Comparison of the Efficacy and Safety of Human Coronavirus Immune Plasma (HCIP) vs. Control (SARS-CoV-2 Non-immune) Plasma Among Outpatients With Symptomatic COVID-19
Phase: PHASE2
Conditions: SARS-CoV 2
Sponsor: Johns Hopkins University

Convalescent Plasma to Limit Coronavirus Associated 
Complications: A Randomized, Double-Blind, Controlled, 
Phase 2 Study Comparing the Efficacy and Safety of Human 
Coronavirus Immune Plasma (HCIP) vs. Control (SARS-CoV-2 
non-immune) Plasma Among Outpatients with Symptomatic 
COVID-19. 
 
 
NCT 04373460 
 
Protocol 
November 4, 2021 (IRB approval date; notified 
November 9, 2021) 
 
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1. PROTOCOL SUMMARY 
 
Long Title: Convalescent Plasma to Limit Coronavirus Associated Complications: A 
Randomized, Double-Blind, Controlled, Phase 2 Study Comparing the Efficacy and Safety 
of Human Coronavirus Immune Plasma (HCIP) vs. Control (SARS-CoV-2 non-immune) 
Plasma Among Outpatients with Symptomatic COVID-19. 
Short Title: CSSC-004 
Clinical Phase: 2 
IND Sponsor: Johns Hopkins University 
Conducted By: Johns Hopkins University 
Sample Size: 1344 
Study Population: Ambulatory/outpatient subjects aged 18 years of age and older who are 
positive by molecular test for SARS-CoV-2 AND have at least one symptom of COVID- 
19. 
Study Duration: April 27, 2020 to December 31, 2022 
Study Products: 
Active Product: Human coronavirus immune plasma (HCIP): Plasma collected by 
apheresis from a volunteer donor who has recovered from COVID-19 and who has 
serum SARS-CoV-2 antibody titer ≥ 1:320 and after July 2021 meets FDA criteria 
for high titer plasma. 
Control Product: Plasma collected from a volunteer donor prior to January 1, 2020 will 
not be tested for SARS-CoV-2 antibodies. Plasma collected after December 31, 2019 
will be confirmed as SARS-CoV-2 seronegative. 
Study Design: 
This randomized, double-blind, controlled, phase 2 trial will assess the efficacy and safety 
of HCIP to reduce the risk of hospitalization or death, the duration of symptoms and 
duration of nasopharyngeal or oropharyngeal viral shedding. Adults 18 years of age or 
older, regardless of risk factors for severe illness may participate. A total of approximately 
1344 eligible subjects stratified 50:50 in the <65 vs > 65 age range will be randomized in a 
1:1 ratio to receive either HCIP or control plasma. 
The following will be assessed in all subjects: 
 Clinical measures of safety and efficacy: Day 0 (baseline) to Day 28 and 90. 
 Serum antibody titer to SARS-CoV-2: Day (-1 or 0), 14, 28 and 90 
 SARS-CoV-2 RNA levels in fluid from nasopharyngeal or oropharyngeal swabs: Day 
(-1 or 0), 14 and 28. 

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Primary Efficacy Objective: 
Evaluate the efficacy of treatment with HCIP in reducing hospitalization and death among 
outpatient adults who have molecular detection test-confirmed COVID-19 AND have 
developed any symptoms of COVID-19 including but not limited to fever, cough, or other 
COVID associated symptoms like anosmia. 
Primary Efficacy Endpoint: 
Cumulative incidence of COVID-19 related hospitalizations or deaths prior to 
hospitalization in treatment versus control groups by Day 28. 
Primary Safety Objective: 
Evaluate the safety of treatment with HCIP and control plasma in symptomatic outpatient 
subjects presenting with a positive SARS-CoV-2 molecular test. 
Primary Safety Endpoints: 
 Cumulative incidence of treatment-related serious adverse events (SAE) categorized 
separately as either severe transfusion reactions or Acute Respiratory Distress 
Syndrome (ARDS) during the study period 
 Cumulative incidence of treatment-related grade 3 and 4 adverse events (AE) during 
the study period 
Secondary Efficacy Endpoints: 
 Compare serum SARS-CoV-2 antibody titers between active and control groups at 
Days (-1 or 0), 14, 28 and 90. 
 Compare the rates and duration of SARS-CoV-2 RNA positivity (by RT-PCR) of 
nasopharyngeal or oropharyngeal fluid between active and control groups at days (-1 or 
0), 14 and 28. 
Tertiary Efficacy Endpoints 
 Compare the levels of SARS-CoV-2 RNA between active and control groups at days (- 
1 or 0), 14 and 28. 
 Compare time to hospital disease severity measured by ICU admission, invasive 
mechanical ventilation or time to death in hospital. 
 Assess rate of participant-reported secondary infection of household contacts 
 Compare blood oxygen saturation levels as measured by pulse oximetry (where 
available) between active and control groups through Day 28. 
 Assess time to resolution of COVID-19 symptoms based on temperature logs and 
symptom score sheets. 
 Assess treatment effect heterogeneity by age (as continuous variable). 
 Compare donor antibody titer to primary, secondary and tertiary endpoints 
Study Population: 
Inclusion Criteria for Enrollment: 
 ≥ 18 years of age 
 Competent and capable to provide informed consent 
 Positive molecular test for presence of SARS-CoV-2 in fluid collected by 
saliva for antigen, oropharyngeal or nasopharyngeal swab 
 Experiencing any symptoms of COVID-19 including but not limited to fever (T> 100.5º 
F), cough, or other COVID associated symptoms like anosmia. 

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 ≤ 8 days since the first symptoms of COVID-19 
 ≤ 8 days since first positive SARS-CoV-2 molecular test 
 Able and willing to comply with protocol requirements listed in the informed consent. 
 SARS-CoV-2 vaccine status can be either no vaccine receipt or vaccine receipt from day 
0 to 90 before onset of symptoms with a positive molecular test. (receipt of COVID-19 
vaccine does not exclude a participant with < 8 days of symptoms and a positive test. 
Exclusion Criteria: 
 Hospitalized or expected to be hospitalized within 24 hours of enrollment 
 Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of 
the principal investigator would affect subject safety and/or compliance 
 History of prior reactions to transfusion blood products 
 Inability to complete therapy with the study product within 24 hours after enrollment 
 Receiving any treatment drug for COVID-19 within 14 days prior to screening 
evaluation (monoclonal antibodies, , compassionate use or study trial related). Steroid 
treatment at any time does not affect study eligibility. 

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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ............................................................................................. 1 
TABLE OF CONTENTS .......................................................................................................... 4 
2. 
BACKGROUND AND SCIENTIFIC RATIONALE.................................................... 8 
2.1 
Experience with Use of Convalescent Plasma Against Coronavirus Disease .................. 9 
2.2 
Overview of Known Potential Risks ............................................................................. 9 
2.3 
Known Potential Benefits ........................................................................................... 10 
3. 
INVESTIGATIONAL PLAN ...................................................................................... 12 
3.1 
Study Objective and Endpoint .................................................................................... 12 
3.1.1 
Primary Efficacy Objective ................................................................................. 12 
3.1.2 
Primary Safety Objective .................................................................................... 12 
Evaluate the safety of treatment with HCIP and control plasma in symptomatic outpatient 
subjects presenting with a positive SARS-CoV-2 RNA test .................................................... 12 
3.1.3 
Secondary Efficacy Endpoint .............................................................................. 12 
3.2 
Definitions ................................................................................................................. 13 
3.3 
Study Population ........................................................................................................ 13 
3.3.1 
Inclusion Criteria ............................................................................................... 13 
3.3.2 
Exclusion Criteria .............................................................................................. 13 
3.3.3 
Subject Withdrawal ............................................................................................ 13 
3.3.4 
Randomization and Intervention ......................................................................... 14 
3.3.5 
Identification, Recruitment and Retention of Subjects .......................................... 14 
3.4 
Study Product ............................................................................................................ 18 
3.4.1 
Overview of Study Product ................................................................................. 18 
3.4.2 
Blood Centers..................................................................................................... 18 
3.4.3 
Control Arm Plasma ........................................................................................... 19 
3.4.4 
Rationale for Dosing .......................................................................................... 19 
4. 
STATISTICAL CONSIDERATIONS ......................................................................... 20 
4.1 
Sample Size and Power Considerations ...................................................................... 20 
4.2 
Statistical Analysis ..................................................................................................... 23 
4.2.1 
General Statistical Considerations...................................................................... 23 
4.2.1.5. Analysis of rates and duration of SARS-CoV-2 PCR Positivity ............................... 25 
4.3 
Endpoints................................................................................................................... 28 
5. 
STUDY PROCEDURES, EVALUATIONS AND SCHEDULES ............................... 30 
5.1 
Clinical Evaluations ................................................................................................... 30 
5.2 
Medical history .......................................................................................................... 30 

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5.2.1 
Physical Examination ......................................................................................... 30 
5.2.2 
Vital Signs .......................................................................................................... 30 
5.2.3 
Clinical (local) and Central Laboratory Evaluations .......................................... 30 
5.2.4 
Concomitant Medications ................................................................................... 31 
5.2.5 
Prohibited Medications ...................................................................................... 31 
5.2.6 
Hospital Rescue Treatments After Primary Endpoint .......................................... 31 
5.3 
Efficacy, Virologic and PK Measures ......................................................................... 31 
5.4 
Study visits ................................................................................................................ 32 
6. 
RISKS AND BENEFITS ............................................................................................. 36 
6.1 
Potential Benefits of treatment ................................................................................... 36 
6.2 
Definitions ................................................................................................................. 36 
6.3 
Reporting Processes ................................................................................................... 38 
7. 
SAFETY OVERSIGHT ............................................................................................... 40 
7.1 
Monitoring Plan ......................................................................................................... 40 
7.2 
Study Monitoring ....................................................................................................... 41 
7.3 
Halting Criteria for the Study ..................................................................................... 41 
7.4 
Special considerations for ARDS ............................................................................... 42 
7.5 
Planned Interim Analysis ........................................................................................... 43 
7.5.1 
Stopping guidelines ............................................................................................ 43 
7.6 
Rules for Halting Plasma Transfusion......................................................................... 44 
8. 
ETHICS/PROTECTION OF HUMAN SUBJECTS................................................... 45 
8.1 
Ethical Standard ......................................................................................................... 45 
8.2 
Institution Review Board ............................................................................................ 45 
8.3 
Informed Consent Process .......................................................................................... 45 
8.4 
Subject Confidentiality ............................................................................................... 48 
8.5 
Future Use of Stored Specimens ................................................................................. 48 
8.6 
Data Management and Monitoring ............................................................................. 49 
8.6.1 
Source Documents .............................................................................................. 49 
8.6.2 
Data Management Plan ...................................................................................... 49 
8.6.3 
Data Capture Methods ....................................................................................... 49 
8.6.4 
Study Record Retention ...................................................................................... 49 
REFERENCES ........................................................................................................................ 52 
APPENDIX A .......................................................................................................................... 56 

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List of Abbreviations and Definition of Terms 
 
AABB 
American Association of Blood Banks 
ADR 
Adverse Drug Reaction 
ADE 
Antibody-mediated enhancement of infection 
AE 
Adverse Event/Adverse Experience 
ARDS 
Acute Respiratory Distress Syndrome 
CCC 
Clinical Coordinating Center 
CDA 
Center for Clinical Data Analytics 
CDC 
United States Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendment of 1988 
COI 
Conflict of Interest 
COVID-19 
Coronavirus Disease 
C-RAC 
Community Research Advisory Council 
CRF 
Case Report Form 
CMP 
Comprehensive Metabolic Panel 
CRMS 
Clinical Research Management System 
DCC 
Data Coordinating Center 
DMC 
Data Management Center 
DMID 
NIH Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
her 
Electronic Health Record 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCIP 
Human Coronavirus Immune Plasma 
HCV 
Hepatitis C virus 
HEIC 
Hospital Epidemiology and Infection Control 
HIV 
Human immunodeficiency virus 
HTLV 
Human T-cell lymphotropic virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent (Informed Consent Form) 
ICH 
International Conference on Harmonization 

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ICU 
Intensive Care Unit 
ICTR 
Institute for Clinical and Translational Research 
IEC 
Independent ethics committee 
IND 
Investigational New Drug Application 
IRB 
Institutional review board 
ISBT 
International Society of Blood Transfusion 
ISM 
Independent Safety Monitor 
IWRS 
Interactive web response system 
MERS 
Middle East Respiratory Syndrome 
NYBC 
New York Blood Center 
OP 
Oropharyngeal 
PER 
Protocol Event Report 
PK 
Pharmacokinetic 
PPE 
Personal Protective Equipment 
SAE 
Serious adverse event 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SMC 
Safety Monitoring Committee 
TACO 
Transfusion-associated circulatory overload 
T. cruzi 
Trypanosoma cruzi 
TRALI 
Transfusion-related acute lung injury 
UP 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 
ZIKV 
Zika virus 

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2. BACKGROUND AND SCIENTIFIC RATIONALE 
There are currently no proven treatment options for coronavirus disease (COVID-19), 
which is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). 
Human convalescent plasma has been successfully used for prevention and treatment of 
other infections and thus may provide an option for treatment of COVID-19 and could be 
rapidly available from people who have recovered from disease and can donate plasma. 
Passive antibody therapy involves the administration of antibodies against a given 
infectious agent to a susceptible or ill individual for the purpose of treating an infectious 
disease caused by that agent. In contrast, active vaccination requires the induction of an 
immune response to the vaccine that takes time to develop and varies depending on the 
vaccine recipient. Some immunocompromised patients fail to achieve an adequate immune 
response. Thus, passive antibody administration, in some instances, represents the only 
means of providing immediate immunity to susceptible persons and more predicable 
immunity for highly immunocompromised patients. 
Passive antibody therapy has a storied history going back to the 1890s. It was the inaugural 
form of antimicrobial therapy and the only way to treat certain infectious diseases prior to 
the development of antimicrobial therapy in the 1940s1, 2. Experience from prior outbreaks 
with other coronaviruses, such as SARS-CoV-1 shows that convalescent plasma contains 
neutralizing antibodies to the relevant virus3. In the case of SARS-CoV-2, the anticipated 
mechanism of action by which passive antibody therapy would mediate protection is viral 
neutralization. However, other mechanisms may be possible, such as antibody dependent 
cellular cytotoxicity and/or phagocytosis. Convalescent serum was also used in the 2013 
African Ebola epidemic. A small non-randomized study in Sierra Leone revealed a 
significant increase in survival for those treated with convalescent whole blood relative to 
those who received standard treatment4. 
The only antibody type that is currently available for immediate use is that found in human 
convalescent plasma and monoclonals. As more individuals contract COVID-19 and 
recover, the numberof potential donors will continue to increase. 
When used for therapy, antibody is most effective when administered shortly after the onset 
of symptoms. The reason for temporal variation in efficacy is not well understood but could 
reflect that passive antibody works by neutralizing the initial inoculum, which is likely to 
be much smaller than that of more established disease. Another explanation is that antibody 
works by modifying the inflammatory response, which is also easier during the initial 
immune response, which may be asymptomatic5. As an example, passive antibody therapy 
for pneumococcal pneumonia was most effective when administered shortly after the onset 
of symptoms and there was no benefit if antibody administration was delayed past the third 
day of disease6. 
For passive antibody therapy to be effective, a sufficient amount of antibody must be 
administered. When given to a susceptible person, this antibody will circulate in the blood, 
reach tissues and provide viral neutralization. Depending on the antibody amount and 

