Convalescent Plasma to Reduce Complications Associated With COVID-19 Infection: A Randomized Trial Comparing the Efficacy and Safety of High-Titer Anti-SARS-CoV-2 Plasma vs. Standard Plasma in Hospitalized Patients With COVID- 19 Infection
Phase: PHASE1
Conditions: COVID
Sponsor: Stony Brook University

1 
 
 
 
ID: SBU-COVID19-
ConvalescentPlasma 
    Convalescent Plasma vs. Standard Plasma for 
COVID-19 
    NCT04344535 
 
Convalescent Plasma to Reduce Complications Associated with COVID-19 Infection: A 
Randomized Trial Comparing the Efficacy and Safety of High-Titer Anti-SARS-CoV-2 Plasma vs. 
Standard Plasma in Hospitalized Patients with COVID- 19 Infection  
 
Dated: October 16, 2020 
 
 

2 
 
Convalescent Plasma to Reduce Complications Associated with COVID-19 Infection: A 
Randomized Trial Comparing the Efficacy and Safety of High-Titer Anti-SARS-CoV-2 Plasma vs. 
Standard Plasma in Hospitalized Patients with COVID- 19 Infection  
 
Version 1.8 
Dated: October 16, 2020 
 
Protocol signature page: 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board determinations; all applicable in-country, state, and local laws and 
regulations; and other applicable requirements (e.g., US National Institutes of Health, Division of AIDS) 
and institutional policies. 
 
 
Elliott Bennett-Guerrero, M.D.  
x 
 
 
 
 
 
 
 
Name of Investigator of Record 
 
Signature of Investigator of Record   
Date 
 
 
 
In developing this protocol, we reviewed, adopted and adapted some of the helpful strategies 
and language outlined in the National COVID-19 Convalescent Plasma Project protocols that 
are posted for free and immediate use (https://ccpp19.org/status.html ; 3 protocols listed 
from John Hopkins as well as the Mayo Clinic). We are grateful for these examples. 
 
 

3 
 
PROTOCOL 
 
Long Title: Convalescent Plasma to Reduce Complications Associated with COVID-19 Infection: 
A Randomized Trial Comparing the Efficacy and Safety of High-Titer Anti-SARS-CoV-2 Plasma vs. 
Standard Plasma in Hospitalized Patients with COVID- 19 Infection  
Short title:  Convalescent Plasma vs. Standard plasma for COVID-19 Infection 
Clinical Phase: 1/2 
IND Sponsor:  Elliott Bennett-Guerrero, M.D. 
Conducted by: Stony Brook University  
Study Locations: Stony Brook University Hospital locations (Stony Brook Hospital and 
Southampton Hospital). Convalescent plasma that has been collected and stored frozen at 
Stony Brook Hospital’s blood bank will be transported frozen, stored, thawed, and dispensed by 
Southampton Hospital’s blood bank, which is also a licensed blood bank. Written authorization 
has been obtained from the FDA on May 29, 2020 that no shipping license is required for 
shipment of this COVID-19 convalescent plasma to the blood bank of the IRB approved 
location/site. 
Sample Size: 500 (interim DSMC safety/efficacy assessments at 100 and 250 patients 
randomized) 
Study Population: Hospitalized patients >18 years of age with a PCR confirmed diagnosis of 
COVID-19, and within 14 days from admission to Stony Brook Hospital or any hospital.   
Study Duration: 90 days post randomization 
Study Design: This randomized placebo-controlled trial will assess the efficacy and safety of 
anti-SARS-CoV-2 convalescent plasma in hospitalized patients with a PCR confirmed diagnosis of 
COVID-19 and within 14 days from admission to Stony Brook Hospital (or another hospital if 
transferred to Stony Brook).  A total of 500 eligible subjects will be randomized in a 4:1 ratio to 
receive either high titer anti-SARS-CoV-2 plasma or control (standard plasma). For individuals 
who are eligible for the study, but there is no eligible compatible convalescent plasma available 
at that time, these patients will be followed as a non-randomized third study group. If plasma 
becomes available within the eligible time period (within 14 days from admission to Stony 
Brook Hospital or another hospital), then patients will be removed from this group and 
randomized.   
Randomization will be stratified by illness severity, defined as hospitalized patients not on a 
ventilator vs. patients on a ventilator at the time of randomization. 

