A Phase 2 Randomized, Double-blinded Trial to Evaluate the Efficacy and Safety of Human Anti-SARS-CoV-2 Plasma for Early Treatment of COVID-19
Phase: PHASE2
Conditions: SARS-CoV 2, COVID-19
Sponsor: Andrew Eisenberger

 
 
 
 
 
A Phase 2 Randomized, Double-blinded Trial to Evaluate the Efficacy 
and Safety of Human Anti- SARS-CoV-2 Plasma for Early Treatment of 
COVID-19 
 
 
Unique Protocol ID: AAAT0052 
NCT04390503 
 
Protocol (Population B) 
Version 8June2021 
 
 
 

Protocol (Population B) V 8JUNE2021 
 
1
PROTOCOL SUMMARY: 
 
Long title:  A Phase 2 Randomized, Double-blinded Trial to Evaluate the Efficacy 
and Safety of Human Anti- SARS-CoV-2 Plasma for Early Treatment of COVID-19 
 
Short title: Convalescent Plasma for Early Treatment of COVID-19  
 
Clinical Phase: 2 
 
IND Sponsor: Andrew B. Eisenberger, MD 
 
Principal Investigator: Jessica Justman, MD  
 
Conducted by: Columbia University 
 
Sample Size:  SARS-CoV-2 positive nasal swab at baseline: 150 subjects 
 
Study Population: High risk1 for severe COVID-19 case who are 18 years of age or 
older and SARS-CoV-2 positive and asymptomatic or mildly to moderately 
symptomatic at baseline.   
 
Study Duration: Accrual will take 4-6 months to complete and subjects will be 
followed for 90 days after enrollment.  
   
Study Design: Double-blinded, randomized control trial to assess the efficacy and 
safety of anti-SARS-CoV-2 convalescent plasma as early treatment. Participants will 
be randomized 2:1 to receive either convalescent plasma qualitatively positive for 
SARS-CoV-2 antibody (“anti-SARS-CoV-2 plasma”) or control (albumin 5%). 
 
Study Locations:   National Institute of Infectious Diseases Evandro Chagas (INI) at 
Oswaldo Cruz Foundation (Instituto Nacional de Infectologia Evandro Chagas-
FIOCRUZ (INI-FIOCRUZ)(Avenida Brasil, 4365 – Manguinhos, Rio de Janeiro, Rio de 
Janeiro, Brazil, 21040-900); Laboratorio de Pesquisa em DST e AIDS do 
IPEC/FIOCRUZ (LAPCLIN/AIDS) (Avenida Brasil, 4365 – Manguinhos, Rio de 
Janeiro, Rio de Janeiro, Brazil, 21040-900); Laboratório Central do Instituto 
Nacional de Infectologia Evandro Chagas (Avenida Brasil, 4365 – Manguinhos, Rio 
de Janeiro, Rio de Janeiro, Brazil, 21040-900); Laboratório de Virus Respiratórios e 
Sarampo (IOC/FIOCRUZ) (Avenida Brasil, 4365 – Manguinhos, Rio de Janeiro, Rio de 
Janeiro, Brazil, 21040-900); Laboratório Richet de Pesquisa e Fisiopatologia 
Humana Ltda (Av. das Américas, 4801 - loja D - Barra da Tijuca, Rio de Janeiro, Rio 
de Janeiro, Brazil, 21040-900); Agência Transfusional - Laboratório Central INI 
(Avenida Brasil, 4365 – Manguinhos, Rio de Janeiro, Rio de Janeiro, Brazil, 21040-
900);  
 
 
1 See Section 2.3.1 for definition of high risk  

Protocol (Population B) V 8JUNE2021 
 
2
 
Center for Infection and Immunity (722 West 168th Street, 17th Floor, NY, NY 
10032).  
 
Study Agent:  
 
• Anti-SARS-CoV-2 plasma: convalescent plasma (2 units of ~200-250 mL, 
total 400-500 mL) collected by apheresis from a volunteer who recovered 
from COVID-19 disease (collection and qualification covered by IRB protocol 
AAAS9845 [Convalescent plasma donors])) 
• Control (albumin 5%): 2 units of 250mL, total 500 mL  
 
Primary Efficacy Objective:  
To evaluate the efficacy of early treatment with anti-SARS-CoV-2 plasma 
versus control (albumin 5%) at day 28  
 
Primary Endpoint: The primary study endpoint will be a rating of disease severity 
on Day 28, or the last rating evaluated, using a seven-category severity scale: 
 
1. Not hospitalized, negative PCR for SARS-CoV-2 
2. Not hospitalized, positive PCR for SARS-CoV-2 without symptoms 
3. Not hospitalized, positive PCR for SARS-CoV-2 with symptoms 
4. Non-ICU hospitalization, not requiring supplemental oxygen 
5. Non-ICU hospitalization, requiring supplemental oxygen 
6. Requiring mechanical ventilation and/or in ICU 
7. Death 
 
Time to various dichotomizations on the severity scale. 
 
Primary Safety Objective: To evaluate the safety of anti- SARS-CoV-2 plasma 
versus control (albumin 5%)  
 
Primary Safety Endpoints: 
1. Cumulative incidence of grade 3 and 4 adverse events during the study 
period  
2. Cumulative incidence of serious adverse events during the study period 
 
Secondary Objectives:   
1. To compare the anti-SARS-CoV-2 titers between the recipients of anti-SARS-
CoV-2 plasma versus control (albumin 5%) at days 3, 7, 14, 28 and 90. 
2. To compare the proportion and duration of SARS-CoV-2 PCR positivity (RT 
PCR) between the recipients of the anti-SARS-CoV-2 plasma versus control 
(albumin 5%) at days 0, 3, 7, 14 and 28 
3. To compare the levels of SARS-CoV-2 RNA between the recipients of anti-
SARS-CoV-2 plasma and control (albumin 5%) at days 0, 3, 7, 14 and 28 
 

Protocol (Population B) V 8JUNE2021 
 
3
 
Exploratory Objective: 
1. 
To assess the correlation between SARS-CoV-2 PCR positivity from nasal  
swab specimens, based on RT PCR, and detection of viable SARS-CoV-2 from nasal 
swab specimens based on viral culture assays 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol (Population B) V 8JUNE2021 
 
4
LIST OF ABBREVIATIONS 
ADR: Adverse Drug Reaction 
ADE: Antibody-mediated enhancement of infection 
AE: Adverse Event/Adverse Experience 
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  
CRF: Case Report Form 
DMC: Data Management Center 
DSMB: Data and Safety Monitoring Board 
EUA: Emergency Use Authorization 
FDA: Food and Drug Administration 
GCP: Good Clinical Practice 
HBV: Hepatitis B virus 
HCIP: Human Coronavirus Immune Plasma 
HCV: Hepatitis C virus 
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 
ICU: Intensive Care Unit 
IEC: Independent ethics committee 
IND: Investigational New Drug Application 
IRB: Institutional review board 
ISBT: International Society of Blood Transfusion 
IWRS: Interactive web response system 
MERS: Middle East Respiratory Syndrome  
OP: Oropharyngeal 
RT-PCR: Reverse Transcriptase Polymerase chain reaction 
PK: Pharmacokinetic 
PPE: Personal Protective Equipment 
PTID: Participant ID number 
SAE: Serious adverse event 
SARS: Severe Acute Respiratory Syndrome 
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2 
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 
 
 

Protocol (Population B) V 8JUNE2021 
 
5
Table of Contents 
PROTOCOL SUMMARY: ............................................................................................................. 1 
LIST OF ABBREVIATIONS ......................................................................................................... 4 
1. 
BACKGROUND AND SCIENTIFIC RATIONALE ............................................................. 7 
1.1. 
Experience with the use of convalescent plasma against coronavirus 
diseases .................................................................................................................................................. 8 
1.2. 
Overview of known potential risks ................................................................................ 9 
1.3. 
Known potential benefits ............................................................................................... 10 
1.4. 
Albumin (Human) 5% as Control Study Product ................................................... 10 
1.5. 
SARS-CoV-2 testing............................................................................................................ 11 
2. 
INVESTIGATIONAL PLAN .............................................................................................. 12 
2.1. 
Study Objectives................................................................................................................. 12 
2.1.1. 
Primary Efficacy Objective: ....................................................................................................................... 12 
2.1.2. 
Primary Safety Objective: ........................................................................................................................... 12 
2.1.3. 
Secondary Objectives: .................................................................................................................................. 12 
2.1.4 
Exploratory Objectives: ............................................................................................................................... 12 
2.2    Definitions ................................................................................................................................ 13 
2.3    Study population .................................................................................................................... 13 
2.3.1 Inclusion Criteria for Enrollment .................................................................................................................. 13 
2.3.2 Exclusion Criteria for Enrollment ................................................................................................................. 14 
2.3.3 Recruitment Process: .......................................................................................................................................... 15 
2.3.3.1 Recruitment Process for Confirmed & Suspected COVID-19 Patients ...................................... 15 
2.3.3.2 Pre-Screening Potential Participants ....................................................................................................... 15 
2.3.4   Subject Withdrawal ........................................................................................................................................... 18 
2.3.5 Stratified Randomization .................................................................................................................................. 18 
2.3.6   Intervention .......................................................................................................................................................... 19 
2.4    Study Product Considerations .......................................................................................... 19 
2.4.1 Collection ................................................................................................................................................................. 20 
2.4.2 Collection and processing ................................................................................................................................. 20 
2.4.3 Control arm ............................................................................................................................................................. 21 
2.4.4 Rationale for dosing ............................................................................................................................................ 21 
2.5   Study drug administration .................................................................................................. 21 
3 STATISTICAL CONSIDERATIONS ..................................................................................... 22 
3.1 Design Overview ....................................................................................................................... 22 
3.2 Statistical Analysis ................................................................................................................... 23 
3.3 Power Consideration ............................................................................................................... 24 
4 
STUDY PROCEDURES ..................................................................................................... 24 
4.1 Day -1 to 0 (Recruitment  Pre Screen) .............................................................................. 24 
4.2 Day -1 to 0 (Screening Visit+) ............................................................................................... 25 
4.3 Day 0 + Baseline ........................................................................................................................ 26 
4.4 Day 1 .............................................................................................................................................. 26 