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composition, the viral neutralization conferred by the transferred immunoglobulin can last 
from weeks to months. 
2.1 
Experience with Use of Convalescent Plasma Against Coronavirus Disease 
In the 21st century, there were two other epidemics with coronaviruses that were 
associated with high mortality, SARS-COV-1 in 2003 and MERS in 2012. In both 
outbreaks, the high mortality and absence of effective therapies led to the use of 
convalescent plasma. The largest study involved the treatment of 80 patients in Hong 
Kong with SARS7. Patients treated before day 14 had improved prognosis defined by 
discharge from hospital before day 22, consistent with the notion that earlier 
administration is more likely to be effective. In addition, those who were PCR positive 
and seronegative for coronavirus at the time of therapy had improved prognosis. The case 
fatality rate was 12% (n=80) with convalescent plasma and 17% (n=1755) without 
convalescent plasma in historic controls*. There is also some anecdotal information on 
the use of convalescent plasma in seriously ill individuals. Three patients with SARS in 
Taiwan were treated with 500 ml of convalescent plasma, resulting in a reduction in 
plasma virus titer and each survived8. Three patients with MERS in South Korea were 
treated with convalescent plasma, but only two of the recipients had neutralizing antibody 
in their plasma9. The latter study highlights a challenge in using convalescent plasma, 
namely, that some who recover from viral disease may not have high titers of neutralizing 
antibody10. Consistent with this point, an analysis of 99 samples of convalescent sera 
from patients with MERS showed that 87 had neutralizing antibody with a geometric 
mean titer of 1:61. This suggests that antibody declines with time and/or that few patients 
make high titer responses. 
 
With Polio in the 1950s gamma globulin provided 80% protection from acquiring polio 
virus for 5 weeks11. In Argentine hemorrhagic fever the Case fatality rate was 1% (n=91) 
with convalescent plasma and 16% (n=97) without convalescent plasma12. During the 
Spanish flu 1918 pandemic the case fatality rate was 16% (n=336) with convalescent 
plasma and 37% (n=1219) without convalescent plasma13. For the H1N1 influenza in 
2009 the severe disease case fatality rate was 20% (n=20) with convalescent plasma and 
54% (n=73) without convalescent plasma14. 
It is also possible that other types of non-neutralizing antibodies are made that contribute 
to protection and recovery as described for other viral diseases15, 16. There are reports that 
convalescent plasma was used for therapy of patients with COVID-19 in China during the 
current outbreak (http://www.xinhuanet.com/english/2020-02/28/c_138828177.htm). 
Although few details are available from the Chinese experience and published studies 
involved small numbers of patients, the available information suggests that convalescent 
plasma administration reduces viral load and was safe. 
2.2 
Overview of Known Potential Risks 
Historical and current anecdotal data on use of convalescent plasma suggest it is safe in 
coronavirus infection. Therefore, the large number of exposed healthcare workers, public 
servants and first responders, in combination with the high mortality of COVID-19, 
particularly in elderly and vulnerable persons, strongly argue that the benefits of 

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convalescent serum outweigh its possible risks in high risk exposed individuals and/or 
those with early disease. However, for all cases where convalescent plasma 
administration is considered, a risk-benefit assessment must be conducted to assess 
individual variables. 
The theoretical risk involves the phenomenon of antibody-mediated enhancement of 
infection (ADE). ADE can occur for several viral diseases and involves an enhancement 
of disease in the presence of certain antibodies. For coronaviruses, several mechanisms 
for ADE have been described and there is the theoretical concern that antibodies to one 
type of coronavirus could enhance infection to another viral strain17. It may be possible to 
predict the risk of ADE of SARS-CoV-2 experimentally, as proposed for MERS. Since 
the proposed use of convalescent plasma in the COVID-19 epidemic would rely on 
preparations with high titers of neutralizing antibody against the same virus, SARS2- 
CoV-2, ADE may be unlikely. The available evidence from the use of convalescent 
plasma in patients with SARS-COV-1 and MERS18, and anecdotal evidence of its use in 
patients with COVID-19 (http://www.xinhuanet.com/english/2020- 
02/28/c_138828177.htm), suggest it is safe. Nevertheless, caution and vigilance will be 
required in for any evidence of enhanced infection. 
Another theoretical risk is that antibody administration to those exposed to SARS-CoV-2 
may avoid disease but modify the immune response such that those individuals mount 
attenuated immune responses, which would leave them vulnerable to subsequent re- 
infection. In this regard, passive antibody administration before vaccination with 
respiratory syncytial virus was reported to attenuate humoral but not cellular 
immunity19.This concern will be investigated as part of this clinical trial by measuring 
immune responses in those exposed and treated with convalescent plasma to prevent 
disease. If the concern proved real these individuals could be vaccinated against 
COVID-19 when a vaccine becomes available. 
Passive antibodies are derived from human plasma. The antibodies used in this study will 
be derived from plasma obtained from convalescent patients and will be subjected to 
testing protocols that are similar to those used by blood banks and transfusion services. 
However, as is the case with any biological product, there is a very small risk of 
allergy/anaphylaxis, transfusion related acute lung injury (TRALI), transfusion associated 
circulatory overload (TACO), passive transfer of potential unknown infectious agents or 
infections, or accidental receipt of an incompatible blood product. Most adverse effects 
are mild and transient including headaches, flushing, fever, chills, fatigue, nausea, 
diarrhea, blood pressure changes and tachycardia. Late adverse events are rare and 
include acute renal failure and thromboembolic events. 
2.3 
Known Potential Benefits 
A potential benefit is societal: If the time to viral clearance is faster, the risk of further 
transmission (R naught) might be reduced and the epidemic slowed. Convalescent plasma 
can be administered to those with clinical disease in an effort to reduce their symptoms 
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anticipated that antibody administration would be more effective in preventing disease 
than in the treatment of established disease. 
Given that historical and current anecdotal data on use of convalescent plasma suggest it 
is safe in coronavirus infection, the high mortality of COVID-19, particularly in elderly 
and vulnerable persons, suggests that the benefits of its use in those at high risk for or 
with early disease outweigh the risks. However, for all cases where convalescent plasma 
administration is considered, a risk-benefit assessment must be conducted to assess 
individual variables. 
 
3. INVESTIGATIONAL PLAN 
3.1 
Study Objective and Endpoint 
3.1.1 
Primary Efficacy Objective 
Evaluate the efficacy of treatment with HCIP in reducing hospitalization and death prior 
to hospitalization among outpatient adults who have molecular detection test-confirmed 
COVID-19 AND have developed any symptoms of COVID-19 including but not limited 
to fever, cough, or other COVID associated symptoms like anosmia. For CSSC-004, the 
following were put into the clinical events scale as hospitalization equivalents: 1) a stay 
of >24 hours for observation in an emergency department, field hospital, or other 
healthcare unit; 2) any receipt of O2 for >24 hours, outside of a hospital. 
Primary Efficacy Endpoint: 
Cumulative incidence of COVID-19 related hospitalizations or deaths prior to 
hospitalization in treatment versus control groups by Day 28. 
3.1.2 
Primary Safety Objective 
Evaluate the safety of treatment with HCIP and control plasma in symptomatic outpatient 
subjects presenting with a positive SARS-CoV-2 molecular test. 
Primary Safety Endpoint: 
1. Cumulative incidence of treatment-related serious adverse events categorized 
separately as either severe transfusion reactions or Acute Respiratory Distress 
Syndrome (ARDS) during the study period 
2. Cumulative incidence of treatment-related grade 3 and 4 adverse events during the 
study period 
3.1.3 
Secondary Efficacy Endpoint 
1. Compare serum anti-SARS-CoV-2 titers between active and control groups at days (- 
1 or 0), 14, 28 and 90 
2. Compare the rates and duration of SARS-CoV-2 RNA positivity (by RNA detection 
test) of nasopharyngeal or oropharyngeal fluid between active and control groups at 
days (-1 or 0), 14 and 28 

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3.1.4 Tertiary Efficacy Endpoint 
1. Compare the levels of SARS-CoV-2 RNA between active and control groups at days 
(-1 or 0), 14 and 28 
2. Compare time to hospital disease severity measured by ICU admission, invasive 
mechanical ventilation or time to death in hospital. 
3. Assess rate of participant-reported secondary infection of household contacts 
4. Compare blood oxygen saturation levels as measured by pulse oximetry (where 
available) between active and control groups through Day 28 
5. Assess time to resolution of COVID-19 symptoms based on temperature logs and 
symptom score sheets. 
6. Assess treatment effect heterogeneity by age (as continuous variable). 
7. Compare donor antibody titer to primary, secondary and tertiary endpoints. 
 
3.2 
Definitions 
1. Enrolled: From time consented to participate until designated as a screen failure or 
have either been discontinued from the study or completed it. 
2. Randomized: when a randomization number is assigned 
3. Screen Failures: signed informed consent, but then determined to be ineligible or 
withdraws before being randomized 
4. Discontinued: randomized, but then withdrawn by investigator or withdraws consent 
5. Completed: Subjects are considered completed when they are followed through to 
Day 90 or died before that. 
6. 6. Hospitalization Equivalent: a stay of >24 hours for observation in an ED, field 
hospital, or other healthcare unit or any receipt of O2 for >24 hours, outside of 
hospital 
3.3 
Study Population 
3.3.1 Inclusion Criteria: 
1. ≥ 18 years of age 
2. Competent and capable to provide informed consent 
3. Positive RNA molecular test for presence of SARS-CoV-2 in fluid collected by 
saliva for antigen, oropharyngeal or nasopharyngeal swab 
4. Experiencing any symptoms of COVID-19 including but not limited to fever (T> 
100.5º F), 
cough, or other COVID associated symptoms like anosmia. 
5. ≤ 8 days since the first symptoms of COVID-19 
6. ≤ 8 days since first positive SARS-CoV-2 molecular test 
7. Able and willing to comply with protocol requirements listed on the informed consent 
8. SARS-CoV-2 vaccine status can be either no vaccine receipt or vaccine receipt from day 0 to 
90 before onset of symptoms with a positive molecular test. (receipt of COVID-19 vaccine 
does not exclude a participant with < 8 days of symptoms and a positive test.. 

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3.3.2 Exclusion Criteria: 
1. Hospitalized or expected to be hospitalized within 24 hours of enrollment 
2. Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of 
the principal investigator would affect subject safety and/or compliance 
3. History of prior reactions to transfusion blood products 
4. Inability to complete therapy with the study product within 24 hours after enrollment 
5. Receiving any treatment drug for COVID-19 within 14 days prior to screening 
evaluation (monoclonal antibodies, off label, compassionate use or trial 
related). Steroid treatment at any time does not affect study eligibility. 
3.3.3 Subject Withdrawal 
1. Subjects can terminate study participation and/or withdraw consent at any time 
without prejudice. 
2. Randomized subjects who withdraw from the study will not be replaced. 
3. The investigator may withdraw subjects if they are lost to follow up, non-compliant 
with study procedures or if the investigator determines that continued participation in 
the study would be harmful to the subject or the integrity of the study data 
4. Discontinuation of the study: The study sponsor, FDA and IRB all have the right to 
terminate this study at any time. 
3.3.4 Randomization and Intervention 
1. Subjects will be recruited for enrollment into two age groups (<65 vs ≥ 65 years of 
age) of approximately equal number. 
2. Subjects within each age group will be randomized using an interactive web response 
system (IWRS) in a 1:1 ratio to receive HCIP or control plasma. 
3.3.5 Identification, Recruitment and Retention of Subjects 
To ensure the trial accrues and retains the number and diversity of participants required to 
assess the primary, secondary and tertiary endpoints, a recruitment and retention risk and 
needs assessment to identify areas of concern and opportunities for engagement will be 
conducted. We will use an ongoing evaluation process, which will include iterative 
feedback from the recruitment reports and study participants and will guide 
implementation activities and adapt as needed. Recruitment methods and intensity may 
be adjusted to achieve enrollment of roughly equal number of subjects into the two age 
groups. Overall, the trial will aim to enroll a trial cohort in which 50% are < 65 and 50% 
are ≥ 65 years old. Depending on the pattern of enrollment, overall and by site, the trial 
leadership may direct some or all sites to modify their recruitment procedures in order to 
achieve the desired age distribution of participants in the trial. 
Community Engagement 
For recruitment of community members, we will engage the Johns Hopkins ICTR’s 
Community Research Advisory Council (C-RAC), led by Cheryl Dennison Himmelfarb, 
PhD, MSN, RN, and the ICTR’s Recruitment Innovation Unit to provide feedback 
regarding community recruitment and retention. In partnership with the Recruitment 
Innovation Unit (RIC) of the CTSA, we have established a variety of recruitment 
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advertisements (ex. brochures, flyers, web pages, etc), direct-to-patient (ex. health system 
portal communications, waiting rooms, or clinical team referrals), and social and 
community networks (ex. social media, community events). Recruitment materials and 
scripts will be approved by the IRB prior to use. 
Broad Targeted Recruitment 
Research recruitment flyers and brochures have been created to be placed in public areas, 
including clinics, COVID-19 testing areas, and medical offices, as well as to be sent to 
local clinicians to share with eligible patients who may be interested in the study. These 
materials include the study website www.CovidPlasmaTrial.org as well as study email 
address. 
We have developed text for use on the ResearchMatch website 
(https://www.researchmatch.org/). Research Match is a secure online tool that matches 
potential participants with research studies. The study can also be found on 
www.clinicaltrials.gov (NCT#04373460) 
Around the country, state and local health departments have set up websites providing 
information on COVID-19 symptoms, treatment, and research opportunities. For 
example, the state of Maryland has set up a website, COVIDConnect 
(https://health.maryland.gov/covidconnect/Pages/Home.aspx). Among user choices is the 
option, “I’m interested in potential research or clinical study opportunities.” As of May 
20, 2020, 630 people have expressed interest in clinical trials and studies. Public interest 
in COVID-19 research is vital for effective and efficient study recruitment, and promotes 
local community stakeholder engagement. As a recruitment tool, we have created a study 
description which includes local study contact information to be posted on state, county, 
and city health department websites near our study sites. Participating study sites will be 
responsible for creating similar listings and for coordination with their state, county, and 
city health departments. 
At the Johns Hopkins site, we will list the study on a list of COVID-19 related studies, 
Trials@Hopkins, and handouts of study information, all created and maintained by the 
JHU ICTR. Local sites may list the study description on similar institutional sites, 
databases, or handouts, as per local institution guidelines and policies. 
At Johns Hopkins site, HOPE is an ICTR-maintained registry of COVID-19 studies. This 
study will be listed on the ICTR RIU website of enrolling studies for review by the 
general public. The ICTR will be using social media campaigns to drive people to this 
landing page highlighting how they can participate in COVID-19 studies. 
The study website address may be reached through the domain name 
www.CovidPlasmaTrial.org. This domain name points to the URL 
https://hopkinsinfectiousdiseases.jhmi.edu/research/convalescent-plasma-studies/. The 
website is hosted on the Johns Hopkins Infectious Diseases website. A script has been 
developed for the videotaping of Dr. David Sullivan describing the study. The video may 
be posted on the study website. Users will be directed to the website in our brochures, 
flyers, email auto reply, MyChart text, and ResearchMatch text. 

