Convalescent Plasma to Stem Coronavirus: A Randomized, Blinded Phase 2 Study Comparing the Efficacy and Safety Human Coronavirus Immune Plasma (HCIP) vs. Control (SARS-CoV-2 Non-immune Plasma) Among Adults Exposed to COVID-19
Phase: PHASE2
Conditions: Coronavirus, Convalescence
Sponsor: Johns Hopkins University

Convalescent Plasma to Stem Coronavirus: A Randomized
Controlled Double Blinded Phase 2 Study Comparing the
Efficacy and Safety of Human Coronavirus Immune Plasma
(HCIP) vs. Control (SARS-CoV-2 non-immune plasma) among
Adults Exposed to COVID-19
NCT 04323800
Protocol 
Version December 23, 2020 

CSSC-001 
December 23, 2020 
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1. PROTOCOL SUMMARY:
Long title:  Convalescent Plasma to Stem Coronavirus: A Randomized Controlled Double Blinded 
Phase 2 Study Comparing the Efficacy and Safety of Human Coronavirus Immune Plasma (HCIP) 
vs. control (SARS-CoV-2 non-immune plasma) among Adults Exposed to COVID-19 
Short title: CSSC-001 
Clinical Phase: 2 
IND Sponsor: Johns Hopkins University 
Conducted by: Johns Hopkins University as lead institution for a consortium of sites 
Sample Size: 500 
Study Population: High-risk subjects aged 18 years of age and older who have experienced a 
close contact exposure to a person with COVID-19 in the past 120 hours AND have not yet 
themselves developed symptoms of COVID-19 
Study Duration: April 1, 2020 to December 31, 2022 
Study Design: This randomized, controlled, double-blinded phase 2 trial will assess the efficacy 
and safety of Anti- SARS-CoV-2 convalescent plasma as prophylaxis following exposure to 
COVID-19 (as defined in the inclusion criteria). Adults 18 years of age and older with high risk 
exposure as defined by CDC may participate. A total of 500 eligible subjects will be randomized 
in a 1:1 ratio to receive either high titer anti-SARS-CoV-2 plasma or control (SARS-CoV-2 non-
immune plasma). 
The following will be assessed in all subjects: 
•
Safety and efficacy: Day 0 (baseline), 1, 3, 7, 14, 28, 60 and 90. May be performed by
telemedicine on days when laboratory testing not scheduled.
•
Blood antibody titer1 to SARS-CoV-2s: Day -1 to 0, 1, 7, 14 and 90
•
SARS-CoV-2 molecular testing from nasopharyngeal swab, throat samples: Day -1 to 0, 1,7,
14 and 28 and at any time when there is clinical suspicion for COVID-19

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Study Agent:  
 
• SARS-CoV-2 convalescent plasma (1 unit; minimum of 175 mL collected by pheresis from a 
volunteer who recovered from COVID-19 disease and has SARS-CoV-2 antibody titers ≥ 
1:320 
• Control plasma: 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.  
 
Primary Efficacy Objective: Evaluate the efficacy of treatment at Day 28 following high-titer 
Anti- SARS-CoV-2 plasma versus control (SARS-CoV-2 non-immune plasma) in subjects exposed 
to COVID-19 at day 28.  
 
Primary Endpoint: Cumulative incidence of development of COVID-19 disease (symptoms 
compatible with infection and/or + molecular testing) regardless of disease severity. 
 
Primary Safety Objective: Evaluate the safety of treatment with high-titer Anti- SARS-CoV-2 
plasma versus control (SARS-CoV-2 non-immune plasma) in subjects exposed to COVID-19 
 
Primary Safety Endpoints: 
 
1. Cumulative incidence of serious adverse events categorized separately as either severe 
infusion reactions and ARDS during the study period 
2. Cumulative incidence of grade 3 and 4 adverse events during the study period  
 
Secondary Objectives:   
1. Cumulative incidence of disease severity between the anti-SARS-CoV-2 convalescent 
plasma and control groups after individuals develop SARS-CoV-2 infection. Severity of 
disease will be measured using a clinical event scale of disease severity (evaluated up to 
Day 28): 
 
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; 
5. a stay of >24 hours for observation in an ED, field hospital, or other healthcare unit* 
6. any receipt of O2 for >24 hours, outside of hospital* 
7. Not hospitalized, but with clinical and laboratory evidence2 of COVID-19 infection 
 
 
 
2 Positive molecular testing for SARS-CoV-2 
*with surge of infections in December 2020 and hospitals becoming more full, these two were 
put into the clinical events scale as hospitalization equivalents 

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Other Objectives: 
1. Compare the anti-SARS-CoV-2 convalescent plasma and control (SARS-CoV-2 non-
immune plasma) groups’ anti-SARS-CoV-2 titers at days -1 to 0, 1, 7, 14 and 90. 
2. Compare the rates and duration of SARS-CoV-2 molecular testing positivity amongst the 
anti-SARS-CoV-2 convalescent plasma and control (SARS-CoV-2 non-immune plasma) 
groups at days 1, 7, 14 and 28 
3. Compare the levels of SARS-CoV-2 RNA amongst the anti-SARS-CoV-2 convalescent 
plasma and control (SARS-CoV-2 non-immune plasma)  groups at days -1 to 0, 1, 7, 14 
and 28 
Table of Contents 
1. 
PROTOCOL SUMMARY: .................................................................................................. 1 
1.1. 
STUDY POPULATION ................................................................................................... 5 
1.1.1. 
Inclusion Criteria for Enrollment ............................................................................................................ 5 
1.1.2. 
Exclusion Criteria ................................................................................................................................... 5 
2. 
LIST OF ABBREVIATIONS ................................................................................................. 5 
3. 
BACKGROUND AND SCIENTIFIC RATIONALE .................................................................... 6 
3.1. 
Experience with the use of convalescent plasma against coronavirus diseases .....................8 
3.2. 
Overview of known potential risks .....................................................................................9 
3.3. 
Known potential benefits ................................................................................................. 10 
4. 
INVESTIGATIONAL PLAN ............................................................................................... 11 
4.1. 
Study Objectives .............................................................................................................. 11 
4.1.1. 
Primary Efficacy Objective: Evaluate at day 28, the efficacy of treatment with high-titer Anti- SARS-
CoV-2 plasma versus control (SARS-CoV-2 non-immune plasma) in subjects exposed to COVID-19 ................ 11 
4.1.2. 
Primary Safety Objective: .................................................................................................................... 11 
4.1.3. 
Secondary Objectives: ......................................................................................................................... 11 
4.2. 
Definitions ....................................................................................................................... 12 
4.3. 
Study population ............................................................................................................. 12 
4.3.1. 
Inclusion Criteria for Enrollment .......................................................................................................... 12 
4.3.2. 
Exclusion Criteria for Enrollment ......................................................................................................... 12 
4.3.3. 
Subject Withdrawal ............................................................................................................................. 14 
4.3.4. 
Intervention ......................................................................................................................................... 14 
4.3.5. 
Randomization ..................................................................................................................................... 15 
4.4. 
Rationale for dosing ............................................................................................................................. 15 
4.5. 
Study drug administration ................................................................................................ 15 
4.5.1. 
Concomitant medications will be documented on the CRF................................................................. 16 
4.5.2. 
Prohibited Medications: ...................................................................................................................... 16 
5. 
STATISTICAL CONSIDERATIONS ..................................................................................... 16 
5.1. 
Sample Size and Power Considerations ............................................................................. 16 
5.2. 
Statistical Analysis ........................................................................................................... 17 

