CONTAIN COVID-19: Convalescent Plasma to Limit Coronavirus Associated Complications: a Randomized Blinded Phase 2 Study Comparing the Efficacy and Safety of Anti-SARS-CoV2 Plasma to Placebo in COVID-19 Hospitalized Patients
Phase: PHASE2
Conditions: COVID-19, Coronavirus, Coronavirus Infection
Sponsor: NYU Langone Health

1 
 
 
CONVALESCENT PLASMA TO LIMIT CORONAVIRUS ASSOCIATED 
COMPLICATIONS: A RANDOMIZED BLINDED PHASE 2 STUDY COMPARING 
THE EFFICACY AND SAFETY OF ANTI-SARS-COV-2 PLASMA TO PLACEBO IN 
COVID-19 HOSPITALIZED PATIENTS (CONTAIN COVID-19) 
 
 
Protocol Version: 3 
 
Protocol Date: February 11, 2021 
 
IND 20427 
 
ClinicalTrials.gov Identifier: NCT 04364737 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
LIST OF ABBREVIATIONS 
ADR: Adverse Drug Reaction 
ADE: Antibody-mediated enhancement of infection 
AE: Adverse Event/Adverse Experience 
AFib: Atrial fibrillation 
CBC: Complete Blood Count 
CDC: United States Centers for Disease Control and Prevention 
CFR: Code of Federal Regulations 
CHF: Chronic heart failure 
CLIA: Clinical Laboratory Improvement Amendment of 1988 
COI: Conflict of Interest 
COPD: Chronic obstructive pulmonary disease 
COVID-19: Coronavirus Disease  
CRF: Case Report Form 
CRP: C-Reactive Protein 
CP: Convalesced Plasma 
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 
HCV: Hepatitis C virus 
HFNC: High flow nasal cannula 
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 
ILD: Interstitial lung disease 
IND: Investigational New Drug Application 
IRB: Institutional Review Board 
ISBT: International Society of Blood Transfusion 
ISM: Independent Safety Monitor 
IWRS: Interactive Web Response System 
LOS: Length of Stay 
MERS: Middle East Respiratory Syndrome  
NP: Nasopharyngeal 
NYBC: New York Blood Center 
SS:  Saline Solution (defined as half-, quarter- or normal saline) 
OHRP: Office of Human Research Protections 
OP: Oropharyngeal 
OSA: Obstructive sleep apnea 
RT-PCR: Reverse Transcriptase Real-Time Polymerase Chain Reaction 
PK: Pharmacokinetic 
SAE: Serious Adverse Event 
SAP:  Statistical Analysis Plan 
SARS: Severe Acute Respiratory Syndrome 

3 
 
SARS-CoV-2: Severe Acute Respiratory   
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 
 
 

4 
 
PROTOCOL SUMMARY 
 
Long title:  Convalescent Plasma to Limit Coronavirus Associated Complications: A Randomized Blinded 
Phase 2 Study Comparing the Efficacy and Safety of Anti-SARS-CoV-2 Plasma to Placebo in COVID-19 
hospitalized patients (CONTAIN COVID-19) 
 
Clinical Phase: 2 Blinded 
 
Sample Size: Enrollment will be adapted based on continuous Bayesian monitoring as detailed in the SAP. The 
estimated total sample size for the trial is >1000 subjects 
 
Study Population: Hospitalized COVID-19 patients aged ≥18 years of age with respiratory symptoms within 7 
days from the onset of illness OR within 3 days of hospitalization. 
 
Study Composition: NYU Langone Heath will serve as the Clinical and Data Coordinating Center for the study 
under IND 20427.  Collaborating sites will contribute recruitment and conduct the study per the FDA approved 
protocol with oversight by their individual IRBs. 
 
Study Duration: April 17, 2020 to January 31, 2023 
 
Study Design: This trial design is built as a process with the possibility of multiple interventions being 
investigated. The trial is designed to be flexible, and these flexible aspects are designed and planned as part of 
the protocol. This trial may incorporate a flexible number of interventions, with the possibility of these numbers 
evolving as the science evolves. Each period of the study where intervention arms are added or dropped will be 
considered a separate study Stage, though the model will analyze all stages simultaneously. 
 
Study Stages and Interventions: The first stage of the study has been determined. In Stage 1, there will be two 
intervention arms: (1) placebo control, Saline Solution (SS is defined as half-,quarter-, or normal saline), and (2) 
SARS-CoV-2 Convalescent Plasma (1 unit). Stage 2 has not yet been defined given that results from Stage 1 
will guide how to structure the two arms for Stage 2 and subsequent Stages. Once each study Stage is completed 
and prior to initiating the subsequent study Stage, a protocol modification describing the specific arms and 
approach will be made to the IRB for review and approval. 
 
Randomization: Randomization assignments are performed for patients at baseline. Randomization is 
performed separately by two strata, treatment site and risk of severe disease (high versus lower) as defined 
below. The randomization scheme will be determined by the study Stage and its associated group of 
intervention arms (For example, in Stages 1 and 2, subjects will be randomized to 1:1 ratio). Randomization 
should obviate the need for additional adjustment factors but if pre-specified demographic or clinical 
characteristics are unbalanced with respect to treatment group, we will consider adjustment; these 
characteristics include but are not limited to age, sex, race, ethnicity, BMI and COVID severity at baseline. 
 
Risk for severe COVID-19 based on baseline characteristics: 
 High risk: Subjects with age 60 years or, age <60 and at least one of the following:  
 Chronic pulmonary conditions (COPD, OSA, ILD, etc) 
 Chronic heart conditions (CHF with NYHA>= class 2, AFib, ischaemic heart disease, etc) 
 Hypertension 
 Chronic kidney disease with eGFR < 60 mL/min 
 Body Mass Index >=35 
 Diabetes mellitus  

5 
 
 Immunosuppression (CD4<200, on immunosuppressive medications for autoimmune conditions, 
cancers, solid or stem cell transplants, steroids such as prednisone >10mg/day or equivalent) 
 
 Lower risk: Subjects with age <60 and without the presence of any high risk factors listed above.  
 
Data Collection: 
The following will be assessed in all subjects: (detailed schedule of assessments is found in Table 1) 
I. Clinical, Laboratory and Imaging Data 
1. Date of Symptom Onset and history of presenting illness 
2. Demographics: Age, sex, comorbidities, zip code, race/ethnicity, BMI 
3. Vital Signs: Temperature, respiratory rate, blood pressure, oxygen saturation, oxygen requirements 
4. Laboratory Data:  
o Hematologic Markers: CBC with differential (neutrophil, lymphocyte counts and platelet count explicitly 
recorded), PTT, LDH, D-dimer, fibrinogen, ferritin 
o Metabolic Markers: Complete metabolic panel, LFT 
o Cardiac Markers: Troponin, (pro-)BNP 
o Inflammatory Markers: CRP, procalcitonin 
5. Chest imaging (CT or Chest x-ray), EKG, echocardiogram if done: Day 0, Day 3, and Day 14 or discharge 
whichever comes first and times obtained as part of standard care  
6. Venous duplex of lower extremities as clinically indicated 
7. Evaluation for pulmonary embolism as clinically indicated 
 
II. Safety and Efficacy 
1.  Day 0 (baseline), 1, 2, 3, 7, 14, and 28 and once at 2-3 months.  
 
III. SARS-CoV-2 Viral and Antibody Response – to be done at selected Sites 
1. Serum or plasma antibody titer1 to SARS-CoV-2: Day 0, 1, 7, 14, 28, 90 
2. SARS-CoV-2 PCR from nasopharyngeal swab, quantitative if available: Day 0, 7, 14, 28, 90  
 
IV. Outcome measures: 
Primary Outcome:  Status at 14 days using the WHO 11-point ordinal scale for clinical improvement which 
ranges from 0 (uninfected) to 10 (death). Effect size will be measured as the cumulative odds ratio comparing 
treatment to placebo control, estimated using a cumulative proportional odds model that adjusts for initial status 
(indicator for status = 5 or status = 6). 
 