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Healthcare Provider Recruitment 
For targeted recruitment, we will make special efforts to recruit healthcare providers and 
staff who have tested positive for COVID-19. Having a vested interest in early treatment, 
while being exposed to numerous persons with COVID, we feel targeting this population 
will offer a rich pool of participants. We will take special precautions to not put undue 
pressure on this population to consent or continue participation. We will insure healthcare 
employees will not be recruited to enroll in research by their direct supervisor. The 
electronic medical records of healthcare workers will not be used as the initial general 
screening method for potential participants. The electronic medical records can be 
accessed after identification from the list of SARS-CoV-2 positives. To recruit healthcare 
providers, we also plan to place brochures and flyers in locations visited by healthcare 
workers in public spaces such as the cafeteria and public bulletin boards, as well as 
Digital Signage throughout the hospital. In addition, at Johns Hopkins site, we are adding 
a description of the study to the Healthcare workers list of studies maintained by the 
ICTR https://ictr.johnshopkins.edu/coronavirus/hcw-studies/ 
Direct to Patient Recruitment 
EHR-based Recruitment 
We will engage the Center for Clinical Data Analytics (CCDA) (or local equivalent) to 
search the EHR for codes related to COVID testing results and/or COVID illness for 
inpatient (if COVID-19 testing was done while an inpatient), outpatient and Emergency 
Department records. Additionally, referring physicians and Emergency Department 
providers who identify potential participants for the study will be a source of study 
recruitment. At Johns Hopkins, CCDA query of EPIC (local EHR system) will generate a 
daily list of patients who test positive for COVID-19. The list of SARS-CoV-2 positives 
can be other health care centers or testing sites that may refer test positive individuals 
interested in clinical research for contact. Patients meeting study eligibility criteria will 
be contacted by the study team. CCDA results may be used to send MyChart (or 
equivalent EHR-based communication) notifications to adult persons matching CCDA 
search criteria. Participants may also be recruited via other EHR systems (ex. CRISP) as 
per IRB approved IRB Waiver of HIPAA Privacy Authorization (Form 4). Participating 
study sites may use similar EHR-based recruitment methods in compliance with local 
regulations and practices regarding use and deployment as established by their local 
institutions. Recruitment letters, sample text, and other materials will all be approved by 
IRB prior to use. 
Direct Physician Referral 
To reach additional COVID-19 positive patients who may be tested at community testing 
centers (ex. VEIP stations, pharmacy parking lots, Urgent Care centers, etc) and not have 
available test results in EHR system, we plan to reach out to referring physicians directly 
to request that they share study information with their patients. We have created “Dear 
Doctor” letters which describe the study and will accompany study flyers or brochures. 
These materials will be emailed to local physicians who treat or refer patients for 
COVID-19 testing (ex. Primary care physicians, internists, pulmonologists, ENTs, 
geriatric specialists, etc) with a request to share forward the information to any patients 
who may be interested in and eligible for the study. Participating study sites will be 
responsible for contacting local physicians at their locations. 

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Digital Signage Displays 
To increase research participant recruitment, at Johns Hopkins site we will contract with 
the Department of Brand Management and Production, to display elements of our 
recruitment poster as digital signage on the electronic plasma screens at all locations 
throughout JH Medicine in the Baltimore and Washington metro areas. The poster will be 
included in a rotation of other JHMI messages. It will appear approximately three times 
per hour. The content of the digital poster is the same as the content of our printed 
brochure and will include IRB number and approval date, name of the PI, short 
descriptive study name, and study contact information. Multi-center study sites will be 
responsible for creating similar digital message (if applicable for their location), 
including local site contact information. 
Social and Community Network Recruitment 
Social Media outreach, such as Facebook, Twitter, CraigsList, etc., in our experience has 
proven to be an effective method of research recruitment. We propose several different 
iterations of a social media posting and/or paid ad, including photographs. Our social 
media outreach will include, but not be limited to Facebook and Twitter. A script has 
been developed for the videotaping of Dr. David Sullivan describing the study; the video 
may be posted on social media platforms. At Johns Hopkins site, we will utilize existing 
JH social media outlets, including but not limited to the JH ICTR, JHU SOM, BSPH, 
and SON. Multi-center study sites will be responsible for creating similar social media 
listings, with space for their local site contact information. 
Media resources such as newspaper advertisements, television news channel feature 
reports, radio public service announcements, etc. may be additional recruitment resources 
to be considered in the future. All such media advertisements will be approved by IRB 
and coordinated with local institution Media Relations team and/or Communications 
team to ensure compliance with institutional guidelines. 
Survey 
To supplement the need for a call center, yet capture participant contact information in 
response to our recruitment efforts, we are utilizing a HIPAA-compliant survey tool. The 
survey link will appear on our web page: www.CovidPlasmaTrial.org. Survey text is 
included in the IRB application. In addition to participant contact information, the survey 
solicits basic COVID-19 related questions to ascertain if the survey responder may be a 
potential candidate for study inclusion. Via the survey, participants will be provided with 
a list of participating study sites and their addresses, so that the participant may choose at 
which study site they wish to participate. If a participant’s residence is not within a 200- 
mile radius of a study site, the participant will be informed we do not have a study site 
near them, but to please contact their local hospital for potential COVID-19 research 
participation opportunities. The study team will have access to survey responses and will 
contact the potential participants who select their study site as location of participation. 
Pre-Screen/Screening 
Phone calls will be made by the study team to potential participants identified through 
EHR, registries, survey responses, direct physician referrals, and those individuals who 

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respond to research ads and recruitment materials. 
Study coordinators will maintain the Telephone Pre-Screening Log which will be used to 
record contact by persons interested in study participation. The log will record the subject 
name, screening number, and recruitment method and eligibility inclusion/exclusion 
criteria. The log will be reviewed on a regular basis to identify issues which limit 
inclusion. 
An IRB-approved Telephone Pre-Screening Script will be used to direct conversation 
with potential participants who respond to recruitment materials. Potential participants 
will be asked “how did you hear about the study” in an effort to gauge effectiveness of 
recruitment methods. 
The script provides information about the study and asks screening questions related to 
inclusion and exclusion criteria. If at the end of the interview it is determined the person 
may be a candidate for study enrollment, an in-person screening visit is scheduled. 
 
Potential participants will be encouraged to share study information and study contact 
phone number with friends/family who may be interested in participating in the study. 
The local study team will be responsible for participant attrition and missed visits. Team 
leaders will provide missed visit status reports including the reason why the visit was 
missed to the Data Coordinating Center (DCC). The DCC will compile reports to 
generate a master log of participant attrition and missed visits. This log will be monitored 
to guide and inform continuous process improvement. 
3.4 
Study Product 
3.4.1 Overview of Study Product 
Study product: The investigational product, HCIP, is anti-SARS-CoV-2 convalescent 
plasma. HCIP will be collected by apheresis from healthy adults identified as having 
recovered from COVID-19. Healthy adult donors with SARS-CoV-2 antibody titers ≥ 
1:320 by an FDA approved test will donate plasma to be used in the trial. After July 2021 
the new March 9 EUA for high titer hospital plasma may be used to qualify plasma for 
study use including Euroimmun ration >3.5. The antibody testing will be performed in a 
CLIA certified laboratory. Potential donors who meet these qualification standards will 
be referred to an FDA-registered blood center where donors will be evaluated according 
to current blood donation requirements; plasma will then be collected as fresh frozen 
plasma (FFP) or plasma frozen within 24 hours of phlebotomy (PF24). Plasma will be 
distributed to the participating study site’s hospital for blinding. 
Control plasma will be provided to the participating site’s hospital from FDA-registered 
blood centers as fresh frozen plasma (frozen within 8 hours) or plasma frozen within 24 
hours (PF24) collected prior to 1/1/2020 and will not be tested for SARS-CoV-2 
antibodies. Plasma collected after December 31, 2019 will be confirmed as SARS-CoV-2 
seronegative. 
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arm will receive a minimum of 175 ml of HCIP. Control arm will receive a minimum of 
175 ml of control plasma 
Both active and control products will be provided to the transfusion team in standard 
plasma unit bags, with a study specific ISBT label and will be identical in appearance. 
3.4.2 Blood Centers 
All activities pertaining to donor recruitment, enrollment, and collection and processing 
will initially take place at New York Blood Center/NYBC and/or other FDA-registered 
blood centers like Vitalant, American Red Cross or others. Subsequent donations may be 
obtained locally at FDA-registered blood centers, including Johns Hopkins/AAMC 
(detailed in protocol IRB00248402). 
 
3.4.3 Control Arm Plasma 
The control arm plasma follows identical collection and processing procedures but will 
have been collected from community blood donors prior to documented SARS-CoV-2 in 
the United States. Control arm plasma from collections prior to 1 January 2020 will not 
be tested for SARS-CoV-2 antibodies. Plasma collected after December 31, 2019 will be 
confirmed as SARS-CoV-2 seronegative. Fresh frozen plasma is safely stored for more 
than a year. We will secure sources for the ~750 doses necessary study at the outset. 
3.4.4 Rationale for Dosing 
Dose calculation is based on 1 unit (200-250 mL) of plasma with anti-SARS-CoV-19 
titers of >1:320 and 1 unit of standard control plasma. For the purposes of the proposed 
trial, we required titers ≥1:320. The current FDA Guidance (April 2020) recommends 
neutralizing antibody titers ≥ 1:160. A pilot study in China showed most (39/40) 
convalescent donors had titers ≥1:160 (Duan K, et al.medRxiv. 
2020:2020.03.16.20036145). On March 9, 2021 the FDA issued a new EUA for use of 
convalescent plasma for hospitalized patients restricting to high titer defined by Euroimmun ration 
greater than 3.5 as well as more than a dozen other tests 
(https://www.fda.gov/media/141477/download). In April 2021, serial communication 10 (CRMTS 
13251). The FDA agreed that the new high titer standard with a EUROIMMUN ratio greater than 
3.5 may be used to qualify plasma for study use going forward. 
A plasma dose of 200 mLs is 7% of the total plasma volume for a 60kg individual with 
titer reduction to about 1:15 after dilution into the recipient. 
Study Drug Administration 
 Plasma will be administered within 24 hours of enrollment. 
 Transfusions will be performed by qualified/skilled personnel in settings equipped to 
handle potential complications of transfusion. We have planned to administer 
transfusion of convalescent plasma in a hospital or ambulatory clinic setting. 
 Transfusion rate  500 mL/hour 
 Medicines to minimize mild transfusion reactions during occurrence (e.g. 
acetaminophen, diphenhydramine) may be given at the discretion of the investigator. 
 If an AE develops during transfusion, the transfusion may be slowed or stopped as per 

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investigator’s decision. 
 Management of transfusion-associated AE will follow AABB guidelines; anything 
more than a simple allergic transfusion reaction, the transfusion will be discontinued 
and investigated appropriately (i.e. per standard practice guidelines). 
 