4 
 
The following will be assessed in all subjects at the time of randomization (or consent if in the 
“observational” arm who have no matching plasma) and then at pre-specified time points up to 
maximum 90 pays post randomization: 
 Age, sex, comorbidities, date of symptoms, level of care (ICU vs not), vital signs including 
temperature, respiratory rate, oxygen saturation, oxygen requirement, and CBC with 
neutrophil counts, lymphocytes count, CRP, chest x-ray, chest CT (if available from 
routine care)  
 Safety (AEs) and efficacy: Day 0 (baseline), 1, 2, 3, 7, 14, and 28 days and once monthly 
at 60 (50-70) and 90 (80-100) days post randomization through review of the electronic 
medical record (EMR) and telephone calls to the subject.   
 Antibody titer (either a drop of blood for point of care [POC] test or 3 ml EDTA tube for 
each time period, or total of 18 ml for these) to SARS-CoV-2: Days 0, 1, 7, 14, 21 and 28 
through hospital discharge and only required in the first 100 subjects randomized. If 
available, a drop of blood will also be tested on a “research only” plate for antibodies to 
the spike protein (FDA approved plate we are using measures antibodies to the NP 
portion of the virus).   
 Type and Screen, if one for this admission does not already exist (6 ml tube by 
venipuncture or from an indwelling catheter) 
 Outcome measures: number of days on mechanical ventilation, time to extubation, new 
incidence of intubation, ICU admission, ICU length of stay, total hospital LOS, all-cause 
mortality, resolution of symptoms (normalization of temperature and reduced need for 
oxygen [example, 50% facemask down to 2 L Nasal Cannula]).  
 
Study Agent:  
 SARS-CoV-2 convalescent plasma (equivalent to 2 units of plasma, or approximately 
total volume of 450-550 mL collected by apheresis from a volunteer who recovered 
from COVID-19 infection and has high IgG levels of antibody to SARS-CoV-2 antibody 
determined by a FDA EUA approved (FDA 2020) quantitative IgM and IgG assay 
(Chembio Diagnostics, Inc. Medford, NY).  See FDA “Policy for Diagnostic Tests for 
Coronavirus Disease-2019 during the Public Health Emergency”, March 16, 2020. Goal is 
for antibody titers approximately > 1:320 but per FDA’s April 3, 2020 guidance we can 
go down to a titer of 1:80 if higher titer plasma is not available.  
 Standard plasma (equivalent to 2 units of plasma, or approximately total volume of 450-
550 mL) with presumed or documented low levels of IgG as per above. 
 
Primary Efficacy Objective: Reduction in progression of COVID-19 associated pulmonary 
dysfunction manifested by high oxygen and in some case ventilator requirements.    
Primary Endpoint:  Ventilator free days through 28 days post randomization.  This endpoint is 
established in critical care trials (e.g. ICU-ROX trial; NEJM 2020).  Patients who never require 
mechanical ventilation through 28 days are assigned 28 days, i.e. best outcome. Patients who 

5 
 
die are assigned the worst outcome, i.e. 0 ventilator free days.  We define a ventilator day as 
one that either requires endotracheal intubation, or tracheostomy with any need for a 
ventilator, even if only pressure support ventilation. Non-invasive ventilation (e.g. BIPIP, CPAP, 
Hi-flow NC) are not considered “ventilator days”. 
Secondary endpoints: 
1. Death (rates and time to event) through 90 days post randomization 
2. Length of Hospital Stay 
3. Length of ICU stay 
4. Oxygen requirement (highest, i.e. lowest PaO2/FiO2 ratio per day,) will be recorded 
from routine clinical data on Day 0 (baseline), 1, 2, 3, 7, 14, and 28 but only while the 
subject is hospitalized. 
5. Change in antibody levels to SARS-CoV-2 post transfusion of plasma 
6. Resolution of clinical symptoms (normalization of temperature, reduced need for 
oxygen) 
7. Improvement of ≥2 points in World Health Organization (WHO) Ordinal Scale for oxygen 
requirement 
8. Quality of life (SF-36) at approximately 90 days post randomization. 
 