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5.2.1. 
Analysis of AE data ............................................................................................................................... 18 
5.2.2. 
Analysis of anti-SARS-CoV-2 titers ....................................................................................................... 18 
5.2.3. 
Analysis of rates and duration of SARS-CoV-2 PCR Positivity .............................................................. 19 
5.2.4. 
Analysis of SARS-CoV-2 RNA ................................................................................................................ 19 
5.3. 
Endpoints ........................................................................................................................ 20 
6. 
STUDY PROCEDURES .................................................................................................... 20 
Day -1 to 0 ................................................................................................................................... 20 
Day 0 ........................................................................................................................................... 21 
Day 1, (+/-) 1 day ......................................................................................................................... 21 
Day 3, (+/-) 1 day ......................................................................................................................... 21 
Day 7, (+/-) 1 day ......................................................................................................................... 22 
Day 14, (+/-) 3 days ...................................................................................................................... 22 
Day 28, (+/-) 3 days ...................................................................................................................... 22 
Day 60, (+/-) 3 days ...................................................................................................................... 22 
Day 90, (+/-) 8 days ...................................................................................................................... 22 
6.1. 
EFFICACY, VIROLOGIC AND PK MEASURES ........................................................................ 24 
7. 
RISKS AND BENEFITS .................................................................................................... 25 
7.1. 
Reporting Interval ............................................................................................................ 27 
8. 
SAFETY OVERSIGHT ...................................................................................................... 28 
8.1. 
Monitoring Plan ............................................................................................................... 28 
8.2. 
Study monitoring ............................................................................................................. 29 
8.3. 
Halting Criteria for the Study ............................................................................................ 30 
9. 
ETHICS/PROTECTION OF HUMAN SUBJECTS .................................................................. 33 
9.1. 
Ethical Standard ............................................................................................................... 33 
9.2. 
Institutional Review Board ............................................................................................... 34 
9.3. 
Informed Consent Process ................................................................................................ 34 
9.4. 
Subject Confidentiality ..................................................................................................... 37 
9.5. 
Future Use of Stored Specimens ....................................................................................... 38 
9.6. 
Data management and monitoring ................................................................................... 38 
9.6.1. 
Source Documents ............................................................................................................................... 38 
9.6.2. 
Data Management Plan ....................................................................................................................... 39 
9.6.3. 
Data Capture Methods ........................................................................................................................ 39 
9.6.4. 
Study Record Retention ....................................................................................................................... 39 
10. 
COORDINATING CENTER FUNCTIONS AND MULTI-SITE STUDIES ................................ 39 
 

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1.1. 
STUDY POPULATION 
1.1.1. Inclusion Criteria for Enrollment 
 
1. Subjects must be 18 years of age or older 
2. Close contact  exposure (as defined by CDC guidelines) to person with COVID-19 within 
96 hours of randomization (and 120 hours of receipt of plasma)  
1.1.2. Exclusion Criteria 
 
1. Medical, psychiatric, or cognitive illness or recreational drug/alcohol use that in the 
opinion of the principal investigator, would affect subject safety and/or compliance 
2. Symptoms consistent with COVID-19 infection at time of screening (sudden onset of at 
least one of the following: fever, cough, shortness of breath)  
3. Laboratory evidence of COVID-19 infection at time of screening 
4. History or known laboratory evidence of previous COVID-19 infection 
5. History of or known prior allergic reaction to transfusion blood product 
6. Receipt of SARS-CoV-2 Vaccine 
2. LIST OF ABBREVIATIONS 
 
AABB: American Association of Blood Banks 
AAMC: Anne Arundel Medical Center 
ADR: Adverse Drug Reaction 
ADE: Antibody-mediated enhancement of infection 
AE: Adverse Event/Adverse Experience 
ARDS: Acute Respiratory Distress Syndrome  
CCC: Clinical Coordinating Center  
DCC: Data Coordinating Center  
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  
CRMS: Clinical Research Management System  
CRF: Case Report Form 
DMC: Data Management Center 
DMID: NIH Division of Microbiology and Infectious Diseases  
DSMB: Data and Safety Monitoring Board 
EHR: Electronic Health Record  
EUA: Emergency Use Authorization 
FDA: Food and Drug Administration 

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GCP: Good Clinical Practice 
HBV: Hepatitis B virus 
HCIP: Human Coronavirus Immune Plasma 
HCP: Health care personnel 
HCV: Hepatitis C virus 
HEIC: Johns Hopkins Medicine Healthcare 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 
ICTR: Institute for Clinical and Translational Research  
ICU: Intensive Care Unit 
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 
RT-PCR: Reverse Transcriptase Polymerase chain reaction 
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 
 
3. BACKGROUND AND SCIENTIFIC RATIONALE 
 
There are currently no proven treatment or prophylaxis 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 other infection prevention and 
treatment and thus may provide an option for prevention and treatment of COVID-19 and 

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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 preventing or treating an infectious 
disease caused by that agent. In contrast, active vaccination requires the induction of an 
immune response that takes time to develop and varies depending on the vaccine recipient. 
Some immunocompromised patients fail to achieve an adequate immune response. 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 1940s [Casadevall A, and Scharff MD. Return to the 
past: the case for antibody-based therapies in infectious diseases. Clin Infect Dis. 1995;21(150-
61) and Casadevall A, Dadachova E, and Pirofski L. Passive antibody therapy for infectious 
diseases. Nature Microbiol Rev. 2004;2(695-703.)]. Experience from prior outbreaks with other 
coronaviruses, such as SARS-CoV-1 shows that convalescent plasma contains neutralizing 
antibodies to the relevant virus [Zhang JS, Chen JT, Liu YX, Zhang ZS, Gao H, Liu Y, Wang X, Ning 
Y, Liu YF, Gao Q, et al. A serological survey on neutralizing antibody titer of SARS convalescent 
sera. Journal of medical virology. 2005;77(2):147-50]. In the case of SARS-CoV-2, the anticipated 
mechanism of action by which passive antibody therapy would mediate protection is viral 
neutralization. However, other mechanisms may be possible, such as antibody dependent 
cellular cytotoxicity and/or phagocytosis. Convalescent serum was also used in the 2013 African 
Ebola epidemic. A small non-randomized study in Sierra Leone revealed a significant increase in 
survival for those treated with convalescent whole blood relative to those who received 
standard treatment [Sahr F, Ansumana R, Massaquoi TA, Idriss BR, Sesay FR, Lamin JM, Baker S, 
Nicol S, Conton B, 256 Johnson W, et al. Evaluation of convalescent whole blood for treating 
Ebola Virus Disease in 257 Freetown, Sierra Leone. The Journal of infection. 2017;74(3):302-9.].  
 
The only antibody type that is currently available for immediate use is that found in human 
convalescent plasma. As more individuals contract COVID-19 and recover, the number of 
potential donors will continue to increase. 
 