 
4. STATISTICAL CONSIDERATIONS 
4.1 
Sample Size and Power Considerations 
The planned sample size for the trial is a total of 1344 (1280*1.05 to allow a 5% 
oversample) subjects with a target goal (but not binding) of at least an equal number 
among those <65 and ≥ 65 years of age (n=672) or a slight bias towards those ≥65 years 
of age (no more than 40%:60% ratio), randomized in a 1:1 ratio to HCIP vs SARS-CoV-2 
non-immune control plasma. 
To evaluate the power of the study, the following assumptions were made: 
1. The primary analysis will compare the efficacy of convalescent plasma in reducing 
the risk of hospitalization. We assume a one-sided Type I error rate (alpha) of 0.05 as 
we are interested in superiority and Type II error rate (beta) of 0.2. We also present in 
Table 1 below the sample size needed under 90% power. 
2. We assumed that the probability of hospitalization for those <65 years of age is 0.15 
and for those ≥65 years of age is 0.30 (data from CDC MMWR21). We then allowed 
the sample to be equally weighted among young to old (i.e., 50:50) as well as 40:60, 
30:70, and 20:80. Therefore, we weighted the age specific risk for hospitalization 
accordingly to determine the overall samples risk under control plasma. We want to 
ensure that there are both younger and older individuals represented in the trial so we 
can assess effect heterogeneity by continuous age as a tertiary objective. 
3. It is anticipated that very few of these subjects will be randomized and not start study 
plasma transfusion (and so be excluded from the primary analysis) or be lost to 
follow-up prior to resolution of symptoms (and so have missing data for the primary 
endpoint). 
4. Furthermore, we assume that the treatment effect of HCIP will be a reduction in risk 
between 15% and 60%. To estimate the sample size, we used the weighted age 
stratified risks and assumed this risk was by day 15 (such that the cumulative 
incidence for hospitalization or death prior to hospitalization no longer increases 
afterwards) for the controls and the treated group was the control risk reduced 
between 15 to 75%. Using these assumptions and data, we used an exponential model 
to identify the lambda parameter and the package ‘powerSurvEpi’ for the R statistical 
software was then used to calculate the sample sizes for these scenarios. 
5. In Table 1 below, we provide the total sample size according to three of the 
recruitment ratios of <65:≥65 years of age, 80 or 90% power, and three effect sizes of 
25%, 30% and 35% as percent reduction in the rate of hospitalization. In Figure 1 
below we provide under 80% power, the sample sizes needed to detect the treatment 
effect between 15 and 60% reduction in risk and according to different age 
recruitment ratios. In table 2 with inclusion of 268 (~300) subjects with a target of a 
minimum ratio of 50:50 for <65:≥65 years of age, we expect to detect at least a 50% 

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reduction in hospitalizations under 80% power. This is a 20% hospital rate in control 
and 10% in convalescent plasma treated. If the effect size in hospital rate reductions is 
40% than a sample size of 455 will be needed. An overall reduction in hospital rates 
from 20% to 10% necessitates a sample size of 268 with 80% power. 85 subjects will 
be the sample size for a reduction rate from 20% to 5%. 
 
6. Therefore, with a sample size of 1344 (1280*1.05 to allow for potential losses) with a 
target of a minimum ratio of 50:50 for <65:≥65 years of age, we expect to detect at 
least a 25% reduction in the rate of hospitalization under 80% power and a 30% 
reduction in rate of hospitalization with 90% power. From the curve in Figure 1, an 
overall reduction in hospital rates from 20% to 10% necessitates a sample size of 268 
with 80% power. Eighty-five subjects will be the sample size for a reduction rate 
from 20% to 5%. 
Table 1 
Sample sizes according to effect sizes, recruitment ratios of younger to 
older participants, and two levels of power 
 
Power: 
80% Power 
90% Power 
Hospital 
rate 
Reduction 
25% 
30% 
35% 
25% 
30% 
35% 
< 65: ≥ 65 
50:50 
1280 
864 
615 
1772 
1196 
852 
40:60 
1134 
767 
546 
1571 
1062 
757 
30:70 
1052 
712 
507 
1457 
985 
703 
Table 2 
Sample sizes according to effect sizes, recruitment ratios of younger to 
older participants, and two levels of power 
Power: 
80% Power 
90% Power 
Hospital 
rate 
Reduction 
40% 
50% 
60% 
40% 
50% 
60% 
< 65: ≥ 65 
50:50 
455 
268 
167 
630 
371 
232 
40:60 
404 
239 
149 
560 
331 
207 
30:70 
376 
222 
139 
521 
308 
193 
Figure 1 
Sample size by treatment effect for HCIP as a percent hospital rate 
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Note: Sample size by treatment effect for HCIP as a percent hospital rate reduction for four 
different ratios of recruitment of those <65 to ≥ 65 years of age. Hospital events are 20% in this 
figure. Assumed an exponential model, alpha of 0.05, power of 0.8, risk by day 15 is a weighted 
average of the age specific CDC data21. 
 
Sample Size Re-Estimation Plan 
Our original sample size calculation was based on assumptions reflective of the event rate 
and associated age distribution in the control population at the beginning of the 
pandemic. If the event rate in the control group differs from our assumptions during the 
design of CSSC-004, we may see a decrease in power. To reduce the risk of an 
underpowered study, we propose to conduct a sample size re-estimation at the first safety 
interim analysis (5% of participants completing 28-day follow-up) and again at 25% of 
participants completing 28-day follow-up. We propose to use the overall rate of the 
primary outcome for the purpose of sample size re-estimation. If this rate is lower than 
our assumptions for the sample size calculation, additional participants may be needed to 
achieve adequate statistical power. We will consult with the DSMB on any proposed 
changes to the sample size estimation. This decision will include considerations for safety 
data from CSSC-004 that will also be provided to the DSMB. The study team along with 
our collaborators at the Department of Defense will determine the feasibility of the 
increased sample size based on the availability of convalescent plasma and impact on 
funding. 

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4.2 
Statistical Analysis 
4.2.1 General Statistical Considerations. 
All subjects that enter the study will be accounted for in the final clinical report, whether 
or not they are included in the analysis. All reasons for exclusion will be documented for 
those subjects. For continuous variables, descriptive statistics will include the number of 
non-missing values, mean, standard deviation, median, minimum, and maximum. For 
categorical variables, descriptive statistics will include counts and percentages per 
category. Baseline values for all parameters will be the most recent value prior to 
administration of any dose of study product. SAS/STAT (release 15.1 or higher) will be 
used for the clinical data analyses. 
4.2.1.1 Analysis of AE Data 
All subjects who received any amount of study drug will be included in the safety 
population. A summary of all adverse events that were reported will be presented by 
Medical Dictionary for Regulatory Activities® (MedDRA®-version 23.0 or higher, March 
2020) coded (System Organ Class and Preferred Term) by highest severity. There will be 
one report by highest severity for each subject for that adverse event. Relationship to 
study treatment, action taken, event, and event outcome will be summarized within and 
across dosing groups. AE will be compared between randomized arms using Fisher’s 
Exact Test. 
Serious adverse events will be described in narratives that include subject demographics, 
treatment date, event, date of onset, relationship to study treatment and the descriptions of 
actions and outcomes during the event. Any deaths occurring in the study will be 
summarized in narrative with the demographics, treatment duration, cause of death, date 
of death and additional information surrounding that serious adverse event. Deaths, 
SAEs, and events resulting in study discontinuation will also be tabulated. 
Safety laboratory data will be transformed prior to analysis as defined in the SAP. 
Summaries and changes from baseline will be presented for each evaluation time point. 
Changes from baseline will also be presented using shift tables for selected laboratory 
parameters. 
4.2.1.2 Final Statistical Analysis Plan (SAP) 
A final SAP for the analysis and presentation of data from this study will be prepared 
before database lock. The following is an overview of planned analyses. 
4.2.1.3 Overview of Planned Analyses 
Primary endpoint: Our primary hypothesis is that by providing anti-SARS-CoV-2 
plasma, the cumulative incidence of hospitalization or death prior to hospitalization will 

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be lower than those receiving control plasma over the course of follow-up. Therefore, our 
analysis will be a time to event analysis examining the effect of anti-SARS-CoV-2 
plasma. We will estimate the survival function for each treatment arm in order to estimate 
the risk difference over time as well as the restricted mean survival time which is the area 
under the survival function and provides the expected mean time to hospitalization, as 
defined in section 3.2, or death up to time t22. Our approach will be to estimate the 
cumulative incidence using the doubly robust estimator based upon targeted minimum 
loss based estimator as described by Diaz et al (2019). Results of the analysis for the 
primary endpoint will be presented both as unadjusted (crude) and adjusted for 
covariates. By adjusting for baseline covariates that are related to the outcome, we 
increase precision. This TMLE based approach was shown to increase precision by 
around 10% to 20% over an inverse probability weighted or augmented inverse 
probability weighted estimator [Diaz 2019]. 
Variables chosen for adjustment are specifically for increasing precision in estimates of 
treatment efficacy and thus must be predictive of disease outcome [Diaz et al, Lifetime 
Data Anal (2019):25]. To identify the adjustment variables, we will utilize a hybrid 
approach of pre-specifying some variables and using an algorithmic approach to identify 
variables to adjust for among pre-specified candidate variables. Variables that we are near 
certain to be predictive of outcome will be adjusted for. Age has been consistently related 
to worse outcomes for COVID-19 and therefore will be included in analyses for 
adjustment. Other pre-specified variables that will be candidates for inclusion in primary 
analysis will be determined via an algorithmic approach and these variables will include: 
clinical site, race, ethnicity, sex, category of exposure, hematology factors and other 
laboratory markers (i.e., CBC and metabolic panels), body mass index, ABO blood 
group, targeted physical exam, time between SARS-CoV-2 exposure or symptom onset 
and transfusion of plasma, time between when plasma was donated and transfusion of 
plasma, distance between where donor provided plasma and participant being transfused, 
and prior comorbidities that have specifically been associated with worse COVID-19 
outcomes including: asthma, chronic kidney disease, chronic lung disease (COPD, 
idiopathic pulmonary fibrosis, cystic fibrosis), diabetes, hemoglobin disorders 
(thalassemia, sickle cell disease), immunocompromised (cancer, HIV, organ 
transplantation, prolonged use of corticosteroids), chronic liver disease, hypertension, and 
serious heart conditions (heart failure, coronary artery disease, cardiomyopathies, 
pulmonary hypertension), smoking status, dementia, down syndrome, pregnancy, 
stroke/cerebrovascular disease, and substance use disorder [updated to reflect CDC 
website revised on 5/4/2021 and Guan et al Eur Respir J. 2020 May; 55(5)]. 
To determine which of these pre-specified candidate variables to be included, we will 
conduct variable selection by random survival forest in the entire sample (i.e., not 
including an indicator term for treatment arm) and blinded to treatment allocation. The 
variable importance and 95% confidence intervals [Ishwaran et al Statistics in Medicine. 
2019;38] shall be used to identify predictive variables for the outcome and included in 
analytical models. Specifically, variables in which the 95% CI for the variable 
importance from the random forest does not contain 0 will be adjusted for. This should 
reduce the number of variables that the analysis adjusts in order to minimize the degrees 
of freedom that are use while allowing the analysis to include the variables that have the 
most correlation with the outcome in order to maximize precision. This hybrid approach 

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will be done on the full sample and not include the treatment arm (i.e., among entire 
sample without controlling for convalescent or control plasma) in order to identify the 
prognostic baseline variables for entire sample. 
 
Intention-to-Treat Approach. All analyses will be conducted with a modified intention- 
to-treat approach, which excludes randomized subjects who do not initiate infusion 
transfusion of the study plasma. Furthermore, because this is essentially non-adherence to 
the randomization process, we will use inverse probability of selection weights to account 
for the individuals who do not initiate the treatment to which they were randomized26-28. 
Finally, statistical inference will use a one-sided Type 1 error rate of 0.05 and 95% 
confidence intervals (see below under section 8.3 Halting Criteria for Study for effect of 
interim analyses). 
4.2.1.4 Analysis of Anti-SARS-CoV-2 Antibody Titer 
Analysis of titers will also primarily be descriptive, comparing the geometric mean titers 
at days -1 or 0, 14, 28 and 90 between the randomized arms. Furthermore, it is 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 in order to 
describe whether there is a shift or change in the titer distribution between randomized 
arms 29. Quantile regression does not require the assumption of a parametric or any other 
type of distribution as it identifies the titer at each percentile (e.g., what is the 10th, the 
15th, …, 50th [the median], …, 90th percentiles of anti-SARS-CoV-2 titers). Given that 
this is a repeated measurement at days -1 or0, 14 and 28, we will account for the 
correlation within individuals using a cluster bootstrap in order to properly estimate the p- 
value and 95% confidence intervals. 
4.2.1.5. Analysis of rates and duration of SARS-CoV-2 PCR Positivity 
Analysis of the rate and duration of SARS-CoV-2 PCR positivity between the 
randomized arms will primarily be descriptive examining proportion positive at days (-1 
or 0), 14,28 and 90 then among those who are positive whether individuals lose positivity 
status at a subsequent visit. To determine the proportion that are positive at each visit, we 
will do a pooled complementary log-log model in order to describe the cumulative 
incidence of SARS-CoV-2 PCR positivity over time. The pooled complementary log-log 
model is a discrete time-to-event-analysis that estimates the log hazard rate at each 
discrete time point. From this a cumulative incidence of positivity can be estimated. To 
determine the duration of positivity, the analysis is complicated by the exact day that an 
individual becomes positive and the exact day that an individual becomes negative is not 
known since SARS-CoV-2 PCR positivity will only be acquired at days (-1 or 0), 14 and 
28. 
However, we can estimate a minimum and maximum amount of time that an individual 
was positive. For instance if an individual first negative at day 3 after positive on day 1, 
then we know that this individual became negative between day 1 and 3. Across all 
individuals we can describe the duration of positivity either using a non-parametric 

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approach for time-to-event analysis, but more likely given the sample size a parametric 
model. We will assess several parametric distributions aiming for parsimony in the 
number of parameters being estimated due to the interval censored data which results in 
increased uncertainty in the model. To determine the best model, we will use Akaike’s 
Information Criterion (AIC) to choose the best model fit. However, if the sample that 
becomes positive is really small, then we will only be able to describe the observations 
without a formal statistical model. 
4.2.1.6 Analysis of SARS-CoV-2 RNA levels 
Similar to the secondary aim of comparing the anti-SARS-CoV-2 antibody titers, the 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 above of applying 
quantile regression. 
4.2.1.7 Analysis of Disease Severity 
A secondary hypothesis is that individuals receiving anti-SARS-CoV-2 convalescent 
plasma are likely to have less disease severity than control. Our primary endpoint 
examines time to hospitalization, for this we will examine our clinical event scale for 
disease severity at the 28th day visit (allowing for visit window). The event scale is: 
1. Death 
2. Requiring mechanical ventilation and/or in ICU 
3. non-ICU hospitalization, requiring supplemental oxygen; 
4. non-ICU hospitalization, not requiring supplemental oxygen 
or 
a stay of >24 hours for observation in an ED, field hospital, or other healthcare unit* 
or 
any receipt of O2 for >24 hours, outside of hospital* 
5. Not hospitalized, but with clinical and laboratory evidence1 of COVID-19 infection 
(symptomatic infection) 
The analysis for this will the doubly robust estimator that will be used is that as outlined by 
Benkeser et al. (2020) based upon a non-parametric extension of the log-odds ratio by Diaz et al. 
(2016). 
4.2.1.8 Rate of Participant Reported Secondary Infection of Housemates 
Participants will be assessed for the number of individuals that live in the same house as 
well as by the end of follow-up the number of individuals that became sick during their 
convalescence. Therefore, in order to estimate whether anti-SARS-CoV-2 plasma has had 
an effect on secondary infections, we will use a binomial model in which each individual 
living in the house is a Bernoulli trial. We will account for clustering by household using 
generalized estimating equations. 
4.2.1.9 Oxygen Saturation Levels Over Time 
 