Protocol (Population B) V 8JUNE2021 
 
6
4.5 Day 3 ± 2....................................................................................................................................... 26 
4.6 Day 7 ± 1....................................................................................................................................... 27 
4.7 Day 14 ± 3 .................................................................................................................................... 27 
4.8 Day 28 ± 7 .................................................................................................................................... 27 
4.9 Day 60 ± 7 .................................................................................................................................... 27 
4.10 Day 90 ± 7 ................................................................................................................................. 28 
5 
EFFICACY, VIROLOGIC AND PK MEASURES ............................................................. 28 
6 
RISKS AND BENEFITS .................................................................................................... 28 
6.1 Potential benefits of treatment ........................................................................................... 28 
6.2 Potential risks of study procedures ................................................................................... 29 
6.3 
Potential risks of genetic testing ................................................................................. 29 
6.4 
Alternatives ......................................................................................................................... 29 
6.5 
Infection prevention and control measures ............................................................ 29 
6.6 
Safety monitoring .............................................................................................................. 30 
6.7 
Adverse Event Reporting ................................................................................................ 30 
7 
SAFETY OVERSIGHT ....................................................................................................... 33 
7.1 Monitoring Plan ........................................................................................................................ 33 
7.2 Study monitoring ...................................................................................................................... 34 
7.3 Halting Criteria for the Study ............................................................................................... 34 
8  
ETHICS/PROTECTION OF HUMAN SUBJECTS ......................................................... 35 
8.1 Ethical standard ........................................................................................................................ 35 
8.2 Institutional Review Board ................................................................................................... 36 
8.3 Informed consent process ..................................................................................................... 36 
8.4 Subject confidentiality ............................................................................................................ 36 
8.5 Future use of stored specimens .......................................................................................... 37 
8.6 Data management and monitoring .................................................................................... 38 
8.6.1 Source Documents ............................................................................................................................................... 38 
8.6.2 Data Management Plan ...................................................................................................................................... 38 
8.6.3 Study Record Retention ..................................................................................................................................... 39 
9  
REFERENCES .................................................................................................................... 39 
 
 
 

Protocol (Population B) V 8JUNE2021 
 
7
1. BACKGROUND AND SCIENTIFIC RATIONALE 
 
There are currently no proven treatments for mild coronavirus disease (COVID-19) 
nor are there prophylaxis options for those who have been exposed to the illness,  
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 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, 
Dadachova, & Pirofski, 2004; Casadevall & Scharff, 1995). Experience from prior 
outbreaks with other coronaviruses, such as SARS-CoV-1 shows that convalescent 
plasma contains neutralizing antibodies to the relevant virus (Zhang et al., 2005). 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 73 non-randomized study in Sierra Leone revealed a significant 
increase in survival for those 74 treated with convalescent whole blood relative to 
those who received standard treatment (Sahr et al., 2017).  
 
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 & Pirofski, 2003). 

Protocol (Population B) V 8JUNE2021 
 
8
As an example, passive antibody therapy for pneumococcal pneumonia was most 
effective when administered shortly after the onset of symptoms and there was no 
benefit if antibody administration was delayed past the third day of disease 
(Casadevall & Scharff, 1994). 
 
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. 
1.1. 
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 et al., 2005). 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 et al., 2005). 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 et al., 2018). 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 et al., 2016). Consistent with this 
point, an analysis of 99 samples of convalescent sera from patients with MERS 
showed that 87 had neutralizing antibody with a geometric mean titer of 1:61. This 
suggests that antibody declines with time and/or that few patients make high titer 
responses.  
 
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 (Gunn et 
al., 2018; van Erp, Luytjes, Ferwerda, & van Kasteren, 2019). There are reports that 
convalescent plasma was used for therapy of patients with COVID-19 in China 
during the current outbreak (Xinhua, 2020). 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. 
 
Convalescent plasma, compared to normal control plasma, was recently shown to 
confer lower mortality in New York City and Brazil among adults hospitalized with 

Protocol (Population B) V 8JUNE2021 
 
9
severe COVID-19; overall clinical status based on an ordinal scale at Day 28, 
however, did not differ between the two arms (O’Donnell, 2021)  
1.2. 
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 et al., 2020). 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 et al., 2015), and anecdotal evidence of its use 
in patients with COVID-19 (Xinhua, 2020), 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, Firestone, & Murphy, 2001). 
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 serum.  The antibodies used in this 
study will be derived from serum 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 

Protocol (Population B) V 8JUNE2021 
 
10
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. 
1.3. 
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 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. 
 
1.4. 
Albumin (Human) 5% as Control Study Product  
Participants randomized to the control arm will receive albumin (human) 5% 
infusion. The albumin will be prepared in bags that are as similar as possible to the 
bags used for plasma. The similar appearance of albumin and plasma will facilitate 
maintaining the blinded status of subjects and most of the study staff. Saline 

Protocol (Population B) V 8JUNE2021 
 
11
solution or standard of care (no intervention at all) would not allow the subjects to 
remain blinded and if not blinded, subjects who receive convalescent plasma may 
alter their behavior, resulting in additional exposure to SARS-CoV-2 and risk of 
COVID-19.   
 While normal plasma is only very rarely associated with adverse reactions such as 
febrile, allergic, anaphylactic and hemolytic events, the risks of albumin infusions 
are even less frequent. Albumin infusions are rarely associated with rigors, 
hypotension/decreased BP, tachycardia/increased heart rate, pyrexia, feeling cold 
(chills), nausea, vomiting, dyspnea/bronchospasm, rash/pruritus as per the package 
insert. The risk of an anaphylactoid reaction to albumin is not described in the 
package insert but was observed with only 0.01% of over 60,000 units of infused 
albumin [Gales BJ and Erstadt BL, 1993]. Since then, the purification methods for 
albumin have improved even further. There is no risk of an ABO mismatch with 
albumin. The main risk of albumin infusion, as with plasma, is related to the risk of 
rapid volume expansion.  The risk of volume overload will be mitigated by 
transfusing study product (CP plasma or albumin) over a 1- to 4-hour period, at the 
clinician’s discretion, depending on the subject’s medical history and clinical 
status.     
 
1.5. 
SARS-CoV-2 testing  
The Laboratorio de Pesquisa em DST e AIDS do IPEC/FIOCRUZ (LAPCLIN/AIDS),  
Laboratório de Virus Respiratórios e Sarampo (IOC/FIOCRUZ)  or the Center for 
Infection and Immunity (CII) laboratory  will conduct both a quantitative PCR assay 
and serologic assay. No clinical decisions will be made based on these results.  
 
For asymptomatic individuals, PCR testing alone will be used for screening. For 
symptomatic individuals, two swabs will be collected from each potential 
participant, one for ID NOW (or comparable rapid antigen test) and one for a PCR-
based test. The ID NOW test results are available in minutes and will make 
recruitment more efficient. In view of the high specificity of the ID NOW test 
(99.7%) (Dinnes, et al., 2021), if either the ID NOW and/or the PCR test results is 
positive, the individual will be confirmed as SARS-CoV-2 positive.  
 
PCR testing will be conducted for all participants at screening, days 0, 3, 7, 14 and 28 
and the viral load will be estimated. Results from the baseline ID NOW COVID-19 or 
PCR tests will be reported to subjects as SARS-CoV-2 positive or negative.  
Subsequent PCR results will not be shared with the subjects or the clinical research 
team in order to reduce bias. 
 