Primary Safety Objective: Evaluate the safety of treatment with high-titer anti-SARS-CoV-2 
plasma versus control (standard plasma) in hospitalized patients with COVID-19 infection. 
 
Primary Safety Endpoints: 
1. Acute (within 60 minutes) deterioration of respiratory or clinical status on transfusion of 
SARS-CoV-2 convalescent plasma  
2. Cumulative incidence of serious adverse events: transfusion reaction (fever, rash) during 
and within 1 hours after infusion, transfusion related acute lung injury (TRALI), 
transfusion associated circulatory overload (TACO), transfusion related infection within 
28 days of infusion 
 
These safety endpoints, and other AEs, will be reviewed by the trials internal blinded Safety 
Monitor and sent to the DSMB, IRB, and FDA as appropriate (see section 7). 
2. Study Population 
To ensure fairness, potential subjects will be pre-screened according to a process that includes 
a daily “lottery”: to determine the order in which to approach patients (see SOP). 
 
Inclusion Criteria for Enrollment 
1. Patients must be 18 years of age or older 

6 
 
2. Hospitalized with COVID-19 infection and a confirmed diagnosis of  COVID-19 
SARS-CoV-2 from RT-PCR testing.   
3. Patient (or Legally Authorized Representative) is willing and able to provide 
written informed consent and comply with all protocol requirements.  
4. If female must not be pregnant and/or breastfeeding.  
 
Exclusion Criteria 
1. Female subjects with positive pregnancy test, breastfeeding, or planning to 
become pregnant/breastfeed during the study period. The protocol will be 
amended to allow participation of these individuals when processes are in place 
that can ensure the safety of the donated plasma to the pregnant woman and 
fetus/baby.  
2. In the treating physician’s opinion, the patient cannot tolerate a 450-550 mL 
infusion of plasma over up to 8 hours (4 hours max per unit), even if prophylaxed 
with intravenous diuretic, e.g. furosemide 20-80 mg, which is commonly done in 
critically ill or low EF patients 
3. Receipt of pooled (polycolonal) immunoglobulin or any intravenous polyclonal 
immunoglobulin (IVIG) in past 30 days. Receipt of a monoclonal antibody is not an 
exclusion. 
4. Contraindication to transfusion or history of prior reactions to transfusion blood 
products 
5. Unable to randomize patient within 14 days of admission to Stony Brook 
Hospital (or any other hospital if a transfer to Stony Brook Hospital). This 
definition is consistent with our desire to focus on patients relatively early in 
the disease process, e.g. NOT patients many weeks into the disease. Admission 
date is an objective measure, unlike “onset of symptoms”, which is very 
challenging to accurately predict in many patients. The time from onset of 
symptoms may play a role in plasma treatment response (Roback 2020). A prior 
study using convalescent plasma during the 2003 SARS outbreak showed that 
patients who received the transfusion earlier had better outcomes (Cheng 2003). 
Preliminary data from Chembio serial assays, and anecdotal reports from other 
investigators, suggest that many individual do not mount an immune response 2-
3 weeks after infection, so convalescent plasma may be effective in this early 
stage window. 
 
Above prescreening for eligibility should occur within 72 hours prior to randomization if eligible.  
 
3. Background 
 
 
COVID-19 infection from the SARS-CoV-2 virus has become a global pandemic.  It is 
estimated that approximately 50% of humans on Long Island might become infected by May of 

7 
 
2020, leading to significant human suffering, death, and economic disruption.  Mortality rates 
are very high in the elderly and in patients with underlying comorbidities. However, even 
relatively healthy individuals of middle age with COVID-19 infection often require ICU care and 
in some cases mechanical ventilation. 
Currently there are no specific treatments for COVID-19 pneumonia and its associated 
acute respiratory distress syndrome (ARDS), other than routine supportive ICU care. In the 
absence of proven, effective anti-viral agents for SARS-CoV2, the use of “plasma therapy” may 
be our only option for the next few months or so. Serum or plasma therapy for infectious 
diseases dates to the 1890s, and has been used as a potential treatment in the SARS (Mair-
Jenkins 2015), MERS, and now in recent COVID-19 (Shen 2020) outbreaks. However, clinical 
trials are necessary in order to show that this therapy can be useful in COVID-19 (Tanne 2020). 
This is especially true since some well-controlled trials of convalescent serum in other 
respiratory viral diseases have failed to show benefit (Beigel et al. 2019; Anti-influenza immune 
plasma for the treatment of patients with severe influenza A: a randomised, double-blind, 
phase 3 trial). 
Plasma from many individuals who have recovered from COVID-19 appears to contain 
antibodies to the virus that can be used as a potential therapy, although there are currently 
limited data on whether these antibodies are neutralizing/protective. The objectives of 
randomized placebo controlled trial are to determine if the administration of convalescent 
plasma can reduce complications associated with COVID-19.  
 