A general principle of passive antibody therapy is that it is more effective when used for 
prophylaxis than for treatment of disease. When used for therapy, 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 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 asymptomatic [Casadevall A, and 
Pirofski LA. Antibody-mediated regulation of cellular immunity and the inflammatory response. 
Trends Immunol. 2003;24(9):474-8]. As an example, passive antibody therapy for pneumococcal 

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pneumonia was most effective when administered shortly after the onset of symptoms and 
there was no benefit if antibody administration was delayed past the third day of disease 
[Casadevall A, and Scharff MD. "Serum Therapy" revisited: Animal models of infection and the 
development of passive antibody therapy. Antimicrob Agents Chemotherap. 1994;38(1695-
702)]. 
 
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 protection against infection. Depending on the antibody amount and 
composition, the protection conferred by the transferred immunoglobulin can last from weeks 
to months. 
3.1. 
Experience with the use of convalescent plasma against coronavirus 
diseases  
 
In the 21st century, there were two other epidemics with coronaviruses that were associated 
with high mortality, SARS1 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 SARS [Cheng Y, Wong R, Soo YO, Wong WS, Lee 
CK, Ng MH, Chan P, Wong KC, Leung CB, and Cheng G. Use of convalescent plasma therapy in 
SARS patients in Hong Kong. European journal of clinical microbiology & infectious diseases: 
official publication of the European Society of Clinical Microbiology. 2005; 24(1):44-6.]. 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. There is also some anecdotal information on the use of convalescent 
plasma in seriously ill individuals. Three patients with SARS in Taiwan were treated with 500 ml 
of convalescent plasma, resulting in a reduction in plasma virus titer and each survived [Yeh 
KM, Chiueh TS, Siu LK, Lin JC, Chan PK, Peng MY, Wan HL, Chen JH, Hu BS, Perng CL, et al. 
Experience of using convalescent plasma for severe acute respiratory syndrome among 
healthcare workers in a Taiwan hospital. The Journal of antimicrobial chemotherapy. 2005; 
56(5):919-22.]. Three patients with MERS in South Korea were treated with convalescent 
plasma, but only two of the recipients had neutralizing antibody in their plasma [Ko JH, Seok H, 
Cho SY, Ha YE, Baek JY, Kim SH, Kim YJ, Park JK, Chung CR, Kang ES, et al. Challenges of 
convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single 
centre experience. Antiviral therapy. 2018; 23(7):617-22.].  The latter study highlights a 
challenge in using convalescent plasma, namely, that some who recover from viral disease may 
not have high titers of neutralizing antibody [Arabi YM, Hajeer AH, Luke T, Raviprakash K, 
Balkhy H, Johani S, Al-Dawood A, Al-Qahtani S, Al- Omari A, Al-Hameed F, et al. Feasibility of 
Using Convalescent Plasma Immunotherapy for MERS-283 CoV Infection, Saudi Arabia. 
Emerging infectious diseases. 2016; 22(9):1554-61.]. Consistent with this point, an analysis of 99 
samples of convalescent sera from patients with MERS showed that 87 had neutralizing 

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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.  
 
It is also possible that other types of non-neutralizing antibodies are made that contribute to 
protection and recovery as described for other viral diseases [van Erp EA, Luytjes W, Ferwerda 
G, and van Kasteren PB. Fc-Mediated Antibody Effector Functions During Respiratory Syncytial 
Virus Infection and Disease. Frontiers in immunology. 2019;10(548), Gunn BM, Yu WH, Karim 
MM, Brannan JM, Herbert AS, Wec AZ, Halfmann PJ, Fusco ML, Schendel SL, Gangavarapu K, et 
al. A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against 
Ebola Virus. Cell host & microbe. 2018; 24(2):221-33. e5.]. 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. 
3.2. 
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 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 strain [Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, 
Chen Y, Wu J, and Shi Z. Molecular mechanism for antibody-dependent enhancement of 
coronavirus entry. Journal of Virology. 2020; 94(5)]. 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 SARS1 and MERS [Mair-Jenkins J, 
Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, Makki S, Rooney KD, Nguyen-Van-
Tam JS, and Beck CR. The effectiveness of convalescent plasma and hyperimmune 
immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a 
systematic review and exploratory meta-analysis. The Journal of infectious diseases. 2015; 
211(1):80-90.)], and anecdotal evidence of its use in patients with COVID-19 

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(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 immunity [Crowe JE, Firestone C-Y, and Murphy 
BR. Passively acquired antibodies suppress humoral but not cell-mediated immunity in mice 
immunized with live attenuated respiratory syncytial virus vaccines. The Journal of Immunology. 
2001; 167(7):3910-8.]. 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), and transfusion associated circulatory overload 
(TACO) or passive transfer of potential unknown infectious agents or infections. 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.  
3.3. 
Known potential benefits 
 
A benefit of convalescent plasma administration is that it can prevent infection and subsequent 
disease in those who are at high risk for disease following close contacts of patients with 
COVID-19. This is especially so for those with underlying medical conditions. Many who will 
qualify for prophylaxis are health care workers and first responders who are critical to 
maintenance of stability of the healthcare system. Passive antibody administration to prevent 
disease is already used in clinical practice. For example, patients exposed to hepatitis B and 
rabies viruses are treated with hepatitis B immune globulin (HBIG) and human rabies immune 
globulin (RIG), respectively. Botulism Immune Globulin Intravenous (Human) (BIG-IV) is an 
intravenous preparation for infant botulism. In addition, passive antibody is used for the 
prevention of severe respiratory syncytial virus (RSV) disease in high-risk infants. Until recently, 
polyclonal hyperimmune globulin (RSV-IG) prepared from donors selected for having high 
plasma titers of RSV neutralizing antibody, was used but these preparations have now been 
replaced by palivizumab, a humanized murine monoclonal antibody.  
 
Another potential benefit is societal: If the frequency with which exposed persons become 
infected decreases, the risk of further transmission (R naught might be reduced and the 

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epidemic slowed. Another avenue (not pursued in this protocol) is as a treatment for 
established infection.  Convalescent plasma would be administered to those with clinical 
disease in an effort to reduce their symptoms and mortality. Based on the historical experience 
with antibody administration, it can be anticipated that antibody administration 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. 
 
4. INVESTIGATIONAL PLAN 
4.1. 
Study Objectives 
4.1.1. Primary Efficacy Objective: Evaluate at day 28, the efficacy of treatment with 
high-titer Anti- SARS-CoV-2 plasma versus control (SARS-CoV-2 non-immune 
plasma) in subjects exposed to COVID-19 
 
4.1.2. Primary Safety Objective: Evaluate the safety of treatment with high-titer Anti- 
SARS-CoV-2 plasma versus control (SARS-CoV-2 non-immune plasma) in subjects 
exposed to COVID-19 
4.1.3. Secondary Objectives: 
I. Cumulative incidence of disease severity between the anti-SARS-CoV-2 convalescent 
plasma and control groups after individuals develop SARS-CoV-2 infection. Severity of 
disease will be measured using a clinical event scale of disease severity (evaluated up 
to Day 28): 
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; 
5. Not hospitalized, but with clinical and laboratory evidence3 of COVID-19 infection 
4.1.4. Other Objectives: 
 