ID NOW COVID-19 assay performed on the ID NOW Instrument is a rapid molecular 
in vitro diagnostic test utilizing an isothermal nucleic acid amplification technology 
intended for the qualitative detection of nucleic acid from the SARS-CoV-2 viral RNA 
in direct nasal, nasopharyngeal or throat swabs from individuals who are suspected 

Protocol (Population B) V 8JUNE2021 
 
12
of COVID-19 by their healthcare provider within the first seven days of the onset of 
symptoms.  ID NOW COVID-19 received Emergency Use Authorization from the US 
FDA in September 2020. 
2. INVESTIGATIONAL PLAN 
2.1. 
Study Objectives 
2.1.1. Primary Efficacy Objective:  
The primary study endpoint will be a rating of disease severity on Day 28, or 
last rating evaluated, using a seven-category severity scale:  
 
1. 
Not hospitalized, negative PCR for SARS-CoV-2 
2.   
Not hospitalized, positive PCR for SARS-CoV-2 without symptoms 
3. 
Not hospitalized, positive PCR for SARS-CoV-2 with symptoms 
4. 
Non-ICU hospitalization, not requiring supplemental oxygen 
5. 
Non-ICU hospitalization, requiring supplemental oxygen 
6. 
Requiring mechanical ventilation and/or in ICU 
7. 
Death 
 
Time to various dichotomizations on the severity scale will be assessed 
2.1.2. Primary Safety Objective:  
To evaluate the safety of anti- SARS-CoV-2 plasma versus control (albumin 
5%) 
2.1.3. Secondary Objectives: 
1. To compare the anti-SARS-CoV-2 titers between the recipients of anti-SARS-
CoV-2 plasma versus control (albumin 5%) at days 3, 7, 14, 28 and 90 
2. To compare the proportion and duration of SARS-CoV-2 PCR positivity (RT-
PCR) between the recipients of the anti-SARS-CoV-2 plasma versus control 
(albumin 5%) at days 0, 3, 7, 14 and 28 
3. To compare the levels of SARS-CoV-2 RNA between the recipients of anti-
SARS-CoV-2 plasma and control (albumin 5%) at days 0, 3, 7, 14 and 28 
2.1.4 Exploratory Objectives: 
To assess the correlation between SARS-CoV-2 PCR positivity from nasal 
swab2 specimens, based on RT PCR, and detection of viable SARS-CoV-2 from 
nasal swab specimens based on viral culture assays. 
 
 
2 A nasopharyngeal (NP) or nasal mid-turbinate (NMT) swab, also called a Deep Nasal Swab (may be self-
collected by each research subject as per CDC guidance; https://www.cdc.gov/coronavirus/2019-
ncov/lab/guidelines-clinical-specimens.html) are both acceptable 

Protocol (Population B) V 8JUNE2021 
 
13
2.2    Definitions  
 
I. 
Enrolled: from time consented to participate until designated as a screen 
failure or have been discontinued from the study or completed it.  
II. 
Randomized: when a randomization PTID number has been assigned 
III. 
Screen Failures: signed informed consent and received a screening PTID, 
but then determined to be ineligible or withdrew before being 
randomized 
IV. 
Discontinued: randomized, but then withdrawn by investigator or 
withdrew consent 
V. 
Completed: Subjects are considered completed when they are followed 
through to day 28 or if they die before day 28 
2.3    Study population  
2.3.1 Inclusion Criteria for Enrollment  
 
1. Subjects must be 18 years of age or older 
2. a. Recent close contact3* with a person with COVID-19, i.e. last 
close contact occurred within 7 days of anticipated infusion of 
study product.  It is anticipated that most contacts will be 
household contacts with extensive interaction.  All must meet the 
CDC criteria for close contacts. This includes healthcare workers at 
higher risk of developing severe disease.  
OR 
b. Recent self-reported or documented evidence of infection by 
nasal swab ID NOW or PCR that is positive for SARS-CoV-2, i.e., 
nasal sample was collected within 7 days or 10 days of anticipated 
infusion of study product for those who are asymptomatic or 
symptomatic, respectively. 4  
3. Evidence of infection by nasal swab ID NOW or PCR that is positive 
for SARS-CoV-2 at screening visit5  
 
 
3 Close contact is defined by CDC as being within approximately 6 feet (2 meters) of a COVID-19 case 
for a prolonged period of time (without PPE); close contact can occur while caring for, living with, 
visiting, or sharing a healthcare waiting area or room with a COVID-19 case. 
4 7 days (if asymptomatic at prescreening) or 10 days (if minimally to moderately symptomatic during 
prescreening) are based on the number of days from specimen collection date to anticipated infusion date 
5 A repeat ID NOW and PCR at screening is required for all participants. However, for participants with 
documented evidence of infection by nasal swab PCR that is positive for SARS-CoV-2  in the prior week, a 
positive swab is not required to enroll the participant since they were already positive in the past week and 
will be tested by PCR during the Infusion Visit.  At screening, two swabs will be collected from each 
participant, one for ID NOW (or comparable rapid antigen test) and one for a PCR-based test. If ID NOW 
is positive, it will not be necessary to wait for the PCR based test result to confirm the positive. If the ID 
NOW is negative, it will be necessary to wait for the PCR test result: PCR negative will mean individual is 
not eligible and PCR positive will mean they are potentially eligible if all the other inclusion criteria are 
met. 

Protocol (Population B) V 8JUNE2021 
 
14
4. May or may not be hospitalized 
5. No symptoms or no more than 7 days of moderate symptoms at 
the time of screening. 
Moderate symptoms6 may include: 
a. Moderate rhinorrhea 
b. Moderate sore throat or throat irritation 
c. Moderate cough 
d. Moderate fatigue (may interfere with ability to perform 
ADLs) 
e.  Moderate chills, measured temperature and/or feeling 
feverish, muscle pain  
6. Calculated Risk Score for severe COVID-19 [based on CDC 
description7] of 0 points if on supplemental oxygen at enrollment; 
otherwise Calculated Risk Score of   1.  
• Age 65-74: 1 point 
• Age 75:  2 points 
• Known cardiovascular disease (including hypertension): 1 
point 
• Diabetes mellitus: 1 point  
• Pulmonary disease (COPD, moderate to severe asthma, 
current smoking or other): 1 point 
• Morbid obesity: 1 point 
• Immunocompromised state: 1 point 
Received a bone marrow or solid organ transplant at any 
time, received chemotherapy for a malignancy within the 
past 6 months, has an acquired or congenital 
immunodeficiency, currently receiving immunosuppressive 
or immune modulating medications, HIV with non-
suppressed viral load and/or CD4+ T cell count <200 
cells/mL). 
7. Those who do not require more than 4 LPM of supplemental 
oxygen at enrollment. 8 
 
2.3.2 Exclusion Criteria for Enrollment 
 
1. Receipt of any blood product in past 120 days. 
2. Psychiatric or cognitive illness or recreational drug/alcohol use 
that in the opinion of the principal investigator, would affect 
subject safety and/or compliance. 
 
 
6 Moderate symptoms are rated by the participant as moderate and may interfere with normal daily 
activities; https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50 
7 https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/groups-at-higher-risk.html 
8 Nasal cannula permitted for inclusion in study  

Protocol (Population B) V 8JUNE2021 
 
15
3. Confirmed or self-reported presumed COVID-19, with 
symptoms that began more than 7 days prior to enrollment, 
and SARS-CoV-2 ID NOW or PCR positive sample that was 
collected more than 7 days prior to anticipated infusion for an 
asymptomatic participant or more than 10 days prior to 
anticipated infusion for a patient with mild to moderate 
symptoms at screening. 
4. Symptoms consistent with COVID-­­19 infection that are more 
than moderate (as defined above) at time of screening.   
5. Symptoms that have worsened in the period between screening 
and enrollment such that the subject is deemed to be medically 
unstable on the day of planned enrollment.   
6. History of allergic reaction to transfusion blood products  
7. Inability to complete infusion of the product within 48 hours 
after randomization. 
8. Resident of a long term or skilled nursing facility 
9. Known prior diagnosis of IgA deficiency 
10. Participation in another clinical trial of anti-viral agent(s) for 
COVID-19 
 
2.3.3 Recruitment Process:  
 
Recruitment for this protocol will involve approaching two groups of 
subjects: 1) patients with confirmed COVID-19 (asymptomatic or mildly to 
moderately symptomatic) and 2) patients with suspected COVID-19 
(asymptomatic or mildly to moderately symptomatic).  
 
2.3.3.1 Recruitment Process for Confirmed & Suspected COVID-19 
Patients  
Patients (including healthcare workers) who are asymptomatic or have mild 
to moderate symptoms (see Section 2.3.1.5) and have confirmed OR 
suspected COVID-19 will be approached by study staff, in-person, to 
introduce the study and see if they are interested in participating.  Study 
staff may opt to phone potential participants after the ID NOW or PCR result 
becomes available to complete the assessment of eligibility and schedule the 
screening visits.   
2.3.3.2 Pre-Screening Potential Participants  
Potential participants will be approached by study staff and introduced to 
the study. The study staff will ascertain whether: 
1. the potential subject has interest in the study and is willing to be 
screened, AND   

Protocol (Population B) V 8JUNE2021 
 
16
2. the potential subject has had recent close contact with a COVID-19 
case (see Section 2.3.1.2) or has recent self-reported or documented 
evidence of infection by nasal swab ID NOW or PCR that is positive for 
SARS-CoV-2, AND  
3. the potential subject is at risk for severe COVID-19 disease based on 
age and/or their medical co-morbidities (see Section 2.3.1.6), AND 
4. the potential subject is currently asymptomatic or minimally or 
moderately symptomatic of COVID-19 disease 
 
Potential subjects who meet the above criteria and have a risk score for 
COVID-19 [0 risk if on supplemental oxygen at enrollment; otherwise > 1 
risk] will be invited to attend a screening visit at the site within the next 1-2 
business days.   
After the study is explained in detail, written consent will be obtained, and 
screening questionnaires, locator forms and required lab work will be 
completed.  Those who provide consent will be eligible to enroll in the study 
when their screening nasal swab is positive for SARS CoV-2. 