Study Product:  
 SARS-CoV-2 CP (1-2 units; ~250-500 mL with antibodies to SARS-CoV-21 per May 1, 2020 directive 
https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-
process-cber/recommendations-investigational-covid-19-convalescent-plasma, obtained from New York 
Blood Center (NYBC) collected per their protocol (https://www.nybc.org/donate-blood/covid-19-and-
blood-donation-copy/convalescent-plasma/).  
 Equivalent volume of SS  
 
Primary Objective: Evaluate the efficacy of convalescent plasma from people who have recovered from 
COVID-19 containing antibodies to SARS-CoV-2 versus control (SS) to prevent worsening respiratory status or 
death in hospitalized patients with COVID-19 who are within 3 days of presentation to the hospital or within 7 
days of symptom onset. 
 
                                              
1 Vetted for SARS-CoV-2 IgG by platform used by NYBC. 

6 
 
Primary Endpoint:  
Primary Outcome:  Status at 14 days using the WHO 11-point ordinal scale for clinical improvement which 
ranges from 0 (uninfected) to 10 (death). Effect size will be measured as the cumulative odds ratio comparing 
treatment to placebo control, estimated using a cumulative proportional odds model that adjusts for initial status 
(indicator for status = 5 or status = 6). 
 
WHO ordinal scale for clinical improvement  
 
Patient State 
Score 
Descriptor 
Uninfected 
0 
Uninfected; no viral RNA detected 
Ambulatory 
1 
Asymptomatic; viral RNA detected 
2 
Symptomatic; Independent 
3 
Symptomatic; assistance needed 
Hospitalized: Mild disease 
4 
Hospitalized; no oxygen therapy 
5 
Hospitalized; oxygen by mask or nasal prongs  
Hospitalized: Severe disease 
6 
Hospitalized; oxygen by NIV or High flow 
7 
Intubation & Mechanical ventilation; pO2/FIO2 >/= 150 or SpO2/FIO2 >/=200 
8 
Mechanical ventilation pO2/FIO2 < 150  (SpO2/FIO2 <200) or vasopressors 
9 
Mechanical ventilation pO2/FIO2 < 150 and vasopressors, dialysis or ECMO 
Death 
10 
Dead 
 
Secondary Objectives:   
Secondary outcome; same as above at 28 days. 
 
Exploratory objectives (To be performed on selected sites): 
1. Serum or plasma anti-SARS-CoV-2 IgM, IgG, IgA on Days 0, 1, 7, 14, 28, 90 
2. Serum or plasma SARS-CoV-2 neutralizing activity and antibody dependent cytotoxicity (ADCC) on 
Days 0, 1, 7, 14, 28, 90  
3. Rates, levels and duration of SARS-CoV-2 RNA in NP swabs using RT-PCR on days 0, 7, 14, 28, 90. 
Other  specimen types may be tested as available (e.g., BAL fluid, tracheal secretions, sputum, etc.). 
4. Lymphocyte and neutrophil counts on days 0, 1, 3, 7, 14 or as obtained in care. 
5. Hematological measurements (D-dimer, fibrinogen) on days 0, 1, 3, 7, 14 or as obtained in care. 
6.  Lymphocyte subsets and cytokine panel on days 0, 1, 7, 14, 28, 90 
 
Safety objectives: 
 Safety monitoring will be per DSMB 
 
Study population: 
Inclusion Criteria 
1. Patients ≥18 years of age  
2. Hospitalized with laboratory confirmed COVID-19 
3. One or more of the following respiratory signs or symptoms: cough, chest pain, shortness of breath, 
fever, oxygen saturation ≤ 94%, abnormal CXR/CT imaging 
4. Hospitalized for ≤ 72 hours OR within 7 days from first signs of illness 
5. On supplemental oxygen, non-invasive ventilation or high-flow oxygen  
6. Patients may be on other randomized controlled trials of pharmaceuticals for COVID -19 and patients 
who meet eligibility criteria will not be excluded on this basis. 
 

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Exclusion Criteria 
1. Receipt of any Covid-19 vaccine or participation in a Covid-19 vaccine study as a subject. 
2. Receipt of pooled immunoglobulin in past 30 days  
3. Contraindication to transfusion or history of prior reactions to transfusion blood products 
4. Invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 
5. Volume overload secondary to congestive heart failure or renal failure  
6. Unlikely to survive past 72 hours from screening based on the assessment of the investigator  
7. Unlikely to follow-up or clinical assessment will be hindered by patient’s poor functional status 
 
RATIONALE/BACKGROUND: 
1. Background and scientific rationale  
 
There are currently no proven treatment options for coronavirus disease (COVID-19) and the related 
pneumonia, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) beyond supportive 
care. Human convalescent plasma is a treatment option for COVID-19 and could be rapidly available when 
there are enough people who have recovered and donate high titer (anti- SARS-CoV-2) neutralizing 
immunoglobulin-containing plasma. As more individuals contract COVID-19 and recover, the number of 
potential donors will continue to increase, to allow greater use. 
 
Use of convalescent plasma is a form of passive antibody therapy that involves the administration of antibodies 
to a given agent to a susceptible individual for the purpose of preventing or treating the infectious disease it 
causes. In contrast, active vaccination requires the induction of an immune response that takes time to develop 
and varies in efficacy depending on the vaccine recipient. Some immunocompromised patients fail to achieve 
an adequate immune response to active vaccination and at present, there are no vaccines to prevent COVID-19. 
When given to a susceptible person, antibody used for therapy will circulate in the blood, reach tissues and 
hopefully mediate a beneficial effect by anti-microbial anti-inflammatory activity (1). Depending on antibody 
amount and composition, protection conferred by transferred immunoglobulin can last from weeks to months. 
 
Passive antibody administration is the only means of providing immediate immunity to susceptible persons and 
immunity of any measurable kind for susceptible, including immunocompromised patients with COVID-19. 
This kind of antibody therapy has a storied history going back to the 1890s and was the only means of treating 
certain infectious diseases prior to the development of antimicrobial therapy in the 1940s (2, 3). Experience 
from prior outbreaks with other coronaviruses, such as SARS-CoV-1 shows that such convalescent plasma 
contains neutralizing antibodies to the relevant virus (4). In the case of SARS-CoV-2, the anticipated 
mechanism of action by which passive antibody therapy would mediate protection is viral neutralization. 
However, other mechanisms may be possible, such as antibody dependent cellular cytotoxicity and/or 
phagocytosis. Convalescent serum was also used in the 2013 African Ebola epidemic. A small non-randomized 
study in Sierra Leone revealed a significant increase in survival for those treated with convalescent whole blood 
relative to those who received standard treatment (5).  
 
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 (6). For 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 (2). Clinical outcomes after 
convalescent antibody therapy were better when it was administered to ill patients SARS-CoV-1 within 14 days 
after onset of symptoms (discussed below) (7).  Our goal is to treat patients who are sick enough to warrant 
hospitalization but do not have severe respiratory disease and/or ARDS.   

8 
 
 
2. 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 (7). Consistent with historical data that earlier administration of antibody is more likely to be effective, 
30 patients treated a mean of 11.7 (+/- 2.3) days after symptom onset had improved prognosis defined by 
discharge from hospital before day 22, whereas 47 patients who received plasma a mean of 16 days after 
symptom onset died before day 22 or had a late discharge. The mortality rates in the two groups were 6.3% and 
21.9%, respectively (P=0.08), and those who were nasal swab 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 (8). Three patients with 
MERS in South Korea were treated with convalescent plasma, but only two of the recipients had neutralizing 
antibody in their plasma (9).  The latter study highlights a challenge in using convalescent plasma; some who 
recover may not have high titers of neutralizing antibody (10). An analysis of 99 samples of convalescent sera 
from patients with MERS showed 87 had neutralizing antibody with a geometric mean titer of 1:64. This 
suggests that antibody declines with time and/or only a few patients make high titer responses. Our study 
addresses this issue by screening plasma for antibody titers to SARS-CoV-2 and using high titer antibody for 
treatment. Although the optimal titer for treatment of SARS-CoV-2 is not established, plasma with a 
neutralizing titer of at least 1:64 should be administered. However, it is possible non-neutralizing antibodies 
may also contribute to protection as described for other viral diseases (11, 12).  
 
