IGHID 12021 - A Randomized, Phase II Study Comparing the Efficacy and Safety of Standard Versus High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Neutralizing Antibody Plasma in Hospitalized Patients With COVID-19
Phase: PHASE2
Conditions: COVID-19
Sponsor: University of North Carolina, Chapel Hill

 
IGHID 12021 – UNC CCP RCT_18 November 2020_v3.1 
i 
IGHID 12021 - A RANDOMIZED, PHASE II STUDY 
COMPARING THE EFFICACY AND SAFETY OF STANDARD 
VERSUS HIGH-TITER ANTI-SARS-COV-2 NEUTRALIZING 
ANTIBODY PLASMA IN HOSPITALIZED PATIENTS WITH 
COVID-19 
Principal Investigator: Luther Bartelt, MD 
Version 3.1 
18 November 2020  
IND Number:  IND 22282 
ClinicalTrials.gov Identifier: NCT04524507 
 
Funding Source: University of North Carolina at Chapel Hill, School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
IGHID 12021 – UNC CCP RCT_18 November 2020_v3.1 
ii 
IGHID 12021 - A RANDOMIZED, PHASE II STUDY 
COMPARING THE EFFICACY AND SAFETY OF STANDARD 
VERSUS HIGH-TITER ANTI-SARS-COV-2 NEUTRALIZING 
ANTIBODY PLASMA IN HOSPITALIZED PATIENTS WITH 
COVID-19 
 
SIGNATURE PAGE 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable protocol-related 
documents. I agree to conduct this study in compliance with United States (US) Health and Human Service 
regulations (45 CFR 46); applicable U.S. Food and Drug Administration regulations; standards of the International 
Conference on Harmonization Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics 
Committee determinations; all applicable in-country, state, and local laws and regulations; and other applicable 
requirements (e.g., US National Institutes of Health, Division of AIDS) and institutional policies.  
  
Investigator of Record: _______________________________________________  
Print/Type  
  
Signed: ___________________________________ Date: ____________________  
  
 Title: _____________________________________  
  

  
IGHID 12021 – UNC CCP RCT 18 November-2020_v3.1 
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Table of Contents 
PROTOCOL TEAM .................................................................................................................................................... 1 
STATEMENT OF COMPLIANCE............................................................................................................................. 2 
1 
PROTOCOL SUMMARY .............................................................................................................................. 3 
1.1 
Synopsis ............................................................................................................................................... 3 
1.2 
Schema ................................................................................................................................................. 6 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale ................................................................................................................................... 8 
2.2 
Background .......................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment ................................................................................................................. 11 
2.3.1 
Known Potential Risks .................................................................................................. 11 
2.3.2 
Known Potential Benefits.............................................................................................. 13 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 14 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 14 
4 
STUDY DESIGN .......................................................................................................................................... 16 
4.1 
Overall Design ................................................................................................................................... 16 
4.2 
Scientific Rationale for Study Design ............................................................................................. 16 
4.3 
Justification for Dose ........................................................................................................................ 17 
4.4 
End of Study Definition ..................................................................................................................... 17 
5 
STUDY POPULATION ................................................................................................................................ 17 
5.1 
Inclusion Criteria ................................................................................................................................ 17 
5.2 
Exclusion Criteria .............................................................................................................................. 18 
5.3 
Strategies for Recruitment and Retention ..................................................................................... 18 
6 
STUDY INTERVENTION ............................................................................................................................ 18 
6.1 
Study Intervention(s) Administration .............................................................................................. 18 
6.1.1 
Study Intervention Description ..................................................................................... 18 
6.1.2 
Dosing and Administration ........................................................................................... 18 
6.2 
PREPARATION/Handling/Storage/Accountability ....................................................................... 19 
6.3 
measures to minimize bias .............................................................................................................. 19 
7 
STUDY INTERVENTION DISCONTINUATION  PARTICIPANT               
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 19 
7.1 
Discontinuation of Study  ................................................................................................................. 20 
7.2 
Participation Termination .................................................................................................................. 20 
7.3 
Participant Discontinuation/Withdrawal from the Study ............................................................... 20 
7.4 
Lost to Follow-Up .............................................................................................................................. 21 
8 
Study Assessments and Procedures ........................................................................................................ 21 
Safety and Other Assessments .......................................................................................................................... 21 
8.1 
Efficacy Assessments ....................................................................................................................... 21 
8.2 
safety and other assessments ......................................................................................................... 24 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 25 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 25 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 25 
8.3.3 
Classification of an Adverse Event ............................................................................. 25 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 26 
8.3.5 
Adverse Event Reporting.............................................................................................. 27 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 27 
8.3.7 
Reporting Events to Participants ................................................................................. 28 

  
IGHID 12021 – UNC CCP RCT 18 November-2020_v3.1 
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8.4 
New safety information ..................................................................................................................... 28 
8.4.1 
Definition of new safety information (NSI) .................................................................. 28 
8.4.2 
New Safety Information Reporting .............................................................................. 28 
8.4.3 
Reporting New safety Information to Participants..................................................... 29 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 29 
9.1 
Statistical Hypotheses ...................................................................................................................... 29 
9.2 
Sample Size Determination ............................................................................................................. 29 
9.3 
Populations for Analyses .................................................................................................................. 29 
9.4 
Statistical Analyses ........................................................................................................................... 29 
9.4.1 
SAfety analyses ............................................................................................................. 29 
9.4.2 
General Approach ......................................................................................................... 30 
9.4.3 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 31 
9.4.4 
Sub-Group Analyses ..................................................................................................... 31 
9.4.5 
Exploratory Analyses .................................................................................................... 31 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 33 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 33 
10.1.1 
Informed Consent Process ........................................................................................... 33 
10.1.2 
Study Discontinuation and Closure ............................................................................. 33 
10.1.3 
Confidentiality and Privacy ........................................................................................... 34 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 35 
10.1.5 
Key Roles and Study Governance .............................................................................. 35 
10.1.6 
Safety Oversight ............................................................................................................ 35 
10.1.7 
Clinical Monitoring ......................................................................................................... 36 
10.1.8 
Quality Assurance and Quality Control ...................................................................... 36 
10.1.9 
Data Handling and Record Keeping ........................................................................... 37 
10.1.10 
Protocol Deviations ....................................................................................................... 37 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 38 
10.1.12 
Conflict of Interest Policy .............................................................................................. 38 
10.2 
Abbreviations ..................................................................................................................................... 38 
10.3 
Protocol Amendment History ........................................................................................................... 40 
11 
REFERENCES ............................................................................................................................................. 42 
 

IGHID 12021 - A Randomized Study Comparing the Efficacy and Safety of CCP Hospitalized Patients  
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PROTOCOL TEAM 
Principal Investigator 
Luther A. Bartelt, MD 
Assistant Professor of Medicine, Department of 
Medicine 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
120 Mason Farm Road, 7314 Medical Biomedical 
Research Building, Campus Box (CB) 7032 
Chapel Hill, NC 27599-7032 
Phone: (919) 966-6152 
E-mail: luther_bartelt@med.unc.edu 
 
Co-Principal Investigator 
David M. Margolis, MD 
Professor of Medicine, Microbiology & Immunology 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
120 Mason Farm Road, 2060 Genetic Medicine 
Building, CB 7042 
Chapel Hill, NC 27599-7042 
Phone: (919) 966-6388 
E-mail: dmargo@med.unc.edu 
 
Co-Investigator  
David van Duin, MD PhD 
Associate Professor, Department of Medicine 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
120 Mason Farm Road, Bioinformatics, CB 7030 
Chapel Hill, NC 27599-7032 
E-mail: david_vanduin@med.unc.edu 
 
Statistician 
Sonia Napravnik, PhD 
Associate Professor of Medicine, Epidemiology 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
130 Mason Farm Road, 2nd Floor Bioinformatics 
Building, CB 7030 
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 966-3875 
E-Mail: napravs@med.unc.edu 
 
Clinical Program Manager 
JoAnn Kuruc, MSN, RN 
Clinical Program Director, The UNC Cure Center 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
130 Mason Farm Road, 2nd Floor Bioinformatics 
Building, CB 7030 
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 966-8533 
Fax: (919) 843-7625 
E-Mail: joann_kuruc@med.unc.edu 
 
 
 
 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonization Good Clinical Practice 
(ICH GCP), applicable United States (US) Code of Federal Regulations (CFR). The Principal Investigator will assure 
that no deviation from, or changes to the protocol will take place without prior agreement from the 
Investigational New Drug sponsor, funding agency, and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved 
in the conduct of this study have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the IRB for review and approval.  Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled.  Any amendment to the protocol will require review and approval by the IRB before 
the changes are implemented to the study.  All changes to the consent form will be IRB approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants who 
provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
 
A Randomized, Phase II Study Comparing the Efficacy and Safety of 
Standard versus High-Titer Anti-SarS-CoV-2 Neutralizing Antibody Plasma 
in Hospitalized Patients with COVID-19 
 
Study Description: 
This randomized, double-blinded, phase 2 trial will assess the efficacy and 
safety of anti-SARS-CoV-2 convalescent plasma in hospitalized patients 
with less than 8 days of symptoms. Eligible participants will receive 
institutional-guided standard-of-care (SOC) and ABO-compatible 
convalescent COVID-19 plasma (CCP). The CCP units will be tested for the 
presence of anti-SARS-CoV-2 antibodies and pre-assigned as high-titer 
(CCP1) or standard-titer (CCP2) in a 1:1 randomization. Participants and 
clinical investigators will be blinded to the CCP titer group identities. 
 
Participants will be randomized within 48 hours of admission to a COVID 
service and will receive convalescent plasma within 24 hours of 
randomization. At least two units of CCP will be transfused 4-24 hours 
apart on study Day 0. If available, a third unit may be administered. All 
participants will undergo a series of safety and efficacy assessments pre-, 
during, and post-transfusion. Samples for research will be collected on Day 
0 through Day 28, unless previously discharged. Additionally, after 
discharge, participants can provide longitudinal samples collected at 1, 3, 
and 6-month timepoints after the infusion.   
 
 
Objectives: 
 
Primary Objectives 
Evaluate the safety of high neutralization titer anti-SARS-CoV2 plasma in 
patients hospitalized due to COVID-19, compared to standard 
neutralization titer anti-SARS-CoV2 plasma. 
 
Evaluate the efficacy of high versus standard neutralization titer anti-SARS-
CoV2 plasma to decrease length of hospitalization stay among patients 
hospitalized due to COVID-19. 
 
Exploratory Objectives 
 
Evaluate the efficacy of high versus standard neutralization titer anti-SARS-
CoV2 plasma to improve clinical outcomes and mortality among patients 
hospitalized due to COVID-19. 
 
Evaluate the safety and efficacy of high vs. standard total antibody titer 
anti-SARS-CoV-2 plasma to increase survival and speed of hospital 
discharge in patients hospitalized due to COVID-19. 
 
Evaluate the safety and efficacy of high vs. standard antigen-specific titers 
of anti-SARS-CoV2 plasma to increase survival and speed of hospital 
discharge in patients hospitalized due to COVID-19. 

IGHID 12021 - A Randomized Study Comparing the Efficacy and Safety of CCP Hospitalized Patients  
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Compare length of hospitalization, clinical outcomes, and mortality among 
patients hospitalized due to COVID-19, who consented to concurrent UNC 
IRB approved observational studies but did not receive anti-SARS-CoV2 
plasma. 
 
Compare SARS-CoV2 viral recovery from anatomic sites in patients 
hospitalized due to COVID-19, who received high vs. low neutralization 
titer anti-SARS-CoV2 plasma. 
 
Compare anti-SARS-CoV2 total antibody, antigen-specific antibody, and 
neutralizing antibody titers at 28 days, 3 months, and 6 months in 
participants who received high vs. low neutralization titer anti-SARS-CoV2 
plasma. 
 
Compare biomarkers obtained for clinical care in patients hospitalized due 
to COVID-19, who received high vs. standard neutralization titer anti-SARS-
CoV2 plasma. 
 
Primary endpoint: 
 
 
 
 
 
Exploratory endpoints: 
The primary safety endpoint will be assessed by the cumulative incidence 
of serious adverse events (SAEs) at study Day 14. 
 
The primary efficacy endpoint will be assessed by days to hospital 
discharge (or discharge equivalent) following first dose of CCP.  
 