4. Investigational Plan 
 
Subject Withdrawal 
 
I. 
Subjects can terminate study participation and/or withdraw consent at any time 
without prejudice.  
II. 
Randomized subjects who withdraw from the study will not be replaced. 
III. 
The investigator may withdraw subjects if they are lost to follow up, non-compliant 
with study procedures or if the investigator determines that continued participation 
in the study would be harmful to the subject or the integrity of the study data 
IV. 
Discontinuation of the study: The study sponsor, FDA and IRB all have the right to 
terminate this study at any time 
 

8 
 
Intervention including Study product acquisition, Study product administration, Study 
product accountability 
 
I. 
Subjects are randomized in a 4:1 ratio to receive treatment with SARS-CoV-2 
convalescent plasma vs. SARS-CoV-2 non-immune plasma. This allows for potential 
benefit for a high percentage of patients (80%) but still allows for a control group to 
assess safety and efficacy of this unproven therapy. 
II. 
Study Drug: The investigational product is anti-SARS-CoV-2 convalescent plasma. Patients 
identified as having recovered from COVID-19 will serve as potential donors. Testing using 
the CHEMBIO DIAGNOSTICS quantitative IgM and IgG antibody assay (described below, and 
conditionally FDA approved- see Package Label) will identify those with presumed titers 
>1:320 for donation, as evidenced by an IgG reader value approximately >300. However, 
per FDA’s April 3, 2020 guidance we can go down to a titer of 1:80 if higher titer plasma is 
not available. Potential donors (see donor eligibility section) will be screened for all routine 
transfusion-transmitted infections (e.g. HIV, Hep BV, Hep CV, West Nile virus, HTLV-I/II, T. 
cruzi , syphilis /T. Pallium and Babesia) and will be collected using apheresis technology. 
This is similar to standard blood bank protocols. Type compatible (type-specific or ABO-
compatible) convalescent plasma units will be issued to suitable patients by trained hospital 
staff.  Type and screen will be obtained in potential recipients to be screened for 
ABO and Rh determinations and unexpected antibodies. 
III. 
The active arm will receive convalescent plasma, which will be delivered by 
intravenous transfusion at a dose of approximately 2 units (total volume range  450-
550 ml, each unit over approximately 1-4 hours (maximum) (see VI. below). 
IV. 
The control arm will receive approximately 2 units (total volume range 450-550) of 
non-immune plasma, each unit over approximately 1-4 hours (maximum) (see VI 
below).  See rationale for this comparator group below. 
V. 
The Blood Bank will not be blinded to study arm assignment, however, patients, 
clinicians, and study personnel will be blinded using a Blood Bank approved label for 
the bag.  Some unblinded study personnel (Team M) are assigned to interface with 
the Blood Bank, randomize patients, transport plasma,  and measure antibody levels 
in plasma and/or whole blood, but they will not be involved in any other study 
activities for any subjects. 
VI. 
The duration of plasma infusion can be longer, e.g. up to maximum 8 hours 
(maximum 4 hours per approximate 250 ml unit), if significant ventricular 
dysfunction (e.g. LV or RF Ejection Fraction< 40%, or if the patient has overt volume 
overload). A diuretic, e.g. furosemide 20-80 mg IV push, can be co-administered if 
there is concern for volume overload. Extending the duration to this maximum or 
co-administering diuretic will be left to the discretion of the treating physician, e.g. 
hospitalist or intensive care M.D. 
VII. 
All patients will be actively monitored during this time for allergic or other 
immediate reactions as per routine hospital policy. Continued monitoring for 
changes in clinical status will occur after the transfusion, including checking vital 
signs (heart rate, blood pressure, temperature, respiratory rate, and blood oxygen 