Protocol (Population B) V 8JUNE2021 
 
17
Table: Schedule of Events 
 
Study period 
Screen 
Baseline 
Infusion 
Follow up 
Day 
-1 to 0 
0 
0 
1 
3±2 
7±1 
14±3 
28±7 
60±7 
90±7 
Procedure 
 
 
 
 
 
 
 
 
 
 
Eligibility 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Demographic and 
Medical history 
x 
 
 
 
 
 
 
 
 
 
COVID-19 symptom 
screen 
x 
 
x 
 
 
 
 
 
 
 
SARS-CoV-2 ID NOW 
and RT-PCR obtained 
for eligibility 
x9 
 
 
 
 
 
 
 
 
 
Pregnancy test 10 
x 
 
 
 
 
 
 
 
 
 
ABO11 
x 
 
 
 
 
 
 
 
 
 
Study Drug  Administration 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
Drug infusion 
 
 
x 
 
 
 
 
 
 
 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
COVID-19 Symptom 
screen 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
Other symptoms 
screen 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
Concomitant 
medications 
x 
 
x 
x 
x 
x 
x 
 
 
 
Vital signs 
x 
 
x12 
 
x 
x 
x 
 
 
 
Targeted physical 
examination  
x 
 
x 
 
 
x 
x 
 
 
 
 
 
9 A repeat ID NOW and PCR at screening is required for all participants. However, for participants with 
documented evidence of infection by nasal swab PCR that is positive for SARS-CoV-2 in the prior week, a 
positive swab is not required to enroll the participant since they were already positive in the past week and 
will be tested by PCR during the Infusion Visit. At screening, two swabs will be collected from each 
participant, one for ID NOW (or comparable rapid antigen test) and one for a PCR-based test. If ID NOW 
is positive, it will not be necessary to wait for the PCR based test result to confirm the positive. If the ID 
NOW is negative, it will be necessary to wait for the PCR test result: PCR negative will mean individual is 
not eligible and PCR positive will mean they are potentially eligible if all the other inclusion criteria are 
met. 
10 Urine pregnancy test for women of childbearing potential 
11 Assessment of ABO type on file; requires two tubes of blood drawn 5 minutes apart, as per NYP Blood Bank 
procedures 
12 Vital sign testing: Immediately prior to infusion, 10-20 minutes after start of infusion, at completion of 
infusion and 15-60 minutes after the end of the infusion 

Protocol (Population B) V 8JUNE2021 
 
18
Study period 
Screen 
Baseline 
Infusion 
Follow up 
Day 
-1 to 0 
0 
0 
1 
3±2 
7±1 
14±3 
28±7 
60±7 
90±7 
Procedure 
 
 
 
 
 
 
 
 
 
 
Assessment of 
composite outcome of 
disease severity13 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Adverse event 
monitoring 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Laboratory testing  
 
CBC and CMP14 
x 
 
 
 
 
x 
x 
 
 
 
SARS-CoV-2 RT-
PCR15,16  
x 
 
x 
 
x 
x 
x 
x 
 
 
SARS-CoV-2 antibody 
x 
 
 
 
x 
x 
x 
x 
 
x 
Blood for future 
testing  
x 
 
 
 
x 
x 
x 
x 
 
 
Viral culture17 
x 
 
 
 
 
x 
 
 
 
 
Blood for PBMC for 
future testing 
x 
 
 
 
 
 
 
 
 
 
 
2.3.4   Subject Withdrawal 
 
1. Subjects can terminate study participation and/or withdraw consent at 
any time without prejudice.  
2. Randomized subjects who withdraw from the study will not be replaced. 
3. The investigator may withdraw subjects if they are non-compliant with 
study procedures or if the investigator determines that continued 
participation in the study would be harmful to the subject or the integrity 
of the study data 
4. Discontinuation of the study: The study sponsor, FDA and IRB all have 
the right to terminate this study at any time 
 
2.3.5 Stratified Randomization 
 
1. 
Subjects enrolled in the study will be stratified and randomized 
using an interactive web- based system 
 
 
13 Assessment evaluates whether subject has shifted from “no clinical or laboratory evidence of COVID-19 
infection to any of the composite outcomes of disease severity 
14 Comprehensive metabolic panel 
15 Nasal swab 
16 Includes sequencing for viral variants  
17 10 % sample of the nasal swabs 

Protocol (Population B) V 8JUNE2021 
 
19
2. 
Subjects will be stratified by steroid administration (prior oral or IV 
steroids within prior 2 weeks at time of enrollment or prior inhaled 
steroids within prior 24 hours at time of enrollment) and by 
vaccination status (prior COVID-19 vaccine at time of enrollment) 
and then randomized in a 2:1 ratio to either CP or albumin 5%  
 
 
2.3.6   Intervention 
 
I. 
Subjects will be randomized within each population in a 2:1 ratio to 
receive anti-SARS-CoV-2 plasma versus control (albumin 5%). 
II. 
Study drug: The investigational product is anti-SARS-CoV-2 plasma. 
Patients identified as having recovered from COVID-19 will serve as 
potential donors. Testing will confirm presence of anti-SARS-CoV-2 
antibody prior to donation. Plasma donors 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. 
Active arm will receive 2 units (200 – 250 mL each, 400-500 mL total) of 
anti-SARS-CoV-2 plasma from the same donor. These units have been 
verified to have a neutralizing titer of 1:320 each.  
IV. 
Control arm will receive 2 units of 250mL (500 mL total) of albumin 5%  
V. 
Both active and control drugs will be in standard plasma unit bags, with a 
study-specific ISBT label with the statement, “Caution: New Drug--
Limited by Federal (or United States) law to investigational use.” 
 
2.4    Study Product Considerations  
 

Protocol (Population B) V 8JUNE2021 
 
20
The preparation of the anti-SARS plasma will take place at the New York Blood 
Center and the CUIMC-NYPH Blood Bank will dispense the plasma products to Brazil 
sites. The plasma collection procedures are not part of this research protocol and 
are described in separate protocols, which has separate IRB approval (AAAS9845). 
The description below provides a summary of study product considerations as 
context.     
2.4.1 Collection 
 
Donors will be pre-qualified for blood donation via study procedures 
described in IRB protocol AAAS9845. This will ensure that all convalescent 
plasma units in the CUIMC-NYPH Blood Bank will have high titers of IgG. All 
activities pertaining to the collection and processing of plasma will take place 
at [New York Blood Center/NYBC]. NYBC is one of the largest independent, 
community-based, nonprofit blood centers in the United States. It is 
operational in multiple states i.e. it is not confined to New York. NYBC has a 
longstanding research program and is well versed in the regulatory and 
ethical aspects of research, including clinical trials. The organization is FDA-
licensed to produce convalescent plasma and AABB (American Association of 
Blood Banks) accredited, attesting to robust quality oversight of all 
operations.  
 
2.4.2 Collection and processing 
 
• Standard apheresis plasma collection will be performed per routine standard 
operating procedure at the collection facility (NYBC). 
• As per routine practice, samples will be collected at time of donation for 
testing for transfusion-transmissible infections (all donors), ABO and red cell 
antibodies (all donors) and HLA antibodies (female donors with prior 
pregnancies).  
• Target collection volume: ~450-600mL; this will allow for later splitting 
(separation) into 200-250mL daughter units. 
• The plasma will be processed per routine practice; it will be frozen within 24 
hrs of collection per AABB standards. 
• The plasma will be maintained in quarantine at the blood center pending 
laboratory test results (i.e. infectious screening, ABO and RhD status, Red cell 
and HLA antibodies). 
• If laboratory testing is acceptable (i.e. negative infectious and antibody 
screening), the products will be distributed to hospital blood bank for 
storage.  
• In the event of an abnormal test result, the product will be discarded and the 
donor will be notified by the blood center as is standard practice.  

Protocol (Population B) V 8JUNE2021 
 
21
2.4.3 Control arm 
 
The control (albumin 5%) will be prepared by the Brazil Research Pharmacy 
in bags that are identical to the bags used for plasma. 
 
2.4.4 Rationale for dosing 
 
We will infuse 2 units (200-250 mL each, 400-500 mL total) of plasma with 
an anti-SARS-CoV-2 antibody 1:320 and 2 units of 250mL of albumin 5%, 
500 mL total. Assuming a plasma volume of 3,500 ml, 500 ml of plasma with 
an antiviral titer of 1:320 would yield a final antiviral titer of 1:45. Dosing is 
based on a previous report wherein convalescent plasma therapy showed 
efficacy in COVID-19 patients following infusion of 200ml of convalescent 
plasma with a titer of 1:640 (Duan et al.,  2020).  We have not been able to 
identify sufficient numbers of plasma units with this titer to conduct this 
trial. Hence, we will employ two units with neutralizing titers of 1:320.    
 