• 
Change in World Health Organization (WHO) ordinal clinical status 
scale while hospitalized and at Days 14 and 28 
• 
Change in National Early Warning Score (NEWS) while hospitalized and 
at Days 14 and 28 
• 
Days of supplemental oxygen or greater, days of NIV/high-flow oxygen 
or greater, days mechanical ventilation/ECMO while hospitalized and 
respiratory support at Days 14 and 28 
• 
In-hospital mortality 
• 
28-day mortality 
• 
Change in SARS-CoV-2 RT-PCR Day 0, 3 (+/-1), 7 (+/-1) (and/or 
discharge date), 21, and 28 (if still hospitalized) from nasopharyngeal, 
endotracheal, fecal, and blood specimens  
• 
Change in anti-SARS-CoV-2 total antibody, antigen-specific antibody, 
and neutralizing antibody titers on Day 28, 3 months, and 6 months 
 
Study Population: 
This study will enroll up to 150 men and women, aged ≥ 18 years of age, 
hospitalized with COVID-19 infection, and reporting less than 8 days of 
symptoms prior to admission to a COVID service. 
 
For the purpose of this study we define symptoms as self-reported fever 
or documented fever ≥ 38.0 °C (100.4 °F). 
 
Phase: 
Phase II 
 

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Description of 
Sites/Facilities Enrolling 
Participants: 
UNC Medical Center 
 
 
 
Description of Study 
Intervention: 
This randomized phase II study will assess the administration of at least 2 
units of CCP.  Participants will be randomized 1:1 to the blinded receipt of 
high or standard neutralizing SARS-CoV2 antibody on study Day 0.  Clinical 
investigators will also be blinded to the CCP titer group identities. 
Standard of care will be defined as current standard treatment for 
hospitalized patients.  
 
Study Duration: 
Up to 12 months 
 
Participant Duration: 
An individual participant may be in this study for up to 6 months. The 
study participant will complete the study at Day 28, but we would like to 
follow the participant if participant is able for up to 6 months following the 
transfusions for observation of immune response over time.  
 
 

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Up to 150:  Obtain informed consent. Complete screening; confirm eligibility; 
obtain  medical history. Analysis will be done when 56 enrolled and in receipt of 
CCP. Enrollment will continue through analysis. 
1.2 
SCHEMA 
 
Prior to 
 
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 3: 
Day 0  
 
 
 
 
 
 
 
Visits 4-9: 
Day 1, 3, 7 
14, 21, 28 
 
 
 
Visits 10 & 11: 
Day 49 and 
Month 3 
 
 
 
 
 
Visit 12: 
Month 6 
 
 
Perform baseline and enrollment clinical status assessments, risk assessment, 
examination, collect blood and mucosal epithelial lining fluid  specimens (as 
available) 
Administer convalescent plasma: 2 units (optional 3rd infusion) approximately 4 
to24 hours (prefer 4-8 hours) apart 
Perform follow-up clinical status assessments, examination, and collect research 
samples. 
Perform follow-up per schedule of activities, all clinical status assessments, 
examination, collect blood and mucosal epithelial lining fluid specimens (as 
available)  
Final Assessments 
Clinical status assessments,  
examination, and collect research 
samples  
Group 2 
CCP 2 (N=75) 
Enrollment/Randomization 
Group 1  
CCP 1 (N=75) 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening Visit 1  
Baseline, 
Enrollment 
Randomization
Study Visit 3 
(CCP Transfusion) 
Study Visit 4 
Study Visit 5 
Study Visit 6 
 
Study Visit 7 
(if hospitalized) 
Study Visit 8 
 (if hospitalized) 
Study Visit 9 
End of Study (EOS) 
Visit 10 
Outpatient 
Longitudinal  Visit  
Study Visit 11 
Outpatient 
Longitudinal  Visit  
Final Study Visit 12 
Outpatient 
Longitudinal  Visit  
Visit Day # 
-2 
-2 
to 0 
0 
1 
3 
7 
14 
21 
28 
49 
90 
180 
Visit Window in days 
 
 
 
 
+/- 1 
+/- 2 
+/- 2 
+/- 2 
+/- 7 
+/- 10 
+/- 14 
+/- 14 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics1 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history1  
X 
 
 
 
 
 
 
 
 
 
 
 
ABO typing ◊ 
X 
 
 
 
 
 
 
 
 
 
 
 
Record Admission ECG1 
 
X 
 
 
 
 
 
 
 
 
 
 
Confirmed SARS-CoV-2 infection 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Assign Partcipant ID (PID) 
X 
 
 
 
 
 
 
 
 
 
 
 
Assign Randomization ID (RID) 
 
X 
 
 
 
 
 
 
 
 
 
 
Administer CCP◊ 
 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication review 
 
X1 
 
X1 
X 1,8 
X 1,8 
X 1,8 
X 1,8 
X1,9 
X9 
X9 
X9 
Physical exam 
X1 
X1 
X1 
X1 
X 1,8 
X 1,8 
X 1,8 
X 1,8 
X1,9 
 
 
 
Height  
 
X1 
 
 
 
 
 
 
 
 
 
 
Risk Assessment  
 
X1 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X1 
X1 
X1 
X 1,8 
X 1,8 
X 1,8 
X 1,8 
X 1,9 
X9 
X9 
X9 
SOFA score 
 
X1 
X1 
X1 
X 1,8 
X 1,8 
X 1,8 
X 1,8 
X 1,9 
 
 
 
NEWS score 
 
X1 
X1 
X1 
X 1,8 
X 1,8 
X 1,8 
X 1,8 
X 1,9 
X9 
X9 
 
WHO Ordinal status 
 
X1 
X1 
X1 
X 1,8 
X 1,8 
X 1,8 
X 1,8 
X 1,9 
X9 
X9 
X9 
Adverse event assessment 
 
 
X1 
X1 
X 1,8 
X 1,8 
X 1,8 
X 1,8 
X 1,9 
X9 
X9 
X9 
Laboratory Procedures⸸ 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology1,2 
 
X 
X 
X 
X8 
X8 
X8 
X8 
X8 
 
X 
 
Coagulation1,2 
 
X 
X 
X 
X8 
X8 
X8 
X8 
X8 
 
 
 
Serum chemistry1,2 
 
X 
X 
X 
X8 
X8 
X8 
X8 
X8 
 
 
 
Pregnancy test 1,3 
X 
 
 
 
 
 
 
 
 
 
 
 
Mucosal Lining Fluids 4, 5 
 
 
X6,10 
 
X6 8 
X6,8,10 
X6,8 
X6,8 
X6,9 
X9,10 
X9,10 
X9,10 
Record Radiologic/Imaging 
assessment 1,7 
 
X 
X 
X 
X8 
X8 
 
 
 
 
 
 
Blood for Immunology & 
virologic assays 6 
 
 
X 
 
X8 
X8 
X8 
X8 
X9 
 
 
 
Blood for Immunology & 
virologic assay (optional study 
component) 5,10   
 
 
X 
 
 
X8 
 
 
X 
X 
X 
X 
# Identify the day of discharge day as # of days from Day 0. Complete a chart note based on the events required (and obtainable) per the next scheduled study 
visit. Collect remnant samples and data as available from this day. The collection of optional samples may or may not occur due to unknown nature of date 
and time of discharge.  
◊ Per Hospital policy and guidelines.  
⸸ Please reference the study-specific laboratory schedule of sample collections to verify all collections and amounts.  
1 Information abstracted from medical record, as necessary and if available.  
2 CBC, differential, PT/INR, PTT, d-dimer, fibrinogen, albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, AST, ALT, sodium, C-reactive protein, IL-6. Collect if testing results available through routine clinical care. 
3 Serum pregnancy test on all women less than 60 years of age.  
4  Mucosal Lining Fluids include: Nasal fluids (NP swab, and/or nasal epithelial lining strips (NELFS), Oral fluids (saliva), Intestinal (stool) and Respiratory 
(endotracheal secretions on intubated inpatient as available).   
5 Collections will be deferred if the participant refuses or is too clinically unstable to undergo sample collection. 
6 Collect remnant samples acquired for clinical care. Collect remnant NP swab if obtained within 48 hours prior to CCP transfusion, if available in McLendon Lab. 

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7 Chest x-ray and/or CAT scan (CT) chest if performed as part of routine clinical care. 
8 These samples and data will not be collected on participants once discharged from hospital. 
9  These data and samples will be collected from participants returning for outpatient visits.  
10 Collect samples for optional immunology research (page 23). 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Convalescent plasma has appeared to be of benefit for the treatment of certain infectious diseases, including 
infections from respiratory viruses. [1,2] Preliminary evidence indicates that CCP may possibly be of benefit for 
some patients with COVID-19, leading to improvement. [3,4]  
2.2 
BACKGROUND  
The current outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel virus that 
causes the clinically variable but often severe viral respiratory syndrome now known as COVID-19, is now a global 
pandemic that threatens the lives of millions of people across the world. As of April 16th, 2020, there have been 
632,548 confirmed cases and 31,071 deaths due to COVID-19 in the United States alone, with the former likely 
being a gross underestimate of the actual incidence and prevalence (U.S. Centers for Disease Control and 
Prevention [CDC] 2020). Reported mortality rates have demonstrated some variability between countries; 
however, all data to date indicate that SARS-CoV-2 is a highly infectious and lethal virus in the elderly population, 
as well as in patients with comorbidities that are exceedingly common in the U.S., and can in fact be fatal in 
patients of any age.  
 
Compounding the formidable natural course of SARS-CoV-2 is the absence of any pre-existing immunity to it in the 
human population and the resulting exponential growth of clinically severe infections. 
 
Current options for treatment 
Currently, the treatment of patients hospitalized with COVID-19 is supportive, ranging from supplemental oxygen 
to invasive ventilation in nearly 75% of those admitted to the ICU. [5] Multiple investigational therapies are 
currently under study in clinical trials; however, no therapy has been proven. Importantly, many of these 
therapies, including the RNA-dependent RNA polymerase inhibitor, remdesivir, that is effective in pre-clinical 
animal models [6], were not specifically developed to target SARS-CoV-2. Similarly, although hydroxycholoroquine 
might inhibit endosomal-mediated viral cellular injury, this agent is not specifically active against SARS-CoV-2. In 
addition, while anti-IL-6, anti-IL1β, and other monoclonal antibodies might attenuate disease severity by 
modulating cytokine release syndrome, the mechanisms of these agents are not expected to enhance innate or 
adaptive immune responses to promote viral clearance. Lastly, even if these agents are effective, the ability to 
mass-produce on a scale necessary to address this global pandemic is limited. SARS-CoV-2 is highly transmissible 
and is likely to spread in regions that may lack access to novel pharmaceuticals, but have existing blood donation 
and re-infusion capacity. 
 
Rationale for the use of CCP for the treatment of severe COVID-19 
COVID-19 convalescent plasma (CCP) represents the only current therapeutic option against SARS-CoV-2 that has 
the potential to augment virus-specific immune responses and is also scalable to deploy rapidly. The hypothesis 
for the efficacy of CCP is that plasma from COVID-19-recovered patients contains antibodies that are directed 
against, and could neutralize, SARS-CoV-2. This concept of passive antibody therapy is established in clinical 
practice through the use of intravenous immune globulin (IVIg). [7-9] IVIg provides concentrated passive antibody 
to augment humoral immunity and therefore can prevent and have therapeutic activity against some viral and 