A recently performed pilot study in Wuhan, China collected convalescent plasma from COVID-19 positive 
patients 3 weeks following the onset of illness and 4 days post-discharge and treated patients diagnosed with 
‘severe COVID-19’ as defined by WHO Interim Guidance and the Guideline of Diagnosis and Treatment of 
COVID-19 National Health Commission of China (13). Ten patients were treated with one dose of convalescent 
plasma (200ml, >1:640 titer by neutralization assay) at a median of 16.5 days (11-19.3 days) post-onset of 
symptoms. A COVID-19 positive control cohort was retrospectively identified and matched by demographics, 
comorbidities, and severity of illness. There were no serious adverse reactions or safety events recorded with 
convalescent plasma, including no reported transfusion related reactions, transfusion-related acute lung injury, 
or antibody-mediated enhancement of infection. In the treatment group, there were 0 deaths, 3 discharges and 7 
patients improved, whereas there were 3 deaths and 7 patients who improved in the control group (p < 0.001). 
In addition, 2 of 3 patients in the treatment on mechanical ventilation were weaned to high flow nasal canula, 
which was discontinued in one patient. There was a reduction in blood RNA viral load in 7 of 10 patients on 
day 6 post-convalescent plasma therapy as well as improvement in laboratory markers. There were also varying 
degrees of improvement in pulmonary lesions on chest CT after convalescent plasma therapy. In another case 
series from China, five severely ill patients with COVID-19, all on mechanical ventilation received  
convalescent plasma within 22 days of admission (14). Temperatures normalized in 4 of 5 patients within 3 
days, and there was improvement in oxygenation and ARDS resolution. All survived, with 3 discharged home 
and 2 in stable condition. These reports suggest convalescent plasma may hold promise for ameliorating the 
severity of COVID-19 and deserves immediate investigation for this indication.  
 
There are limited data on use of convalescent plasma in pregnancy. A non-randomized comparative study that 
evaluated use of convalescent plasma for Ebola Virus Disease reported that eight out of 84 participants were 
pregnant and that mortality was 25% among pregnant women and 32% among non-pregnant individuals after 
receiving plasma treatment (15).  A case series of 4 Chinese patients, among whom one was pregnant, received 
convalescent plasma and had recovered from SARS-CoV-2 infection (16).  We do not have robust data of using 

9 
 
convalescent plasma in pregnancy as most trials have excluded pregnant patients.  IVIG therapy however is safe 
to give during pregnancy and is often used in those with inflammatory disorder and/or autoimmune conditions.    
 
INVESTIGATIONAL PLAN:  
 
1.  Study Objectives 
 
Primary Objective: Evaluate the efficacy of convalescent plasma from people who have recovered from 
COVID-19 containing antibodies to SARS-CoV-2 versus control (SS) to prevent worsening respiratory status or 
death in hospitalized patients with COVID-19 who are within 3 days of presentation to the hospital or within 7 
days of symptom onset. 
 
Primary Endpoint:  
Primary Outcome:  Status at 14 days using the WHO 11-point ordinal scale for clinical improvement which 
ranges from 0 (uninfected) to 10 (death). Effect size will be measured as the cumulative odds ratio comparing 
treatment to placebo control, estimated using a cumulative proportional odds model that adjusts for initial status 
(indicator for status = 5 or status = 6). 
 
WHO ordinal scale for clinical improvement  
 
Patient State 
Score 
Descriptor 
Uninfected 
0 
Uninfected; no viral RNA detected 
Ambulatory 
1 
Asymptomatic; viral RNA detected 
2 
Symptomatic; Independent 
3 
Symptomatic; assistance needed 
Hospitalized: Mild disease 
4 
Hospitalized; no oxygen therapy 
5 
Hospitalized; oxygen by mask or nasal prongs  
Hospitalized: Severe disease 
6 
Hospitalized; oxygen by NIV or High flow 
7 
Intubation & Mechanical ventilation; pO2/FIO2 >/= 150 or SpO2/FIO2 >/=200 
8 
Mechanical ventilation pO2/FIO2 < 150  (SpO2/FIO2 <200) or vasopressors 
9 
Mechanical ventilation pO2/FIO2 < 150 and vasopressors, dialysis or ECMO 
Death 
10 
Dead 
 
Secondary Objectives:   
Secondary outcome; same as above at 28 days. 
 
Exploratory objectives (To be performed at selected sites): 
1. Serum or plasma anti-SARS-CoV-2 IgM, IgG, IgA on Days 0, 1, 7, 14, 28, 90 
2. Serum or plasma SARS-CoV-2 neutralizing activity, antibody dependent cytotoxicity (ADCC) and 
phagocytosis (ADCP) on Days  0, 1, 7, 14, 28, 90  
3. Rates, levels and duration of SARS-CoV-2 RNA in NP swabs using RT-PCR on days 0, 7, 14, 28, 
90. Other  specimen types may be tested as available (e.g., BAL fluid, tracheal secretions, sputum, 
etc.). 
4. Lymphocyte and neutrophil counts on days 0, 1, 3, 7, 14 or as obtained in care. 
5. Hematological measurements (D-dimer, fibrinogen) on days 0, 1, 3, 7, 14 or as obtained in care. 
6. Lymphocyte subsets and cytokine panel on days 0, 1, 7, 14, 28, 90 
 
2.  Definitions  

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 Enrolled: From time consented to participate until designated as (i) ineligible based on the 
inclusion/exclusion criteria or withdraws, (ii) been discontinued from the study or (iii) completed the 
study.  
 Randomized: when a randomization number is assigned. 
 Screen Failures: signed informed consent, but then determined to be ineligible or withdraws before 
being randomized. 
 Discontinued: randomized, but then withdrawn by investigator or subject withdraws consent 
 Completed: Subjects are considered completed when they are followed through to day 28, had an 
adverse event or death occurred prior to day 28. Patients will be asked to have day 60 and day 90 study 
visits as well. 
 
3. Study Population 
 
Inclusion Criteria: 
1. Patients ≥18 years of age  
2. Hospitalized with laboratory confirmed COVID-19 
3. One or more of the following respiratory signs or symptoms: cough, chest pain, shortness of breath, 
fever, oxygen saturation ≤ 94%, abnormal CXR/CT imaging 
4. Hospitalized for ≤ 72 hours OR within 7 days from first signs of illness 
5. On supplemental oxygen, non-invasive ventilation or high-flow oxygen  
6. Patients may be on other randomized controlled trials of pharmaceuticals for COVID -19 and patients 
who meet eligibility criteria will not be excluded on this basis. 
 
Exclusion Criteria: 
1. Receipt of any Covid-19 vaccine or participation in a Covid-19 vaccine study as a subject. 
2. Receipt of pooled immunoglobulin in past 30 days  
3. Contraindication to transfusion or history of prior reactions to transfusion blood products 
4. Invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 
5. Volume overload secondary to congestive heart failure or renal failure  
6. Unlikely to survive past 72 hours from screening based on the assessment of the investigator  
7. Unlikely to follow-up or clinical assessment will be hindered by patient’s poor functional status 
 
4. Subject Withdrawal 
 
 Subjects can terminate study participation and/or withdraw consent at any time without prejudice.  
 Randomized subjects who withdraw from the study will not be replaced. 
 The investigator may withdraw subjects if the investigator determines that continued participation in the 
study would be harmful to the subject or the integrity of the study data 
 
Table 1: Schedule of Assessments  
                                              
1 Inpatient labs can be performed ±1 day from visit. If patient is discharged before day 14, the next visits will be days 14, 28, 90. Outpatient labs 
can be performed if able to be obtained in outpatient setting ±7 days from visit. Follow-up visits after discharge can be done ±5 days from the time-
point.   
Study period 
Screen 
Baseline 
Transfusion 
Follow up1 
Day 
-3 to 0 
0 
0 
1 
3 
7 
14 
28 
60 
90 
Procedure 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Informed consent 
x 
 
 
 
 
 
 
 
 
 

11 
 
                                              
2 Performed within prior 7 days 
3 Prior active results may be used if available 
4 Chest imaging on admission or thereafter, before randomization. Optional repeat at day 14 or discharge, whichever comes first 
5 Vital sign testing: Immediately prior to infusion, 10-20 minutes after start of infusion, at completion of infusion and 30-60 minutes after the end of 
the infusion. 
6 If able to be obtained when not performed as part of standard clinical care 
7 To be done additionally at discharge day 
8 As dictated by clinical indications (suspicion of thromboembolism) 
9 As indicated clinically for patients on coumadin 
Demographic and 
Medical history 
x 
 
 
 
 
 
 
 
 
 
COVID-19 
symptom screen 
x 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-
PCR for eligibility 
x2 
 
 
 
 
 
 
 
 
 
Pregnancy test  
x 
 
 
 