 
 
 
2.5   Study drug administration 
 
• Drug will be administered within 48 hours (24 hours if possible) of 
randomization 
• Infusion rate  250 mL/hour at physician discretion 
• Pretreatment to minimize transfusion reactions (e.g. acetaminophen, 
diphenhydramine) will not be given, but will be available as needed to 
treat fever or allergic reactions. For severe allergic reactions 
corticosteroids (e.g., 125 mg methylprednisolone IV or comparable) may 
be used. For rare severe anaphylaxis, epinephrine will be available.  
• If an AE develops during infusion, the infusion may be slowed or stopped 
as per investigator’s decision.  
o Most reactions to plasma are relatively minor and the infusion can 
generally be continued. Infusion site burning and non-allergic 
systemic effects can generally be managed with slowing of the 
infusion. Infusion is generally stopped in cases of itching; 
participant is treated and then infusion cautiously re-started. 
o Severe allergic reactions generally require discontinuation of the 
infusion. These include: 
▪ Respiratory compromise: dyspnea, wheezing, stridor, 
hypoxemia 

Protocol (Population B) V 8JUNE2021 
 
22
▪ 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 > 130 
bpm; 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 
o Concomitant medications used during the infusion will be 
documented on the CRF 
3 STATISTICAL CONSIDERATIONS 
3.1 Design Overview 
This is a double-blinded, randomized phase 2 trial to evaluate the efficacy and 
safety of human SARS-CoV-2 immune plasma in individuals who are close 
contacts to person with COVID-19 within 7 days according to the CDC definition. 
This will also serve as an internal pilot in the seamless phase 2/3 study.  
 
Eligible participants will be randomized to receive high-titer anti-SARS-CoV-2 
immune plasma or control (albumin 5%) in a 2:1 ratio.  We plan to enroll a total 
of 150 participants, with a maximum of 100 receiving the plasma and 50 
receiving the control.    
 
Each participant will be followed for 28 days after randomization and treatment, 
and will tested and evaluated at baseline and on Days 3, 7, 14, 28 using a seven-
category severity scale: 
 
1. Not hospitalized, negative PCR for SARS-CoV-2 
2. Not hospitalized, positive PCR for SAR-CoV-2 without symptom 
3. Not hospitalized, positive PCR for SAR-CoV-2 with symptoms 
4. Non-ICU hospitalization, not requiring supplemental oxygen 
5. Non-ICU hospitalization, requiring supplemental oxygen 
6. Requiring mechanical ventilation and/or in ICU 
7. Death 
 
The primary study endpoint is the rating on Day 28, or last rating evaluated. We 
will also consider time to various dichotomizations on this scale as secondary 

Protocol (Population B) V 8JUNE2021 
 
23
outcomes, including time to death, time to requiring critical care, and time to 
requiring hospitalization 
 
Other endpoints include:  
• Anti-SAR-CoV-2 titers (Days 3, 7, 14, 28, 90 in addition to baseline) 
• SAR-CoV-2 PCR positivity (Days 0, 3, 7, 14, 28 in addition to baseline) 
• SAR-CoV-2 RNA (Days 0, 3, 7, 14, 28 in addition to baseline) 
 
Exploratory objective: 
• To assess the correlation between SARS-CoV-2 PCR positivity 
from nasal swab specimens, based on RT PCR, and detection of 
viable SARS-CoV-2 from nasal swab specimens based on viral 
culture assays 
 
Serious adverse events, and grades ≥3 adverse events will be monitored during 
the study period. 
3.2 Statistical Analysis 
 
Primary Analysis and go/no-go decision: The severity scale of the two groups 
will be compared using stratified, Mann Whitney test. Specifically, a one-sided 
P<0.15 favoring the immune plasma arm will constitute a “go decision” in this 
phase 2 trial, suggesting evidence of promise for further investigation in an 
expanded Phase 3 study.  The results in this trial will then be used to plan the 
Phase 3 sample size, with possibility that the data in this Phase 2 trial will be 
included in the final analysis using adjusted P values.  Details of sample size re-
estimation and adjusted analysis, as well as the final statistical analysis plan, will 
be determined before unblinding the study data.  
 
This analysis will be intent-to-treat.  Given the short study duration and the 
nature of the treatment, however, we anticipate minimal non-compliance and 
loss to follow-up. 
 
Subgroup Analysis: If the stratified analysis reaches the go decision, with P<0.15, 
we will explore the treatment effect within each stratum using Mann Whitney 
test. 
 
Secondary Analyses: All secondary efficacy analyses will be intent-to-treat.  
Time-to-event variables (e.g. time to death) will be analyzed using Cox 
proportional hazard model.  Longitudinal data collected over multiple days (e.g., 
PCR positivity) will be analyzed explored using generalized linear mixed models.  
Treatment effects on these variables will be estimated with 95% confidence 
intervals.   
 

Protocol (Population B) V 8JUNE2021 
 
24
Safety Analyses: Serious adverse events will be summarized by grades and types 
using proportions and 95% confidence intervals for the two study arms, and the 
two arms will be compared using Fisher’s exact test. 
 
3.3 Power Consideration 
 
Assuming a shift odds ratio of 2 under a proportional odds model on the 
severity rating scale, with a sample size of 150, the study will have 74% to 
80% power of reaching the go decision in the scenarios we considered. The 
actual power will depend the distribution of the severity scale in the control 
arm. Table 2 gives the power of the two extreme scenarios: Scenario 1 
describes scenario with higher rates for more severe outcomes, and Scenario 
2 with majority of participants remaining or becoming PCR negative; the 
outcome distributions are identical between the two strata in these 
scenarios. We have evaluated the power for in-between scenarios and 
scenarios where non-infected and infected strata are different; the power is 
within the range 74% and 80% in all scenarios we have considered. 
 
Table 2: Power Calculation & Distribution of severity rating scale in the 
study  
Category 
Scenario 1 
 
Scenario 2 
 
Control 
(albumin 
5%) 
Immune 
plasma 
 
Control 
(albumin 
5%) 
Immune 
plasma 
PCR negative 
0% 
0% 
 
60% 
75% 
PCR positive, asymptomatic 
0% 
0% 
 
0% 
0% 
PCR positive with symptom 
70% 
82% 
 
28% 
19% 
Hospitalization 
10% 
7% 
 
4% 
2% 
Hospitalization requiring 
oxygen 
10% 
6% 
 
4% 
2% 
ICU/ventilation 
5% 
3% 
 
2% 
1% 
Death 
5% 
2% 
 
2% 
1% 
Study power 
74% 
 
80% 
 
 
4 STUDY PROCEDURES 
 
4.1 Day -1 to 0 (Recruitment  Pre Screen) 
 
1. Script information about study protocol 
2. Verification that the potential subject has interest in the study and is 
willing to attend a screening visit at the site on the next day 
3. Verification that the potential subject had significant close contact with 
the COVID-19 case within the prior seven days OR has self-reported or 
documented recent evidence of infection by nasal swab (ID NOW or PCR) 
that is positive for SARS-CoV-2  

Protocol (Population B) V 8JUNE2021 
 
25
4. Medical eligibility questionnaire 
• Ascertainment that the potential subject has risks for severe 
COVID-19 disease based on CDC risk criteria-age of the potential 
subject and their medical co-morbidities (hypertension, 
cardiovascular disease, pulmonary disease [including COPD or 
moderate to severe asthma], other immune suppressing 
condition) 
• Verification that the potential subject is currently asymptomatic or 
minimally or moderately symptomatic of COVID-19 disease for < 7 
days 
 
4.2 Day -1 to 0 (Screening Visit+) 
 
 
1. Informed consent (obtained before performing study related 
activities) and assignment of screening PTID 
2. New York Presbyterian Hospital (NYPH) blood transfusion 
consent (this is the standard procedure for all transfusions of 
blood products at NYPH)  
3. Verification of eligibility (inclusion/exclusion) 
4. Locator form 
5. Demographics (age, sex ethnicity, race) 
6. Medical history (timing of exposure to COVID-­­19 source patient, acute 
and chronic medical condition, medications, allergies. Any medical 
condition arising after randomization and infusion of study product 
should be recorded as AE 
7. COVID-­­19 symptom screen (fevers, cough, rhinorrhea, sore throat, 
diarrhea, shortness of breath, ADLs) 
8. Vital signs (pulse, blood pressure, weight, height, temperature, oxygen 
saturation) 
9. Targeted physical examination 
10. ID NOW COVID-19 and PCR test to confirm positivity for SARS-CoV-218  
11. Laboratory Evaluation 
• SARS-CoV-2 testing (RT-­­PCR) from nasal swab (10% of the swabs 
will also be submitted for viral culture). 
• ABO Blood typing (two tubes), CBC, comprehensive metabolic panel 
• Serological testing: anti-­­SARS CoV-­­2 titers 
• Blood samples for future studies, including sample for peripheral 
blood mononuclear cells 
• Urine or serum pregnancy test for females of childbearing potential. 
 
 
18 At screening, two swabs will be collected from each participant, one for ID NOW (or comparable rapid 
antigen test) and one for a PCR-based test. If ID NOW is positive, it will not be necessary to wait for the 
PCR based test result to confirm the positive. If the ID NOW is negative, it will be necessary to wait for the 
PCR test result: PCR negative will mean individual is not eligible and PCR positive will mean they are 
potentially eligible if all the other inclusion criteria are met. 