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bacterial infections. Historically, plasma from recovered patients has been used to treat other viral respiratory 
infection outbreaks including SARS-CoV-1 and Influenza. [1, 10] 
Experience from SARS-CoV-1 shows that such convalescent plasma (CP) contains neutralizing antibodies to the 
relevant virus. [11] During 2009 H1N1, there was an 80% reduction in risk of death in severely ill patients who 
received CP versus controls who declined it (OR: 0.2, 95% CI: 0.06-0.69, P=0.011). [1] 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. [12] A systematic review of CP use in severe acute respiratory infections identified 32 studies between 
1919 and 2011 that collectively suggested a similar reduction in risk of death with this approach (OR: 0.25, 95% CI: 
0.14-0.45, I2=0%). [13] Although this historical using CP for viral outbreaks, CCP as a plausible intervention for 
COVID-19, randomized controlled trials are needed to establish the efficacy of CCP. 
Two uncontrolled case series encompassing 15 CCP-treated patients in China have been published. [3, 4] Both of 
these studies reported signs of clinical improvement days after receiving CCP in doses of either 1 unit (200 mL) or 
2 units (400 mL). There were no reports of harm. CCP-treated patients in one study were found to have lower 
levels of IL-6, IL-10, and TNFα compared to controls at corresponding timepoints, suggesting that CCP could 
potentially exert a dampening effect on the cytokine release syndrome (CRS) suspected to be involved in the 
pathogenesis of severe COVID-19. [3, 14] In another pilot study in Wuhan, China CCP collected from SARS-CoV-2 
positive patients 3 weeks following the onset of illness was used to treat patients diagnosed with ‘severe COVID-
19’ as defined by WHO Interim Guidance and the Guideline of Diagnosis and Treatment of COVID-19 National 
Health Commission of China. [4] Ten patients were treated with one dose of CCP (200ml, >1:640 titer by 
neutralization assay) at a median of 16.5 days (11-19.3 days) post-onset of symptoms. A COVID-19 positive control 
cohort was retrospectively identified and matched by demographics, comorbidities, and severity of illness. There 
were no serious adverse reactions or safety events recorded with convalescent plasma, including no reported 
transfusion-related reactions, transfusion-related acute lung injury, or antibody-mediated enhancement of 
infection. In the treatment group, there were 0 deaths, 3 discharges, and 7 patients improved, whereas there 
were 3 deaths and 7 patients who improved in the control group (p < 0.001). [4] In addition, 2 of 3 patients in the 
treatment on mechanical ventilation were weaned to high flow nasal canula, which was discontinued in one 
patient. There was a reduction in blood RNA viral load in 7 of 10 patients on day 6 post-convalescent plasma 
therapy as well as improvement in laboratory markers. There were also varying degrees of improvement in 
pulmonary lesions on chest CT after convalescent plasma therapy. In another case series from China, five severely 
ill patients with COVID-19, all on mechanical ventilation received convalescent plasma within 22 days of 
admission. [3] Temperatures normalized in 4 of 5 patients within 3 days, NEWS scores decreased, and there was 
improvement in oxygenation and Acute Respiratory Distress Syndrome (ARDS) resolution. All survived, with 3 
discharged home and 2 in stable condition. These reports suggest convalescent plasma may hold promise for 
ameliorating the severity of COVID-19 and deserves immediate investigation for this indication.  
Justification for a randomized FDA-standard versus high-anti anti-SARS-CoV-2 neutralizing antibody titer plasma 
design 
The therapeutic benefit of CCP is hypothesized to be due to the presence of high concentrations of antibodies 
that neutralize the virus. When present in high concentrations, these neutralizing antibodies interrupt viral 
replication and halt disease progression. [15] Data from China suggests that by 14 days after onset of symptoms 
from SARS-CoV-2, most patients have developed evidence of antibody responses. [16] Although this humoral 
immune response appears nearly universal, there is variability in the neutralizing properties of the serum of these 
individuals. In a study comparing total antibody to neutralizing antibody using serum neutralization assays, the 
presence of co-morbidities was associated with lower titers of neutralizing antibody at similar timepoints of the 
disease process. [17] Co-morbidities also associate with more severe COVID-19 outcomes and more prolonged 
viral shedding. [18]. This suggests that the ‘quality’ and/or quantity of neutralizing antibodies varies between 

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individuals. In addition, data from humoral responses in SARS-1 also demonstrates that specific antibodies persist 
for >3 months. [19] 
When used for therapy, the optimal dose of neutralizing antibody in plasma has not been well defined. Either 
under-dosing by using plasma with inadequate neutralizing antibody titer, or over-dosing could alter the safety 
and efficacy profile. A theoretical, but unproven complication of administering CCP is the phenomenon of 
antibody-dependent enhancement of infection (ADE). ADE occurs when cross-reacting antibodies and/or low 
levels of neutralizing antibody against a viral pathogen can paradoxically worsen the viral syndrome. Although the 
ADE phenomenon has not been described for COVID-19, this risk needs to be considered. [20] The clinical 
relevance of ADE has been best elucidated in dengue disease, wherein secondary infection by the dengue 
flavivirus can be considerably more severe than primary infection due to the enabling of viral entry into FcγR-
expressing cells by antibodies generated against the initial viral serotype. A recent study of a long-term pediatric 
cohort in Nicaragua suggests that this process occurs within a narrow window of pre-existing antibody levels, 
above which the patient is protected from clinically significant ADE. [21] Human coronavirus infection is not 
known to be clinically exacerbated by ADE, although ADE has been demonstrated to occur in a feline coronavirus 
model. [22] ADE has been demonstrated to occur in both SARS-CoV-1 and MERS-CoV infection in vitro via 
conformational change of the spike protein induced by neutralizing antibody ligation that triggers antibody-
dependent and non- endosomal viral entry into FcγR-expressing cells. In this model, enhanced viral entry can be 
overcome by higher antibody levels that saturate the FcγRs. [23] Although the historical data on CP use during 
past viral outbreaks do not suggest that ADE-mediated worsening of COVID-19 severity is likely to occur, these 
data nevertheless suggest that it remains a possibility, which adds further justification for an randomized control 
trial (RCT) design.  
Publications to date have infused CCP with neutralizing antibody titers ranging from ≥1:40 [3] to ≥1:640 [4] to 
treat COVID-19. The FDA has authorized the use of CCP on a compassionate use basis with a recommended 
minimum neutralizing antibody titer of ≥1:160 or ≥1:80 if rare ABO-type matching is required. While there is little 
evidence to establish a minimum effective neutralizing antibody titer for SARS-2, in a prospective cohort of 
patients with H1N1 who consented to CP with neutralizing antibody titer of ≥1:160, there was a significant 
reduction in mortality (20.0% vs 54.8%; P=0.01) and more rapid decline in respiratory tract viral loads when 
compared with patients who declined plasma. [1] In a Phase II study, a greater proportion of patients receiving CP 
with neutralizing antibody titer ≥1:80 in addition to standard of care, compared with standard of care alone, 
improved clinical status by day 7 (20% vs 38%; p=0.041). [2] A phase III, blinded randomized study compared CP 
with anti-influenza neutralizing antibody titer ≥1:80 given early after symptom onset, compared with low-titre CP 
(≤ 1:10), failed to show any significant benefit.  [24] All patients also received anti-viral therapy with oseltamivir, a 
drug with proven anti-influenza activity.  
A large number of patients with COVID-19 will receive CCP through the FDA authorized compassionate use 
mechanism. This registry should provide important safety data, and will be informative regarding efficacy; 
however, the level of evidence will not achieve that of a randomized control trial. Several have proposed to use 
fresh-frozen plasma (FFP) as a placebo. FFP as a placebo has the benefit of blinding, and addresses the possibility 
that components of CCP other than the neutralizing antibodies themselves could exert a therapeutic effect, which 
could favorably impact clinical outcomes. However, absent a standard of care arm, an FFP compared with CPP 
design will not allow for recognition of possible benefits from FFP. We therefore propose an alternative trial 
design that compares the FDA-recommended minimum titer of ≥1:160 with CCP containing very high titer 
neutralizing antibody ≥1:640. This allows all participants to receive potential benefit, while intentionally 
evaluating the paradigm the most beneficial component of CCP is neutralizing. Our study will also centralize the 
neutralizing antibody assay, which can be difficult to interpret across various assay methods. If high-titer-CCP 
rather than FDA-standard-titer CCP ultimately proves to improve clinical outcomes in the study population, it 
would provide support that clinical benefit would be attributable to the antibody present in the convalescent 
donor source, and not to components common to all donor plasma. A dose-dependent clinical benefit would 

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inform screening criteria for possible CCP donors, including inter-individual factors that might be identified as 
predicting high-neutralizing titer plasma as well as intra-individual factors such as time since viral diagnosis and/or 
viral clearance. Knowing how donor factors predict neutralizing antibody titer could help focus CCP collections to 
increase the likelihood of banking CCP with the maximum therapeutic potential. 
Given that the expected role of CCP is to leverage passive immunity to accelerate viral clearance, CCP would best 
be given early in the disease course. 50% of patients develop a humoral response within the first 7 days of 
symptoms. [16] It is therefore optimal to intervene with CCP at this earlier timepoint if possible. One potential 
side effect of passive antibody therapy, however, is interference in the development of humoral immunity in the 
host. This phenomenon is well-described in the setting of Measles vaccine responses in infants where-in the 
presence of maternal anti-measles antibodies attenuate post-vaccine seroconversion. [25] Thus, CCP at different 
titer ranges might not only have different dose-dependent effects during acute infection, but could differentially 
alter natural immune development during the convalescent period. It is not yet known whether natural immunity 
to SARS-2 is sustained. In the absence of an available vaccine, it is important to evaluate not only the effect of CCP 
during acute severe illness, but the potential resulting modulation in host-derived humoral immunity, and 
therefore risk of re-infection.  
There are limited data on use of convalescent plasma in pregnancy. A non-randomized comparative study that 
evaluated use of convalescent plasma for Ebola Virus Disease reported that eight out of 84 participants were 
pregnant and that mortality was 25% among pregnant women and 32% among non-pregnant individuals after 
receiving plasma treatment. [26] A case series of 4 Chinese patients, among whom one was pregnant, received 
convalescent plasma and had recovered from SARS-CoV-2 infection. [27] We do not have robust data of using 
convalescent plasma in pregnancy as most trials have excluded pregnant patients.  IVIg therapy, however, is safe 
to give during pregnancy and is often used in those with inflammatory disorder and/or autoimmune conditions. 
Given the limited experimental treatment options for women with SARS-CoV2, we will not exclude pregnant 
women from this trial. We will document the presence or absence of pregnancy prior to administering study 
product, and ensure that participants are informed if they are pregnant prior to receipt of CCP. 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
1. Risks of receiving CCP: 
Convalescent plasma represents a licensed blood product, for which the risks are well described. In a 
safety analysis of 5,000 patients treated with CCP, the risk of a severe transfusion reaction (c or d 
below) was less than 1% and no fatalities were attributed to CCP. The risks associated with the 
administration of plasma include but are not limited to the following transfusion reactions: 
a. allergic transfusion reactions (1- 3%),  
b. anaphylactic reactions (<0.01%),  
c. transfusionassociated circulatory overload (TACO) (1%),  
d. transfusion-related acute lung injury (TRALI) (<0.1%),  
e. hemolytic transfusion reactions (<1% or very rare), 
f. viral and bacterial infections (very rare or <1%), and  
g. febrile non-hemolytic transfusion reactions (<1%)  
 
Plasma is collected per FDA Guidelines. [28] There are additional FDA requirements for COVID-19 
plasma donations which include: 
a. Evidence of COVID-19 documented by a laboratory test either by: 
i. A diagnostic test (e.g., nasopharyngeal swab) at the time of illness 

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OR 
ii. A positive serological test for SARS-CoV-2 antibodies after recovery, if prior diagnostic 
testing was not performed at the time COVID-19 was suspected.  
b. Complete resolution of symptoms at least 14 days prior to donation. 
CCP units collected at the University of North Carolina’s (UNC) Blood Donation Center (BDC) will be 
tested for the presence of anti-SARS-CoV-2 antibodies prior to transfusion or units. 
 
There are several theoretical risks associated with the administration of convalescent plasma: 
a. Antibody-mediated enhancement of infection (ADE). ADE can occur in viral diseases, such as 
dengue and involves an enhancement of disease in the presence of certain antibodies. For 
coronaviruses, several mechanisms of ADE have been described, including the theoretical 
concern that antibodies to one type of coronavirus could enhance infection to another strain. 
[23] It may be possible to predict the risk of ADE in SARS-CoV-2 experimentally, as proposed 
for MERS. [23] Preliminary studies in the Baric and De Silva laboratories at UNC (unpublished) 
suggest minimal or no cross-reactivity between SARS-CoV-2 antibodies and other 
coronaviruses known to circulate in our community. Since the proposed use of convalescent 
plasma in the COVID-19 epidemic would rely on preparations with high titers of antibody 
against the same virus, SARS2-CoV-2, ADE may be unlikely. Available evidence from the use 
of convalescent plasma in patients with SARS-1 and MERS demonstrated it is safe [13] and 
there were no adverse effects in a pilot study of patients with COVID-19. [4] Nevertheless, 
caution and vigilance will be exercised to use clinical and laboratory measures to detect 
evidence of enhanced infection. 
b. Risk is that antibody administration to those exposed to SARS-CoV-2 may prevent disease but 
modify the immune response such that those who are treated may mount attenuated 
immune responses. This may leave them vulnerable to subsequent re-infection. Passive 
antibody administration before vaccination with respiratory syncytial virus attenuated 
humoral but not cellular immunity. [27] This will be investigated as part of this clinical trial by 
comparing early (first month) and late (up to 6 months) immune responses in those who 
receive standard of care and those who additionally received convalescent plasma. If 
responses differ, those with attenuated levels could be vaccinated against COVID-19 when a 
vaccine becomes available.  
 
There is also the risk that convalescent plasma may be ineffective. 
 