3 Validated test for presence of SARS-CoV-2 

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I. 
Compare the anti-SARS-CoV-2 convalescent plasma and control (SARS-CoV-2 
non-immune plasma) groups for anti-SARS-CoV-2 titers at days -1 to 0, 1, 7, 14 
and 90 
II. 
Compare the rates and duration of SARS-CoV-2 molecular testing positivity 
amongst the anti-SARS-CoV-2 convalescent plasma and control (SARS-CoV-2 non-
immune plasma) groups at days  1, 7, 14 and 28 
III. 
Compare the levels of SARS-CoV-2 RNA amongst the anti-SARS-CoV-2 
convalescent plasma and control (SARS-CoV-2 non-immune plasma) groups at 
days -1 to 0, 1, 7, 14 and 28 
IV. 
Understand how the immune system responds to COVID-19 infections and try to 
understand why some people have mild symptoms and other people have life-
threatening disease. 
4.2. 
Definitions  
 
I. 
Enrolled: From time consented to participate until designated as a screen failure 
or have either been discontinued from the study or completed it.  
II. 
Randomized: when a randomization number is assigned 
III. 
Screen Failures: signed informed consent, but then determined to be ineligible 
or withdraws before being randomized 
IV. 
Discontinued: randomized, but then withdrawn by investigator or withdraws 
consent 
V. 
Completed: Subjects are considered completed when they are followed through 
to day 28 or died before that.  
4.3. 
Study population  
4.3.1. Inclusion Criteria for Enrollment 
 
1. Subjects must be 18 years of age or older 
2. Close contact exposure (as defined by CDC guidelines)to person with COVID-19 
within 96 hours of randomization (and 120 hours of receipt of plasma) 
4.3.2. Exclusion Criteria for Enrollment 
 

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1. Medical, psychiatric, or cognitive illness or recreational drug/alcohol use that in the 
opinion of the principal investigator, would affect subject safety and/or compliance 
2. Symptoms consistent with COVID-19 infection at time of screening (sudden onset of 
at least one of the following: fever, cough, shortness of breath)  
3. Laboratory evidence of COVID-19 infection at time of screening 
4. History or known laboratory evidence of previous COVID-19 infection 
5. A history of or known prior allergic reaction to transfusion blood product 
6. Receipt of SARS-CoV-2 Vaccine  
 
Table: Schedule of Events 
 
Study period 
Screen 
Baseline 
Transfusion 
Follow up 
Day 
-1 to 0 
0 
0 
1 
3 
7 
14 
28 
60 
90 
Window 
 
 
 
+/- 
1 
day 
+/- 
1 
day 
+/- 
1 
day 
+/- 3 
days 
+/- 3 
days 
+/- 3 
days 
+/- 8 
days 
Procedure 
 
 
 
 
 
 
 
 
 
 
Eligibility 
 
Informed consent  
x 
 
 
 
 
 
 
 
 
 
Demographic and Medical 
history 
x 
 
 
 
 
 
 
 
 
 
COVID-19 symptom survey 
x 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 molecular 
testing for eligibility 
x 
 
 
 
 
 
 
 
 
 
Pregnancy test 4 
x 
 
 
 
 
 
 
 
 
 
ABO5 
x 
 
 
 
 
 
 
 
 
 
Study Drug  Administration 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
Drug infusion 
 
 
x 
 
 
 
 
 
 
 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
Vital signs 
x 
x 
xxxx6 
x 
 
x 
x 
 
 
 
Physical examination  
 
 
x 
 
 
 
 
 
 
 
COVID-19 symptom screen 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Concomitant medications 
x 
x 
x 
 
 
 
 
 
 
 
Assessment of clinical event 
scale of disease severity7 
 
x 
 
x 
x 
x 
x 
x 
x 
 
Adverse event monitoring 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
4 Result of urine or serum pregnancy test for women of childbearing potential must be 
documented prior to transfusion 
5 Assessment of ABO type on file or determination of ABO type if not on file 
6 Vital sign testing: Immediately prior to infusion, 10-20 minutes after start of infusion, at 
completion of infusion and 30-60 minutes after the end of the infusion 
7 Assessment evaluates whether subject has shifted from “no clinical or laboratory evidence of 
COVID-19 infection to any of the clinical event scale of disease severity 

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Laboratory testing  
 
CBC and CMP 
x 
 
 
x 
 
x 
x 
 
 
 
SARS-CoV-2 molecular 
testing8  
x 
 
 
x 
 
x 
x 
x 
 
 
Blood for future testing9  
x 
 
 
x 
 
x 
x 
 
 
x 
 
4.3.3. Subject Withdrawal 
 
I. 
Subjects can terminate study participation and/or withdraw consent at any time 
without prejudice.  
II. 
Randomized subjects who withdraw from the study will not be replaced. 
III. 
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 
IV. 
Discontinuation of the study: The study sponsor, FDA and IRB all have the right to 
terminate this study at any time 
4.3.4. Intervention 
 
I. 
Subjects will be randomized in a 1:1 ratio to receive treatment vs SARS-CoV-2 non-
immune plasma 
II. 
Study drug: The investigational product is anti-SARS-CoV-2 convalescent plasma. 
Patients identified as having recovered from COVID-19 will serve as potential 
donors. Donors with SARS-CoV-2 antibody titers ≥ 1:320 by validated ELISA will be 
used for the trial. The ELISA testing will be performed in a CLIA certified laboratory. 
Potential donors and samples will be screened for transfusion-transmitted 
infections (e.g. HIV, HBV, HCV, WNV, HTLV-I/II, T. cruzi, ZIKV) and plasma will be 
collected using apheresis technology. This is similar to standard blood bank 
protocols. 
III. 
Samples of convalescent plasma will be reserved by the blood bank for further 
testing  
IV. 
Active arm will receive 1 unit of anti-SARS-CoV-2 plasma with titers ≥ 1:320) 
V. 
Control arm will receive 1 unit of SARS-CoV-2 non-immune plasma  
VI. 
Both active and control drugs will be in standard plasma unit bags, with a study-
specific ISBT label. 
VII. 
For blood that will be collected locally (Johns Hopkins) the source of donor plasma 
will be as detailed in protocol JHM IRB00248402. 
VIII. 
all subjects must be negative for active SARS-CoV-2 via a validated molecular test 
within 24 hours preceding the plasma infusion.  
 
8 Sites could include nasopharyngeal, throat  
9 Includes anti-SARS CoV-2 titers.  
 

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4.3.5. Randomization 
 
I. 
Subjects enrolled in the study will be randomized using an interactive web response 
system (IWRS) to receive study drug vs control at a 1:1 ratio.  
II. 
Randomization will occur after the result of the initial coronvirus testing is known to 
be negative. 
 