1 Positive molecular testing for SARS-CoV-2 
*with surge of infections in December 2020 and hospitals becoming more full, these two were put 
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Participants will self-assess their oxygen saturation levels using home pulse oximetry, 
when available. Therefore, we will compare the oxygen saturation levels between 
treatment arms during follow-up using quantile regression similar to above analyses. 
4.2.1.10 
Time to Resolution of COVID-19 Symptoms 
One of our secondary hypotheses is that among those randomized to anti-SARS-CoV-2 
plasma, the time to resolution of symptoms from the symptom score sheet that are 
included in the CDC guidelines for quarantine will be reduced. Therefore, our analysis 
will be a time to event analysis examining the effect of anti-SARS-CoV-2 plasma. 
Furthermore, we wish to assess the effect heterogeneity due to age. We will estimate the 
survival function for each treatment arm in order to estimate the risk difference over time 
as well as the restricted mean survival time which is the area under the survival function 
and provides the expected mean time to resolution of symptoms up to time t22. The 
analysis of time to resolution of symptoms is complicated by the fact that some 
individuals will be precluded from having this event due to another event. Specifically, 
some individuals may die during the course of their disease. Therefore, this is a setting 
which is known as competing risks and an area with which we have much expertise29-33. 
We will treat death during COVID-19 as a competing event to our primary outcome of 
interest being resolution of symptoms. However, we do not expect the number of deaths 
to be large but will be different by age. We have powered this study to identify 
treatment effect at day 3 and will estimate the risk difference between the cumulative 
incidence curves over the entirety of follow-up until day 90. A specific interest in 90 
day symptoms exists due to the potential for post-acute sequelae of SARS-CoV-2. Our 
approach will be to estimate the cumulative incidence using a non-parametric estimator 
for competing risks (i.e., Aalen- Johansen estimator) stratified by age intervals and 
treatment group. In order to increase power in a clinical trial, we will adjust for baseline 
covariates that are related to the outcome using inverse probability of treatment 
weights25, 23. Furthermore, we will also estimate a parametric survival model for 
competing risk settings which will also increase efficiency. Specifically, we will use a 
parametric mixture model34, 35, 30. Because a parametric model assumes a specific 
distribution which may not always be an appropriate assumption, we will use a flexible 
distribution. Specifically, specifically a flexible Weibull parametric model that allows 
for a variety of curvature to the hazard function and thus reduce the required 
distributional assumptions for parametric time-to-event models will be used25. 
Furthermore, we will allow for interaction between covariates and time to allow for 
non-proportionality. The factors that we will adjust for are those that likely to 
contribute to development of infection such as age, being immunocompromised, and 
presence of additional comorbidities. In order to check the fit of the parametric model, 
we will graphically assess the parametric cumulative incidence curves to that of the 
non-parametric estimator. If a good fit is not achieved, we will add additional splines to 
the flexible Weibull parametric model and/or modify the interaction between covariates 
and time to allow for additional flexibility in the model over follow-up time. The 
current recommendation for competing risk data is to estimate both the cause- specific 
hazard ratio (or each cause-specific hazards) and the sub distribution hazard ratios or 
the cumulative incidence function. This is to provide as much information such that 
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36-38. 
Given the interest in PASC, we will also assess the number of symptoms between 
treatment arms at the 28th day visit and 90th day visit using a Poisson or negative 
binomial model depending on potential for over dispersion choosing the best model by 
the lowest Aaike’s Information Criterion. We will adjust for potential variables as above 
using the algorithmic approach. 
 
4.2.1.11 
Assessing for the Potential Treatment Effect Heterogeneity by Age 
We will assess whether the treatment effect varies by age. The trial will be recruiting 
individuals regardless of age and therefore, we shall attempt to analyze treatment 
heterogeneity by age. This will be done by allowing for interaction terms between the 
indicator for treatment arm and age as a continuous variable using the methods 
described for the primary analysis. The relationship between the modification of 
treatment effect by age may not be linear with age and therefore we will allow for non- 
linearity using splines. Additionally, we will examine treatment heterogeneity by age 
using categories (for example <40, 40-<65, ≥65) as well as by a binary indicator for age 
being above the median age (see statistical analysis plan for more details). 
4.2.1.12 
Medical Condition Risk Factors 
We have designed the initial study by using age related risk for serious COVID-19 
infection by weighting proposed target sample by age rather than by risk factors for 
medical conditions like diabetes, lung, heart or liver disease within the age strata. While 
we are including pregnant women, the outcome of plasma during pregnancy will require 
a larger subgroup recruitment just the medical risk factors. Nevertheless, we will assess 
treatment effect heterogeneity by medical co-morbidities. One approach will be to use 
each type of co-morbidity, a sum of number of co-morbidities, or a scale such as the 
Charlson Comorbidity Index. 
 
4.2.1.13 
Analysis of secondary and tertiary endpoints if participant receives 
convalescent plasma after endpoint hospitalization through expanded access. 
Individuals may receive convalescent plasma through the National Expanded Access or 
other IND programs occurs after randomization. While this does not lead to confounding, 
analyses that are affected by this (i.e., secondary efficacy endpoints) may be biased due to 
the potential of selection bias if we try to analyze the data as per-protocol. The intention 
to treat analysis is not biased but no longer truly reflect the efficacy that was originally 
envisioned in a hypothetical perfect trial. Essentially, these individuals are not adhering 
to the protocol for the treatment arm they were randomized to. In order to deal with this 
and estimate a per-protocol effect, we can artificially censor these individuals when they 
deviate from the protocol of the single transfusion at baseline that they were randomized 
to. In order to mitigate the selection bias that censoring these individuals when they 
receive convalescent plasma in the hospital that may occur, we will use inverse 
probability censoring weights, which allows for informative censoring. 
 
4.3 
Endpoints 

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Primary Efficacy Objective: Evaluate the efficacy of treatment with HCIP in outpatient 
adults who have molecular detection test-confirmed COVID-19 AND have developed 
any symptoms of COVID-19 including but not limited to fever, cough, or other COVID 
associated symptoms like anosmia. 
Primary Efficacy Endpoint: 
Cumulative incidence of COVID-19 related hospitalizations or deaths prior to 
hospitalization in treatment versus control groups by the Day 28 visit. COVID- 
19 related hospitalizations will be adjudicated using a three member panel. 
Each member will independently come to a decision on whether the 
hospitalization was or was not related to COVID-19 using as much information 
that could be provided such as hospital discharge forms. Classification of 
whether the hospitalization was due to COVID-19 will be by majority decision 
of the panel. 
Primary Safety Objective: Evaluate the safety of treatment with HCIP and control 
plasma in symptomatic outpatient subjects presenting with a positive SARS-CoV-2 
molecular test. 
Primary Safety Endpoints: 
1. Cumulative incidence of treatment-related serious adverse events categorized 
separately as either severe transfusion reactions or Acute Respiratory Distress 
Syndrome (ARDS) during the study period. 
2. Cumulative incidence of treatment-related grade 3 and 4 adverse events during the 
study period. 
Secondary Efficacy Endpoints: 
1. Compare anti-SARS-CoV-2 titers between active and control groups at days (-1 or 0), 
14, 28 and 90 
2. Compare the rates and duration of SARS-CoV-2 RNA positivity (by RNA detection 
test) of nasopharyngeal or oropharyngeal fluid between active and control groups at 
days (-1 or 0), 14 and 28. 
Tertiary Efficacy Endpoint 
1. Compare the levels of SARS-CoV-2 RNA between active and control groups at days 
(-1 or 0), 14 and 28 
2. Compare time to hospital disease severity measured by ICU admission, invasive 
mechanical ventilation or time to death in hospital. 
3. Assess rate of participant-reported secondary infection of household contacts 
4. Compare blood oxygen saturation levels as measured by pulse oximetry (where 
available) between active and control groups through Day 28 
5. Assess time to resolution of COVID-19 symptoms based on temperature logs and 
symptom score sheets 
6. Assess treatment effect heterogeneity by age (as continuous variable). 
7. Compare donor antibody titer to primary, secondary and tertiary endpoints 

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5. STUDY PROCEDURES, EVALUATIONS AND SCHEDULES 
5.1 
Clinical Evaluations: 
The following clinical evaluations will be performed at the times indicated in Section 6 
(Study Visits) and Appendix A (Schedule of Events). Any abnormalities identified during 
the evaluations listed below will be graded according to the EDC dictionary. 
5.2 
Medical history: 
Study staff will interview subjects to collect personal medical histories, including 
illnesses, surgeries, and medications; and demographic data, including name, sex, age, 
race, and ethnicity. 
5.2.1 Physical Examination: 
Complete physical exam by study team member will include a skin examination (partially 
disrobed); height, weight, vital sign measurements (oral temperature, respiratory rate, 
heart rate, and blood pressure); examination of the head, eyes, ears, throat, lungs, heart, 
abdomen, extremities, joints, spine, and other sites as directed by symptoms by a study 
physician. 
5.2.2 Vital Signs: 
Vital signs will be collected as indicated in Section 7. Vital sign evaluation will include 
measurement of temperature, pulse rate, respiratory rate, and blood pressure (systolic and 
diastolic). 
5.2.3 Clinical (local) and Central Laboratory Evaluations: 
The following clinical laboratory tests will be completed at time points as specified in 
Section 6.4 (Study Visits) and Appendix A (Schedule of Events) 
Complete Blood Count: (approximately 5 ml blood): WBC, RBC, Hemoglobin, 
Hematocrit, MCV, MCH, MCHC, RDW, Platelet Count, MPV and Differential (Absolute 
- Neutrophils, Lymphocytes, Monocytes, Eosinophils, and Basophils) 
Serum Chemistry: (approximately 4 mL blood): Albumin, Alkaline Phosphatase, ALT, 
AST, Calcium, Bicarbonate, Chloride, Creatinine, Glucose, Potassium, Sodium, Total 
Bilirubin, Total Protein, Urea Nitrogen C-Reactive Protein 
Blood oxygen saturation: Percent oxygen saturation of blood as measured by finger 
pulse oximetry (where available) 
Other Laboratory Evaluations to be processed centrally: The following laboratory 
tests will be completed at time points as specified in Section 6 (Study Visits) and 
Appendix A (Schedule of Events) 

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Antibody levels: Serum SARS COV-2 antibody by ELISA, neutralization test or other 
FDA-approved test 
SARS-CoV-2 levels: Upper respiratory tract fluid (nasopharyngeal or oropharyngeal 
swab) for presence and level of SARS-CoV-2 RNA by RT-PCR 
5.2.4 Concomitant Medications 
 Prescription medications 
 Blood products 
5.2.5 Prohibited Medications 
Before enrollment, any approved or investigational drug with established activity against 
SARS-CoV-2. 
5.2.6 Hospital Rescue Treatments After Primary Endpoint 
In the event that a participant is hospitalized, the subject and study coordinators shall 
remain blinded. The participant can receive “rescue” therapy with Expanded Access 
Program convalescent therapy or other allowed or approved medications for hospital 
treatment of severe COVID-19. The date of receipt of rescue therapy whether additional 
convalescent therapy or another measure shall be recorded in the data capturesystem. The 
participant should still attend follow up research appointments upon discharge. The 
research study team should obtain research blood and swab on day 14 or 28 if applicable 
in the hospital in the allowable windows. Hospitalization is not an event for which the 
participant or research study staff change blinding status. 
5.3 
Efficacy, Virologic and PK Measures 
Clinical Efficacy (clinical event scale of disease severity) 
1. Death 
2. Requiring mechanical ventilation and/or in ICU due to COVID-19 
3. non-ICU hospitalization due to COVID-19, requiring supplemental oxygen; 
4. non-ICU hospitalization due to COVID-19, not requiring supplemental 
oxygen; 
5. Hospital visit but not admitted 
6. A stay of >24 hours for observation in an ED, field hospital, or other healthcare unit 
7. any receipt of O2 for >24 hours, outside of hospital 
8. Rate of participant-reported secondary infection of housemates 
9. Compare levels of oxygenation between treatment arms over course of follow- 
u 
Virologic measures 
1. Rates and duration of SARS-CoV-2 PCR positivity (RT PCR) at days (-1 or 
0), 14 and 28 
2. Peak quantity levels of SARS-CoV-2 RNA at days (-1 or 0), 14 and 28 
 
 
 
Pharmacokinetic (PK) measures: Anti-SARS-CoV-2 titers at days (-1 or 0), 14, 28 

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and 90. 
 