2. Risk of Blood Draw (<1%)  
Blood drawing may cause pain, bruising, and may infrequently cause a feeling of lightheadedness or 
fainting. Rarely, it may cause infection, vein irritation (called phlebitis) or blood clot at the site where 
the blood is taken. We will minimize risk by using aseptic technique and universal precautions.  
 
The risks to participants entailed by this study are minimal as research labs will be collected as part of 
the clinical care and other research studies, eliminating a separate collection and phlebotomy for 
these blood samples. This will also decrease the burden of large amount of extra blood collected on 
participants acutely ill.   
 
3. Risks of Intravenous (IV) Infusion  
Problems from use of an IV are generally mild and may include pain, bruising, minor swelling or 
bleeding at the IV site, and rarely, infection, vein irritation (called phlebitis), or blood clot. Risk will be 
minimized by using sterile technique and universal precautions.  
 

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The placement of an intravenous catheter can allow for the development of bacteremia because of 
the contact between the catheter and unsterile skin when it is inserted. This will be prevented 
through careful decontamination of local skin prior to catheter placement and through the use of 
infection control practices during infusion. Product contamination will be prevented by the use of 
aseptic technique in the pharmacy and universal precautions during product administration. 
 
4. Risk of Nasopharyngeal (NP) Swab, Oropharyngeal (OP) Swab, Nasal Swab, Nasal Strips and other 
body fluid collections  
Collecting a respiratory swab may cause transient discomfort. Collection of the nasal epithelial lining 
fluid via nasal swab or strips may cause transient discomfort or the very rare risk (<1%) of aspiration 
of the filter paper. Discomfort and risk will be minimized by using experienced clinical staff at each 
site, and samples will be taken at the same time as clinical samples in order to minimize these risks. 
Nasal strips and/or nasal swabs will be self-collected when possible by the participants.  
 
Collection of stool, endotracheal and saliva secretions is not expected to cause any excessive 
discomfort. Stool and saliva will be self-collected when possible by the participants. 
 
5. Unknown Risks   
New therapies can lead to unexpected, incidental findings that could have a potential effect on the 
participant’s health. Upon confirmation of a potential health or reproductive effect, the study team 
will notify participants impacted by the new information and will advise proper medical follow-up 
when indicated. If findings require more immediate medical attention, the study PI in conjunction 
with the study coordinator will assist participants in getting an appropriate medical care appointment.   
 
6. Risk of breach of confidentiality:  
Data gathered on study participants will include but not be limited to the following: their age, gender, 
race, laboratory-confirmed COVID-19 infection, and COVID-19 specific symptoms history. In the early 
phase of the epidemic, a COVID-19 diagnosis may carry significant stigma. Standard measures will 
ensure confidentiality of participants and data generated, as described later in the protocol. 
 
2.3.2 
KNOWN POTENTIAL BENEFITS  
The most important potential benefit is that CCP may reduce progression to respiratory failure in 
patients with COVID-19 and early respiratory symptoms, such as shortness of breath, cough, chest 
pain, and pulmonary infiltrates. The benefit of plasma is expected to result in improvements in 
symptoms, oxygenation, and preventing the need for mechanical ventilation and possibly reduced 
mortality, earlier hospital discharge, and better clinical outcomes. Based on historical experience with 
antibody administration, it is expected to be effective if administered relatively early in the disease 
course. [15] CCP was safe, appeared to reduce symptoms, and improved oxygenation in a non-
randomized open label study of patients with more advanced COVID-19 disease in Wuhan, China. [3, 
4] 
 
There may be no potential benefit of collection of samples other than the knowledge that one is 
helping advance science that may lead to understand ways to promote improved treatment. 
 
The experimental agent remdesivir may soon be available to some patients with COVID-19 via an 
expanded access program. While the clinical criteria to allow expanded access to remdesivir are not 
currently known, it is likely that many COVID-19 patients eligible for CCP may not be eligible for 
remdesivir. However, if patients are eligible for remdesivir and desire to receive CCP, to avoid 

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depriving them of a possible benefit, we will allow co-enrollment (if allowed by the remdesivir 
program). 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Given historical data showing convalescent plasma was safe and possibly effective in patients with 
SARS-1, [10, 13] and emerging data from China suggest it is safe and possibly effective in patients with 
severe COVID-19 along with the relative lack of other readily available therapeutic options for severe 
or life-threatening disease, the benefits of its use in those at high risk for severe disease outweigh the 
risks. 
 
However, for all patients in whom CCP administration is considered, a risk-benefit assessment will be 
conducted to assess all individual variables. This protocol proposes a randomized controlled trial to 
assess the efficacy of CCP in preventing respiratory progression in patients with COVID-19. A recent 
JAMA editorial by experts note the importance of randomized clinical trials to demonstrate efficacy of 
this approach and to change the course of the epidemic. [3] 
 
There are limited data on potential risks and/or benefits for pregnant women and possible effects on 
the fetus.  Pregnancy can cause changes in the coagulation and fibrinolytic systems and CCP may 
potentially benefit individuals by providing the coagulation factors.   
  
There is sufficient expectation that the proposed NP swabs, OP swabs, nasal swab, nasal 
strips,plasma, stool, endotracheal, saliva, and blood collections will be safe and well tolerated.  
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
Primary 
 
Evaluate the safety of high neutralization titer anti-SARS-CoV2 
plasma in patients hospitalized due to COVID-19, compared to 
standard neutralization titer anti-SARS-CoV2 plasma. 
Evaluate the efficacy of high versus standard neutralization titer 
anti-SARS-CoV2 plasma to decrease length of hospitalization 
stay among patients hospitalized due to COVID-19. 
The primary safety objective will be assessed 
by the cumulative incidence of serious adverse 
events (SAEs) at study Day 14. 
The primary efficacy endpoint will be assessed 
by days to hospital discharge (or discharge 
equivalent) following CPP first dose.   
 
Exploratory 
 
1. Evaluate the efficacy of high versus standard neutralization 
titer anti-SARS-CoV2 plasma to improve clinical outcomes and 
mortality among patients hospitalized due to COVID-19. 
 
 
 
 
 
 
 
 
1. Change in WHO ordinal clinical status scale 
while hospitalized and at Day 28 
 
Change in National Early Warning Score 
(NEWS) while hospitalized and at Day 14 and 
Day 28 
 
Days of supplemental oxygen (if applicable) 
while hospitalized at Day 14 and Day 28 
 

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OBJECTIVES 
ENDPOINTS 
 
 
 
 
 
 
 
 
 
 
 
2. Evaluate the safety and efficacy of high vs. standard total 
antibody titer anti-SARS-CoV2 plasma to increase survival and 
speed of hospital discharge in patients hospitalized due to 
COVID-19. 
 
 
3. Evaluate the safety and efficacy of high vs. standard antigen-
specific titers of anti-SARS-CoV2 plasma to increase survival and 
speed of hospital discharge in patients hospitalized due to 
COVID-19. 
 
4. Compare length of hospitalization, clinical outcomes, and 
mortality among patients hospitalized due to COVID-19, who 
consented to concurrent UNC IRB approved observational 
studies but did not receive anti-SARS-CoV2 plasma. 
 
5. Compare SARS-CoV2 viral recovery from anatomic sites in 
patients hospitalized due to COVID-19, who received high vs. 
standard neutralization titer anti-SARS-CoV2 plasma. 
 
 
 
6. Compare anti-SARS-CoV-2 total antibody, antigen-specific 
antibody, and neutralizing antibody titers at 28 days, 3 months, 
and 6 months in participants who received high vs. low 
neutralization titer anti-SARS-CoV2 plasma. 
 
 
7. Compare biomarkers obtained for clinical care in patients 
hospitalized due to COVID-19, who received high vs. standard 
neutralization titer anti-SARS-CoV2 plasma. 
Days of NIV/high-flow oxygen (if applicable) 
while hospitalized and at Day 14 and Day 28 
 
Days of Invasive ventilation/ECMO (if 
applicable) while hospitalized and at Day 14 
and Day 28 
 
In-hospital mortality 
 
28-day mortality 
 
 
2. Same as above 
 
 
 
 
3. Same as above 
 
 
4. Same as above 
 
 
5. SARS-CoV-2 RT-PCR on Day 0, 3 (+/-1), 7 (+/-
1) (and/or discharge date), 21, and 28 (if still 
hospitalized) from nasopharyngeal, 
endotracheal, fecal, and blood specimens 
 
6. Serum anti-SARS-CoV-2 total antibody, 
antigen-specific antibody, and neutralizing 
antibody titers on Day 28, 3 months, and 6 
months 
 
7. Lymphocyte and neutrophil counts, 
hematological and coagulation measurements 
(D-dimer, fibrinogen, PT), renal and liver 
function, and inflammatory markers (ferritin, 
CRP, and IL-6 if available) during 
hospitalization on Days 0, 1, 3, 7 (and/or day 
of discharge), 14, 21, and 28. 
 
 

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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This randomized, double-blinded, phase 2 trial will assess the efficacy and safety of anti-SARS-CoV-2 convalescent 
plasma in hospitalized patients with less than 8 days of symptoms. Symptoms for this study are defined as self-
reported fever or documented fever ≥ 38.0°C. 
We plan to enroll up to 150 participants and all will receive CCP. Participants will be randomized in a 1:1 ratio to 
receive institution-guided standard-of-care together with CCP of either high or standard titer of SARS-CoV2 
neutralizing antibodies.  Information collected following plasma administration will include adverse events, 
participant, demographics, clinical status and laboratory and radiographic data collected for routine clinical care, 
acute care resource utilization, and characteristics of the CCP administered. The study will undergo primary 
analysis when 56 participants are enrolled and received CCP. Enrollment will continue during the analysis period 
to provide potential for benefit to hospitalized persons as well as to increase enrollment number for additional 
analysis. Following primary analysis we will close the study if a conclusion can be made, or propose an additional 
analysis plan for additional enrollees. 
The study will also create a biobank of blood and mucosal lining fluids inclusive of nasal fluids (NP swab, and/or 
nasal epithelial lining strips (NELFS), oral fluids (saliva), intestinal (stool), and respiratory (endotracheal secretions) 
from hospitalized participants who received CCP early in the disease process. The study will collect samples prior 
to the first administration of CCP through 28 days following this transfusion participation through 6 months is 
optional. The study will primarily collect remnant blood and tissue samples on all participants during their 
hospitalization. We will collect real time samples on a subset of participants who agree to provide optional 
samples. 
 
Biospecimens will also be obtained at timepoints per SOA, section 1.3. The study will attempt to collect as many 
specimens as possible, understanding that many collections will not be possible due to COVID-19 restrictions, 
access, and participant’s clinical condition. The purpose of these biospecimens will be to  measure the relationship 
between administration of CCP and viral load dynamics (from blood, nasal/respiratory fluids, saliva, and stool), 
immune responses, and biological indicators of COVID-19 disease severity. Biospecimens will be used to study and 
develop research assays to understand the antibody and cellular responses to SARS-CoV-2 coronavirus after 
human infection. 
 
The study will collect data from hospitalized patients, who opted not to be on this study and whose data is 
captured in the UNC IRB Study #: 20-1095 entitled: IGHID 12018 - UNC COVID Cohort (UCC). 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Convalescent plasma collected from individuals who have recovered from a prior viral infection for the passive 
transfer of antibodies has been used at various times over the past century. There has been some evidence for 
benefit against hepatitis B, polio, measles, influenza, Ebola, and other pathogens. [12] Results from small case 
series during the prior MERS and SARS coronavirus outbreaks documented safety and faster viral clearance 
following convalescent plasma administration, particularly when given early in the disease course. Additionally, 
there is preliminary clinical evidence that suggests that convalescent plasma might provide benefit to individuals 
with SARS-CoV-2 infection and manifestations of COVID-19. [3, 4] Patients with COVID-19 who have received 
convalescent plasma in these reports also received various other therapies, including anti-virals, anti-bacterial, 
and immune modulators. The use of such empiric therapies is currently a common practice in medical centers 

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treating hospitalized patients with COVID-19. As such, the additional benefit and/or safety of convalescent plasma 
to local standard of care practices is unknown. Several current randomized control trials in hospitalized patients 
with moderate and/or severe disease are designed to compare the effect of convalescent plasma to non-
convalescent FFP. However, such a trial design cannot account for the effect of non-antibody components plasma 
that could modify the disease course. Based on the preliminary evidence of possible efficacy of convalescent 
plasma, and an expected evolution in local standard of care practices, this protocol is designed to ascertain the 
dose-dependent safety and efficacy of convalescent plasma with neutralizing antibody in standard compared with 
high titer range. In addition to standard of care in individuals with documented SARS-CoV-2 disease at acute care 
facilities who are within 8 days of onset of symptoms, defined as self-reported fever or fever ≥38.0 °C.  
The study design allows for the collection of blood and tissue samples for research to expand our ability to 
understand SARs-CoV-2 and the efficacy of CCP through the analysis of convalescent blood derived from different 
de-identified donors and the clinical and biological outcomes of patients treated with CCP. 
 