 
4.4. 
Rationale for dosing 
 
Dose calculation is based on 1 unit (minimum of 175 mL) of plasma with anti-SARS-CoV-19 titers 
of >1:320 and 1 unit of standard plasma. For the purposes of the proposed trial, we will require 
titers ≥1:320. The current FDA recommendations target titers that are optimally greater than 1: 
320 in the event that testing is available. We have favored a more conservative ≥1: 320 given 
findings from a pilot study in China that showed most (39/40) convalescent donors had titers 
≥1:160 (Duan K, et al.medRxiv. 2020:2020.03.16.20036145). We intend to infuse a minimum of 
175 ml (1 unit) of plasma to all individuals.  
4.5. 
Study drug administration 
 
• Drug will be administered within 24 hours of randomization 
• Transfusions for Johns Hopkins site participants will be performed at HEIC and 
Blood Bank approved JHM locations such as: 1) The Adult Clinical Research Unit 
(CRU) on Blalock 3 at Johns Hopkins Hospital and 2) the Neurosciences Consultation 
and Infusion Center at Green Spring Station, Pavilion 2, Suite 115, room #5. 
• If infusion takes place at the Adult CRU, Adult CRU registered nurses (RN’s) will 
administer the infusion per JH policy. They will attend to the participant throughout 
the infusion and post infusion observation period. For infusion at any HEIC 
approved JHM location, registered nurses (RN’s) from Johns Hopkins will administer 
the infusion per JH policy.  They will attend to the participant throughout the 
infusion and post infusion observation period.  All RNs  are BLS trained. A study 
physician or advanced practice clinician with clinical privileges at JH will be available 
by phone and within 5 minutes physical response time to respond to any emerging 
event during the infusion. 
• For non-Johns Hopkins sites, infusion will take place in the area designated for this 
research project.  All infusions will be performed and monitored by appropriate 
personnel as defined by institutional policy for blood product transfusion. 
• Infusion rate  500 mL/hour 
• Vital signs will be taken immediately prior to infusion, 10-20 minutes after start of 
infusion, at completion of infusion, and 30-60 minutes after the end of the infusion. 

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16
• Medicines for transfusion reactions (e.g. acetaminophen, diphenhydramine) may be 
given. 
• If an AE develops during infusion, the infusion may be slowed or stopped as per 
investigator or infusion monitor decision.   
o Management of transfusion-associated AE will follow AABB guidelines; 
Outside of a simple allergic transfusion reaction, the transfusion will be 
discontinued and investigated appropriately (i.e. per standard practice 
guidelines).  
 
• Following completion of the infusion, the participant will remain in the infusion 
area under observation for 30-60 minutes.  If after that time the participant is not 
experiencing any adverse events, they may be discharged home.  A written post- 
infusion information sheet will be given to the participant prior to discharge.  The 
sheet will list risk and possible complications of blood transfusion.  Depending on 
the severity and nature of the complication, the participant is advised to contact 
their healthcare provider or call 911. 
4.5.1. Concomitant medications will be documented on the CRF 
• Prescription medications 
• Blood products 
4.5.2. Prohibited Medications: Any approved or investigational drug with established 
activity against SARS-CoV-2 (Unless subject becomes ill with COVID-19 and 
qualifies for treatment) 
 
5. STATISTICAL CONSIDERATIONS 
5.1. 
Sample Size and Power Considerations 
 
The planned sample size for the trial is 500 subjects, randomized in a 1:1 ratio to 
convalescent titer anti-SARS CoV-2 plasma vs SARS-CoV-2 non-immune plasma.  
 
To evaluate the power of the study, the following assumptions were made: 
 
a. The primary analysis will compare efficacy/prevention in the convalescent titer and SARS-
CoV-2 non-immune plasmas groups using proportional odds model and a one-sided Type I 
error rate (alpha) of 0.05 (i.e., for superiority) and Type II error rate (beta) of 0.2 
 
b. It is anticipated that very few of these subjects will be randomized and not start study 
plasma infusion (and so be excluded from the primary analysis) or be lost to follow-up prior 
to Day 28 (and so have missing data for the primary endpoint).  

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c. 13% incidence of symptomatic disease in exposed individuals treated with SARS-CoV-2 
non-immune plasma 
d. 6.5% incidence of symptomatic disease in exposed individuals treated with anti-SARS 
CoV-2 plasma 
 
We estimate a sample size of 488 patients (244 in each arm) would be sufficient to detect a 
difference in outcomes between those two arms with a power of 0.8. To allow for some 
loss-to-followup, we have rounded our target sample to 500 patients.  
5.2. 
Statistical Analysis 
 
Primary endpoint: 
Our primary hypothesis is that by providing anti-SARS-CoV-2 plasma, the cumulative 
incidence of the development of COVID-19 will be lower among the individuals receiving 
HCIP as compared to those receiving control plasma over the course of follow-up. 
Therefore, our primary endpoint is the development of COVID-19 regardless of severity.  
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 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 [Díaz, I., Colantuoni, E., Hanley, D.F. et al. Improved precision in the analysis of 
randomized trials with survival outcomes, without assuming proportional hazards.Lifetime 
Data Anal 25, 439–468 (2019)].  By adjusting for baseline covariates that are related to the 
outcome, we increase precision. The TMLE based approach was shown to increase precision 
by around 10% to 20% over an inverse probability weighted or augmented inverse 
probability weighted estimator. As stated above, we will use a hybrid approach of adjusting 
for pre-specified variables (age) and an algorithmic approach to identify additional variables 
related to the outcome. Specifically, a random survival forest will be used to identify 
variables that are related to the outcome in order to increase precision. We will use a 
random survival forest blinded to the treatment arm allocation and not including an 
indicator variable for treatment. The following pre-randomization variables will be 
considered: 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, 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, 

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18
hypertension, and serious heart conditions (hear failure, coronary artery disease, 
cardiomyopathies, pulmonary hypertension) [Guan W-j, Liang W-h, Zhao Y, et al. 
Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. 
Eur Respir J 2020; 55: 2000547, https://www.cdc.gov/coronavirus/2019-ncov/need-extra-
precautions/groups-at-higher-risk.html].  
 
The primary outcome analysis will be the adjusted comparison of proportions of cumulative 
incidence of SARS-CoV-2 infection (symptoms compatable with infection and RT-PCR 
positive) at day 28 comparing the risk-difference and restricted mean survival time between 
treatment groups with a significance threshold of p=0.047 (p-value adjusted for interim 
analysis) for a one-sided test.  
 
Finally, statistical inference will use a one-sided Type 1 error rate of 0.05 for superiority and 
95% confidence intervals (note: interim analyses are based upon O’Brian-Flemming 
spending function see below under section 8.3 Halting Criteria for Study). 
5.2.1. 
Analysis of AE data 
Analysis of AE data will primarily be descriptive based on MedDRA coding of events. The 
proportion of subjects experiencing an SAE and the proportion experiencing a Grade 3 or 
higher. AE will be compared between randomized arms using Fisher’s Exact Test. 
 
5.2.2. 
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. Therefore, this analysis is restricted to 
individuals who have developed a SARS-CoV-2 infection. We have devised a clinical event 
scale for disease severity based on the COVID clinical severity scale which is composed of 
clinical events that range from being symptomatic and not hospitalized, to being 
hospitalized, to mechanical ventilation/ICU, to death. 
 
We will separately analyze each of the clinical events by determining the cumulative 
incidence from time from randomization. Similarly to the primary analysis, we will utilize 
the TMLE based estimator and adjust for age and any pre-specified candidate variables 
selected via the algorithm as described above. If individuals jump in severity (e.g., progress 
from symptomatic not hospitalized to ICU without being hospitalized in non-ICU) then we 
will interval censor the lower events between the two time points prior to more severe and 
time of severe clinical event. This will allow individuals to contribute to the progression 
through the clinical events. 
5.2.3. 
Analysis of anti-SARS-CoV-2 titers 
Analysis of titers will also primarily be descriptive, comparing the geometric mean titers at 
days 0, 1, ,7,  14, 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 

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19
there is a shift or change in the titer distribution between randomized arms [Roger Koenker, 
Quantile Regression. Cambridge University Press, May 5, 2005].  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 0, 
1, 7, 14, and 90 we will account for the correlation within individuals using a cluster 
bootstrap in order to properly estimate the p-value and 95% confidence intervals. 
 