 
 
 
 
 
 
ABO for plasma 
compatibility3 
x 
 
 
 
 
 
 
 
 
 
Chest imaging 
(CXR or CT scan) 
x4 
 
 
 
 
 
 
 
 
 
Oxygenation Level 
x 
 
 
 
 
 
 
 
 
 
(Pro-)BNP 
x6 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
Randomization 
 
x 
 
 
 
 
 
 
 
 
Drug infusion 
 
 
x 
 
 
 
 
 
 
 
Study Procedures 
Vital signs 
x 
x 
xxxx5 
x 
x 
x 
 
 
 
 
Physical 
examination  
x 
 
x 
x 
x 
x 
x6 
 
 
 
Symptom screen 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
 
 
 
x 
x 
x 
x 
x 
Assessment with 
11-point ordinal 
scale 
 
x 
 
x 
x7 
x7 
x7 
x7 
x 
x 
Chest imaging 
(CXR or CT scan)  
 
 
 
 
x6 
 
X6 
 
 
 
EKG 
x6 
 
 
 
x6 
 
x6 
 
 
 
Echocardiogram 
and/or left heart 
catherization data 
 
 
 
 
x6 
 
 
 
 
 
Duplex US of 
extremities8 
 
 
 
x8 
x8 
x8 
x8 
 
 
 
INR monitoring9 
 
 
 
x9 
x9 
x9 
x9 
 
 
 
Adverse event 
monitoring 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 

12 
 
5. Treatment 
 
1. Subjects will be randomized in a 1:1 ratio to receive 1 unit of study product (CP) or placebo control 
(equivalent volume of SS) randomization will be stratified at each site by risk in Stage 1.  In Stage 2, 
randomization will also be based on a 1:1 ratio but study arms have not yet been defined and will depend on 
the outcome in Stage 1. 
2. Study drug: The investigational product is anti-SARS-CoV-2 convalescent plasma. Patients identified as 
having recovered from COVID-19 will serve as potential donors as per FDA guidelines 
(https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-
process-cber/recommendations-investigational-covid-19-convalescent-plasma) and NYBC protocol 
(https://www.nybc.org/donate-blood/covid-19-and-blood-donation-copy/convalescent-plasma/).  
Donors will be assessed for eligibility by the NYBC: https://www.nybc.org/donate-blood/covid-19-and-
blood-donation-copy/convalescent-plasma/ 
3. Potential donors and samples will be screened per FDA May 1, 2020 guidelines 
(https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-
                                              
10 If unable to obtain at all visits, can collect at baseline and then at selected visits during hospitalization 
11 Repeat during discharge if able 
12 Blood bank collects and ships segment from plasma bag tail for antibody testing 
13 Samples to be shipped to Einstein/Montefiore Biorepository 
14 ARUP labs (https://www.aruplab.com/) - 95892 
15 ARUP labs (https://www.aruplab.com/) – 51394 
Laboratory testing 
CBC with 
differential  
 
x 
 
x 
x 
x 
x 
 
 
 
CMP (or BMP) 
 
x 
 
x 
x 
x 
x 
 
 
 
LFT 
 
x 
 
x 
x 
x 
x 
 
 
 
D-dimer10 
 
x 
 
x10 
x10 
x10 
x10 
 
 
 
LDH10 
 
x 
 
x10 
x10 
x10 
x10 
 
 
 
CRP10 
 
x 
 
x10 
x10 
x10 
x10 
 
 
 
Ferritin10 
 
x 
 
x10 
x10 
x10 
x10 
 
 
 
CPK 
 
x6 
 
x6 
x6 
x6 
x6 
 
 
 
Fibrinogen 
 
x6 
 
x6 
x6 
x6 
x6 
 
 
 
Procalcitonin 
 
x6 
 
x6 
x6 
x6 
x6 
 
 
 
PTT 
 
x6 
 
x6 
x6 
x6 
x6 
 
 
 
Troponin 
 
x6 
 
x6 
x6 
x6 
x6 
 
 
 
(Pro-)BNP 
 
x6 
 
 
x6 
 
 
 
 
 
SARS-CoV-2 RT-
PCR11 
 
 
 
 
 
x11 
x1 
x1 
 
x1 
SARS-CoV-2 
antibody13 
 
x13 
x1213 
x13 
 
x13 
x1,13 
x1,13 
 
x1,13 
Lymphocyte 
subset14 
 
x6 
 
x6 
 
x6 
x1,6 
x1,6 
 
x1,6 
Cytokine panel15 
 
x6 
 
x6 
 
x6 
x1,6 
x1,6 
 
x1,6 
Blood for future 
testing (To be 
collected by 
selected sites) 
 
x6 
 
x6 
 
x6 
x1,6 
x1,6 
 
x1,6 

13 
 
process-cber/recommendations-investigational-covid-19-convalescent-plasma) and NYBC protocols 
(https://www.nybc.org/donate-blood/covid-19-and-blood-donation-copy/convalescent-plasma/). 
4. Treatment arm will receive 1-2 units of CP antibodies to SARS-CoV-2, Stage 1. 
5. Control arm will receive equivalent volume of SS, Stage 1. 
6. CP will be in standard plasma unit bags, with a study specific International Society of Blood Transfusion 
(ISBT) label 
7. Both study drugs will be blinded to minimize unblinding of the bedside nurse, research staff, and the patient.  
 
Randomization assignments are performed for patients at baseline. Randomization is performed separately by 
two strata, treatment site and risk of severe disease (high versus lower) as defined below. The randomization 
scheme will be determined by the study Stage and its associated group of intervention arms (For example, in 
Stages 1 and 2, subjects will be randomized to 1:1 ratio). Randomization should obviate the need for additional 
adjustment factors but if pre-specified demographic or clinical characteristics are unbalanced with respect to 
treatment group, we will consider adjustment; these characteristics include but are not limited to age, sex, race, 
ethnicity, BMI and COVID severity at baseline. The collaborating sites will be using the interactive web response 
system (IWRS) developed for randomization. 
 
6. Rationale for Dosing 
 
One to two units of convalescent plasma (250-500mL) containing anti-SARS2-CoV-19 IgG, as determined by 
the NYBC protocol prior to dispensing the plasma as “convalescent plasma,” will be used in the treatment 
group. The NYBC tests potential plasma for SARS-CoV-2 IgG prior to distributing it as “convalescent plasma.” 
Given that the NYBC testing platform provides a qualitative SARS-CoV-2 determination, SARS-CoV-2 IgG 
and neutralizing titers will be determined retrospectively as per FDA guidelines (https://www.fda.gov/vaccines-
blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-
investigational-covid-19-convalescent-plasma). At the discretion of the treating physician, two units (~500 mL) 
may be administered. 
 
Based on previous use of CP therapy in SARS-1, 5 mL/kg of plasma at titer  1:160 was utilized (7), for a 70 
Kg person. For CP therapy for COVID-19, plasma volume is estimated to be 2800mL (40 mL/kg x70 kg) with 
baseline anti-SARS-CoV-2 titer of 0; therefore, if protective titer was 1:25 and each unit had titer of 1:160, 
500mL can achieve this ([500/(2800+500)] x 1:160>1:25). If titer is ≥1:320, 250mL can achieve this titer.  
 
Convalescent plasma units come from single individuals with anti-SARS-CoV-2 IgG. It is not a pooled product. 
If a patient receives one unit it will have come from a single person. If two units are given, it will come from 
one person or two different people. This is not something we will know. We will know that the samples have 
anti-SARS-CoV-2 IgG.  
 
The control group will receive an equivalent volume (250-500ml) of SS. 
 
Attempts will be made to blind the appearance of the solution being administered, in order to minimize the risk 
of unblinding the treatment the patient, bedside nurse, and research staff.   
 
7. Study product administration 
 
1. Study product will be administered within 24 hours of randomization 
2. Infusion rate  500 mL/hour 
3. Pretreatment to minimize transfusion reactions (e.g. acetaminophen, diphenhydramine) may be given. 
Individual institutional guidelines/SOPs for the administration of plasma should be followed, including 
the use of any premeditations, such as acetaminophen and diphenhydramine.  