Upon recruitment of 20 donors, we will measure the viral growth 
inhibition titers of SARS-CoV-2 neutralizing antibodies compared to the current 
FDA benchmark neutralizing titer of 1:8160. However, the ability to detect 
neutralizing antibodies for SARS-CoV-2 through true viral neutralization in 
culture is time consuming. Other approaches include in-house ELISA tests for the 
receptor binding subdomain on the external spike glycoprotein trimer, which 
correlate with viral culture neutralization in previous coronavirus work. Finally, 
there are an increasing number of non-FDA validated, commercial ELISA tests 
with the entire spike glycoprotein trimer or nucleocapsid as capture proteins. The 
viral specificity of these commercial ELISA assays for antibodies to the more 
frequent common cold beta coronavirus like OC43 or the rare SARS-CoV-1 as 
well as sensitivity for SARS-CoV-2 antibodies is evolving in the ongoing 
pandemic. Therefore, we will compare the SARS-CoV-2 donor plasma 
neutralizing titer levels to the whole protein commercial ELISAs being adopted 
by hospitals versus the receptor binding domain ELISAs. The goal will be to 
accurately determine the correlation of serum antibody titers measured by the two 
ELISA assays to virus neutralization titers determined with SARS-CoV-2 live 
virus. 
5.4 
Study visits 
Day -1 or 0 Visit (in person in an appropriate location for patients with positive 
COVID-19 per local policy) 
 Informed consent (obtained before performing study related activities preferably 
by remote consent) 
 Screening (must be completed before randomization) 
 Baseline Evaluation (at screening) 
Screening 
1. Demographics (Age, sex, ethnicity, race) 
2. Medical history dates of first and last exposure to COVID-19 source patient 
(if known), acute and chronic medical condition, medications, allergies. Any 
medical condition arising after consent should be recorded as AE. Date and 
source institution of positive result of previous SARS-CoV-2 positive test) 
3. COVID-19 symptom screen (dates of onset and resolution of fever, cough, 
shortness of breath, diarrhea, anosmia); date and level of highest recorded 
temperature 
4. Vital signs (temperature, degrees F; pulse, beats per minutes; respirations per 
minute; BP, systolic and diastolic, mm Hg) 
5. Physical examination (neurological, respiratory, cardiac, abdomen, skin 
6. Collection of nasopharyngeal or oropharyngeal swab for COVID-19 testing 
(RNA detection test) prior to transfusion (not for clinical testing) 
7. Collection of blood for: 
o ABO typing, unless documentation of ABO type from medical record 
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o Comprehensive metabolic panel (CMP) and CRP- CLIA 
o Complete blood count (CBC) CLIA 
o Stored plasma and serum specimen for future studies 
8. Urine or serum pregnancy test for females of childbearing potential. Results 
from laboratory tests obtained up to 7 days before enrollment may be used for 
the pregnancy test. Results must be received and documented on the case 
report form prior to transfusion. 
9. Determination of eligibility as per inclusion/exclusion criteria 
10. Provision of daily diary form for subject to complete twice daily (preferably 
morning and evening) through Day 14, including cough (frequency and 
intensity of episodes), shortness of breath (frequency and intensity of 
episodes), anosmia (frequency and intensity of episodes), other symptoms 
(frequency, intensity, time of onset), oral temperature, and blood oxygen 
saturation. 
11. Provision of oral digital thermometer and pulse oximeter (where available) 
and training on use. Staff-observed and subject-acquired data should be 
entered on CRF as the temperature, pulse and blood oxygen saturation. 
Day 0 (in person in an appropriate location for patients with positive COVID-19 per 
local policy) 
Treatment Visit 
1. Randomization of eligible subject in IWRS 
2. COVID-19 symptom screen (fevers, cough, shortness of breath) 
3. Assessment of clinical status (composite outcome of disease severity) 
4. Collection and review of AE, New medical conditions, concomitant 
medication, AE evaluation 
5. Physical examination 
6. Collection of nasopharyngeal or oropharyngeal swab for COVID-19 testing if 
not obtained on Day -1 (RNA detection test) prior to transfusion (not for 
clinical testing) 
7. Collection of blood if not obtained on day -1 for 
i. SARS-CoV-2 antibody (Stored for later research analysis) 
ii. Comprehensive metabolic panel (CMP) and CRP- CLIA 
iii. Complete blood count (CBC) CLIA 
iv. Stored plasma and serum specimen for future studies 
8. Study Plasma Administration: A single unit of plasma will be transfused. 
Time at start and end of transfusion will be recorded and Vital signs will be 
measured immediately prior to transfusion, 10-20 minutes after start of 
transfusion, at completion of transfusion and 30-60 minutes after the end of 
the transfusion. 
9. Draw plasma and serum 15 to 30 minutes after transfusion for research 
antibody levels for peak antibody levels 
Day 1 (Phone Call) window of +1 day 
Phone call to recipient for review of subject diary, symptom screen and AE 
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Day 3 (Phone Call) window of -1 or +1 day 
Phone call to recipient for review of subject diary, symptom screen and AE 
assessment. 
Day 5 (Phone Call) window of -1 or +1 day 
Phone call to recipient for review of subject diary, symptom screen and AE 
assessment. 
Day 7 (Phone Call) window of -1 or +1 day 
Phone call to recipient for review of subject diary, symptom screen and AE 
assessment. 
Day 10 (Phone Call) window of -1 or +1 day 
Phone call to recipient for review of subject diary, symptom screen and AE 
assessment. 
Day 14 window of -3 or +3 days (in person in an appropriate location for patients 
with positive COVID-19 per local policy)* 
1. Vital signs 
2. Blood oxygen saturation 
3. Review of subject diary, symptom screen and AE assessment 
4. Physical examination 
5. Blood specimens for CBC, CRP, CMP 
6. SARS-CoV-2 antibody, plasma and serum specimens for future studies 
(Stored for later research analysis) 
7. Nasopharyngeal or oropharyngeal swab for SARS-CoV-2 testing (RNA 
detection test) (not for clinical testing) 
Day 28 (Clinic) window of -3 or +3 days 
1. Vital signs 
2. Blood oxygen saturation 
3. AE assessment 
4. Physical examination 
5. Blood specimens for CBC, CRP & CMP CLIA 
6. SARS-CoV-2 antibody, plasma and serum specimens for future studies 
(Stored for later research analysis) 
7. Nasopharyngeal or oropharyngeal swab for SARS-CoV-2 testing (RNA 
detection test) (not for clinical testing) 
Day 90 (Clinic) window of -8 or +8 days 
1. Interim medical history and AE assessment 
2. Vital signs 
3. Physical examination (if indicated) 
4. Blood specimens for CBC, CRP&CMP- CLIA 
5. SARS-CoV-2 antibody, plasma and serum specimens for future studies 
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A chart review for vaccine status will be conducted for all participants, including those who have 
completed their day 90 visit. 
Unscheduled pre-vaccine- Optional unscheduled visit prior to receipt of vaccine for CBC, CMB, 
CRP and research plasma and serum. Continue with other regular schedule visits. 
Procedure for determination of COVID-19 positive or COVID-19 negative clinic visit. 
Current CDC criteria for release from quarantine which aligns with present JHH 
guidelines are inclusive of all of the below. These are subject to change and future 
changes to instructions for protective isolation will be followed during the 
implementation of this protocol. 
 
i. At least 3 days (72 hours) have passed since recovery defined as resolution of fever 
without the use of fever-reducing medications AND 
ii. Improvement in respiratory symptoms (e.g., cough, shortness of breath) AND 
iii. At least 7 days have passed since symptoms first appeared. 
Because a viral swab will be performed on Day 14 and the duration of viral infectivity, 
irrespective of RNA viral levels after onset of symptoms has yet to be determined, the 
participant should receive the viral swab in the COVID-19 positive clinic on Day 14. The 
day 28 clinic visit and day 90 can be performed in a non COVID-19 clinic in accord to 
CDC and local HEIC guidelines. 
Current JHH HEIC clinic guidelines for patients based on changing data and the situation 
are found at these links: 
https://intranet.insidehopkinsmedicine.org/heic/ 
https://intranet.insidehopkinsmedicine.org/heic/_docs/2019-nCoV_phone_triage.pdf 
https://intranet.insidehopkinsmedicine.org/heic/_docs/2019- 
nCoV_patient_discharge_protocol.pdf 
 
1. RISKS AND BENEFITS 
1.1 
Potential Benefits of treatment. 
The potential benefits of antiviral treatment with anti-SARS CoV-2 plasma in patients with 
COVID-19 will decrease the risk of developing progressive symptomatic disease or 
decrease the severity of illness should it develop. 
Potential benefits of clinical monitoring and virologic testing 
Subjects enrolled in the study will undergo close clinical and virologic monitoring that 
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individual, their family and the community at large. 
Potential risks 
1. Risks of plasma: Fever, chills, rash, headache, serious allergic reactions, TRALI, 
TACO, transmission of infectious agents 
2. Risks of phlebotomy: local discomfort, bruising, hematoma, bleeding, fainting, 
3. Total blood draws will not exceed 500 mL 
4. Risks of oropharyngeal and throat swab: local discomfort, vomiting 
Alternatives to Participation 
The alternative to participation in this study is routine care and monitoring following 
close contact with an individual with COVID-19 
Safety measures 
1. Safety Evaluations will assess the safety of HCIP and control plasma and compare 
rates and severity of transfusion-related and not related adverse events. 
2. Clinical evaluations: Vital signs and symptom screen as described in Section 6, Study 
Procedures, Evaluations and Schedules 
3. Safety laboratory tests will be performed as described in Section 6, Study Procedures, 
Evaluations and Schedules 
1.2 
Definitions 
Adverse Event (AE): Any untoward medical occurrence in a clinical investigation 
subject who has received a study intervention and that does not necessarily have to have a 
causal relationship with the study product. An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of the study product, whether or not 
considered related to the study product. 
Serious Adverse Event (SAE) 
1. An SAE is any adverse event that results in any of the following outcomes: 
2. Death; 
3. Life-threatening (immediate risk of death); 
4. Inpatient hospitalization or prolongation of existing hospitalization; 
5. Persistent or significant disability or incapacity; 
6. Congenital anomaly/birth defect; 
7. Important medical events that may not result in death, be life threatening, or 
require hospitalization 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, or the development of 
drug dependency or drug abuse. 
8. Unexpected Adverse event: (UAE): An adverse reaction, the nature or severity of 
which is not consistent with the investigator’s brochure. 

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Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
Investigators should report SUSARs to Johns Hopkins University within 5 
calendar days. Johns Hopkins will submit the SUSARs to the FDA within 15 
calendar days. Fatal or life-threatening SUSARs should be reported to Johns 
Hopkins as soon as possible and no later than 3 calendar days. Fatal or life- 
threatening SUSARs will be reported to the FDA within 7 calendar days. 
An expedited IND safety report will be used to notify the FDA IND division of 
each serious unexpected suspected adverse reactions according to FDA 
regulations, part 312 and Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDS and BA/BE Studies effective March 28, 2011. 
In accordance with these regulations, this protocol has a pre-specified monitoring 
plan for determining if subjects receiving the intervention are at higher risk for 
mortality and will only report a death as an expedited IND safety report if there is 
evidence of a causal relationship between the intervention and/or the study drug 
and the event resulting in death. In addition, an expedited IND safety report will 
be used to notify the FDA if there is an imbalance between the arms suggesting 
there is a reasonable possibility that the intervention or the control caused any of 
the pre-specified safety endpoints. Otherwise, the occurrence of these safety 
endpoints will be reported on an annual basis. 
Written IND Safety reports will include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32. All safety reports previously filed 
by the investigator with the IND concerning similar events will be analyzed and 
the significance of the new report in light of the previous, similar reports 
commented on. 
Written IND safety reports with Analysis of Similar Events will be submitted to 
the FDA, the JHM sIRB, and all participating investigators for local IRB review 
within 15 calendar days of the CCC first learning of the event. 
Unanticipated Problem (UP) 
Unanticipated Problem that is not an Adverse Event (e.g. breaches of 
confidentiality, accidental destruction of study records, or unaccounted-for study 
drug. 
Protocol Deviation 
Deviation from the IRB-approved study procedures. Designated major and minor: 
1. Major Protocol Deviation: Protocol deviation that compromises trial integrity 
and/or the safety, welfare or rights of subjects or others 
2. Minor Protocol Deviation: Other protocol deviation 
 
 
 
1.3 
Reporting Processes 

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Documentation of AEs. All AEs and SAEs will be documented on the CRF from 
time of signing of the informed consent form. All AEs and SAEs will be followed 
until resolution even if this extends beyond the study-reporting period. 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. 
Investigator’s Assessment of Adverse Events. 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. 
Laboratory Abnormalities. Laboratory abnormalities will be reported as AEs if 
they are considered clinically significant by the investigator. 
Assessment of Seriousness 
Event seriousness will be determined according to the protocol definition of an 
SAE 
Assessment of Severity 
Event severity will be assigned according to the MedDRA parameters in the EDC, 
which correspond to the following definitions: 
1  = Mild: Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required.) 
2 = Moderate: Mild to moderate limitation in activity-some assistance may be 
needed; no or minimal medical intervention/therapy required) 
3 = Severe: Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible 
4 = Life-threatening: Extreme limitation in activity, some assistance usually 
required; medical intervention/therapy required, hospitalization or hospice care 
probable 
5= Death 
Assessment of Association. 
Is the event related to investigational treatment categories to be used for this study are: 
 Not related 
 Unlikely 
 Possible 
 Probable 
 Definite 
The investigator must provide an assessment of association or relationship of AEs 
to the study product based on: 
 Temporal relationship of the event to the administration of study product; 
 Whether an alternative etiology has been identified; 
 Biological plausibility; 
 Existing therapy and/or concomitant medications. 