9 
 
levels) and sending laboratory tests as necessary. Halting Criteria/Rules for Subject 
Infusion are detailed below and all halting events will be reported to the DSMB (see 
section 7). 
VIII. 
Whole blood or plasma antibody titer (either a drop of blood for POC test or 3 ml EDTA 
tube for each time period, or total of 18 ml for these) to SARS-CoV-2 will be measured at 
Days 0, 1, 7, 14, 21 and 28 only through hospital discharge and is only mandatory in the first 
100 subjects. If available, a drop of blood will also be tested on a “research only” 
plate for antibodies to the spike protein (FDA approved plate we are using measures 
antibodies to the NP portion of the virus).   
IX. 
Type and Screen (6 ml tube) obtained by venipuncture or from an indwelling 
catheter, if not already available for this hospital admission. 
X. 
For all of the above testing, i.e. Type and Screen (6 ml), and serial antibody testing 
(up to 18 ml), the maximum blood removed will be 24 ml. 
XI. 
NO SPECIMENS ARE BEING COLLECTED FOR FUTURE UNSPECIFIED RESEARCH. Per 
FDA’s request (April 13, 2020 Guidelines) whenever feasible, we will collect 1-2 ml 
of plasma to be frozen for later measurement of neutralizing anti-COVID antibody 
levels once this assay is up and running at Stony Brook. FDA states “When 
measurement of neutralizing antibody titers is not available, consider storing a 
retention sample from the convalescent plasma donation for determining antibody 
titers at a later date.”  
XII. 
Unused convalescent plasma, not being tested for antibodies to SARS-CoV-2, will be 
destroyed per Hospital guidelines. 
 
Halting Criteria/Rules for Subject Infusion 
Infusion of study drug will be paused/halted if any of the following manifestations of 
anaphylaxis develop: 
 Skin or mucous membrane manifestations: hives, pruritus, flushing, swollen lips, tongue 
or uvula 
 Respiratory compromise: dyspnea, wheezing, stridor, worsening hypoxemia 
 A >30% decrease from baseline in mean arterial pressure. 
 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 
 

10 
 
If a reaction is detected, the infusion will be paused and the treating team will employ standard 
treatment including antihistamines, H2 blockers and small doses of hydrocortisone if needed, 
as well as epinephrine injections in severe cases. The treating team, with consultation with the 
Transfusion Service physician on call, will evaluate if, and when, it is safe to restart the infusion 
following standards of transfusion reactions. 
 
Rationale for Dosing  
There are no specific data for plasma dosing in COVID-19 infection to support a specific 
dose.  However, the general consensus is that with these initial trials, we need to administer a 
large enough volume, e.g. approximately 500 ml, to avoid treatment failures due to insufficient 
dosing. This is important since we are not concentrating the IgG, which while potentially useful, 
will take more time for centers to develop. The vast majority of patients will tolerate 2 units of 
plasma over 4 hours (maximum 8 hours for the 2 units, i.e. maximum 4 hours per unit, in rare 
cases), especially since the protocol allows for concomitant administration of a rapid acting 
diuretic such as furosemide 20-80 mg IV push. We will amend the protocol to modify the dose 
volume if new data emerge that provide justification for changing our dose. The table below 
show data we have compiled. Note that 4 of these 5 studies have no rigorous control group. 
The Hopkins study is more of a prophylaxis trial, which is why a lower volume (200-250 ml) may 
be effective in those patients.   
In addition, in an NIH funded multicenter randomized blinded trial for treatment of 
influenza (Beigel et al. 2019. Anti-influenza immune plasma for the treatment of patients with 
severe influenza A: a randomised, double-blind, phase 3 trial), 2 units of convalescent plasma 
were not effective compared with 2 units of standard plasma. This supports the idea that a 
control arm is needed in these protocols. That being said, the virus being treated in this 
negative trial was different, which may explain  the lack of efficacy observed. 
 