Protocol (Population B) V 8JUNE2021 
 
26
Results from laboratory tests obtained up to 7 days before 
enrollment may be used for the pregnancy test. 
• Volume overload 
o Volume status will be assessed via  (1) medical history: history of 
congestive heart failure and use of heart failure medications; and (2) 
physical exam:  vital signs, lung exam, assessment for peripheral 
edema. 
o Enrollment will be deferred for patients who have active volume 
overload in order to avoid cardiovascular decompensation from the 
receipt of additional volume. Once the patient’s volume status has 
improved, enrollment may then proceed. [note this is not an 
exclusion] 
o For these patients, the potential risk of a recurrence of volume 
overload will be mitigated by infusing the plasma or albumin (a total 
of 400-500 mL) more slowly, i.e., over 2 - 4 hours. 
4.3 Day 0 + Baseline 
 
1. Subjects will be contacted and scheduled for an infusion window 
2. Randomization will then be done using an interactive web-based system 
to receive study convalescent plasma (CP) versus control (albumin 5%) 
at a 2:1 ratio 
3. Study Product Administration: Two units of immune plasma or control 
(albumin 5%) 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 
between 15-60 minutes after the end of the infusion.  
4. COVID-19 symptom screen (fevers, cough, shortness of breath) 
5. Assessment of clinical status (composite outcome of disease severity) 
6. New medical conditions, concomitant medication, AE evaluation 
7. Physical examination 
8. SARS-CoV-2 testing (RT-PCR) from nasal samples 
 
For follow-up visits, home visits by qualified phlebotomists and/or visiting nurses 
will be permitted.  
 
4.4 Day 1  
    
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (composite outcome of disease severity) 
3. New medical conditions, AE evaluation 
4.5 Day 3 ± 2 
 
1. Vital signs  

Protocol (Population B) V 8JUNE2021 
 
27
2. COVID-19 symptom screen (fevers, cough, shortness of breath) 
3. Assessment of clinical status (composite outcome of disease severity) 
4. New medical conditions, AE evaluation 
5. SARS-CoV-2 testing (RT-PCR) from nasal samples  
6. Serological testing: anti-SARS-CoV-2 titers  
7. Stored samples for future studies 
4.6 Day 7 ± 1 
 
1. Vital signs  
2. COVID-19 symptom screen (fevers, cough, shortness of breath) 
3. Assessment of clinical status (composite outcome of disease severity) 
4. New medical conditions, AE evaluation 
5. Targeted physical examination 
6. SARS-CoV-2 testing (RT-PCR) from nasal samples  
7. Serological testing: anti-SARS-CoV-2 titers  
8. Comprehensive metabolic panel and CBC 
9. Stored samples for future studies 
4.7 Day 14 ± 3 
 
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (composite outcome of disease severity) 
3. New medical conditions, AE evaluation 
4. Targeted physical examination 
5. CBC, comprehensive metabolic panel 
6. SARS-CoV-2 testing (RT-PCR) from nasal samples  
7. Serological testing: anti-SARS-CoV-2 titers  
8. Stored samples for future studies 
4.8 Day 28 ± 7 
 
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (composite outcome of disease severity) 
3. New medical conditions, AE evaluation 
4. SARS-CoV-2 testing (RT-PCR) from nasal samples  
5. Serological testing: anti-SARS-CoV-2 titers  
6. Stored samples for future studies 
 
       4.9 Day 60 ± 7  
 
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (composite outcome of disease severity) 

Protocol (Population B) V 8JUNE2021 
 
28
3. New medical conditions, AE evaluation 
4.10 Day 90 ± 7 
 
1. Serological testing: anti-SARS-CoV-2 titers  
 
+ In order to minimize exposure to SARS-Cov-2 virus, at the clinician’s 
discretion, face to face interactions may be minimized by collecting 
information by phone or by telemedicine (Zoom HIPAA compliant 
conferencing) 
 
5 EFFICACY, VIROLOGIC AND PK MEASURES 
 
5.1 Clinical Efficacy (composite outcome of disease severity) 
 
1. Not hospitalized, negative PCR for SARS-CoV-2 
2. Not hospitalized, positive PCR for SARS-CoV-2 without symptom 
3. Not hospitalized, positive PCR for SARS-CoV-2 with symptoms 
4. Non-ICU hospitalization, not requiring supplemental oxygen 
5. Non-ICU hospitalization, requiring supplemental oxygen 
6. Requiring mechanical ventilation and/or in ICU 
7. Deceased 
 
 
5.2 Virologic measures  
 
• Rates and duration of SARS-CoV-2 PCR positivity (RT PCR) at days 0, 3, 7, 14 
and 28 
• Peak quantity levels of SARS-CoV-2 RNA at days 0, 3, 7,14 and 28 
• Culture positivity at baseline and at day 7 in a subset of specimens 
• Correlation between viral culture positivity and PCR positivity for SARS-CoV-
2  
 
5.3 Serologic titers  
 
• Serologic measures: Anti-SARS-CoV-2 titers at days 3, 7, 14, 28 and 90 days 
after infusion. 
 
6 RISKS AND BENEFITS 
6.1 Potential benefits of treatment 
 

Protocol (Population B) V 8JUNE2021 
 
29
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.  
6.2 Potential risks of study procedures 
1. Risks of plasma: Fever, chills, rash, headache, serious allergic reactions, 
TRALI, TACO, transmission of infectious agents 
2. Risk of albumin: chills, fever, low blood pressure, fast heart rate, urticaria, 
skin rash, nausea, TACO 
3. Risks of phlebotomy: local discomfort, bruising, hematoma, bleeding, fainting 
4. Total blood draws will not exceed 125 mL over the 90-day follow up period 
5. Risks of nasal swab: local discomfort, vomiting 
6. Risks of IV placement: bleeding, infection, thrombosis 
6.3 
Potential risks of genetic testing 
Samples obtained for future research may include a search for genetic 
correlates of COVID-19 susceptibility or severity.  Specimens will be labeled 
by study IDs, rather than names. This information will not be released to 
participants and will not become part of their medical records.  Risks related 
to discrimination or other problems are deemed highly unlikely. 
6.4 
Alternatives  
 
The alternative to participation in this study is routine care and monitoring 
following close contact with an individual with COVID-19 or enrollment in a 
different clinical trial. 
6.5 
Infection prevention and control measures 
 
Care will be taken throughout the study to minimize the risk of transmission 
of the SARs-CoV-2 virus during study visits.  
 
1. Participants will be provided with a surgical mask upon entry to the 
medical center and asked to wear a mask during their visit (other than 
during nasal swabbing) and during transit to and from the study site. 
2. Participants will be asked not to use public transportation during the 
first two weeks of the study and will be provided with transportation 
reimbursement to study visits in a single occupancy vehicle.  
3. Study staff will wear surgical masks, eye protection, gown and gloves 
during visits with study participants during visits -1 to 30 and at any 
time that community transmission of SARS-Cov-2 is reported by the 

Protocol (Population B) V 8JUNE2021 
 
30
NYS Department of Health. 
4. Scheduling of visits will be done with the goal of minimizing wait times 
at the study site. 
5. Participants will be immediately placed in single exam rooms upon 
arrival. 
6. All areas of participant contact will be wiped down with an approved 
viricidal agent after each visit.  Doorknobs and other high touch areas 
will be cleaned at regular intervals as per medical center IPC guidelines. 
7. At the clinician’s discretion, face to face interactions may be minimized 
by collection of data from participants by phone or by telemedicine 
(using Zoom HIPAA compliant conferencing) 
8. All clinical specimens will be transported according to hospital policy in 
biohazard bags using clinical carriers. 
6.6 
Safety monitoring  
 
1. Safety evaluations will assess for the safety of anti-SARS-CoV-2 plasma and 
determine if risks are higher, lower or the same as control (albumin 5%) 
2. Clinical evaluations: Vital signs and symptom screen on days -1, 0,3,7,14 and 
symptom screens on days 1, 28 and 60.  Parameters requiring referral for 
urgent medical care are included in each evaluation 
3. Safety laboratory tests, including ABO blood type (day -1) pregnancy testing 
(day -1), CBC and comprehensive metabolic panel (days -1, 7 and 14), will be 
performed at the local CLIA-certified clinical laboratory  
6.7 
Adverse Event Reporting  
 
An Adverse Event (AE) is any untoward or unfavorable medical occurrence 
in a human subject, including any abnormal sign, symptom or disease, 
temporally associated with the subject’s participation in research, whether 
or not considered related to the subject’s participation in the research.  
Serious Adverse Event (SAE):  any adverse event temporarily associated 
with the subject's participation in research that meets any of the following 
criteria:   
• 
Results in death;  
• 
Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred);  
• 
Requires inpatient hospitalization or prolongation of existing 
hospitalization;  
• 
Results in a persistent or significant disability/incapacity;  
• 
Results in a congenital anomaly/birth defect; or  
• 
Any other adverse event that, based upon appropriate medical 
judgment, may jeopardize the subjects' health and may require 
medical or surgical intervention to prevent one of the other outcomes 
listed in this definition.  

Protocol (Population B) V 8JUNE2021 
 
31
 
An Unanticipated Problem (UP) is any incident, experience or outcome 
involving risk to subjects or others in any human subjects research that 
meets all of the following criteria:   
• 
Unexpected (in terms of nature, severity or frequency) given (a) the 
research procedures that are described in the IRB-approval protocol 
and informed consent document, and (b) the characteristics of the 
subject population being studied;   
• 
Related or possibly related to participation in such research (i.e., there 
is a reasonable possibility that the incident, experience or outcome 
may have been caused by the procedures involved in such research); 
and   
• 
Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic or social harm) than 
was previously known or recognized   
  
A Suspected Adverse Reaction (SAR) is any AE for which there is a reasonable 
possibility that it was caused by the drug.  
  
Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  Examples of reasonable possibility 
are:  
• 
A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure.  
• 
One or more occurrences of an event that is not commonly associated 
with drug exposure, but is otherwise uncommon in the population 
exposed to the drug.  
• 
An aggregate analysis of specific events observed in a clinical trial that 
indicates that those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group.  
  
The S-I must report the following SARs:  
• 
To the FDA, as soon as possible, but no later than 7 calendar days after 
the S-I's initial receipt of the information, any unexpected fatal or life-
threatening SAR.  
• 
To the FDA and all participating investigators, as soon as possible but no 
later than 15 calendar days after the S-I determines that information 
qualifies for reporting, in an IND safety report, any SAR that is both 
serious and unexpected.  
• 
To the FDA and all participating investigators, as soon as possible but no 
later than 15 calendar days after the S-I determines that the information 
qualifies for reporting, any findings from epidemiological studies, 
pooled analysis of multiple studies or clinical studies, whether or 
not conducted under an IND or by the S-I, that suggest a significant 
risk in humans exposed to the drug.   
• 
To the FDA and all participating investigators, as soon as possible, but no 
later than 15 calendar days after the S-I determines that the information 

Protocol (Population B) V 8JUNE2021 
 
32
qualifies for reporting, any findings from animal or in vitro testing, 
whether or not conducted by the S-I, that suggest a significant risk in 
humans exposed to the drug.   
• 
To the FDA and all participating investigators, as soon as possible, but no 
later than 15 calendar days after the S-I determines that the information 
qualifies for reporting, any clinically important increase in the rate of 
a Serious SAR over that listed in the protocol or Investigator 
Brochure.  
• 
Expected SAEs and AEs should be included in the IND Annual Reports.  
  
Follow-up information to a safety report should be submitted as soon as the 
relevant information is available.  However, if the results of a sponsor’s 
investigation show that an adverse drug experience not initially determined to 
be reportable are so reportable, the sponsor must report such experience as 
soon as possible, but no later than 15 calendar days after the determination is 
made.  
  
 
To IRB:  
1. Unanticipated Problems (UPs) must be reported promptly, but not later 
than 7 calendar days following the occurrence of the UP or the Principal’s 
Investigator’s acquiring knowledge of the UP.  
2. Expected AEs must be reported at the time of continuing review of a 
protocol.  
 
 
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.  
 
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 generate medical 
intervention (treatment and/or procedures) or are considered clinically 

Protocol (Population B) V 8JUNE2021 
 
33
significant and are not linked to a reported clinical AE. If a laboratory 
abnormality is related to a clinical AE, grading will be related to clinical AE. The 
grading of the laboratory AEs will be based on the toxicity tables in the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5, Nov 27, 2017.  
 
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 Toxicity Tables. For 
parameters not included in the Toxicity Table the following definitions will 
be used: 
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. 
7 
SAFETY OVERSIGHT 
7.1 Monitoring Plan 
1. All AEs and SAEs will be reviewed by the study team in real time.   
2. A data safety monitoring board (DSMB) composed of independent experts 
without conflict of interests will be established. The Board will review the 

Protocol (Population B) V 8JUNE2021 
 
34
study before initiation and quarterly thereafter. The Board will review study 
data to evaluate the safety, efficacy, study progress, and conduct of the study 
7.2 Study monitoring  
As per ICH-GCP 5.18 and FDA 21 CFR 312.50, clinical protocols are required to 
be adequately monitored by the study sponsor. 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.  
7.3 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: 
1. Unexpected death of a dosed subject in relation to infusion  
2. Occurrence of a life-threatening allergic/hypersensitivity reaction 
(anaphylaxis), manifested by bronchospasm with or without urticaria or 
angioedema requiring hemodynamic support with pressor medications or 
mechanical ventilation.  
3. One subject with an unexpected SAE associated with study product. 
4. Two subjects with a Grade 3 or higher toxicity for the same parameter 
associated with study product. 
5. An overall pattern of symptomatic, clinical, or laboratory events that the  
DSMB 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. 
6. Any other event(s) which is considered to be a serious adverse event in the 
good clinical judgment of the responsible physician.  This will be 
appropriately documented. 
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 an indication for need of mechanical ventilation. In 
monitoring the number of subjects that progresses to this stage, we will present 
these data to the DSMB masked so that they may objectively evaluate and determine 
whether they would like to be unmasked. 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 (1) see a 
clinically meaningful difference between trial arms that trigger an unmasking of the 

Protocol (Population B) V 8JUNE2021 
 
35
DSMB and (2) if so do they require a formal interim analysis. At any point should the 
DSMB asked to be unmasked and require a formal interim analysis, we will examine 
the difference in treatment arms for need for mechanical ventilation. This interim 
analysis will adjust for factors related to need for mechanical ventilation including 
age and presence of cardiopulmonary comorbidities.  
Upon completion of this review, DSMB will determine if study entry or study dosing 
should be interrupted or if study entry and study dosing may continue according to 
the protocol. Should the trial not be stopped at this time point, the final analysis 
would need to account the number of interim analyses that were conducted. 
Therefore, we would penalize any final analysis dividing our 0.05 alpha in half for 
each interim analysis. 
 
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 
8  
ETHICS/PROTECTION OF HUMAN SUBJECTS 
8.1 Ethical standard 
The investigators are committed to the integrity and quality of the clinical 
studies it coordinates and implements.  The investigators will ensure that the 
legal and ethical obligations associated with the conduct of clinical research 
involving human subjects are met.  The information provided in this section 
relates to all 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, the 
investigators will review these evolving standards in relation to the proposed 
activities and will advise the investigators on those that may apply. 

Protocol (Population B) V 8JUNE2021 
 
36
 
In addition, The Trustees of Columbia University in the City of New York, has a 
Federalwide Assurance (FWA) number on file with the Office for Human 
Research Protections (OHRP).  The FWA number for CU is FWA00002636. 
 
This assurance commits a research facility to conduct all human subjects’ 
research in accordance with the ethical principles in The Belmont Report and 
any other ethical standards recognized by OHRP.  Finally, per OHRP regulations, 
the research facility will ensure that the mandatory renewal of this assurance 
occurs at the times specified in the regulations. 
8.2 Institutional Review Board 
 
The Columbia University Irving Medical Center (CUIMC) IRB will review this 
protocol and all protocol-related documents and procedures as required by 
OHRP and local requirements before subject enrollment. The CUIMC IRB 
currently holds and will maintain a US FWA issued by OHRP for the entirety of 
this study. 
8.3 Informed consent process 
 
The subject will be formally consented and will sign the informed consent 
document at the screening visit, before any procedures are undertaken for the 
study. A copy of the signed informed consent document will be given to the 
subject for their records. 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. 
8.4 Subject confidentiality 
 
Subject confidentiality is strictly held in trust by the participating investigators, 
their staff, and the sponsors and their agents. No information concerning the 
study or the data will be released to any unauthorized third party without prior 
written approval of the sponsor. The results of the research study may be 
published, but subjects’ names or identifiers will not be revealed.  Records will 

Protocol (Population B) V 8JUNE2021 
 
37
remain confidential.  To maintain confidentiality, the PI will be responsible for 
keeping records in a locked area and results of tests coded to prevent association 
with subjects’ names.   
 
Data entered into computerized files will be accessible only by authorized 
personnel directly involved with the study and will be coded.  Subjects’ records 
will be available to the FDA, the NIH, the manufacturer of the study product and 
their representatives, investigators at the site involved with the study, and the 
IRB. 
8.5 Future use of stored specimens 
 
Subjects will be asked for consent to use their samples for future testing before 
the sample is obtained.  The confidentiality of the subject will be maintained. 
They will be no plans to re-contact them for consent or to inform them of results.  
The risk of collection of the sample will be the small risk of bruising or fainting 
associated with phlebotomy however these samples will be taken at the same 
time as other protocol required samples. 
 
Other use of stored specimens may include genetic testing with the goal of 
understanding why some individuals are resistant to SARS-CoV-2 and others 
develop severe or even fatal disease. In the future, we plan to conduct genetic 
testing that consists of RNA sequencing of whole blood (PAXgene tubes) and 
genetic and epigenetic studies of DNA in peripheral blood mononuclear cells 
from subjects.  We hope these studies will identify biomarkers that differentiate 
treatment response and will further our understanding of pathogenesis.  We 
anticipate that other Columbia investigators will want to search for host factors 
in treatment response as well. Whole genome sequencing will not be conducted.  
 
These studies have the potential to lead to treatments that reduce COVID 
morbidity and mortality. This research is done only to the extent authorized in 
the study informed consent form, or as otherwise authorized under applicable 
law. 
 
Additional research on specimens will occur only after review and approval by 
the protocol team and the IRB/EC of the researcher requesting the specimens. 
The informed consent form is written so that the participant either explicitly 
allows or does not allow their samples to be used in other research when they 
sign the form. Participants who initially agree to other use of their samples may 
rescind their approval once they enter the study; such participants will remain 
in this study and their samples will only be used for the studies described in this 
protocol. If a participant decides against allowing other research using his or her 
samples, or at any time rescinds prior approval for such other use, the study PI 
must notify the CII in writing not to use samples from these participants for 
other purposes. 
 