4.3 
JUSTIFICATION FOR DOSE 
Two units of plasma (approximately 200-250 mL each) containing anti-SARS2-CoV-19 antibodies at a minimum 
titer of 1:160 per May 1, 2020 FDA guidelines (https://www.fda.gov/vaccines-blood-biologics/investigational-new-
drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma) 
will be infused. Functional neutralization assays are performed at UNC-CH. Should functional neutralization assays 
not be available, an ELISA targeting SARS-2-specific IgG will be used as a surrogate to determine titer. ELISA is a 
widely available methodology and the de Silva and Baric laboratories at UNC-CH are cross-validating these two 
methods. For standard titer units, the neutralization assay titers will range from ≥1:160 ≤1:640  and for the high-
titer units the neutralization assay titers will exceed 1:640. 
Dosing is based on experience with previous use of convalescent plasma therapy in SARS-1 where 5 mL/kg of 
plasma at titer ≥ 1:160 was utilized. [10] For a 70 kg person, plasma volume is estimated at 2800 mL (40 mL/kg 
x70 kg) with baseline anti-SARS-CoV-2 titer of 0. For example, if protective titer was 1:25 and each unit had titer of 
1:160, ~250 mL can achieve this ([250/(2800)] x 1:160>1:25).  
 
4.4 
END OF STUDY DEFINITION 
The end of study is defined as participants completing study follow-up through Day 28, or had an adverse event ≥ 
Grade 3 related to study product or death occurring prior to Day 28. Optional outpatient follow-up visits extend 
through month 6 for observation of immune response over time.  
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
1. Age at least 18 years  
 
2. Ability and willingness of participant or Legally Authorized Representative (LAR) to give written informed 
consent. 
 
3. Laboratory confirmed diagnosis of infection with SARS-CoV-2 by PCR 
 
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• 
COVID-19 associated respiratory symptoms include but are not limited to: cough, 
shortness of breath, difficulty breathing, or sore throat  
• 
COVID-19 associated GI symptoms include but are not limited to: loss of taste, loss of 
sense of smell, diarrhea, nausea, or vomiting, 
 
Note: Respiratory and GI symptoms other than those listed above, must be noted as acceptable and 
signed by study PI or designee.    
 
5.2 
EXCLUSION CRITERIA 
1. Receipt of pooled immunoglobulin in past 30 days 
2. Current or prior enrollment in a SARS-CoV-2 antibody or T- cell therapeutic study. 
Note: Patients enrolled on other randomized controlled trials of pharmaceutical and/or non-
pharmaceutical interventions for COVID-and meeting eligibility criteria will not be excluded, as 
determined by study PI (or designee) on a case-by-case basis and as allowed by eligibility criteria of the 
other trials. 
3. Contraindication to transfusion or history of prior reactions to transfusion blood products. This may 
include religious or cultural objections to receiving blood products and transfusions.  
4. ABO-compatible titered plasma is not available 
5. > 10 days from noted COVID-related subjective or objective fever at randomization. Patients without 
subjective or objective fever, > 10 days from symptom onset as determined by study PI.  
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Patients eligible for this trial will be identified by their treating providers. Study coordinators will follow up with 
participants during their hospitalization and after discharge.  
6 
STUDY INTERVENTION  
Participants will be randomized in a 1:1 ratio to receive standard of care and study product (CCP) of high or 
standard titer. Standard of care will be defined as current standard treatment for hospitalized patients at 
respective study site. It is expected that standard of care may vary as advances are made in therapeutic options 
and data from ongoing trials becomes available. 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
ABO compatible CCP will be obtained from the Institution’s Transfusion Medicine Service. CCP will be 
administered 
according 
to 
standard 
hospital 
procedures 
per 
May 
1, 
2020 
guidelines 
(https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-
process-cber/recommendations-investigational-covid-19-convalescent-plasma). Plasma units will be 
labeled with an International Society of Blood Transfusion (ISBT) label.  
6.1.2 DOSING AND ADMINISTRATION 

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Two units (a total of ~ 400-500 mL) of plasma with antibodies to SARS-CoV-2 measuring a minimum 
neutralization titer of 1:160 as per May 1, 2020 FDA guidelines will be administered. The standard titer 
group will receive units ranging from ≥ 1:160 ≤ 1:640 and high-titer group will receive units exceeding 
1:640. Whenever possible, both units will be derived from the same donor. The 2 units will be 
administered between 4-24 hours apart, and preferentially between 4-8 hours apart when feasible. If 
available, a third unit from a matched donor may be infused. At the discretion of the treating physician, 
one unit may be administered if the patient experiences an adverse reaction after the first transfusion 
and/or is deemed to be at high risk of circulatory overload. 
1. CCP will be administered within 24 hours of randomization. 
 
2. CCP will be infused at rate per institutional guidelines/SOPs for the administration of plasma. 
 
3. Premedications may be given per institutional guidelines/SOPs for the administration of plasma. 
Pretreatment will be administered to minimize transfusion reactions (e.g., acetaminophen, 
diphenhydramine).  
 
4. If an AE develops during infusion, the infusion may be slowed or stopped per the treating provider’s 
decision per institutional guidelines/SOPs for the administration of plasma.. Most reactions to plasma 
transfusions are relatively minor and the infusions are generally continued. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
All convalescent plasma units will be prepared and stored per instiutitional SOPs as governed by the the FDA CFR 
Title 21. 
6.3 
MEASURES TO MINIMIZE BIAS 
 
Randomization 
Participants will be randomized 1:1 to one of two treatment arms:  
CCP1: SOC and high titer anti-SARS-CoV-2 antibody plasma 
CCP2: SOC and standard titer anti-SARS-CoV-2 antibody plasma   
Enrolled patients will be assigned to an arm using a permuted block randomization, with block size randomly 
varied between 2, 4, or 6. We will generate a list of random numbers using the SAS procedure PLAN.  
 
Blinding  
Study personnel, participants, providers and investigators will be blinded to treatment arm assignment. 
Clinical investigators will be blinded to identity of the group assignment (CCP1 or CCP2) that includes plasma with 
the higher neutralizing antibody end-point titer. 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
 
 
 

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7.1 
DISCONTINUATION OF STUDY  
Discontinuation of the study: The study sponsor, FDA, and IRB all have the right to terminate this study at any 
time. 
7.2 
PARTICIPATION TERMINATION 
 
Participants will be considered terminated if: 
 
consent was withdrawn by the participant,  
 
the study Principal Investigator discontinues the participant from study for severe lack of compliance,  
 
or the participant is lost to follow-up. 
 
7.3 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
1. Participants can terminate study participation and/or withdraw consent at any time without prejudice.  
2. Randomized participants who withdraw from the study will not be replaced. If participant withdrawal 
occurs prior to plasma transfusion, the participant will have inadequate data, and therefore “new” 
replacement participants can be enrolled.   
3. The investigator may withdraw participants if the investigator determines that continued participation 
in the study would be harmful to the participant. 
4. Under certain circumstances, an individual participant’s receipt of CCP will be prematurely or 
permanently discontinued. Specific events that will result in stopping a participant’s infusions in this 
study include: 
a. Failure to meet requirements established for safety 
b. Withdrawal from study  
c. Adverse event related to plasma administration  
d. Intercurrent illness that is not expected to resolve prior to the next scheduled transfusion 
which is assessed by the study PI or designee to require withdrawal of 2nd transfusion. 
e. Clinically significant reaction associated to plasma transfusion.  
f. Death  
 
If the study PI (or designee) decides that a participant should be withdrawn from further plasma transfusions, the 
protocol team must be alerted within 24 hours. All participants who discontinue treatments should comply with 
protocol-specified visits and follow-up as required by the protocol and evaluation by the study PI (or designee). 
The only exception to this requirement is when a participant withdraws consent for all study procedures. If a 
participant is withdrawn before completing the study, the reason for withdrawal must be documented 
appropriately in the study documents. 
 
Premature Discontinuation of Evaluations 
For participants who begin but do not complete both plasma infusions, the continued collection of virologic, 
immunologic, and other samples will be determined on a case-by-case basis in discussion with the protocol team.  
The ability to complete virologic and immunologic endpoint analysis will be determined on a case-by-case basis in 
discussion with the protocol team.  
 
 
 

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7.4 
LOST TO FOLLOW-UP 
 
Participants classified as lost to follow-up (LTFU) need to meet both of the following criteria:  
 
Failure to respond or reply to 3 documented phone contact attempts by the study staff, followed by  
 
Failure to respond to a certified letter sent to the address provided by the participant.  
Only after documentation of these failed attempts to connect with the participant, will they be determined to be 
LTFU. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES  
 
SAFETY AND OTHER ASSESSMENTS 
 
8.1 
EFFICACY ASSESSMENTS  
 
This section provides a general description of the procedures and assessments associated with this study. 
 
Informed Consent 
Prior to performing any study-related procedures or assessments, the investigator or study coordinator discusses 
the study with the potential participant (or their legally authorized representative) and obtains signed informed 
consent. This communication will be documented.  
 
Screening  
Screening for participant eligibility will be performed within 24 hours of hospital admission to a COVID service and 
within 24 hours of enrollment. Only those participants who meet all eligibility criteria specified in Section 5.1 
Inclusion Criteria and Section 5.2 Exclusion Criteria will be enrolled. A unique PID will be assigned during the 
screening visit.  
 
Baseline and Enrollment  
Assign risk assessment (refer to page 33)  and complete clinical status assessments using the WHO ordinal scale*, 
National Early Warning Score (NEWS)* [24], and SOFA* [29] at enrollment. Clinical status assessments will include 
calculations done at enrollment (within 24 hours prior to plasma infusion). Screening, enrollment, and 
randomization can occur on the same day provided eligibility criteria is met. 
As feasible, enrollment assessments will be performed by study coordinators or investigators. Given the nature of 
the COVID-19 pandemic, if hospital policies and/or PPE shortages prohibit in-person independent investigator 
physical exams and clinical status assessments, these parameters will be obtained by review of the electronic 
medical record (EMR). 
 
*These illness severity assessment scales and scoring tools are described and available in the study-specific  
procedures. 
 
Randomization   
Participants will be randomized to CCP1 or CCP2 at enrollment.   
 
CCP Transfusion  
Participants will be assessed on study Day 0 (pre-dose), and following transfusions per SOA (Section 1.3) while 
hospitalized and after discharge.  
 
 
 
 
 

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Other Assessments 
 
• 
Physical Examination (PE). Will be recorded as documented in the EMR by clinical care team during 
hospitalization. The PE at the Day 28 timepoint will be completed by PI, co-investigator, primary care provider, 
or appropriately licensed study staff, when possible.  
o Complete PE will include examination of skin, head, eyes, ears, nose, throat, lymph nodes, heart, 
chest, lungs, abdomen, extremities, and neurologic system.  
o The PE information obtained from the EMR (due to limitations imposed by COVID-19 restrictions) will 
be inclusive of system assessments as documented in the EMR and may not include all the 
information listed above. 
 
• 
Medical History 
Significant medical history in most cases will be obtained by the admitting physician upon hospital  admission. 
All concurrent medical conditions in the last 30 days and any significant medical conditions (e.g., 
hospitalizations, surgeries, prior medical history) should be collected as available in the participant’s medical 
record. Medical history obtained will include demographic information (e.g., date of birth, gender, race, and 
ethnicity, etc.), participant’s medical history, and medication history. This information can be obtained from 
the EMR as necessary.  
Participants will be asked if they have any cultural or religious objections to receiving CCP during this 
assessment.  
• 
Concomitant Medications 
At enrollment, document concomitant medications taken by participant prior to hospitalization through EOS.  
These medications can be recorded from the EMR and will include the following:  
1. Prescription medications 
2. Over-the-counter medications 
3. Herbal treatments/nutritional supplements 
4. Blood products 
5. Prior and current receipt of medications used as therapies for COVID-19 
 
• 
Signs and Symptoms Assessments  
At entry, all signs and symptoms, regardless of grade, that occurred within the 2 weeks before entry will be 
recorded as medical history. Assessment of adverse events (AEs) will be done at every study visit after the first 
unit of CCP is transfused. Post-transfusion signs and symptoms, Grade ≥ 2, will be recorded. All signs or 
symptoms, definitely, possibly, or probably related to study interventions, will be recorded, regardless of 
grade. Information will be obtained from EMR$. 
 