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7. SAFETY OVERSIGHT 
7.1 
Monitoring Plan 
1. All AE and SAE will be reviewed by protocol team twice monthly, or more 
frequently if needed. 
2. A medical monitor has been appointed for safety oversight of the clinical study. The 
independent medical monitor, mutually agreed upon with the DoD sponsor, will have 
the authority to A.) stop a research study in progress; B.) remove individual from a 
study; and C.) take any steps to protect the safety and well-being of participants until 
the IRB can assess the problem or event: 
Ronald Rodriguez, MD., PhD 
Henry B. and Edna Smith Dielmann Memorial Professor of Urologic Science 
Doctor’s Hospital Renaissance Distinguished University Chair of Urology 
University of Texas Health Science Center at San Antonio 
3. A Data and Safety Monitoring Board (DSMB), composed of experts without conflicts 
of interest, will be established. The Board will review the study before initiation and 
at least monthly thereafter. The Board will review safety, efficacy (including the 
interim analysis), study progress, and conduct of the study. The following have 
accepted and will serve on DSMB (and are working on their contracts) : 
· 
Pablo Tebas University of Pennsylvania (as DSMB Chair) 
· 
Roy F. Chemaly, MD Anderson Cancer Center 
· 
Joe Massaro, Boston University School of Public Health 
· 
Keith Kaye, University of Michigan 
DSMB Charter –This document will be drafted using the DCRI DSMB charter template 
and will be developed in collaboration with the statistical help of Bryan Lau at JHBSPH 
(i.e. a comprehensive SAP (statistical analysis plan)). 
Maya McKean-Peraza 
Project Leader for the DSMB for CSSC001 and CSSC004 
Government Trials & Networks 
Duke Clinical Research Institute 
300 W. Morgan Street, Office 425 
Durham, NC 27701 
maya.mckean.peraza@duke.edu | trialinnovationnetwork.org | dcri.org 
A Clinical Events Committee (CEC) has been established by the Grant Principal Investigators 
consisting of three expert members, including the Chairman, without conflicts of interest to 
independently review Serious Adverse Events (SAEs) of patients who were hospitalized to 
evaluate the relatedness to COVID and the severity of hospitalization and determine clinical safety 
and efficacy outcomes. Any SAE event that does achieve consensus for hospitalization related to 
COVID or severity of hospitalization will be discussed with all three adjudicators to review 

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definitions and provide any other documentation for that event that may assist in achieving 
consensus.  If non-consensus remains, Dr Rodriguez, CEC Chairman will have the deciding vote. 
Ron Rodriguez, MD Member and Chairman 
Virology and Trial Safety 
Joanna Daily, MD Member 
Microbiology and Immunology 
Panagis Galiatsatos, MD Member 
Pulmonary and Critical Care Medicine 
 
7.2 
Study Monitoring 
As per ICH-GCP 5.18 and FDA 21 CFR 312.50, clinical protocols are required to be 
adequately monitored by the study sponsor. Research monitors will be managed by: 
Emissary International LLC 
CEO: Steven W. Mayo, PD, CCRA, PMP 
10900 Research BLVD, Suite 160C-1020 
Austin, TX 78732 
 
Research monitors will verify that: 
1. There is documentation of the informed consent process and signed informed consent 
documents for each subject 
2. There is compliance with recording requirements for data points 
3. All SAEs narratives are reported as required 
4. Individual subjects’ study records and source documents align 
5. Investigators are in compliance with the protocol. 
6. Regulatory requirements as per Office for Human Research Protections-OHRP), 
FDA, and applicable guidelines (ICH-GCP) are being followed. 
7.3 
Halting Criteria for the Study 
The study enrollment and dosing will be stopped, potentially permanently, 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, subject safety is at risk of being compromised: 
1. Unexpected death of a dosed subject in relation to transfusion 
2. An overall pattern of symptomatic, clinical, or laboratory events that the medical 
monitor, DSMB consider associated with study product and that collectively may 
represent a serious potential concern for safety. 
Furthermore, given that ADE may be an issue with convalescent antibody treatment, out 
of an abundance of caution we will monitor the number of subjects in each trial arm that 
progresses to death. Given that we plan to recruit 300 participants in each arm and with 
the following assumptions 1) 18% in the HCIP treatment arm are expected to progress to 

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hospitalization, and 2) 1.4% of these enrolled individuals progress to death, the 
probability of observing one death in either arm is likely (Table 3). We will monitor the 
number of subjects that die and thoroughly evaluate whether each death is likely due to 
anti-SARS-CoV-2 plasma (definite, probable, possible, or unlikely). These data will be 
presented to the masked DSMB so that they may objectively evaluate and determine 
whether they would like to be unmasked. It is likely if more than 3 deaths occur in 
intervention arm that the DSMB would need to consider stopping due to safety concerns 
as more than 3 deaths would be highly unlikely (Table 4). There will be two planned 
formal reviews of the safety data after approximately 5 percent and 20 percent of 
participants have accumulated 30-day outcome data. These first two interim analyses will 
not involve efficacy data, in an effort to conserve alpha spending. 
 
Table 3 
Binomial probability of at least one death among each treatment arm 
by overall symptomatic case fatality rate and for those >64 years of age as estimated 
in Wuhan, China 
 
Symptomatic Case 
Fatality Rate 
Control Plasma arm 
Expected Symptomatic 
N=148 participants 
Anti-SARS-CoV-2 Plasma 
arm 
Expected Symptomatic 
N=111 participants 
1.4% 
0.88 
0.79 
2.7% 
0.98 
0.95 
Table 4 
For  1,  2,  3,  or  5  deaths  observed  among  the  expected number  of 
symptomatic cases, the event probability of death (95% CI) and the probability that 
this would be observed under the overall symptomatic case fatality rate of 1.4% from 
Wuhan, China 
 
Standard Plasma Arm 
Anti-SARS-CoV-2 Plasma arm 
# of 
deaths 
Point 
Estimate 
of   
Mortality 
95% 
Confidence 
Interval 
Probability 
of occurring 
under true 
symptomatic 
case fatality 
rate of 0.014 
Point 
Estimate 
of   
Mortality 
95% 
Confidence 
Interval 
Probability 
of occurring 
under true 
symptomatic 
case fatality 
rate of 0.014 
1 
0.018 
(0.0004, 
0.533 
0.030 
(0.0007, 
0.372 
0.098) 
0.158) 
2 
0.037 
(0.005, 
0.175 
0.061 
(0.007, 
0.078 
0.127) 
0.202) 
3 
0.056 
(0.012, 
0.040 
0.091 
(0.019, 
0.011 
0.154) 
0.243) 
5 
0.0.093 
(0.031, 
<0.001 
0.152 
(0.0511, 
<0.001 
0.203) 
0.319) 

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7.4 
Special considerations for ARDS 
Given that ARDS is a significant potential consequence of COVID-19 and potentially a 
sign of ADE, we will monitor participants for development of ARDS as a medical 
consequence of concern by monitoring differences between participants receiving control 
plasma and anti-SARS-CoV-2 plasma. Given that we plan to recruit 300 participants in 
each arm and with the following assumptions 1) 18% progress to hospitalization in the 
control arm, 2) 10.8% progress to hospitalization in the treatment arm (a 40% reduction 
in risk), and 3) in an abundance of caution as a worst case scenario we will assume that 
40% of ADE will progress to ARDS (in Wuhan the reported frequency of ARDS was 
3.4% for all subjects and 40% among the group reaching the composite endpoint of ICU 
admission, ventilation or death). Under this scenario of assumed maximum severity, we 
are likely to see at least one case in both treatment arms (Table 5). Specifically, we would 
expect six participants in the control and two participants in the treatment arm to develop 
ARDS (table 6). After at least 50% of trial participants have 28 day follow-up, the 
number of subjects that progress to this stage will be presented to the masked DSMB and 
formally asked whether they (1) see a clinically meaningful difference between trial arms 
that trigger an unmasking of the DSMB and (2) if so, do they require a formal interim 
analysis. At any point should the DSMB ask to be unmasked and require a formal interim 
analysis for safety, we will examine the difference in treatment arms for development of 
ARDS. This interim analysis will adjust for factors related to worsening of COVID-19 
such as age, prior lung disease, and presence of cardiopulmonary comorbidities. 
 
 
Table 5 
Binomial Probability of at least one ARDS case among each treatment 
arm for a worst-case scenario of 40 and 50% of hospitalized participants progressing 
to ARDS 
 
Proportion Developing 
ARDS 
Standard Plasma arm 
Expected Symptomatic 
N=148 participants 
Anti-SARS-CoV-2 Plasma 
arm 
Expected Symptomatic 
N=111 participants 
40% 
>0.999 
>0.999 
50% 
>0.999 
>0.999 
 
 
 
 
 
 
 
 
 
Table 6 
For a given number of observed ARDS cases among the placebo plasma 

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and anti-SARS-CoV-2 plasma treatment arms, the point estimate, 95% confidence 
interval, and probability of ARDS occurring under an assumed true rate of 0.4 among 
those who become hospitalized 
 
Standard Plasma Arm 
Anti-SARS-CoV-2 Plasma arm 
# of 
ARDS 
Point 
Estimate 
of ARDS 
95% 
Confidence 
Interval 
Probability 
of occurring 
under true 
ARDS rate 
of 0.40 
Point 
Estimate 
of ARDS 
95% 
Confidence 
Interval 
Probability 
of    
occurring 
under true 
ARDS of 
0.40 
 
10 
0.30 
(0.156, 0.487) 
0.290 
15 
0.28 
(0.165, 0.416) 
0.072 
0.45 
(0.281, 0.636) 
0.595 
20 
0.37 
(0.243, 0.513) 
0.680 
0.61 
(0.421, 0.771) 
0.0.020 
25 
0.46 
(0.326, 0.604) 
0.405 
0.76 
(0.577, 0.889) 
<0.001 
30 
0.56 
(0.414, 0.691) 
0.0.025 
0.91 
(0.757, 0.981) 
<0.001 
Upon completion of this review, the DSMB will determine if study entry or study dosing 
should be interrupted or if study entry and study dosing may continue according to the 
protocol. Should the trial not be stopped at this time point, the final analysis would need 
to account the number of interim analyses that were conducted. Therefore, we would 
spend some of our alpha level with each interim analysis. 
 
7.5 
Planned Interim Analysis 
7.5.1 
Stopping guidelines 
Stopping guidelines for a formal efficacy evaluation will occur for efficacy and futility 
once 40% of the 28 day outcome data have accumulated. We use a non-binding Hwang- 
Shih-DeCani spending function with gamma=-4, which approximates the O’Brien- 
Flemming boundaries, for both upper and lower bounds. This results in an interim analysis 
Z-value boundary of 2.68 (nominal p=0.0037, spent alpha=0.0037) for the upper bound 
and -0.59 (p=0.277, spent beta=0.0148) for the lower. For final analysis the Z-value is 1.66 
(p=0.049, spent alpha=0.0463, spent beta=0.1852) for a one-sided test with Type 1 of 0.05. 
For a stricter one sided test with Type 1 of 0.025, the Z-value boundaries would be interim: 
2.90; final: 1.98 for the upper bounds and interim:-0.39; final: 1.98 for the lower bounds. 
During this planned interim analysis, the study team may request, after consultation with 
the DSMB, to recalculate the sample size after observation of the primary outcome 
proportion in the control arm if initial estimates of that proportion are not accurate. In this 
case, there would be no adjustment for the effect size to be detected (the detectable 
reduction in the primary outcome in the active study arm relative to the control arm). The 
DSMB will be unmasked for analyses but keeping investigators blinded to the treatment 
arms. This interim analysis will adjust for factors related to mortality including age and 
presence of cardiopulmonary comorbidities. 
 
7.6         Rules for Halting Plasma Transfusion 

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Transfusion of plasma will be halted, and will not be restarted, if any of the following 
manifestations of anaphylaxis develop: 
 Skin or mucous membrane manifestations: hives, pruritus, flushing, swollen lips, 
tongue or uvula 
 Respiratory compromise: dyspnea, wheezing, stridor, hypoxemia 
 A decrease in systolic blood pressure to < 90 mmHg or >30% decrease from baseline 
or a diastolic drop of >30% from baseline. 
 Tachycardia with an increase in resting heart rate to > 130bpm; or bradycardia <40 
that is associated with dizziness, nausea or feeling faint. 
 Syncope 
 Confusion 
 Any other symptom or sign which in the good clinical judgment of the study clinician 
or supervising physician warrants halting the transfusion. For example, the rapid 
onset of gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and cramps, 
for instance, may be manifestations of anaphylaxis and may warrant an immediate 
halt prior to meeting full SAE criteria 
 
 
8. ETHICS/PROTECTION OF HUMAN SUBJECTS 
8.1 
Ethical Standard 
The JHU is committed to the integrity and quality of the clinical studies it coordinates 
and implements. JHU will ensure that the legal and ethical obligations associated with the 
conduct of clinical research involving human subjects are met. The information provided 
in this section relates to all JHU sites participating in this research study 
As the Department of Health and Human Services continues to strengthen procedures for 
human subjects’ protections via new regulations, JHU will review these evolving 
standards in relation to the proposed activities and will advise the investigators on those 
that may apply. 
In addition, JHU has a Federal wide Assurance (FWA) number on file with the Office for 
Human Research Protections (OHRP). The FWA number for JHU is FWA00005834. 
This assurance commits a research facility to conduct all human subjects’ research in 
accordance with the ethical principles in The Belmont Report and any other ethical 
standards recognized by OHRP. Finally, per OHRP regulations, the research facility will 
ensure that the mandatory renewal of this assurance occurs at the times specified in the 
regulations. 
 
 
 
8.2 
Institution Review Board 
The JHU IRB will review this protocol and all protocol-related documents and 

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procedures as required by OHRP and local requirements before subject enrollment. The 
JHU IRB currently holds and will maintain a US FWA issued by OHRP for the entirety 
of this study. 
8.3 
Informed Consent Process 
The informed consent process will be initiated before a volunteer agrees to participate in 
the study and should continue throughout the individual’s study participation. Participants 
in this trial are initially under investigation for SARS-CoV-2 infection, necessitating 
remote consent. Therefore, for we will follow the IRB’s guidance as issued in the 
document “Informed Consent for Human Subjects Research at Johns Hopkins during the 
COVID-19 Emergency.”  Following administration of the Telephone Pre-Screening 
Script and determination that the caller is a study participant, the research coordinator 
will send the written consent form to the participant via email or text for their review. 
Participants without email or text capabilities will be sent a hard copy of the written 
consent form via US Postal Service. 
After the participant has had a chance to review the written informed consent, the IRB- 
approved consent designee and the participant will participate in the consent process 
remotely via phone or other video communication platform. A witness from the JH 
Witness Pool will be used to witness the entire consent process. When available, both the 
consent designee and the witness will receive remote consent training provided through 
the OHSR Compliance Monitoring Program. 
With the permission of the participant, the proceedings will be recorded, if this option is 
available on the video communication platform. All parties will introduce themselves and 
their role in the consenting process. The consent form is reviewed in detail. The 
participant is next invited to ask any questions and to have them addressed by the study 
team. If appropriate, the physician/MLP discusses the studies risks and alternatives per 
the physician/mid-level provider consent policy. The consent will explain that subjects 
may withdraw consent at any time throughout the course of the trial. Adequate time will 
be provided to ensure that the subject has time to consider and discuss participation in the 
protocol. 
If the participant is interested in joining the research study, the participant will be asked 
to sign the consent document. The signature may occur by signing the physical document 
or if the consent is delivered electronically by the participant clicking “I agree” to 
participate. The consent designee and witness must verify the participant physically 
signed the consent document by one of the following methods: by viewing via video 
conference; or obtaining a photo of the signed consent document; or obtaining verbal 
confirmation from the participant that he/she signed the consent form or agreed to 
participate electronically. 
 