14 
 
4. If an AE develops during infusion, the infusion may be slowed or stopped as per investigator’s decision 
in discussion with the blood bank.  
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 can generally be continued in cases of itching or hives after pausing the 
transfusion, administering antihistamines, and observing the patient for worsening.   
o Severe allergic reactions, such as bronchospasm and hypotension, require discontinuation of the 
infusion.  
5. Post-treatment management of fluid overload (i.e. need for furosemide) as per supervising physician on 
a case-by-case basis. 
6. Concomitant medications will be documented on the Case Report Form (CRF) 
 Prescription medications 
 Over the counter medications 
 Herbal treatments/nutritional supplements 
 Blood products 
 Any medications with established activity against SARS-CoV-2 that subject is receiving 
 
STATISTICAL PLAN 
 
1. Statistical Modeling 
Inferences in this trial are based on a Bayesian statistical model, which estimates the posterior probability 
for each intervention based on the evidence that has accumulated during the trial in terms of the observed 
WHO ordinal outcome and assumed prior knowledge in the form of a prior distribution. The statistical 
model considers the variation in outcomes by site, strata, and phase of the trial.  
 
Details 
of 
the 
modeling, 
prior 
distribution 
assumptions, 
decision 
rules, 
and 
proposed 
secondary/exploratory analyses are provided in the Statistical Analysis Plan. 
 
2. Sample Size and Power Considerations 
The planned total sample size for the trial is 1000 subjects, stratified by site and risk of severe disease 
(high versus lower), but target enrollment will be adapted based on continuous Bayesian monitoring as 
detailed in the SAP.  
 
We estimated an initial sample size for Stage 1 study design using simulations assuming a two-sided 
Type I error rate (alpha) of 0.05 and 80% power. We made the following additional assumptions:  
a. 30% incidence of worsening respiratory status (10% death and 20% on invasive 
mechanical ventilation or ECMO, respectively) and 10% of discharged alive in the 
control group estimated by current data from our hospital, 
b. 1.8 odds ratio (OR) of worsening respiratory status between the control group and the 
anti-SARS-CoV-2 convalescent plasma group,  this approximately corresponds to an 
13% absolute reduction in incidence of worsening respiratory status (5% death and 12% 
on invasive mechanical ventilation or ECMO, respectively) and 5% absolute increase of 
discharged alive using anti-SARS-CoV-2 convalescent plasma.  
c. Very few subjects will be randomized and fail to receive study plasma infusion or will be 
lost to follow-up and have missing data for the primary endpoint.  
 
We initially estimated that a sample size of 300 patients (150 in each arm) would be sufficient to detect 
the specified difference in clinical status between the two arms with a power of at least 0.8; therefore, 
the planned total sample size of 1000 subjects is more than sufficient. Stage 1 will complete according to 

15 
 
the monitoring rules described above, and may end with fewer patients due to futility, equivalence or 
superiority. Stage 2 of the study will proceed in a similar manner. 
 
 
STUDY PROCEDURES 
 
Study Protocol by Day: 
 
Day -3 to 0:  
A. Screening (must be completed before randomization) 
B. Informed consent (obtained before performing study related activities) 
C. Baseline Evaluation (at screening) (much of the information will be obtained from the medical record) 
 
1. Demographics:  
 Age, sex, race, ethnicity 
2. Medical history:  
 Timing of exposure to COVID-19 source patient 
 Acute and chronic medical conditions 
 Medications, allergies 
 Any medical condition arising after consent to be recorded as AE. 
3. COVID-19 symptom screen:  
 Symptoms: Fevers, cough, shortness of breath, chest pain 
 History of illness: Onset of symptoms, source of contagion 
4. Vital signs 
5. COVID-19 testing (RT-PCR)  
 Nasopharyngeal, oropharyngeal, tracheal aspirate, bronchoalveolar lavage. Results from 
laboratory tests obtained up to 7 days before enrollment may be used. 
6. Baseline Basic Lab Testing and imaging 
 Blood typing (any prior active results may be used if available), (pro-)BNP (if part of 
standard of care) 
 Chest imaging (CXRAY or CT scan), EKG (if part of standard of care) 
7. Urine or serum pregnancy test  
 For females of childbearing potential or not menopausal 
 Results from laboratory tests obtained up to 7 days before enrollment may be used for the 
pregnancy test 
8. Determination of eligibility  
 Inclusion/exclusion criteria age 
 Consent 
 Documentation of positive for COVID-19 in the prior 7 days 
 Symptoms of cough, shortness of breath, chest pain, fever, or oxygen saturation ≤ 94%, not 
already an ICU patient 
 Oxygen supplementation 
 Within 7 days from first sign of illness or within 72 hours of admission 
 
Day 0:  
1. Randomization of eligible subject in IWRS 
2. Study Plasma Administration:  
a. 1-2 units of plasma will be transfused 
b. Time at start and end of infusion will be recorded  

16 
 
c. Vital signs will be measured immediately prior to infusion, 10-20 minutes after start of infusion, 
at completion of infusion and 30-60 minutes after the end of the infusion 
d. Blood bank will collect plasma bag tail segment for SARS-CoV-2 antibody titers 
3. COVID-19 symptom screen: fevers, cough, shortness of breath 
4. Assessment of clinical status (WHO ordinal scale ) 
5. New medical conditions, concomitant medication, AE evaluation 
6. Physical examination (standard of care/per protocol) 
7. CBC, CMP or BMP, CRP, LFT, D-dimer, LDH, ferritin.  
8. Serological testing: anti-SARS CoV-2 titers  
9. If able to be obtained when not part of standard of care: (pro-)BNP, Fibrinogen, procalcitonin, CPK, 
PTT, troponin, Lymphocyte subsets, and Cytokine panel. 
10. Stored samples for future studies at selected sites 
 
Day 1-14 (as inpatient or for duration of hospitalization): 
1. Vital signs daily 
2. COVID-19 symptom screen (fevers, cough, shortness of breath) 
3. Assessment of clinical status (WHO ordinal scale ) 
4. New medical conditions, concomitant medications, AE evaluation 
5. Physical examination (standard of care/per protocol) 
6. CBC, CMP or BMP, LFT, CRP, LDH, ferritin, and D-Dimer 
7. Serological testing: anti-SARS CoV-2 titers  
8. Nasopharyngeal or throat: SARS-CoV-2 PCR 
9. If able to be obtained when not part of standard of care: (pro-)BNP, Fibrinogen, procalcitonin, CPK, 
PTT, troponin, Lymphocyte subset, and Cytokine panel. 
10. Stored samples for future studies at selected sites 
11. CXR or CT (day 3 if part of standard care and day 14 or at discharge, whichever comes first)  
12. EKG (day 3 and and 14 if patient is still hospitalized and clinically indicated ) 
13. Echocardiogram parameters and right and/or left heart cardiac catheterization data, if performed for 
clinical care 
14. Duplex ultrasound of extremities if performed for clinical care  
 
Day of Discharge: 
1. Define disposition (home or other) 
2. Assessment of clinical status (WHO ordinal scale) 
 
Day 14 (as outpatient, phone call or in-person follow-up): 
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (WHO ordinal scale) 
3. New medical conditions, concomitant medications, AE evaluation 
4. Serological testing: anti-SARS CoV-2 titers (if able to be obtained) 
5. Nasopharyngeal or throat: SARS-CoV-2 PCR (if able to be obtained) 
6. Lymphocyte subsets (if able to be obtained) 
7. Cytokine panel (if able to be obtained) 
8. Define disposition (home, hospital, status) 
9. Pulmonary status (supplemental oxygen) 
10. Stored samples for future studies at selected sites (if able to be obtained) 
 
Day 28 (as outpatient, phone call or in-person follow-up):  
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (WHO ordinal scale ) 

17 
 
3. New medical conditions, concomitant medications, AE evaluation 
4. Serological testing: anti-SARS CoV-2 titers (if able to be obtained) 
5. Nasopharyngeal or throat: SARS-CoV-2 PCR (if able to be obtained) 
6. Lymphocyte subsets (if able to be obtained) 
7. Cytokine panel (if able to be obtained) 
8. Define disposition (home, hospital, status) 
9. Pulmonary status (supplemental oxygen) 
10. Stored samples for future studies at selected sites (if able to be obtained) 
 
Day 60 (as outpatient, phone call or in-person follow-up):  
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (WHO ordinal scale) 
3. New medical conditions, concomitant medications, AE evaluation 
4. Define disposition (home, hospital, status) 
5. Pulmonary status (supplemental oxygen) 
 
Day 90 (as outpatient, phone call or in-person follow-up): 
1. COVID-19 symptom screen (fevers, cough, shortness of breath) 
2. Assessment of clinical status (WHO ordinal scale)  
3. New medical conditions, concomitant medications, AE evaluation 
4. Nasopharyngeal or throat: SARS-CoV-2 PCR (if able to be obtained) 
5. Serological testing: anti-SARS CoV-2 titers (if able to be obtained) 
6. Lymphocyte subsets (if able to be obtained) 
7. Cytokine panel (if able to be obtained) 
8. Define disposition (home, hospital, status) 
9. Pulmonary status (supplemental oxygen) 
10. Stored samples for future studies at selected sites (if able to be obtained) 
 
HUMAN SUBJECTS PROTECTIONS 
 
RISK/BENEFIT ASSESSMENT 
 
1. Known potential risks 
A. The protocol involves blood sample collection (see Table). Blood is collected as part of the routine 
care of nearly all hospitalized patients. The risk of blood collection, or phlebotomy is bruising or 
fainting. Some samples required for this protocol are collected as part of the usual care of the patient 
and others will be specifically collected for the protocol (see Table). The latter will be collected at 
the same time as the former. A separate phelebotomy will only be required for post-discharge 
samples. 
 