• 
Treatment Emergent Adverse Events  
An event that first appears during treatment, which was absent before or which worsens relative to the pre-
treatment state.  
 
• 
Vital Signs 
Vital signs (weight (as available), body temperature, pulse or heart rate, respiratory rate, and blood pressure) 
will be recorded according to the SOA and as recorded in the EMR. Repeat vital signs (EMR documented) may 
also be captured as necessary to elucidate the course of any untoward event or AE. 
 
• 
Electrocardiogram (ECG or EKG) – Collect from EMR, if available and completed as part of hospital admission.  
 
 

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• 
Routine Clinical Procedures  
The study will collect the following information per SOA (Section 1.3) when done as part of clinical care (and 
documented in EMR). The study will collect these results as available in the medical record.  
o Radiographic or other imaging assessments. As performed for routine clinical care. 
o Clinical laboratory evaluations for safety evaluation. Laboratory evaluations performed for routine 
clinical care (reference SOA for laboratory values to be assessed). Safety and clinically relevant labs 
will be performed at UNC McLendon Laboratories.   
 
• 
Special Assays or Procedures.  
Neutralization assays, antibody titer by ELISA and SARS-CoV-2 PCR will be performed at participating research 
laboratories at UNC-Chapel Hill.   
 
• 
Optional Outpatient Longitudinal Visits and Immunology Research Specimens 
Participants will be informed of the opportunity to provide optional immunology samples and/or remain on 
the study through 6 months.  
 
Participant options include the following:  
1. Agree to the collection of optional samples during hospitalization and Day 28 only.  
2. Agree to optional outpatient visits on Days 49, 90, and 180 with the collection of optional samples. 
3. Refuse optional outpatient visits and sample collections. 
 
This option will collect samples at 5 timepoints (Reference Study-Specific Laboratory Manual).  
The samples to be collected include:   
1. Blood samples  
a. The blood samples obtained will be used for measuring primary and memory B-cell responses 
to SARS-CoV-2 and the trafficking and longevity of antibodies after CCP infusion.  
b. Collect these samples at Days 0, 7, 28, 49, 90, and 180.  
i. Persons agreeing to optional sample collection, will have extra blood collected (up to 
37 mL) at the Day 28 visit.  
2. Mucosal lining fluid samples which include but are not limited to: nasal fluids (NP swab, and/or nasal 
epithelial lining strips (NELFS), oral fluids (saliva), intestinal (stool) and/or respiratory (endotracheal 
secretions).  
a. The NELF collection involves the use of two absorbent filter paper strips placed into the nares 
and held there for 2 minutes. The mucosal samples will be used to study the trafficking of 
antibodies in CCP to primary site of SARS-CoV-2 infection.  
i. Collect at Days 0, 7, 49, 90, and 180.  
b. The NP swab – collect only if participant agrees to the collection. Participant can refuse this 
sample and still be part of optional collections.  
i. Collect at Days 0 and 7.  
c. Saliva  
i. Collect at Days 0, 7, 49, 90, and 180. 
d. Stool  
i. Collect if participant is able to provide sample or sample available at inpatient visits 
(Days 0 and 7).  
ii. Collect at outpatient visits – provide participant with kit and directions for collection 
and storage of specimen prior to visits (Days 49, 90, and 180).   
 

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All participants are required to complete the Day 28 visit (inpatient or outpatient) and all samples will be 
collected at this visit (reference SOA). If unable to collect sample, document reason. Inability to collect sample 
or participant refusal to provide sample is allowed.  
 
There are optional sample collections during the Day 0 and 7 inpatient visits; the optional outpatient visits and 
sample collections include Days 49, 90 (3 month), and 180 (6 month).  The Day 28 collections are part of the 
main study and are not optional; however, those participants providing consent for optional samples, will 
have extra blood collected at Day 28.  
 
Specimens generated from these optional immunology samples will be analyzed in collaboration with other 
investigators. 
 
• 
End of Study Visit 
An End of Study (EOS) visit for the primary part of the study will occur at Day 28.  Participants will complete 
the EOS visit per the SOA but will be followed as necessary for acceptable resolution of clinical events related 
to the study product.    
 
• 
Final or Last Study Visit  
The Final Study Visit may occur approximately 6 months after the CCP infusion, depending on the participant 
consent to the optional outpatient visit as well as and can be based on the duration and severity of any 
ongoing, treatment related AEs. An individual participant will be considered to have completed the study if 
the participant was followed through their last protocol-specified visit/assessment. Participants who have a 
new clinical event related to the CCP will be followed on study until the clinical event is resolved or deemed 
stable and irreversible.  
 
• 
Biospecimens  
Biospecimens will be those obtained by the study for research purposes in addition to those collected as part 
of routine clinical care. All biospecimens will be used to address the aims of the study. The research assays will 
be collected from admission (when available) and at the research visits (per SOA, section 1.3). Research assays 
will be processed and stored in associated research laboratories. Additional details on collection, processing, 
storage, and shipping of laboratory samples will be provided in the Study Specific Manual. Appropriate 
selection and timely collection of high-quality specimens, proper storage procedures, and comprehensive 
diagnostic testing will ensure the quality of data.  Appropriate selection and timely collection of high-quality 
specimens, proper storage procedures, and comprehensive diagnostic testing will ensure the quality of data.  
Biosafety procedures will be as per local policy/guidance, in keeping with national and/or international 
regulations, and will be applied to the collection, storage, transfer, and laboratory handling of research 
samples. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
All clinical and laboratory information required by this protocol will be obtained from clinical testing done as part 
of routine clinical care. Some protocol indicated evaluations, not assessed as part of clinical care will be added on 
the labs drawn, when possible and requested by the PI. Otherwise, these labs will be documented as unobtained. 
We will not list these as protocol deviations as the severity of illness and SOC restrictions/isolation procedures 
resulting from COVID-19 infection prohibits additional PPE and possibly additional blood draws. All protocol 
required procedures will be in the source documents. 
 
Clinical Procedures for Safety 
• 
Plasma Administration 
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• 
Post Infusion Management 
Participant will be managed per Institutional standard operational policies and procedures. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Common Terminology Criteria for Adverse Events (CTCAE) Terms  
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. Each CTCAE 
v4.0 term is a MedDRA LLT (Lowest Level Term).. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
Any adverse event that results in any of the following outcomes: 
1. Death 
2. Life-threatening (immediate risk of death) 
3. Prolongation of existing hospitalization 
4. Persistent or significant disability or incapacity 
5. Important medical events that may not result in death, be life threatening, or require intervention or 
escalation of care may be considered a serious adverse event when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias, or 
convulsions that do not result in inpatient hospitalization. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
Grading of study adverse events will be assessed using CTCAE grading scale developed by National Cancer 
Institute (NCI), National Institutes of Health (NIH), https://evs.nci.nih.gov/ftp1/CTCAE/About.html 
8.3.3.1 SEVERITY OF EVENT 
The determination of seriousness, severity, and causality will be made by an on-site investigator who is 
qualified (licensed) to diagnose adverse event information, provide a medical evaluation of adverse 
events, and classify adverse events based upon medical judgment. This includes but is not limited to 
physicians, physician assistants, and nurse practitioners. All AEs will be assessed by the study clinician 
using a CTCAE grading system. 
 
1. Grade 1 or Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
2. Grade 2 or Moderate: minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*.  
3. Grade 3 or Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limited self care ADL** 
4. Grade 4 or Life-threatening; urgent intervention indicated.  
5. Grade 5 or Death related to AE 
 

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*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below.  
 
1. 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
2. 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
3. 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
4. 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship improbable 
(e.g., the event did not occur within a reasonable time after administration of the study 
intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
5. 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
8.3.3.3 EXPECTEDNESS  
The investigators will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
8.3.4 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 a study monitor. 
 

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Any medical condition that is present at the time that the participant is screened and prior to the CCP 
transfusion will be considered baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time after receipt of the study product, it will be recorded as an AE.  
 
Given the nature of severity of the underlying illness, participants will have many symptoms and 
abnormalities in vital signs and laboratory values. AEs and SAEs will be documented following the first 
administration of CCP.  All Grade 3 and 4 AEs will be recorded in the database in this trial. In addition, the 
following AEs will be reported: 
1. All AEs (≥ Grade 2) and SAEs resulting from study product administration will be documented and 
followed until resolution even if AEs extend beyond the study-reporting period. 
2. All AEs including local and systemic reactions related to the CCP transfusion but not meeting the 
criteria for SAEs will be documented. 
3. Any AEs leading to dose modification. 
 
Intermittent abnormal laboratory values or vital sign measurements common in the severely ill 
populations (such as electrolyte abnormalities, low blood pressure, hyperglycemia, etc.) that are part of 
the same clinical diagnosis (e.g., uncontrolled diabetic) can be recorded once with the worst grade for 
each adverse event, with the start and stops dates of the intermittent syndrome. If there is clear 
resolution of the event, and then recurrence, it should be treated as a separate adverse event.  
 
Resolution of an adverse event is defined as the return to pre-treatment status or stabilization of the 
condition with the expectation that it will remain chronic. At any time after completion of the study, if the 
investigator becomes aware of a SAE that is suspected to be related to study product, incident will be 
investigated and reported as required.  
 
IInformation to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All CCP-related AEs will be followed to adequate 
resolution. 
 
AE assessment during the optional outpatient visits will be documented only as they relate to the 
outpatient study procedures and events. All other medical events related to medical history will be 
recorded as medical history and not as an adverse event.  
 
8.3.5 
ADVERSE EVENT REPORTING  
Reporting will only be required for adverse events judged to be potentially or definitely related to the 
administration of the CCP.  
 
Events will be reported starting with the start date of the first transfusion through Day 21 while 
hospitalized. No AE assessment will be required after participant discharge, unless previously reported 
and being followed through resolution.  
 
 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING  
Reporting will only be required for serious adverse events judged to be potentially or definitely related to 
the administration of the CCP.  
 
All SAEs will be documented from the first administration of study product through Day 21. (Reference 
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The PI (or designee) will immediately report to the sponsor any serious adverse event, considered to be 
potentially related to the study intervention, and will include an assessment indicating a reasonable 
possibility that the study intervention caused the event. Study endpoints that are serious adverse events 
(e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the study intervention and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the event to the sponsor. 
 
All study-related serious adverse events (SAEs) will be followed until satisfactory resolution or until the 
site investigator deems the event to be chronic or the participant is stable. Other supporting 
documentation of the event may be requested by the US Food and Drug Administration (FDA) or study 
sponsor and should be provided as soon as possible. 
 
The study PI sponsor will be responsible for notifying the FDA of any unexpected fatal or life-threatening 
suspected adverse reaction potentially related to the study product as soon as possible, but in no case 
later than 7 calendar days after the PI initial receipt of the information.  In addition, the study PI must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
8.3.7 
REPORTING EVENTS TO PARTICIPANTS  
We would inform all study participants by letter or electronic messaging of any AEs determined by the 
Safety Monitoirng Committee to merit such notice.  
8.4 
NEW SAFETY INFORMATION  
 
8.4.1 
DEFINITION OF NEW SAFETY INFORMATION (NSI) 
The Office for Human Research Protections (OHRP) considers NSI involving risks to participants to include, 
in general, any incident, experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 
 NEW SAFETY INFORMATION REPORTING  
The investigator will report any unanticipated NSIs related to the study product to the UNC Institutional 
Review Board (IRB) and the North Carolina Translational and Clinical Sciennces Institute (NC TraCS) Data 
and Safety Monitoring Board (DSMB). The NSI report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB study number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an NSI;  

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• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the NSI. 
 
NSI will be reported per the UNC IRB SOP for NSI reporting.  
 
8.4.3 
REPORTING NEW SAFETY INFORMATION TO PARTICIPANTS  
We would inform all study participants by letter or electronic messaging of any new safety information if 
it is determined by the UNC IRB to merit such notice.  
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
For the primary aim of assessing safety we will not perform any statistical testing. Analysis of adverse event data 
will primarily be descriptive. We anticipate that high and standard titer anti-SARS-CoV-2 convalescent plasma will 
be well tolerated. 
 
For the primary aim of assessing efficacy of high versus low titer anti-SARS-CoV-2 convalescent plasma, our 
primary hypothesis is that by providing high-titer anti-SARS-CoV-2 plasma, the duration of hospitalization will 
decrease as compared to the group receiving standard-titer plasma. 
 