5.2.4. 
Analysis of rates and duration of SARS-CoV-2 molecular testing positivity 
Analysis of the rate and duration of SARS-CoV-2 molecular testing positivity between the 
randomized arms will primarily be descriptive examining proportion positive at days 0, 1, 7, 
14, and 28 and 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 molecular testing 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 molecular testing positivity will only be acquired at days 0, 1, 7, 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 positive visit is at day 1 and then is 
positive at day 7 but negative at day 14, then we know that this individual became positive 
between day 0 and 1 and negative between day 7 and 14. Therefore, the minimum amount 
of time positive is 7 days (day 8 – day 1) and the maximum is 14 days (day 14 – day 0). 
Therefore, we can interval censor these individuals. That is we know that the duration is 
between 7 and 14 days for this example individual. Across all individuals we can describe 
the duration of positivity either using a non-parametric 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. 
5.2.5. 
Analysis of SARS-CoV-2 RNA 
Similar to the secondary aim of comparing the anti-SARS-CoV-2 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.  

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20
5.3. 
Endpoints 
 
Primary Efficacy Endpoint:  
28 day incidence of COVID-19 infection with both clinical and laboratory evidence. 
 
Primary Safety Endpoints: 
1. Cumulative incidence of serious adverse events categorized separately as either 
severe infusion reactions and ARDS during the study period 
2. Cumulative incidence of grade 3 and 4 adverse events during the study period 
 
 
Secondary Endpoints 
1. 28 day incidence of severe COVID-19 infection defined by death or initiation of 
mechanical ventilation. 
2. Anti-SARS-CoV-2 titers at days -1 to 0, 1, 7, 14, and 90. 
3. Rates and duration of SARS-CoV-2 molecular testing positivity at days 1, 7, 14, 
and 28.  
6. STUDY PROCEDURES 
Day -1 to 0 
In-person visit 
A. Screening (must be completed before randomization) 
B. Informed consent (may be obtained prior to Day-1and before performing study 
related activities) 
C. Baseline Evaluation (at screening) 
 
1. Demographics (Age, sex ethnicity, race, number of people in household) 
2. Medical history (timing of exposure to COVID-19 source patient, acute and 
chronic medical condition, medications, allergies. Any medical condition arising 
after consent should be recorded as AE 
3. COVID-19 symptom screen (fevers, cough, shortness of breath) 
4. Vital signs 
6. COVID-19 molecular testing prior to infusion, from nasopharyngeal, throat 
samples (may be omitted if test already performed on same day as part of usual 
care) 
7. Draw and result ABO and Rh  if no documented ABO typing within the past year. 
8. CBC, comprehensive metabolic panel  
9. Stored samples for future studies 

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21
10. Urine or serum pregnancy test for females of childbearing potential. Results 
from laboratory tests obtained up to 7 days before randomization may be used for 
the pregnancy test. 
11. Determination of eligibility as per inclusion/exclusion criteria 
12. Confirmation of emergency contact information in EMR. 
 
To the extent possible and with goal of minimizing exposure of health care workers 
and study team members to risk, there will be a pre-visit explanation and consent 
done using a video platform at sites that permit video platform use.  
 
Day 0 
In-person visit 
1. Randomization of eligible subject in IWRS 
2. Study Plasma Administration: A single unit of plasma will be transfused. Time at 
start and end of infusion will be recorded and Vital signs will be measured 
immediately prior to infusion, 10-20 minutes after start of infusion, at completion of 
infusion and 30-60 minutes after the end of the infusion. 
3. COVID-19 symptom screen (fevers, cough, shortness of breath). Done by 
telephone before they come in for transfusion. 
4. Assessment of clinical status (composite outcome of disease severity) 
5. New medical conditions, concomitant medication, AE evaluation 
6. Physical examination 
Day 1, (+/-) 1 day 
   In-person visit 
 
1. Vital signs 
2. COVID-19 symptom screen (fevers, cough, shortness of breath 
3. Assessment of clinical status (clinical event scale of disease severity) 
4. New medical conditions, AE evaluation 
5. CBC, comprehensive metabolic panel 
6. COVID-19 molecular testing from nasopharyngeal, throat samples 
7. Stored samples for future studies 
Day 3, (+/-) 1 day 
 
Phone Call  
 

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22
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (clinical event scale of disease severity) 
3. New medical conditions, AE evaluation 
Day 7, (+/-) 1 day 
In-person visit 
 
1. Vital signs  
2. COVID-19 symptom screen (fevers, cough, shortness of breath) 
3. Assessment of clinical status (clinical event scale of disease severity) 
4. New medical conditions, AE evaluation  
5. CBC, comprehensive metabolic panel 
6. COVID-19 molecular testing from nasopharyngeal,  throat samples 
7. Stored samples for future studies 
Day 14, (+/-) 3 days 
In-person visit 
 
1. Vital signs  
2. COVID-19 symptom screen (fevers, cough, shortness of breath) 
3. Assessment of clinical status (clinical event scale of disease severity) 
4. New medical conditions, AE evaluation 
5. CBC, comprehensive metabolic panel 
6. COVID-19 molecular testingfrom nasopharyngeal,  throat samples 
7. Stored samples for future studies 
Day 28, (+/-) 3 days 
In-person visit 
 
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (clinical event scale of disease severity) 
3. New medical conditions, AE evaluation 
4. COVID-19 molecular testing from nasopharyngeal,  throat samples 
    Day 60, (+/-) 3 days 
 
Phone Call  

CSSC-001 
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23
 
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (clinical event scale of disease severity) 
3. New medical conditions, AE evaluation 
 
Day 90, (+/-) 8 days 
In-person visit 
 
1. Stored samples for future studies  
 
 
Clinical research sites for infusion and follow-up  
 
Infusion of plasma will occur after subjects have been determined to be at extremely 
low risk for having an active COVID-19 infection. Specifically, these subjects will be 
asymptomatic AND have had a negative validated test for coronavirus in the preceding 
24 hours. This plan has been discussed and approved by Johns Hopkins Medicine Health 
Care Epidemiology and Infection Control (HEIC).  Local sites will follow their institutional 
guidelines regarding location and infection control for COVID-19 related research. 
 
Study staff will wear adequate PPE according to local infection control practices. Local 
sites will follow their institutional guidelines regarding location and infection control for 
COVID-19 related research. Samples that require transport will be delivered by courier 
or a member of the research team and triple packaged for travel (e.g. specimen 
container, leakproof ziplock bag or other container, outer rigid container with marking 
such as biohazard symbol, medical specimen or diagnostic specimen).  
 
These tests will be processed at a central investigational laboratory and the results of 
these tests will not be provided to subjects or their treating physicians in real time. 
Patients who develop signs and symptoms suggestive of COVID-19 will be referred to 
standard of care coronavirus testing.  
 
The research team may use remote data collection, which may include use of 
telemedicine in accordance with the Guidance for Incorporation of Telemedicine into 
Research with Human Participants to interview and view the participant. (Relying sites 
may adhere to their own local policies and guidelines for this remote data 
collection).  For residents at nursing facilities, data that is being routinely collected (e.g. 
vital signs if being done for clinical care purposes or other clinical or medical record 
information that is collected for clinical care purposes) may be obtained from the 
nursing facility with appropriate authorization for release. 
  