B. A theoretical risk of administration of convalescent plasma is the phenomenon of antibody-mediated 
enhancement of infection (ADE). ADE can occur in viral diseases, such as dengue and involves an 
enhancement of disease in the presence of certain antibodies. For coronaviruses, several mechanisms 
of ADE have been described, including the theoretical concern that antibodies to one type of 
coronavirus could enhance infection to another strain (17). It may be possible to predict the risk of 
ADE in SARS-CoV-2 experimentally, as proposed for MERS (17). Since the proposed use of 
convalescent plasma in the COVID-19 epidemic would rely on preparations with high titers of 
antibody against the same virus, SARS2-CoV-2, ADE may be unlikely. Available evidence from the 

18 
 
use of convalescent plasma in patients with SARS1 and MERS (18) demonstrated it is safe and there 
were no adverse effects in a pilot study of patients with COVID-19 (13). Nevertheless, caution and 
vigilance will be exercised to use clinical and laboratory measures to detect evidence of enhanced 
infection. 
 
C. Another theoretical risk is that antibody administration to those exposed to SARS-CoV-2 may 
prevent disease but modify the immune response such that those who are treated may mount 
attenuated immune responses. This may leave them vulnerable to subsequent re-infection. Passive 
antibody administration before vaccination with respiratory syncytial virus attenuated humoral but 
not cellular immunity (19). This will be investigated as part of this clinical trial by comparing 
immune responses in those who receive standard plasma and convalescent plasma. If responses 
differ, those with attenuated levels could be vaccinated against COVID-19 when a vaccine becomes 
available. Nonetheless, these concerns are modest compared to the possible benefit of reducing the 
risk of respiratory failure and avoiding mechanical ventilation. 
 
D. There are also risks associated with any transfusion of plasma including transmission of transfusion 
transmitted viruses (e.g. HIV, HBV, HCV, etc.), allergic transfusion reactions, anaphylaxis to 
transfusion, febrile transfusion reaction, transfusion related acute lung injury (TRALI), transfusion 
associated cardiac overload (TACO), and hemolysis should ABO incompatible plasma be 
administered. To minimize the risks of disease transmission, all plasma will be screened for blood 
borne pathogens, and pathogen reduction techniques will be utilized to prepare the plasma using 
standardly accepted FDA guidelines that oversee plasma collection. In addition, donors will fulfill 
donor requirements which require a history of COVID-19 illness, a positive COVID-19 test, a two-
week period of being asymptomatic post infection and a negative nasopharyngeal swab for SARS-
CoV2 by PCR.  
 
E. COVID-19 can be complicated by coagulopathy, including disseminated intravascular coagulation 
(DIC), which has risk of venous thromboembolism. The incidence of venous thromboembolism 
among COVID-19 patients may be somewhat higher than in other disease conditions (20). One study 
found  a 31% incidence of thrombotic complications in ICU patients with COVID-19 infections 
(21). Transfusion with fresh frozen plasma (FFP) can increase risk of thromboembolism, but it has 
also been shown to protect thrombosis in some patients. A retrospective study of trauma patients 
who received blood products for traumatic hemorrhage had an increased risk of venous 
thromboembolism if they received concomitant packed red blood cell (pRBC) transfusions with 
fresh frozen plasma (22) may have the potential to increase risk of thromboembolism. This is 
unproven and this was not described in reports of CP use in China or Korea (14, 16, 23). It may also 
reduce the risk of COVID-19-associated risk of thrombosis if it is effective therapy. INR will be 
monitored in patients on coumadin. 
 
2. Known potential benefits 
 
The most important potential benefit of CP is that it may reduce progression to respiratory failure in 
patients with COVID-19, particularly in patients with early symptoms of respiratory involvement, 
such as cough and shortness of breath and/or pulmonary infiltrates. The benefit of CP is expected to 
include an improvement in symptoms, oxygenation, the need for mechanical ventilation and possibly 
reduced mortality. Based on historical experience with antibody administration, antibody 
administration is expected to be effective relatively early in disease (1). CP was safe, reduced 
symptoms, and improved oxygenation in a non-randomized open label study of patients with more 
advanced disease in Wuhan, China (13). 
 

19 
 
3. Assessment of potential risks and benefits 
 
Given historical data showing CP was safe and possibly effective in patients with SARS1 (7, 18), and 
emerging data from China suggest it is safe and possibly effective in patients with severe COVID-19. 
Neither the safety nor the risks of CP have been established in randomized, controlled trials. The 
potential benefits of CP amid a humanitarian crisis warrant urgent studies of the efficacy of CP. 
Effective therapies are desperately needed for COVID-19. At present, none exist. Thus, in view of the 
lack of any proven therapy, the benefits of CP outweigh its potential risks. However, for all patients in 
whom CP is considered, a risk-benefit assessment will be conducted to assess individual variables. This 
protocol will use a randomized controlled study design to assess the efficacy of CP. The placebo control 
poses minimal risk, that of additional volume. We note that a recent JAMA editorial by experts noted 
the importance of randomized clinical trials to demonstrate efficacy of this approach and change the 
course of the epidemic (20). 
 
There are limited data on the potential risks and/or benefits of CP in pregnant woman and fetus.  
Pregnancy can cause changes in the coagulation and fibrinolytic systems and CP may potentially benefit 
some individuals by providing the coagulation factors. CP was given to pregnant women in studies of 
patients with Ebola (Van et al. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. 
2016. N Engl J Med 374:33-42)  and with COVID-19 in China (Zhang et al. Treatment with 
convalescent plasma for critically ill patients with SARS-CoV-2 infection. 2020. Chest 
doi:10.1016/j.chest.2020.03.039. 
 
Alternatives: The alternative to participation in this study is routine care 
 
SAFETY 
 
1. Safety measures 
1. Clinical evaluations: Vital signs and symptom screen on days 0-7, 14 if still hospitalized, and symptom 
screens on days 28, 60, and 90. 
2. Laboratory evaluations to include chest radiography (chest x-rays and/or chest CT), EKG 
Safety laboratory tests (ABO typing, urine or serum pregnancy testing, CBC, comprehensive metabolic 
panel, LFT, D-dimer, PTT, LDH, fibrinogen, ferritin, CRP, procalcitonin, troponin) will be performed at 
the local CLIA-certified clinical laboratory on days 0-7 and 14 as specified by above plan.  
3. Monitoring for development of venous thromboembolism if related to plasma infusion. 
 
2. Definitions 
1. Adverse Event (AE): Any untoward medical occurrence in a clinical investigation subject who has 
received a study intervention and that does not necessarily have to have a causal relationship with the 
study product. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of the study 
product, whether or not considered related to the study product. 
 
2. Serious Adverse Event (SAE): Any adverse event that results in any of the following outcomes: 
a. Death 
b. Life-threatening (immediate risk of death) 
c. Prolongation of existing hospitalization 
d. Persistent or significant disability or incapacity 
e. Important medical events that may not result in death, be life threatening, or require intervention 
or escalation of care may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 

20 
 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization. 
 
3. Unexpected Adverse Event (UAE): An adverse reaction, the nature or severity of which is not 
consistent with the investigator’s brochure. 
 