9.2 
SAMPLE SIZE DETERMINATION 
The primary analysis will be done on a planned sample size of  56 participants, randomized in a 1:1 ratio to receive 
high-titer anti-SARS-CoV-2 convalescent plasma versus standard-titer CCP. Sample size estimation was based on 
having sufficient power to detect a clinically meaningful difference in time to hospital discharge comparing 
patients randomized to high versus low titer anti-SARS-CoV-2 convalescent plasma.  
 
For estimating sample size we tested the null hypothesis that a hazard ratio of high versus standard titer CPP was 
equal to 1, versus the alternative hypothesis that the hazard ratio of high versus standard titer CPP was not equal 
to 1. We assumed a median time to discharge of 14 days for the low titer group, a 0.01 probability of death during 
hospitalization and a pre-specified two-sided significance level of 0.05. With an anticipated enrollment for initial 
analysis of N=28 in each arm, N=56 total enrollment, we will have 80% power to detect a hazard ratio of 2.25 for 
time to discharge, corresponding to a probability of remaining hospitalized at Day 14 post-infusion of 0.50 for the 
low titer CPP group, and 0.21 for the high titer CPP group. Our power increases to 0.92 with increasing difference 
in probability of remaining hospitalized at Day 14 post-infusion of 0.35. Given uncertainty of hospitalization length 
of stay, inpatient mortality, and expected efficacy of high versus low titer CPP, we will actively monitor outcomes 
with ongoing accrual.  
 
9.3 
POPULATIONS FOR ANALYSES 
• 
Primary analysis: Intention-to-Treat (ITT) with 2 units of CCP 
• 
Exploratory analyses: Per-protocol analysis of CCP who received both doses prior to admission to ICU 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 
SAFETY ANALYSES 
Analysis of AE data will primarily be descriptive based on MedDRA coding of events. AE data will be 
compared between randomized arms using Fisher’s Exact Test. 

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For the safety endpoint, we will describe all study treatment-related AEs through the end of study 
approximately 24 weeks after getting their first infusion at Day 0. AEs will be coded to the Medical 
Dictionary for Regulatory Activities (MedDRA). Events prior to treatment (e.g., due to study-related 
procedures) will be listed separately in an appendix to the final clinical study report. The following tables 
of AE data will be created to summarize the number and percent of participants who experience at least 
one event of each of the following types: 
• 
All AEs 
• 
CCP-related AEs by severity grade 
• 
AEs by severity grade 
• 
All SAEs (this may be a listing if there are few events) 
• 
CCP-related SAEs 
• 
Fatal AEs (this may be a listing if there are few events) 
• 
AEs that result in study discontinuation 
• 
AEs that lead to withdrawal of study product 
• 
AEs with severity grade 3 or greater 
• 
CCP-related AEs with severity grade 3 or greater 
 
All of these tables will display the number and percent of participants that experience the given event and 
will display events by System Organ Class (SOC) and Preferred Term (PT). Events will be displayed 
alphabetically for SOC and in descending order of overall PT incidence within each SOC. 
 
9.4.2 
GENERAL APPROACH 
Statistical Analysis: Exploratory analyses are planned to evaluate pre-specified factors relevant to CPP 
administration, clinical course, and outcomes. Analyses will be intention-to-treat (ITT), with patients 
analyzed in their assigned arms regardless of compliance with the interventions. In addition to primary ITT 
analysis, we will conduct analyses that explore corrections for compliance with the interventions such as 
dose reduction (receiving only 1 unit instead of 2 due to a transfusion reaction after the first dose) in both 
arms to supplement ITT analyses with information on the actual intervention exposure while retaining the 
validity of the randomization-based inference. Categorical data will be presented in the form of 
frequencies and percentages. Continuous data will be provided with descriptive statistics, including mean, 
standard deviation, median, interquartile range, and full range. Ordinal data will be presented in the form 
of frequencies, median, and percentiles. We will use SAS version 9.4 or R version 4.0.0 for all analyses. 
 
Tests of Hypotheses:  Analyses of dichotomous outcomes by arm will be tested using a Chi-square test for 
proportions. As indicated, we will use nonparametric statistics including Fisher’s exact test to test for 
differences in proportions. Analyses of continuous outcomes by arm will be tested using t-tests, with the 
nonparametric alternative of Mann-Whitney U test used as indicated. For continuous outcomes we will 
assess normality, and as indicated rely on nonparametric tests. Additionally, we will consider re-
parametization and transformation based on the underlying distribution. Analyses of ordinal outcomes by 
arm will be tested using the Wilcoxon test.  
 
The difference in proportions will also be calculated as a measure of effect for dichotomous outcomes. 
For continuous outcomes, the difference in means or a nonparametric equivalent will be calculated as a 
measure of effect. The summary measure of effect for ordinal outcomes will be an odds ratio estimated 
using an ordinal logistic model. For all measures of effect we will calculate 95% confidence limits as 
measures of precision. For time to event analyses we will plot Kaplan-Meier curves and use the log-rank 
test to test for differences in time to event. Kaplan-Meier event rates at various time points with 2-sided 

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confidence intervals will be summarized. In addition, Kaplan-Meier estimates of quartiles (median, 25th 
and 75th percentiles) with 2-sided 95% confidence intervals will be calculated if applicable. All tests will 
be 2-sided with a pre-specified alpha of 0.05. 
 
Given the rapidly evolving COVID-19 pandemic, we are prepared to accommodate new knowledge and 
information and modify our proposed approach and analyses as indicated. 
 
9.4.3 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Event times for discharge from the hospital will be obtained in continuous time (days) from time 0 (day of 
infusion) until the first of date of hospital discharge or date when the patient was last at risk (right 
censoring time, including date of death). Our primary analysis will use the standard Kaplan-Meier 
estimate of the survival or cumulative incidence function. An unadjusted log-rank test will be used to test 
for differences between treatment groups. The proportional hazards regression model will be used to 
adjust for risk (high versus average risk), age (in years), sex, ABO type, levels 2-5 on the WHO ordinal 
outcome scale, and time from symptom onset in days, all measured at time 0. Cox proportional hazards 
regression models will be used to estimate unadjusted and adjusted hazard ratios as measures of effect, 
and 95% confidence intervals as measures of precision. We will assess model fit of the Cox model using 
log likelihood statistics and the proportionality assumption will be assessed relying on graphical analyses 
and statistical testing. If tests of the proportional hazards assumption do not apply, inferences will be 
obtained using robust sandwich estimators of standard error. Additionally, we may use alternate models, 
such as the proportional odds model, transformations of covariates may be considered or time effects 
may be included in the model.  
 
A Cox proportional hazards model with right censoring on death has a valid interpretation as the effect of 
the treatment assignment on the cause-specific hazard function for the event discharge from hospital. 
However, death prior to hospital discharge may be considered a competing risk, and treating deaths as 
right censoring may not be appropriate. In this case we will estimate the cumulative incidence of hospital 
discharge adjusting for the incidence of mortality. We anticipate a high level of completeness of data; 
however, in the event of missing data we will rely on stochastic multiple-imputation to account for 
missingness. Multiple-imputation provides unbiased estimates of the treatment effect and yields 
appropriate precision if data are missing completely at random, or under the weaker assumption that 
data are missing at random conditional on measured variables.  
 
9.4.4 
SUB-GROUP ANALYSES 
At the time of randomization, participants will be assigned to a clinical severity as floor status versus ICU 
status as determined by the treating physician. The primary analysis will include all participants. In the 
sub-group analysis, floor status participants will be analyzed separately from ICU status participants.  
 
9.4.5 
EXPLORATORY ANALYSES 
For exploratory analyses, logistic regression will be used to model dichotomous outcomes. For continuous 
outcomes we will use ordinary least squares regression and non-linear mixed models for modeling outcomes 
that are rare as indicated. For time to event analyses we will use proportional hazards models. All models will 
be adjusted for risk (high versus average risk as indicated below), age (in years), sex, levels 2-5 on the WHO 
ordinal outcome scale, and time from symptom onset in days, all measured at time 0. Adjusted measures of 
effect will be used as indicators of effect size and 95% confidence intervals as indicators of precision.  
 

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• 
Change in WHO ordinal clinical status scale while hospitalized and at Day 28: For the efficacy endpoint of 
the WHO COVID scale on each day of hospitalization beginning on day 0 (pre-infusion) and through Day 
28, we will compute probabilities related to the comparison of high versus standard titer CPP. The 
summary efficacy parameter will be an odds ratio (OR) from an ordinal logistic model, with OR>1 being 
favorable to high titer versus low titer when the ordinal WHO scale ranges from 1=death to 8=no evidence 
of infection. For the ordinal outcome scale, the proportional odds (PO) ordinal logistic semiparametric 
model is an ideal approach as it allows the distribution across the levels to be arbitrary. In addition to the 
dichotomous treatment assignment variable, the PO model will be adjusted for baseline risk factors (high 
versus average risk as indicated below), age (in years), sex, levels 2-5 on the WHO ordinal outcome scale, 
and time from symptom onset in days, all measured at time 0. 
 
• 
Change in National Early Warning Score (NEWS) while hospitalized and at Day 28 (linear regression) 
 
• 
Days of supplemental oxygen, NIV/high-flow oxygen, mechanical ventilation/ECMO while hospitalized 
and at Day 28 (linear regression) 
 
• 
Mortality at Day 28: (logistic regression)  
High risk:  
• WHO ordinal clinical status >4 or 
• ordinal scale ≤ 4 with any one of the following 
• 
≥60 years or age 
• 
immunocompromise (immunosuppressive drugs, solid tumor, solid organ transplant, hematologic 
malignancies, hematologic stem cell transplantation, rheumatological disease on 
immunosuppressants, inflammatory bowel disease on immunosuppressants, asthma or COPD on 
chronic steroid therapy, HIV+ with CD4 count <200 cells/µl) 
• 
diabetes mellitus 
• 
obesity  
• 
uncontrolled hypertension  
• 
cardiovascular disease 
• 
chronic pulmonary disease 
 
Average risk: <60 years of age AND absence any of the above high-risk factors 
 
• 
Analysis of the anti-SARS-CoV-2 titers  
Analysis of titers will primarily be descriptive, comparing the geometric mean titers (total antibody, antigen-
specific, and neutralizing antibody) at Days 0, 3 (+/-1 day), 7 (+/-1 day or at discharge), 21, 28, and at months 
3 and 6 between the randomized arms. It is also of interest to describe the entire distributions of anti-SARS-
CoV-2 titers by randomized arms and contrast these distributions. Therefore, we will use quantile regression 
to describe whether there is a shift or change in the titer distribution between randomized arms. Given that 
repeated measures of titers will be obtained, we will account for the correlation in measures within 
individuals using a cluster bootstrap in order to properly estimate the p-value and 95% confidence intervals.  
 
• 
Analysis of the rates, levels, and duration of SARS-CoV-2 RNA in NP swabs and other body fluids  
This exploratory analysis will be primarily descriptive. The proportion positive at Days 0, 3, 7, 21, and 28 days 
and whether individuals lose positive status at a subsequent time. To determine the proportion that are 
positive, we will do a pooled complementary log-log model in order to describe the cumulative incidence of 
SARS-CoV-2 positivity over time. The pooled complementary log-log model is a discrete time-to-event-analysis 
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goal of this secondary aim is to describe the distribution of SARS-CoV-2 RNA between randomized arms. 
Therefore, we will use the same approach as for the anti-SARS-CoV-2 titers. Because the exact day that an 
individual becomes negative is not known, a minimum and maximum amount of positive time will be used to 
describe the positive duration of each individual. If the sample is adequate, we will describe the duration of 
positivity using a non-parametric approach for time-to-event analysis. 
 
• 
Other biomarkers 
Testing results available through routine clinical care: CBC, differential, PT/INR, PTT, d-dimer, fibrinogen, 
albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, AST, ALT, sodium, C-reactive protein, and IL-6 on Days 0, 1, 3 (+/-1 day), 
6 (+/-1 day), 7 (or day of discharge), 14, 21, and 28. We will use the same approach as above.  
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant (and/or legally authorized representative) and written documentation of informed consent is 
required prior to starting any study procedures and study intervention/administering study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
All participants will be consented, either in person or using virtual options per UNC-CH IGHID Regulatory 
Standard Operating Procedure (SOP). The study can use Adobe Sign for consenting remotely and securely.  
The study team member will review the consent(s) with the potential participant over the phone after 
emailing them the password protected consent(s). Potential participants meeting eligibility criteria will be 
invited by the study team member to participate in the study. If participants express an interest in the 
study, the study will be explained in detail by a study team member during a telephone meeting or in 
person. If the participant agrees to participate in the study, they will electronically sign the study consent 
form(s) if done remotely or sign in writing if done in person.    
10.1.2  STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the Investigational New Drug (IND sponsor and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and funding sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance by participant to protocol requirements 

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• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the funding sponsor, IRB, and/or FDA. 
 