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The testing and specimen collection will be conducted in accordance with the Johns 
Hopkins HEIC policies for managing patients and with recent COVID exposure, and 
protection for study staff (mask, PPE when required) as appropriate.  The HEIC protocols 
are: 
 
https://intranet.insidehopkinsmedicine.org/heic/novel_coronavirus/clinical_resources 
  
https://intranet.insidehopkinsmedicine.org/heic/_docs/2019-
nCoV_outpatient_guidelines.pdf 
  
https://intranet.insidehopkinsmedicine.org/heic/_docs/2019-
nCoV_patient_discharge_protocol.pdf 
 
Local sites will follow their institutional guidelines regarding infection control and PPE for 
COVID-19 related research. 
6.1. 
EFFICACY, VIROLOGIC AND PK MEASURES 
 
Clinical Efficacy (clinical event scale of disease severity) 
 
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; 
5 Not hospitalized, but with clinical and laboratory evidence10 of COVID-19 infection 
 
Virologic measures  
 
1. Rates and duration of SARS-CoV-2 molecular testing positivity at days 1, 7,  14, and 
28 
2. virlogical studies of  SARS-CoV-2 RNA at days -1 to 0, 1, 7 , 14, and 28 
 
Pharmacokinetic (PK) measures: Anti-SARS-CoV-2 titers at days -1 to 0, 1, 7, 14 and 90. 
 
Using samples from 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 
1:320. 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 
 
10 Positive molecular test  for SARS-CoV-2 

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25
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.  
 
7. RISKS AND BENEFITS 
 
Potential Benefits of treatment 
 
The potential benefits of antiviral treatment with anti-SARS CoV-2 plasma in patients at high 
risk for developing COVID-19 due to a close contact with another individual with COVID-19 are 
unknown. However, it is anticipated that treatment will decrease the risk of developing 
symptomatic disease and 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 could 
facilitate earlier diagnosis of development of COVID-19 with associated benefit to the 
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 
 
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 for the safety of high titer anti-SARS-CoV-2 plasma and 
determine if it is higher, lower or the same as SARS-CoV-2 non-immune plasma 
2. Clinical evaluations: In-person vital signs and symptom screen on days 0,1,7,14 and 
remote (phone call) symptom screens on days ,3 and 60 
3. Laboratory evaluations 

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26
4. Safety laboratory tests (ABO typing, pregnancy testing, CBC and comprehensive 
metabolic panel) will be performed at the local CLIA-certified clinical laboratory on days 
-1 to 0,1, 7 and 14 
 
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) 
 
An SAE is any adverse event that results in any of the following outcomes: 
1. Death; 
2. Life-threatening (immediate risk of death); 
3. Inpatient hospitalization or prolongation of existing hospitalization; 
4. Persistent or significant disability or incapacity; 
5. Congenital anomaly/birth defect; 
6. 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. 
Unexpected Adverse event: (UAE): An adverse reaction, the nature or severity of which is not 
consistent with the investigator’s brochure. 
  
Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
Investigators should report SUSARs to Johns Hopkins University within 5 calendar days of 
awareness. 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 of awareness. Fatal or life-threatening SUSARs will be reported to the FDA 
within 7 calendar days. 

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December 23, 2020 
 
27
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 
Sites should follow their IRB guidelines for reporting. 
7.1. 
Reporting Interval 
All AEs and SAEs will be documented from the first administration of study product 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.  
Reporting should also occur at any time after completion of the study, if the investigator 
becomes aware of a SAE that is suspected to be related to study product  
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 will be reported as AEs if they are considered clinically 
significant by the investigator.  
 
Assessment of Seriousness 
I. 
Event seriousness will be determined according to the protocol definition of an SAE  
II. 
Assessment of Severity 
 
Event severity will be assigned according to the MedDRA parameters in the EDC, which 
correspond to the following definitions: 

CSSC-001 
December 23, 2020 
 
28
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 
The association assessment categories that will be used for this study are: 
• Associated – The event is temporally related to the administration of the study product 
and no other etiology explains the event. 
• Not Associated – The event is temporally independent of the study product and/or the 
event appears to be explained by another etiology.  
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. 
8. SAFETY OVERSIGHT 
8.1. 
Monitoring Plan 
1. All AE and SAE will be reviewed by protocol team twice monthly, or more 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:                                             
 

CSSC-001 
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29
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 
 
Pia Mikkelsen Lynch, M.D.  
President & Managing Director  
PML Medical Consulting, Aps. 
Denmark 
 
3. A data safety monitoring board (DSMB), composed of independent experts without 
conflict of interests will be established. The Board will review the study before initiation 
and quarterly thereafter. The Board will review study data to evaluate the safety, 
efficacy, study progress, and conduct of the study  
• The following have accepted and will serve on DSMB (and are working with on 
their contracts): 
• Pablo Tebas  from 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 
and  a comprehensive SAP (statistical analysis plan). 
 
An organizational meeting was held  April 27, 2020 
 
Maya McKean-Peraza 
Project Leader for the DSMB for CSSC001  
Government Trials & Networks 
Duke Clinical Research Institute 
300 W. Morgan Street, Office 425 
Durham, NC 27701 
Office: 919.668.4044 | Mobile 919.316.8281 
maya.mckean.peraza@duke.edu | trialinnovationnetwork.org | dcri.org 
 
8.2. 
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: 

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30
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 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.  
8.3. 
Halting Criteria for the Study 
The study enrollment and dosing will be stopped and an ad hoc review will be performed if any 
of the specific following events occur or, if in the judgment of the study physician, subject safety 
is at risk of being compromised: 
I. 
Unexpected death of a dosed subject in relation to infusion  
II. 
Occurrence of a life-threatening allergic/hypersensitivity reaction (anaphylaxis), 
manifested by bronchospasm with or without urticaria or angioedema requiring 
hemodynamic support with pressor medications or mechanical ventilation.  
III. 
One subject with an unexpected SAE associated with study product. 
IV. 
Two subjects with a Grade 3 or higher toxicity for the same parameter associated with 
study product. 
V. 
An overall pattern of symptomatic, clinical, or laboratory events that the medical 
monitor, ISM, or SMC consider associated with study product and that may appear 
minor in terms of individual events but that collectively may represent a serious 
potential concern for safety. 
VI. 
Any other event(s) which is considered to be a serious adverse event in the good clinical 
judgment of the responsible physician.  This will be appropriately documented. 
 