4. Serious and Unexpected Suspected Adverse Reaction (SUSAR): An adverse reaction, the nature of 
which is not consistent with the investigator’s brochure with severity as defined by SAE above. 
 
5. Unanticipated Problem (UP): Unanticipated Problem that is not an Adverse Event (e.g. breaches of 
confidentiality, accidental destruction of study records, or unaccounted-for study drug). 
 
6. Protocol Deviation: Deviation from the IRB-approved study procedures. Designated serious and non-
serious 
 
7.   Serious Protocol Deviation: Protocol deviation that is also an SAE and/or compromises the safety, 
welfare or rights of subjects or others 
 
3. Safety Reporting Requirements 
 
1. Reporting Interval 
All AEs and SAEs will be documented from enrollment. All AEs and SAEs that are unexpected and 
directly attributable to study drug transfusion will be followed until study end point (Day 90).  
 
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.  
 
All SAEs will be reported to the DSMB within 24hr if:  
o The event has a reasonable possibility of having been related to the study drug infusion 
o All unexpected deaths 
 
2. 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, research nurses, and nurse practitioners.  
 
For tests that are not reflective of progression of COVID-19 (e.g. liver function tests, electrolytes, 
neutrophil counts, bacterial cultures, BNP or pro-BNP), laboratory abnormalities will be reported as AEs 
if they are 5 times the upper limit of normal. Acute kidney injury will be reported if they are 1.5 times 
the upper limit of normal.  Examples of laboratory abnormalities that pertain to progression of COVID-
19 but do not need to be reported as AEs at any level unless requested by the DSMB are: lymphocyte 
counts and lymphocyte subset abnormalities, cytokines, D-dimer, platelet count, ferritin, fibrinogen, 
CRP. 
 
Assessment of Seriousness 
1. Event seriousness will be determined according to the protocol definition of an SAE  
2. Assessment of Severity 
 

21 
 
Event severity will be assigned according to the grade scale scale below 
1 = Mild: Transient or mild discomfort (<48 hours); no medical intervention/therapy required. 
 
2 = Moderate: Some worsening of symptoms but no or minimal medical intervention/therapy required) 
3 = Severe or Medically Significant: Escalation of medical intervention/therapy required 
4 = Life-threatening: Marked escalation of medical intervention/therapy required.  
5 = Death 
 
3. Assessment of Study Product Association 
1. The association assessment categories that will be used for this study are: 
o Definitely Related: The event follows: (a) a reasonable, temporal sequence from study drug or a 
study procedure; and (b) cannot be explained by the known characteristics of the participant’s 
clinical state or other therapies; and (c) evaluation of the participant’s clinical state indicates to 
the investigator that the experience is definitely related to study procedures. 
o Probably or Possibly Related: The event should be assessed following the same criteria for 
“Definitely Related”. If in the investigator’s opinion at least one or more of the criteria are not 
present, then “probably” or “possibly” associated should be selected. 
o Probably Not Related: The event occurred while the participant was receiving study 
drug/intervention or undergoing study procedures but can reasonably be explained by the known 
characteristics of the participant’s clinical state or other therapies. 
o Definitely Not Related: The event is definitely produced by the participant’s clinical state or by 
other therapies administered to the participant. 
o Uncertain Relationship: The event does not meet any of the criteria previously outlined. 
 
2. The investigator must provide an assessment of association or relationship of AEs to the study 
product based on: 
o Temporal relationship of the event to the administration of study product 
o Whether an alternative etiology has been identified 
o Biological plausibility 
o Existing therapy and/or concomitant medications. 
 
4. Safety Oversight  
Monitoring Plan 
1. All AEs and SAEs will be reviewed by protocol team regularly, or more often if needed.  
2. A data safety monitoring board (DSMB) composed of independent experts, without conflict of 
interests will be established. The DSMB reports will be disseminated to all other participating sites 
at least annually. If there is any information that suggests the changed risk of the study or lack of 
benefit, the report will be distributed to other sites within 2 days.  The DSMB will review the study 
before initiation, and then regularly thereafter. The DSMB will review study data to evaluate the 
safety, enrollment, efficacy, study progress, and conduct of the study. 
 
STUDY MODIFICATION 
 
1. Halting Criteria for the Study: The DSMB charter and charter addendum specifies the halting criteria for 
this study. Termination may be suggested by the DSMB at any time.   
 
2. 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 

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 beats per minute; or bradycardia <40 that is 
associated with dizziness, nausea or feeling faint. 
 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 
 
ETHICS 
 
1. Ethical Standard 
All sites conducting this study are committed to the integrity and quality of the clinical studies it coordinates 
and implements according with local institutional and regulatory requirements.  
 
All sites participating in this research have a Federal wide Assurance (FWA) number on file with the Office for 
Human Research Protections (OHRP).   
 
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. 
 
2. Institutional Review Board 
Site specific IRB will review this protocol and all protocol-related documents and procedures as required by 
OHRP and local requirements before subject enrollment.  
 
3. Informed Consent Process 
 
Each site will follow institution specific policy and process for consenting participants of legally authorized 
representatives for the study. A site specific protocol addendum will be provided by each site to the respective 
IRB.  For each study Stage, a separate informed consent form will be developed for which participants will 
consent separately. The collaborating sites may use the electronic consent database developed for this study. 
 
The informed consent process will be initiated before a volunteer agrees to participate in the study and should 
continue throughout the individual’s study participation. The subject will sign the informed consent document 
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.  
 
For subjects who may not have capacity due to acuity of illness or other reasons the participant’s legally 
authorized decision maker may be contacted. If the legally authorized decision maker is willing to consent for 
the participant to enter the trial and is able to provide the participant’s medical history, such participants will be 
included in the study. Subjects will be regularly assessed throughout the study with discussions with the clinical 

23 
 
care team to determine whether or not they have regained or lost the capacity to consent. If subjects regain the 
capacity to consent during the study, they will be provided again with the full informed consent form to indicate 
that they are willing to continue in the study and allow the use of their data.  
 
4. Subject Confidentiality 
 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the sponsors and 
their agents. No information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. The results of the research study may be published, but subjects’ 
names or identifiers will not be revealed. Records will remain confidential. To maintain confidentiality, the PI 
will be responsible for keeping records in a locked area and results of tests coded to prevent association with 
subjects’ names. Data entered into computerized files will be accessible only by authorized personnel directly 
involved with the study and will be coded. Subjects’ records will be available to the FDA, the NYBC or FDA 
registered blood establishment from which plasma was obtained and their representatives, investigators at the 
site involved with the study, and the IRB. 
 
5. Other Studies 
 
Patients will also be notified of the use of de-identified data in other studies, such as pooling analyses, sub-
analyses, and/or meta-analyses. 
 
A third party/honest broker (HB) (i.e. DSMB unblinded statistitian) who has access to the data as part of their 
role in compiling the study’s data for the DSMB and is not involved as a listed researcher on the study will 
access the desired records and provide researchers of other studies with de-identified data or limited data sets 
(where applicable and approved by the IRB and Privacy Board). As requested HB will either strip the data of all 
identifiers and the data set is anonymized or will assign a code to the data. The researchers of the CONTAIN 
trial and any other researchers who will receive the data will not have access to the information linking the code 
to the identifiers of the research subjects. Using the code, researchers can request, through the HB, additional 
information corresponding to the research subject. When the honest broker provides coded data to the research 
but not the method to de-code the data, then the information provided will be considered de-identified or a 
limited data set depending upon the data elements included in the data set. 
 
6. Future Use of de-Identified Patient Information and Stored Specimens 
 
During the consent process, subjects will be asked for permission to use their data and samples for future 
research. The confidentiality of the subject will be maintained as per HIPAA regulations. Each participant will 
be assigned a unique identifier at the time of consent. The identifier links the information it contains about the 
patient and the specimen. De-identified patient information can be used for sub-group analyses after the 
conclusion of the trial and/or upon permission of the DSMB if the trial is still ongoing.  
 
No human genetic testing will be performed on the samples. Five ml of blood samples will be collected at 5 
time points (See Schedule of Events). Blood samples from all trial participating sites will be sent to the 
Biorepository at Albert Einstein College of Medicine. Samples will be de-identified and coded upon receipt. 
Plasma will be separated from whole blood, aliquoted, frozen at -20oF and stored in the Biorepository and 
stored until use for future research.  
 