Protocol (Population B) V 8JUNE2021 
 
38
Blood samples will be collected at 6 time points (Day 0 (screen), 1, 3±2, 
7±2,14±2 and 28±3) (See Schedule of Events).  Plasma 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 
CUIMC unless outside investigators had relevant assays or expertise not 
available to the study investigators. The specimens would remain linked and at 
CUIMC for 5 years. Any use of these specimens not specified in the current 
protocol will be reviewed by the CUIMC IRB. 
8.6 Data management and monitoring 
8.6.1 Source Documents 
 
Source documents may include research records documenting study 
procedures, laboratory test reports, and any medical records that may be 
generated during the study period (e.g. hospitalization due to adverse events 
or disease progression). These 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) will support the data collected and entered into the study 
database/case report form and will be signed and dated by the person 
recording and/or reviewing the data. Data entered into the study database 
will be collected directly from subjects during study visits or will be 
abstracted from subjects’ study records including laboratory test reports.  
8.6.2 Data Management Plan 
 
All paper documents will be maintained under double-locked conditions and 
will be stored separately from all other study records. Similarly, any 
electronically captured data will be stored in a unique database on a secure 
server separate from study databases. Only authorized study staff will have 
access to forms and databases containing study data.  
 
The study database will be programmed using REDCap, which is 21 CFR Part 
11 and HIPAA compliant, and hosted in an Amazon Web Services (AWS). 
AWS has a Business Associates Agreement (BAA) with Columbia University. 

Protocol (Population B) V 8JUNE2021 
 
39
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.  
All study data will be collected during study visits using encrypted and 
password-protected tablets, laptops or computers.  
 
The database will include automated quality checks that flag outliers, 
suspicious distributions and means, values that violate frequency or numeric 
thresholds, and error-prone submissions. 
 
User permissions will be adjusted according to staff role and responsibility. 
Only designated study staff will access study data from the encrypted server 
to conduct data cleaning and quality checks and generate reports to monitor 
study progress. Only authorized staff will access data for the purpose of 
conducting study operations. Study data will be collected at the study site 
and entered into the study database or case report forms. Data entry is to be 
completed on an ongoing basis during the study. 
8.6.3 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, 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. 
 
9  
REFERENCES 
 
Arabi, Y. M., Hajeer, A. H., Luke, T., Raviprakash, K., Balkhy, H., Johani, S., . . . 
Alahmadi, M. (2016). Feasibility of Using Convalescent Plasma Immunotherapy 

Protocol (Population B) V 8JUNE2021 
 
40
for MERS-CoV Infection, Saudi Arabia. Emerg Infect Dis, 22(9), 1554-1561. 
doi:10.3201/eid2209.151164 
Casadevall, A., Dadachova, E., & Pirofski, L. A. (2004). Passive antibody therapy for 
infectious diseases. Nat Rev Microbiol, 2(9), 695-703. doi:10.1038/nrmicro974 
Casadevall, A., & Pirofski, L. A. (2003). Antibody-mediated regulation of cellular 
immunity and the inflammatory response. Trends Immunol, 24(9), 474-478. 
doi:10.1016/s1471-4906(03)00228-x 
Casadevall, A., & Scharff, M. D. (1994). Serum therapy revisited: animal models of 
infection and development of passive antibody therapy. Antimicrob Agents 
Chemother, 38(8), 1695-1702. doi:10.1128/aac.38.8.1695 
Casadevall, A., & Scharff, M. D. (1995). Return to the past: the case for antibody-based 
therapies in infectious diseases. Clin Infect Dis, 21(1), 150-161. 
doi:10.1093/clinids/21.1.150 
Cheng, Y., Wong, R., Soo, Y. O., Wong, W. S., Lee, C. K., Ng, M. H., . . . Cheng, G. 
(2005). Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur 
J Clin Microbiol Infect Dis, 24(1), 44-46. doi:10.1007/s10096-004-1271-9 
Crowe, J. E., Jr., Firestone, C. Y., & Murphy, B. R. (2001). Passively acquired antibodies 
suppress humoral but not cell-mediated immunity in mice immunized with live 
attenuated respiratory syncytial virus vaccines. J Immunol, 167(7), 3910-3918. 
doi:10.4049/jimmunol.167.7.3910 
Dinnes  J, Deeks  JJ, Berhane  S, Taylor  M, Adriano  A, Davenport  C, Dittrich  S, 
Emperador  D, Takwoingi  Y, Cunningham  J, Beese  S, Domen  J, Dretzke  J, 
Ferrante di Ruffano  L, Harris  IM, Price  MJ, Taylor-Phillips  S, Hooft  L, 
Leeflang  MMG, McInnes  MDF, Spijker  R, Van den Bruel  A. Rapid, point‐of‐
care antigen and molecular‐based tests for diagnosis of SARS‐CoV‐2 infection. 
Cochrane Database of Systematic Reviews 2021, Issue 3. Art. No.: CD013705. 
DOI: 10.1002/14651858.CD013705.pub2. Accessed 31 March 2021. 
Duan, K., Liu, B., Li, C., Zhang, H.,  Yu, T., Qu, J., … Yang, X. (2020). Effectiveness of 
convalescent plasma therapy in severe COVID-19 patients. Proceedsing of the 
National Academy of Sciences of the United States of America (PNAS), 117 (17) 
9490-9496; DOI:10.1073/pnas.2004168117 
Fine, J. P., Gray, R. J. (1999). A Proportional Hazards Model for the Subdistribution of a 
Competing Risk. Journal of the Americal Statistical Association, 94(446), 496-
509. doi:10.1080/01621459.1999.10474144 
Gales BJ, Erstad BL. Adverse reactions to human serum albumin. Ann Pharmacother. 
1993;27(1):87–94. doi:10.1177/106002809302700119 
Gunn, B. M., Yu, W. H., Karim, M. M., Brannan, J. M., Herbert, A. S., Wec, A. Z., . . . 
Alter, G. (2018). A Role for Fc Function in Therapeutic Monoclonal Antibody-
Mediated Protection against Ebola Virus. Cell Host Microbe, 24(2), 221-233 
e225. doi:10.1016/j.chom.2018.07.009 
Ko, J. H., Seok, H., Cho, S. Y., Ha, Y. E., Baek, J. Y., Kim, S. H., . . . Peck, K. R. (2018). 
Challenges of convalescent plasma infusion therapy in Middle East respiratory 
coronavirus infection: a single centre experience. Antivir Ther, 23(7), 617-622. 
doi:10.3851/IMP3243 
Lachin, J. M., Foulkes, M. A. (1986). Evaluation of Sample Size and Power for Analyses 
of Survival with Allowance for Nonuniform Patient Entry, Losses to Follow-Up, 
Noncompliance, and Stratification. Biometrics, 42, 507-519. 

Protocol (Population B) V 8JUNE2021 
 
41
Liang, K., Zeger, S. L. (1986). Longitudinal data analysis using generalized linear 
models. Biometrika, 73(1), 13-22.  
Mair-Jenkins, J., Saavedra-Campos, M., Baillie, J. K., Cleary, P., Khaw, F. M., Lim, W. 
S., . . . Convalescent Plasma Study, G. (2015). 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. J Infect Dis, 211(1), 80-90. doi:10.1093/infdis/jiu396 
O’Donnell, M.,…, Eisenberger, A., Lipkin, WI. (2021). A randomized double-blind 
controlled trial of convalescent plasma in adults with severe COVID-19. J Clin 
Invest. https://doi.org/10.1172/JCI150646. 
Sahr, F., Ansumana, R., Massaquoi, T. A., Idriss, B. R., Sesay, F. R., Lamin, J. M., . . . 
Gevao, S. M. (2017). Evaluation of convalescent whole blood for treating Ebola 
Virus Disease in Freetown, Sierra Leone. J Infect, 74(3), 302-309. 
doi:10.1016/j.jinf.2016.11.009 
van Erp, E. A., Luytjes, W., Ferwerda, G., & van Kasteren, P. B. (2019). Fc-Mediated 
Antibody Effector Functions During Respiratory Syncytial Virus Infection and 
Disease. Front Immunol, 10, 548. doi:10.3389/fimmu.2019.00548 
Wan, Y., Shang, J., Sun, S., Tai, W., Chen, J., Geng, Q., . . . Li, F. (2020). Molecular 
Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J Virol, 
94(5). doi:10.1128/JVI.02015-19 
Xinhua. (2020). China puts 245 COVID-19 patients on convalescent plasma therapy.   
Retrieved from http://www.xinhuanet.com/english/2020-02/28/c_138828177.htm 
Yeh, K. M., Chiueh, T. S., Siu, L. K., Lin, J. C., Chan, P. K., Peng, M. Y., . . . Chang, F. 
Y. (2005). Experience of using convalescent plasma for severe acute respiratory 
syndrome among healthcare workers in a Taiwan hospital. J Antimicrob 
Chemother, 56(5), 919-922. doi:10.1093/jac/dki346 
Zhang, J. S., Chen, J. T., Liu, Y. X., Zhang, Z. S., Gao, H., Liu, Y., . . . Yin, W. D. 
(2005). A serological survey on neutralizing antibody titer of SARS convalescent 
sera. J Med Virol, 77(2), 147-150. doi:10.1002/jmv.20431