Halting Criteria for the Study: The study enrollment and study treatment will be stopped and an ad hoc 
review will be performed if any of the specific following events occur or, if in the judgment of the study 
physician, participant safety is at risk of being compromised: 
 
1. 
Death within one hour of plasma infusion 
 
2. 
Occurrence of a life-threatening allergic/hypersensitivity reaction (anaphylaxis), manifested by 
bronchospasm with or without urticaria or angioedema requiring hemodynamic support with pressor 
medications or mechanical ventilation, TRALI, TACO 
 
3. 
One participant with a study product-related SAE.  
 
4. 
Two participants with a Grade 3 or higher lab toxicity for the same parameter associated with study 
product. (Grading will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) 
grading scale developed  by NCI, NIH , https://evs.nci.nih.gov/ftp1/CTCAE/About.html) 
 
5. 
An overall pattern of symptomatic, clinical, or laboratory events that the Safety Monitoring 
Committee considers associated with study product and that may appear minor in terms of individual 
events but that collectively may represent a serious potential concern for safety. 
 
6. 
Any other event(s) which is considered to be a serious adverse event in the good clinical judgment of 
the responsible physician. This will be appropriately documented. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly upheld. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the IND sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the funding sponsor, representatives of the IRB, 
or other regulatory agencies may inspect all documents and records required to be maintained by the 
principal investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
 
The study participant’s contact information will be securely stored at the clinical study site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 

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Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored in the UNC School of Medicine secure server. This will not include the 
participant’s contact or identifying information. Rather, individual participants and their research data will 
be identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by research staff will be secured and password protected. At the end of 
the study, all study databases will be de-identified and archived.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified 
biological samples will be stored at the Shannon Wallet and Aravinda de Silva Laboratories for up to 5 
years.  These samples could be used to research the effectiveness of neutralizing antibodies against SARS-
2, antibody-dependent enhancement of COVID-19 and its complications and other conditions for which 
individuals with COVID-19 are at increased risk, and to improve treatment. The Shannon Wallet and 
Aravinda de Silva Laboratories will also be provided with a code-link that will allow linking the biological 
specimens with the phenotypic data from each participant, maintaining the blinding of the identity of the 
participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
When the study is completed, access to study data and/or samples will be provided through the Principal 
Investigator. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator  
Principal Investigator 
Co-Principal Investigator 
Luther Bartelt, MD 
David Margolis, MD 
University of North Carolina at 
Chapel Hill  
UNC-Chapel Hill School of 
Medicine   
7314A Medical Biomedical 
Research Building  
120 Mason Farm Rd., CB 7032 
University of North Carolina at 
Chapel Hill  
Chapel Hill, NC 27599-7032 
2016 Genetic Medicine Building 
120 Mason Farm Rd., CB 7042 
University of North Carolina at 
Chapel Hill  
Chapel Hill, NC 27599-7042 
919-966-6152 
919-966-6388 
luther_bartelt@med.unc.edu 
dmargo@med.unc.edu  
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of the NC TraCS DSMB. The NC TraCS DSMB will serve as the 
Independent Safety Monitoring Committee, composed of ndividuals with the appropriate expertise, 
including infectious diseases and pulmonary specialists, without conflict of interests, will be established. 
Members should be independent from the study conduct and free of conflict of interest, or measures 
should be in place to minimize perceived conflict of interest.  The DSMB will meet at least every 6 months 
to assess safety and efficacy data on each arm of the study. In addition, should any grade 3 or higher AEs, 

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SAEs, or deaths occur, these will be reported to the DSMB immediately. Reports from DSMB meetings and 
recommendations by the DSMB will be provided by the study team to the FDA and the IRB. 
 
10.1.7 CLINICAL MONITORING 
To ensure the safety of participants in the study, compliance with applicable regulations, and to ensure 
accurate, complete, and reliable data, the study PI will keep records of laboratory tests, clinical notes, and 
participant medical records in the participant files as source documents for the study. 
 
An independent study monitor will monitor the study on a regular basis throughout the study period 
according to the study monitoring plan. The study monitor periodically will conduct a review of a sample 
of the participant data recorded on source documents at the study site. The study PI and site study 
personnel must address all queries in a timely manner. 
 
Participation as an Investigator in this study implies acceptance of the potential for inspection by the 
study Sponsor/Funder and its Representatives, US or non-US government regulatory authorities, IRB, and 
applicable compliance and quality assurance offices. The study PI (or designee) will permit study-related 
audits and inspections and will provide access to all study-related documents (e.g., source documents, 
regulatory documents, data collection instruments, study data, etc.). The study PI will ensure the 
capability for inspections of applicable study-related facilities (e.g., IDS pharmacy, CTRC, etc.). 
 
Minimizing risk to participants 
Procedures to minimize risk to participants in the conduct of this study include: 1) informing participants 
about risks so they can recognize and report harms in partnership with the study team; 2) respecting 
local/national blood draw limits; 3) direct observation of participants after study treatment administration 
with CCP and collection of information regarding side effects for several days post product administration; 
4) having study staff properly trained in administering study procedures that may cause physical harm or 
psychologic distress, such as blood draws and infusions; and 5) providing study monitoring as applicable. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical study site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion.  The site will have a quality management plan 
describing their quality management. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the study site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial-related activities, source data/documents, and 
reports for the purpose of monitoring and auditing by the funding sponsor, and inspection by local and 
regulatory authorities. 
 
 
 

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10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
The clinical research staff is responsible for data collection under the supervision of the site PI (or 
designee). The study PI (or designee) is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
Hard copies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report form 
derived from source documents should be consistent with the data recorded on the source documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into a UNC School of Medicine Database, a 21 CFR Part 
11-compliant data capture system. The data system includes password protection and external quality 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development 
of the study intervention. These documents should be retained for a longer period, however, if required 
by local regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents no 
longer need to be retained. 
 
10.1.10 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Study Specific Procedures Manual requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site principal investigator to use continuous vigilance to identify, document, 
and report protocol deviations. All protocol deviations must be addressed in study source documents and 
reported to UNC IRB per their reporting requirements. The site principal investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. 
 

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10.1.11 PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
• 
NIH Public Access Policy, which ensures that the public has access to the published results of NIH-
funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise 
from NIH funds to the digital archive PubMed Central upon acceptance for publication. 
• 
NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information 
and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will 
be registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov, if required.  
• 
NIH Genomic Data Sharing Policy, which applies to all NIH-funded research that generates large-
scale human or non-human genomic data, as well as the use of these data for subsequent 
research. Large-scale data include genome-wide association studies (GWAS), single nucleotide 
polymorphisms (SNP) arrays, and genome sequence, transcriptomic, epigenomic, and gene 
expression data. 
 
10.1.12 CONFLICT OF INTEREST POLICY 
The University of North Carolina at Chapel Hill recognizes that conflicts of interest will arise from the 
research enterprise, from technology transfer activities, and from the many facets of our investigators’ 
professional activities. UNC seeks to identify and manage these conflicting relationships, restricting 
activities where necessary, to preserve transparency, independent decision-making, protection of 
research participants, and integrity of the educational experience. UNC’s Conflict of Interest Office   will 
have oversight over this study.  
10.2 ABBREVIATIONS 
 
ADE 
Antibody Mediated Enhancement of Infection 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ARDS 
Acute Respiratory Disease Syndrome 
ALT 
Alanine Transaminase 
AST 
Aspartate Aminotransferase 
BDC 
Blood Donation Center 
BUN 
Blood Urea Nitrogen 
CB 
Campus Box 
CBC 
Complete Blood Count 
CCP 
Convalescent COVID-19 Plasma 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
SARS-CoV-2 
CRF 
Case Report Form 
CT 
CAT scan 
CTCAE 
Common Terminology Criteria for Adverse Events 

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CTRC 
Clinical and Translational Research Center 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DRE 
Disease-Related Event 
DSMB 
Data and Safety Monitoring Board  
EC 
Ethics Committee 
ECG/EKG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Forms 
EMR 
Electronic Medical Record 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFP 
Fresh Frozen Plasma 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IGHID 
Institute for Global Health and Infectious Diseases  
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISBT 
International Society of Blood Transfusions 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
IV 
Intravenous 
IVIg 
Intravenous Immune Globulin 
LDH 
Lactate Dehydrogenase 
LSMEANS 
Least-Squares Means 
LTFU 
Lost to Follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCI 
National Cancer Institute 
NCT 
National Clinical Trial 
NC TraCS 
North Carolina Translational and Clinical Sciences Institute 
NEWS 
National Early Warning Score 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NIV  
Non-Invasive Ventilation 
NSI 
New Safety Information  

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OHRP 
Office for Human Research Protections 
OR 
Odds Ratio 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PID  
Participant Identification  
PO 
Proportional Odds 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SNP 
Single Nucleotide Polymorphisms 
SOA 
Schedule of Activities 
SOC 
Standard of Care 
SOFA 
Sequential Organ Failure Assessment Score 
SOP 
Standard Operating Procedure 
TACO 
Transfusion Associated Circulatory Overload 
TRALI 
Transfusion-Related Acute Lung Injury 
UNC 
University of North Carolina 
US 
United States 
WHO 
World Health Organization 
 
10.3 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a description of 
the change and rationale. A Summary of Changes table for the current amendment is located in the Protocol Title 
Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
2.0 
24 Aug 2020  
Modification to reflect changes in 
knowledge about disease entity 
and changes in care.  
 
2.0 
24 Aug 2020  
Modification to Schedule of 
Activities (SOA) 
Removed procedures and clinical 
assessments from screening visit 
to reduce unnecessary procedures 
until study eligibility confirmed  
2.0 
24 Aug 2020 
Modified text in protocol to clarify 
procedures related to sample 
collections and clinical 
assessments for study 
participation. 
Simplified and clarifiedprotocol 
procedures to:  
- identify hospital SOC 
procedures as separate from 
study procedures  
- clarify processes to allow 
modified participant contact 
and reduce unnecessary 
procedures 

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2.0  
24 Aug 2020 
Modification to the inclusion and 
exclusion criteria (sections 5.1 and 
5.2) to clearly define exclusionary 
criteria, especially with the 
initiating of other therapeutics for 
COVID-19 
To account for the development 
of new monoclonal antibody and T 
cells therapeutics since protocol 
inception.  
To define what numbers of days 
that are relevant for study 
exclusion. 
3.0  
30 Oct 2020 
Section 1.3 Schedule of Activities 
(SOA) and Section 8.1 Efficacy 
Assessments:   
Clarified text and collection time 
points related to samples. More 
clearly defined and identified 
study-required visits and samples 
from those that are optional.  
The former protocol version 2.0 
did not accurately identify the 
optional visits and samples, 
leading to a lot of confusion on 
which samples to collect and 
when.  
3.0  
30 Oct 2020  
Sections 1.3 and 8.1:  
Removal of Targeted Physical 
Exams  
The longitudinal visits are for 
sample testing. No clinical data 
required for study analysis. 
3.0  
30 Oct 2020  
Section 1.3 SOA:  
Removed urine from sample 
collections.  
Testing of these samples 
determined to be less important 
than the other epithelial lining 
samples. 
3.0  
30 Oct 2020  
Section 1.3 SOA:  
Changed pregnancy testing to 
include all women who are less 
than 60 years of age 
Since many participants are not 
clinically stable or able to answer 
questions, and medical records 
may not be available to support 
child bearing potential, pregnancy 
testing on all women < 60 years of 
age eliminated the need to ask  
family members personal health 
information on the participant.  
3.0  
30 Oct 2020  
Section 8.1 Efficacy Assessments:  
Broadened terms to avoid 
requiring testing (NP swab) that 
many participants do not want to 
have again. 
Many participants uninterested in 
having any additional NP swab 
samples taken if unnecessary.  
3.0  
30 Oct 2020 
Section 8.3 Adverse Events and 
Serious Adverse Events:  
Clarification of AE reporting 
Although intent of protocol 
remains unchanged, the language 
for grading was clarified due to 
the many confounding AEs that 
occur solely due to the severity of 
the illness and not related or 
associated with the CCP 
transfusions.  

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3.1  
18 Nov 2020 
Allow for continued enrollment up 
to 150 participants. Primary 
analysis will start when 56 
participants are enrolled with 
receipt of CCP.  
While the initial analysis of n=56 is 
ongoing, we will continue to enroll 
given the potential for benefit, 
and for expanded analysis. 
Following initial analysis we will 
make a conclusion and close the 
study, or offer an analysis plan for 
additional enrollees up to 150.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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