Samples will not be shared with investigators other than investigators included in this protocol. The specimens 
will remain linked and at Albert Einstein College of Medicine/Montefiore Medical Center for at least 5 years. 
Storage beyond the study length will be an option.  Any use of these specimens not specified in the current 

24 
 
protocol will be reviewed by the IRB. There will be no plans to re-contact participants or to inform them of 
results. 
 
7. Data management and monitoring 
a. Source Documents 
The primary source documents for this study will be the subjects’ medical records. If the investigators 
maintain separate research records, both the medical record and the research records will be considered 
the source documents for the purposes of auditing the study. The investigator will retain a copy of 
source documents. The investigator will permit monitoring and auditing of these data, and will allow the 
IRB and regulatory authorities access to the original source documents. The investigator is responsible 
for ensuring that the data collected are complete, accurate, and recorded in a timely manner. Source 
documentation (the point of initial recording of information) should support the data collected and 
entered in to the study database and must be signed and dated by the person recording and/or reviewing 
the data. All data submitted should be reviewed by the site investigator and signed as required with 
written or electronic signature, as appropriate. Data entered into the study database will be collected 
directly from subjects during study visits or will be abstracted from subjects’ medical records. The 
subjects’ medical records must record their participation in the clinical trial and what medications (with 
doses and frequency) or other medical interventions or treatments were administered, as well as any AEs 
experienced during the trial. 
 
b.  Data Management Plan 
Study data will be collected at the study site(s) and entered into the study database by the study team or 
by transfer of data from the electronic health record. Data entry is to be completed on an ongoing basis 
during the study. 
 
c. Data Capture Methods 
Clinical data will be entered into a 21 CFR 11-compliant Internet Data Entry System (IDES). The data 
system includes password protection and internal quality checks to identify data that appear inconsistent, 
incomplete, or inaccurate. The collaborating sites will be using the electronic data capture (EDC) system 
developed by NYU for this study. 
 
d. Study Record Retention 
The PI is responsible for retaining all essential documents listed in the ICH GCP Guidelines. The FDA 
requires study records to be retained for up to 2 years after marketing approval or disapproval (21 CFR 
312.62), or until at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational agent for a specific indication. These records are also to be maintained in compliance 
with IRB/IEC, state, and federal medical records retention requirements, whichever is longest. All stored 
records are to be kept confidential to the extent provided by federal, state, and local law.  
 
No study document should be destroyed. 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. 
 
 

25 
 
 
 
Figure 1 Describes what is known about the potential course of patients with COVID-19 pneumonia. The goal 
of this protocol is to administer convalescent plasma in the “green” area to evaluate its ability to improve the 
clinical respiratory status of the patient and avoid the need for respiratory support, mechanical ventilation 
and/or ICU admission. (from Bouadma et al Int Care Med 2020) 

26 
 
 
REFERENCES  
 
1. 
Casadevall A, Pirofski LA. 2020. The convalescent sera option for containing COVID-19. J Clin Invest 
doi:10.1172/JCI138003. 
2. 
Casadevall A, Scharff MD. 1994. Serum therapy revisited: animal models of infection and development 
of passive antibody therapy. Antimicrob Agents Chemotherap 38:1695-1702. 
3. 
Casadevall A, Dadachova E, Pirofski LA. 2004. Passive antibody therapy for infectious diseases. Nat 
Rev Microbiol 2:695-703. 
4. 
Zhang JS, Chen JT, Liu YX, Zhang ZS, Gao H, Liu Y, Wang X, Ning Y, Liu YF, Gao Q, Xu JG, Qin C, 
Dong XP, Yin WD. 2005. A serological survey on neutralizing antibody titer of SARS convalescent 
sera. J Med Virol 77:147-50. 
5. 
Sahr F, Ansumana R, Massaquoi TA, Idriss BR, Sesay FR, Lamin JM, Baker S, Nicol S, Conton B, 
Johnson W, Abiri OT, Kargbo O, Kamara P, Goba A, Russell JB, Gevao SM. 2017. Evaluation of 
convalescent whole blood for treating Ebola Virus Disease in Freetown, Sierra Leone. J Infect 74:302-
309. 
6. 
Casadevall A, Pirofski L. 2003. The damage-response framework of microbial pathogenesis. Nat Rev 
Microbiol 1:17-24. 
7. 
Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, Chan P, Wong KC, Leung CB, Cheng G. 
2005. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect 
Dis 24:44-6. 
8. 
Yeh KM, Chiueh TS, Siu LK, Lin JC, Chan PK, Peng MY, Wan HL, Chen JH, Hu BS, Perng CL, Lu JJ, 
Chang FY. 2005. Experience of using convalescent plasma for severe acute respiratory syndrome among 
healthcare workers in a Taiwan hospital. J Antimicrob Chemother 56:919-22. 
9. 
Ko JH, Seok H, Cho SY, Ha YE, Baek JY, Kim SH, Kim YJ, Park JK, Chung CR, Kang ES, Cho D, 
Muller MA, Drosten C, Kang CI, Chung DR, Song JH, Peck KR. 2018. Challenges of convalescent 
plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience. 
Antivir Ther 23:617-622. 
10. 
Arabi YM, Hajeer AH, Luke T, Raviprakash K, Balkhy H, Johani S, Al-Dawood A, Al-Qahtani S, Al-
Omari A, Al-Hameed F, Hayden FG, Fowler R, Bouchama A, Shindo N, Al-Khairy K, Carson G, Taha 
Y, Sadat M, Alahmadi M. 2016. Feasibility of Using Convalescent Plasma Immunotherapy for MERS-
CoV Infection, Saudi Arabia. Emerg Infect Dis 22:1554-61. 
11. 
van Erp EA, Luytjes W, Ferwerda G, van Kasteren PB. 2019. Fc-Mediated Antibody Effector Functions 
During Respiratory Syncytial Virus Infection and Disease. Front Immunol 10:548. 
12. 
Gunn BM, Yu WH, Karim MM, Brannan JM, Herbert AS, Wec AZ, Halfmann PJ, Fusco ML, Schendel 
SL, Gangavarapu K, Krause T, Qiu X, He S, Das J, Suscovich TJ, Lai J, Chandran K, Zeitlin L, Crowe 
JE, Jr., Lauffenburger D, Kawaoka Y, Kobinger GP, Andersen KG, Dye JM, Saphire EO, Alter G. 2018. 
A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus. 
Cell Host Microbe 24:221-233 e5. 
13. 
Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang 
J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin 
L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, 
Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X. 2020. Effectiveness of 
convalescent plasma therapy in severe COVID-19 patients. Proceedings of the National Academy of 
Sciences doi:10.1073/pnas.2004168117:202004168. 
14. 
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang 
Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, 
Liu Y, Liu L. 2020. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. 
JAMA doi:10.1001/jama.2020.4783. 

27 
 
15. 
van GJ, Edwards T, de L, X, Semple MG, Gallian P, Baize S, Horby PW, Raoul H, Magassouba N, 
Antierens A, Lomas C, Faye O, Sall AA, Fransen K, Buyze J, Ravinetto R, Tiberghien P, Claeys Y, De 
CM, Lynen L, Bah EI, Smith PG, Delamou A, De WA, Haba N. 2016. Evaluation of Convalescent 
Plasma for Ebola Virus Disease in Guinea. N Engl J Med 374:33-42. 
16. 
Zhang B, Liu S, Tan T, Huang W, Dong Y, Chen L, Chen Q, Zhang L, Zhong Q, Zhang X, Zou Y, 
Zhang S. 2020. Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 
infection. Chest doi:10.1016/j.chest.2020.03.039. 
17. 
Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, Chen Y, Wu J, Shi Z, Zhou Y, Du L, Li F. 2020. 
Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry. J Virol 94. 
18. 
Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, Makki S, Rooney KD, 
Nguyen-Van-Tam JS, Beck CR, 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 211:80-90. 
19. 
Crowe JE, Jr., Firestone CY, Murphy BR. 2001. Passively acquired antibodies suppress humoral but not 
cell-mediated immunity in mice immunized with live attenuated respiratory syncytial virus vaccines. J 
Immunol 167:3910-8. 
20. 
Roback JD, Guarner J. 2020. Convalescent Plasma to Treat COVID-19: Possibilities and Challenges. 
JAMA doi:10.1001/jama.2020.4940.