 
To reduce the risk of transmission, the hard-copy consent by the isolated participant will 
not be removed from the participant’s space. A separate copy of the informed consent 
form will be used to secure the following: the signature and date of the consent designee, 

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the signature and date of physician/MLP (“mid-level provider”) on the appropriate 
signature page and the signature and date of the witness on the COVID-19 witness 
attestation page. The consent designee will return all signed components as one 
combined document to a study team member. 
The study team must retain the completed consent document in its entirety (i.e., all pages 
of the consent form) in the study record or participant binder. 
Consenting a LAR for decisionally impaired participants 
It is presumed that in most cases, due to visitor restrictions or the potential for the LAR to 
be in self-quarantine, the LAR will not be physically present to participate in the consent 
process and this process will occur remotely. As with participants, the LAR must be 
provided with a copy of the IRB-approved consent document before the consent process 
begins. An electronic copy of the consent should be provided where possible. In the event 
that this is not possible, the study team must mail a copy of the consent form by US 
Postal Service. 
After the LAR has had a chance to review the written informed consent, the IRB- 
approved consent designee and the LAR will participate in the consent process remotely 
via phone or other video communication platform. A witness from the JH Witness Pool 
will be used to witness the entire consent process. When available, both the consent 
designee and the witness will receive remote consent training provided through the 
OHSR Compliance Monitoring Program. 
With the permission of the LAR, the proceedings will be recorded, if this option is 
available on the video communication platform. All parties will introduce themselves and 
their role in the consenting process. The consent form is reviewed in detail. The LAR is 
next invited to ask any questions and to have them addressed by the study team. If 
appropriate, the physician/MLP discusses the studies risks and alternatives per the 
physician/mid-level provider consent policy. The consent will explain that the LAR may 
withdraw consent at any time throughout the course of the trial. Adequate time will be 
provided to ensure that the LAR has time to consider and discuss participation on behalf 
of the participant in the protocol. 
If the LAR affirms, acting on the prospective participant’s behalf, agrees to join the 
study, the LAR will be asked to sign the consent document by signing the physical 
document; or if the consent is delivered electronically by the participant clicking “I 
agree” to participate. If the consent document has been provided to the LAR by mail or 
email prior to the consent conversation, the full signed and dated consent form can be 
returned to the study team by mail, fax, email or by a photo of the entire signed consent 
document. If emailed, the document or photo should be returned electronically to the 
study team through secure electronic means. If the LAR is not able to deliver the signed 
document electronically, research procedures may be initiated based on the verbal 
attestation of signature but the hard copy must be returned via mail. 
The consent designee and witness will verify and document the LAR signed the consent 
document: By viewing via video conference; or obtaining a photo or scanned copy of the 

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signed consent document or obtaining verbal confirmation from the LAR that he/she 
signed the consent form. 
Once the LAR documentation is confirmed the following signatures must be secured: The 
consent designee will sign and date the primary consent document; the physician/MLP 
will sign the physician/MLP consent signature page, and the witness will sign the 
COVID-19 witness attestation page. The study team will retain the completed consent 
document in its entirety (i.e., all pages of the consent form) in the study record or 
participant binder. 
Mechanisms for Delivering Informed Consent Electronically. 
Our team may pursue the use of MyChart, as a means to deliver the IRB-approved 
consent document electronically to prospective participants or their LARs via MyChart. 
Prospective participants will be asked if they have a MyChart account or be asked to 
establish one in order to access the consent through this platform. The MyChart team 
will assist our team in creating an electronic delivery mechanism for consent that will 
have a built in “agree to participate” component. 
 
Provision of information to participants having a language or hearing impairment and 
non-English speakers will follow IRB recommendations as outlined during the COVID 
pandemic. 
Sites Other than Johns Hopkins 
Remote Consent: Individual sites seeking to use a similar remote consent process to the 
Johns Hopkins clinical site will utilize a plan that complies with FDA guidelines for 
COVID-19 related research and comply with any local procedural guidelines/institutional 
policies for remote consent. 
Electronic Consent: Sites seeking to use e-consenting will ensure the electronic platform 
used is FDA Part 11 compliant and will provide documentation of access to a Part 11 
compliant system to the IRB as part of initial site onboarding or via a subsequent 
participating site modification. Sites will also ensure their local institutional policies, 
guidelines, and practices are followed for electronic consenting. 
8.4 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their 
staff, and the sponsors and their agents. No information concerning the study, or the data 
will be released to any unauthorized third party without prior written approval of the 
sponsor. The results of the research study may be published, but subjects’ names or 
identifiers will not be revealed. Records will remain confidential. To maintain 
confidentiality, the PI will be responsible for keeping records in a locked area and results 
of tests coded to prevent association with subjects’ names. Data entered into 
computerized files will be accessible only by authorized personnel directly involved with 
the study and will be coded. Subjects’ records will be available to the FDA, the NIH, the 
manufacturer of the study product and their representatives, investigators at the site 

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involved with the study, and the IRB. 
8.5 
Future Use of Stored Specimens 
Subjects will be asked for consent to use their samples for future testing before the 
sample is obtained. The confidentiality of the subject will be maintained. They will be no 
plans to re-contact them for consent or to inform them of results. The risk of collection of 
the sample will be the small risk of bruising or fainting associated with phlebotomy 
however these samples will be taken at the same time as other protocol required samples. 
Human genetic testing may be performed on the samples as per participant choice. 
Five ml of blood samples will be collected at 5 time points (See Schedule of Events). 
Serum will be frozen in 1-ml aliquots. These samples will be used to answer questions 
that may arise while the study is underway or after it is completed. If for instance, there 
were unanticipated AEs, serum could be used to run tests that might help determine the 
reason for the AEs. Cytokines could be measured, for example. 
 
Samples would not be shared with investigators other than investigators at JHU unless 
outside investigators have relevant assays or expertise not available to the study 
investigators. The specimens would remain linked and at JHU for 5 years. Any use of 
these specimens not specified in the current protocol will be reviewed by the JHU IRB. 
8.6 
Data Management and Monitoring 
8.6.1 
Source Documents 
Source documents for this study will include the subjects’ medical records and study 
record documents. If the investigators maintain separate research records, both the 
medical record and the research records will be considered the source documents for the 
purposes of auditing the study. The investigator will retain a copy of source documents. 
The investigator will permit monitoring and auditing of these data, and will allow the 
sponsor, IRB and regulatory authorities access to the original source documents. The 
investigator is responsible for ensuring that the data collected are complete, accurate, and 
recorded in a timely manner. Source documentation (the point of initial recording of 
information) should support the data collected and entered into the study database/case 
report form and must be signed and dated by the person recording and/or reviewing the 
data. All data submitted should be reviewed by the site investigator and signed as 
required with written or electronic signature, as appropriate. Data entered into the study 
database will be collected directly from subjects during study visits or will be abstracted 
from subjects’ medical records. The subjects’ medical records must record their 
participation in the clinical trial and what medications (with doses and frequency) or 
other medical interventions or treatments were administered, as well as any AEs 
experienced during the trial. 
8.6.2 
Data Management Plan 
Study data will be collected at the study site(s) and entered into the study database. Data 
entry is to be completed on an ongoing basis during the study. Anonymized individual 

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participant data (IPD) collected in this study, including data dictionaries, will be made 
available to other researchers after the end of the study. 
 
8.6.3 
Data Capture Methods 
Clinical data will be entered into a 21 CFR 11-compliant Internet Data Entry System 
(IDES). The data system includes password protection and internal quality checks to 
identify data that appear inconsistent, incomplete, or inaccurate. 
8.6.4 
Study Record Retention 
The site investigator is responsible for retaining all essential documents listed in the ICH 
GCP Guidelines. The FDA requires study records to be retained for up to 2 years after 
marketing approval or disapproval (21 CFR 312.62), or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational agent for a 
specific indication. These records are also to be maintained in compliance with IRB/IEC, 
state, and federal medical records retention requirements, whichever is longest. All stored 
records are to be kept confidential to the extent provided by federal, state, and local law. 
It is the site investigator’s responsibility to retain copies of source documents until receipt 
of written notification to the sponsor. 
No study document should be destroyed without prior written agreement between the 
sponsor and the Principal Investigator. Should the investigator wish to assign the study 
records to another party and/or move them to another location, the site investigator must 
provide written notification of such intent to sponsor with the name of the person who 
will accept responsibility for the transferred records and/or their new location. The 
sponsor must be notified in writing and written permission must be received by the site 
prior to destruction or relocation of research records. 
10 
COORDINATING CENTER FUNCTIONS AND MULTI-SITE STUDIES 
10.1. Responsibilities. A Clinical Coordinating Center (CCC) will be responsible for 
overall recruitment and retention, data management, monitoring and communication 
among the enrolling sites, and the general oversight of the conduct of this human subject 
research project. The CCC for this trial is the Brain Injury Outcomes (BIOS) Center, 
located at 750 E. Pratt St., Baltimore, MD 21202. The CCC operates under JHM IRB 
approval # NA_00010432 of which Daniel Hanley, MD, is the Principal Investigator. 
10.2. IRB Document Management. There is a plan in place for reviewing site approval 
documents. Two sIRB coordinators oversee the process of reviewing site approval 
documents and consent forms prior to sIRB review. The coordinators collaborate with the 
JHM IRB and conduct web calls with each enrolling site to promptly and adequately pre- 
review site documents prior to site-specific JHM IRB submissions. The sIRB specialists 
confirm that each participating site has on file an FWA with OHRP. Throughout the 
study, the sIRB specialists and CCC site managers will assure that all centers have the 
most current version of the protocol, which will be stored in the electronic trial 
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enrolling site PIs and lead study coordinators via receipt-confirmed email and telephone 
contact follow-up. 
10.3. Screening and Enrollment Tracking. Recruitment and retention at the sites will 
be supported by a centrally managed electronic data collection (EDC) system where data 
will be entered on every screen and enrollment, including reasons for screen failures, 
inclusion and exclusion criteria met, and demographics needed for reporting. The eTMF 
will store any documents involved in the screening and enrollment process. Enrollment 
reports will be generated every two weeks and reported annually as part of the renewal 
process. 
10.4. Reporting Protocol Events and Deviations. A formal Data Management Plan will 
outline the collection and management of data centrally and at the centers. A formal Data 
Safety Monitoring Plan will describe the process for reporting and evaluating protocol 
events and deviations at the enrolling centers. Site-specific protocol events and deviations 
will be collected in the EDC. Protocol deviations will be characterized according to one 
of three types (intentional, identified before they occur, and discovered post occurrence) 
and by which meet the requirement for prompt reporting. Corrective and preventive 
action (CAPA) plans will be shared with and responded to by sites electronically in the 
eTMF. Protocol deviation reports will be generated every two to four weeks and reported 
annually as part of the renewal process. 
 
10.5. Identifying Enrolling Sites. As sites are selected, the CCC will notify the JHM 
IRB, using the template below. Final approval will be withheld until the JHM IRB and 
the OHSR have all required documentation on file. The protocol will be amended, as a 
change in research, as each site is selected and prior to onboarding the site. Johns 
Hopkins will be an enrolling site. If any problems arise with enrolling sites, IRB 
specialists will communicate with the site contact person named in the application, if 
necessary. 
10.6 COVID-19 Research Environment- The selected sites will demonstrate protocol 
review and protocol approval from institutional Hospital Epidemiology and Infection 
Control (HEIC) or equivalent office in regards to a COVID-19 positive clinic. Physical 
areas in which participants will be seen for consent and/or study visits must be in 
compliance with standards set by the local HEIC. The HEIC promotes patient safety by 
reducing the risk of acquiring and transmitting infections. 
 
All local sites must supply sufficient personal protective equipment (PPE) for their study 
personnel and the study participants. Specific types of required PPE and level of 
protection will be determined by the local HEIC or equivalent office. 
 
All local sites must inform the CCC of any local restrictions or requirements related to 
COVID-19 research that may impact the health and safety of the participant and conduct 
of the study. Any limitations or requirements will be evaluated for study impact by the 
CCC on a case-by-case basis. 

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Prior to initiation, study sites will provide documentation of: 
1. Local HEIC approval or equivalent, 
2. Sufficient access to personal protective equipment (PPE) and other resources to 
carry out the protocol to keep both the subjects and the study personnel safe, 
3. Policies about local restrictions and requirements on COVID-19 related research 
 
 
 
Site  
Identification 
Template 
Site name and address 
PI name and contact (phone and email) 
Confirmation that the research can be conducted at that site, has an 
IRB, and that the IRB has completed its approval of the research 
Site FWA number 
An executed agreement to rely on the JHM IRB 
 
10.6 Participating Sites: Participating sites are listed on clinicaltrials.gov (NCT: 
04373460). 

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APPENDIX A 
Schedule of Events 
Study period 
Screen Baseline 
Trans- 
fusion 
Day (windows) 
-1 to 0 0 
0 
1 
(+1) 
3 
(-1 
or 
+1) 
5 
(-1 
or 
+1) 
7 
(-1 
or 
+1) 
10 
(-1 
or 
+1) 
14 
(-3 
or 
+3) 
28 
(-3 
or 
+3) 
90 
(-8 
or 
+8) 
Informed consent 
x 
Demographic and Medical 
history 
x 
COVID-19 symptom 
screen 
x 
SARS-CoV-2 molecular 
test review of prior 
test report 
x 
Pregnancy test1 
x 
Blood typing ABO2 
x 
Randomization 
x 
Drug transfusion 
x 
Study Procedures 
Vital signs 
x 
x 
xxx3 
x 
x 
x 
Phone call 
x 
x 
x 
x 
x 
Physical examination 
neuro, 
lung cardiac, 
abdominal, skin 
x 
x 
x 
x 
x 
Symptom screen (COVID- 
19 related) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse event monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Temperature (self- 
administer) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pulse oximetry (self- 
administer) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CBC, CRP and CMP 
x 
x 
x 
x 
SARS-CoV-2 RNA 
detection test4 
x 
x 
x 
SARS-CoV-2 antibody 
x 
x 
x 
x 
Blood for future testing 
(plasma and serum) 
x 
X post 
transfus 
ion 
x 
x 
x 
1 
Result of urine or serum pregnancy test for women of childbearing potential must be documented prior to 
transfusion 
2 
Assessment of ABO type on file or determination of ABO type if not on file 
3 
Vital sign testing: immediately prior to transfusion, 10-20 minutes after start of transfusion, at completion of 
transfusion and 30-60 minutes after the end of the transfusion 
4 
Sites include nasopharyngeal or oropharyngeal