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31
Interim Analyses for efficacy: There will be two formal review of interim results. The first will 
occur after 15 infections which is expected to occur near 150 participants reaching day 28 and 
the second after 50% of the total recruitment (n=500) has been achieved and these individuals 
followed to at least day 28. Interim analyses will only be adjusted for age. Stopping guidelines 
will be based on O’Brien-Flemming boundary. The interim analysis Z-value boundary of 3.03 
(nominal p-value of 0.0011, spent alpha 0.0011), 2.38 (0.0087, 0.008), and 1.68 (0.464, 0.408) 
for a one-sided test with Type 1 of 0.05. 
Special considerations for death: 
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 75 participants in each arm and with the following 
assumptions 1) 20% of those in standard arm progress to symptomatic infection, 2) 5% in the 
anti-SARS-CoV-2 treatment arm are expected to progress to symptomatic infection, and 3) 1.4% 
of those with symptomatic infection progress to death, the probability of observing one death 
in either arm is unlikely (Table 1). Even with a higher symptomatic case fatality rate of 2.7% that 
has been estimated for those >64 years in Wuhan, China (Table 1) [Wu JT, LeungK, Bushman M, 
et al. Estimating Clinical Severity of COVID-19 from the transmission dynamics in Wuhan, China. 
Nature Med] . However, it is possible that more than one death may be seen by random chance 
in the sample that we accrue. Therefore, 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). The DSMB will be unmasked for all interim analyses and 
reviews for safety. It is likely if 2 deaths occur in intervention arm that the DSMB would need to 
consider stopping due to safety concerns as two deaths would be highly unlikely (Table 2). After 
at least 50% of trial participants have accumulated follow-up, the number of subjects that 
progress to this stage will be presented to the masked DSMB and formally asked whether they 
see a clinically meaningful difference between trial arms that trigger an unmasking of the 
DSMB. This interim safety analysis will adjust for factors related to mortality including age and 
presence of cardiopulmonary comorbidities.  
 
Table 1: 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 
Standard Plasma arm 
Expected Symptomatic  
N=15 participants 
Anti-SARS-CoV-2 Plasma arm 
Expected Symptomatic 
N=4 participants 
1.4% 
0.191 
0.055 
2.7% 
0.337 
0.10 
 
Table 2: For 1, 2, or 3 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 

CSSC-001 
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32
 
 
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  
0.07 
(0.002, 0.319) 
0.19 
0.25 
(0.006, 0.806) 
0.05 
2 
0.13 
(0.017, 0.405) 
0.018 
0.50 
(0.068, 0.932) 
0.001 
3 
0.20 
(0.043, 0.481) 
0.001 
0.75 
(0.194, 0.993) 
<0.0001 
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 75 participants in 
each arm and with the following assumptions 1) 20% of those in standard arm progress to 
symptomatic infection, 2) 5% in the anti-SARS-CoV-2 treatment arm are expected to progress to 
symptomatic infection, and 3) in an abundance of caution as a worst case scenario we will 
assume that 40% 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 1). Specifically, we would expect six participants in 
the control and two participants in the treatment arm to develop ARDS (table 4). After at least 
50% of trial participants have accumulated follow-up, the number of subjects that progress to 
this stage will be presented to the masked DSMB and formally asked whether they see a 
clinically meaningful difference between trial arms. 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 3: Binomial Probability of at least one ARDS case among each treatment arm for a 
worse case scenario of 40 and 50% of those developing symptoms progressing to ARDS 
Proportion Developing ARDS 
Standard Plasma arm 
Expected Symptomatic  
N=15 participants 
Anti-SARS-CoV-2 Plasma arm 
Expected Symptomatic 
N=4 participants 
40% 
>0.999 
0.870 
50% 
>0.999 
0.938 
 
Table 4: For a given number of observed ARDS cases among the control plasma 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 
symptomatic  
 
 
Standard Plasma Arm 
 
Anti-SARS-CoV-2 Plasma arm 

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33
# 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 
1  
0.07 
(0.002, 0.319) 
0.007 
0.25 
(0.006, 0.806) 
>0.99 
2 
0.13 
(0.017, 0.405) 
0.036 
0.50 
(0.068, 0.932) 
>0.99 
3 
0.20 
(0.043, 0.481) 
0.186 
0.75 
(0.194, 0.994) 
0.309 
4 
0.27 
(0.078, 0.551) 
0.430 
1.00 
(0.398, 1.00) 
0.026 
6 
0.40 
(0.163, 0.677) 
>0.99 
 
 
 
9 
0.60 
(0.323, 0.837) 
0.122 
 
 
 
10 
0.67 
(0.384, 0.882) 
0.061 
 
 
 
Upon completion of this review and receipt of the advice of the ISM or SMC, it will be 
determined if study entry or study dosing should be interrupted or if study entry and study 
dosing may continue according to the protocol. 
 
Halting Criteria/Rules for Subject Infusion 
Infusion of study drug will be halted if any of the following manifestations of anaphylaxis 
develop and will not be restarted: 
• 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 infusion.  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 
9. ETHICS/PROTECTION OF HUMAN SUBJECTS 
9.1. 
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 

CSSC-001 
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34
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 FWA00005752. 
 
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. 
 
9.2. 
Institutional Review Board 
The JHU IRB will review this protocol and all protocol-related documents and 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. 
9.3. 
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. The consent will 
explain that subjects may withdraw consent at any time throughout the course of the trial. 
Extensive explanation and discussion of risks and possible benefits of this investigation will be 
provided to the subjects in understandable language. Adequate time will be provided to ensure 
that the subject has time to consider and discuss participation in the protocol.  
 
The consent will describe in detail the study interventions/products/procedures and 
risks/benefits associated with participation in the study. The rights and welfare of the subjects 
will be protected by emphasizing that their access to and the quality of medical care will not be 
adversely affected if they decline to participate in this study. 
 
Johns Hopkins Remote Consent 
If preferred, participants will be offered the option of reviewing and signing the consent in 
person during the first in person visit. However, participants in this trial are initially under 
investigation for SARS-CoV-2 infection, which may necessitate remote consent.  At the Johns 
Hopkins site, when remote consent is preferred,  we will follow the IRB’s guidance as issued in 
the document “Informed Consent for Human Subjects Research at Johns Hopkins during the 

CSSC-001 
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35
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, 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 with EPIC access.  
 
A study team member with EPIC access completes the documentation in EPIC, by opening an 
encounter for the participant, and entering a note in the Progress Note/NoteWriter section.  
For COVID-19 Greater Than Minimal Risk patients, the study team member will enter 
“.COVID19RCHGREATERRISK” for the “COVID-19 Research Consent: Greater Than Minimal Risk” 
statement and hit “Enter.”  The study team member will fax the signed completed consent form 
to EPIC for upload (410-367-7382).  The study team must retain the completed consent 

CSSC-001 
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36
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 signed 
consent document or obtaining verbal confirmation from the LAR that he/she signed the 
consent form. 
 

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37
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. 
 
A study team member with EPIC access completes the documentation in EPIC, by opening an 
encounter for the participant, and entering a note in the Progress Note/NoteWriter section.  
For COVID-19 Greater Than Minimal Risk patients, the study team member will enter 
“.COVID19RCHGREATERRISK” for the “COVID-19 Research Consent: Greater Than Minimal Risk” 
statement and hit “Enter.”  The study team member will fax the signed completed consent form 
to EPIC for upload (410-367-7382).  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 will 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.  
 
Site 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.  
9.4. 
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 

CSSC-001 
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38
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 involved with the study, and the IRB. 
9.5. 
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. There 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. 
No human genetic testing will be performed on the samples without additional consent for 
those types of tests.   
 
Five ml of blood samples for future use 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 had 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. 
9.6. 
Data management and monitoring 
9.6.1. Source Documents 
 
The primary source documents for this study will be the subjects’ medical records. 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 in to 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 

CSSC-001 
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39
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. 
9.6.2. 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. 
9.6.3. 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. 
 
9.6.4. 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, 

CSSC-001 
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40
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 management file (eTMF). Site managers will communicate protocol 
amendments to 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 

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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. 
 
 
 
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