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497-
506.  
3. Casadevall, A., Dadachova, E., and Pirofski, L. A. (2004). Passive antibody therapy for 
infectious diseases. Nat Rev Microbiol 2, 695-703.  
4. Casadevall, A., and Scharff, M. D. (1995). Return to the past: the case for antibody-based 
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