Protocol 
Date on 
file 
Site 
Study Type 
Patients  
Size 
Conv. Plasma 
Placebo 
3/29/2020 
Johns 
Hopkins 
Conv. Plasma 
vs. Control  
Adults Exposed 
to COVID-19 
(not showing 
symptoms) 
150 
1 unit (200-250 
mL) of plasma 
with anti-SARS-
CoV-19 titers 
expected to have 
titer >1:64 
 
1 unit of 
standard 
plasma 

11 
 
3/25/2020 
Johns 
Hopkins 
single-arm 
feasibility 
study to assess 
the safety of 
anti-SARS-CoV-
2 convalescent 
plasma 
Mechanically 
Ventilated 
Patients 
30 
Standard plasma 
dosing is 2 units, 
(~200-250 mL per 
unit) with 
detectable 
COVID-19 
antibody titer.  At 
the discretion of 
the treating 
physician, 
patients less than 
90kg may receive 
1 unit of plasma 
for the first 1-2 
doses and 
increase to 2 units 
per dose if 
tolerated. 
 
x 
3/25/2020 
Mayo clinic 
w /JH 
Convalescent 
Plasma to 
Limit 
Coronavirus 
Associated 
Complications: 
An Open label, 
Phase 2A 
Study of High-
Titer Anti-
SARS-CoV-2 
plasma in 
hospitalized 
patients with 
COVID-19 
 
Hospitalized 
COVID-19 
patients aged 
≥18 years of 
age with 
respiratory 
symptoms 
within 3 to 7 
days from the 
beginning of 
illness 
5 
(1-2 units; ~300-
600 mL at 
neutralization 
antibody titer 
>1:160. (Note this 
is a moving target 
as assays 
develop) 
X 
March 25, 
2020 
Shen, 
Shenzhen 
China 
 (JAMA) 
Treatment of 
critically ill 
patients with 
conv. Plasma  
Severe 
pneumonia and 
mechanical 
ventilation  
5 
2 consecutive 
transfusions of 
200 to 250 mL of 
ABO-compatible 
convalescent 
plasma (400 mL of 
convalescent 
plasma in total)  
(Donor serum 
specific ELISA ab 
titer higher than 
1:1000, 
x 

12 
 
neutralizing 
antibody titer>40) 
3/23/2020 
Duan 
Shanghai 
China 
 
Chi CTR 
2000030048 
 
Not peer 
reviewed  
Treatment of 
critically ill 
patients with 
conv. Plasma  
Severe, 
hospitalized  
 
I think they 
were all on 
another drug – 
“Nine patients 
received 
arbidol-
monotherapy 
or combination 
therapy with 
Remdesivir or 
ribavirin,or 
peramivir, 
while one 
patient 
received 
ribavirin 
monotherapy” 
10 
1 dose of 200 mL 
convalescent 
plasma (CP) 
derived from 
recently 
recovered donors 
with the 
neutralizing 
antibody titers 
above 1:640  
 
x 
 
Rationale for Standard Plasma Control Arm and Blinding 
It is critical that the trial include a blinded control group in order to determine if this 
intervention is safe and effective. The trial’s independent DSMB will review safety data, 
including halting of infusions and SAEs, to determine if there are unacceptable risks to patients 
receiving either convalescent or standard plasma. 
Beigel et al’s study results and discussion (Beigel et al. 2019. Anti-influenza immune plasma for 
the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial) 
highlight the need for a blinded control group of standard plasma. This multicenter NIH funded 
randomized trial showed that 2 units of convalescent plasma were not effective compared with 
2 units of standard plasma. This result would not have been possible without the control arm. 
They discuss the possibility of increased study withdrawals of patients randomized to the 
“control” arm if this is not masked. 
Beigel et al. also mention that there is a lack of alternative strategies to provide a blinded 
comparator. Yellow multivitamin dyed saline and albumin have different colors and/or 
consistency. Studies in critically ill patients suggest that albumin is associated with worse 
outcome (BMJ. 1998 Jul 25;317(7153):235-40. Human albumin administration in critically ill 
patients: systematic review of randomised controlled trials). Therefore, if albumin is used in the 
control group and outcome is worse in this arm we will not know if this is due to a lack of 
antibodies to SARS-CoV-2 or if it is due to a harmful affect from the albumin. If a vitamin is used 

13 
 
as a dye, then our results will be confounded by potential effects of the vitamins including 
vitamin C (Marik PE. J Thorac Dis. 2020 Feb;12(Suppl 1):S84-S88. doi: 10.21037/jtd.2019.12.64. 
Vitamin C: an essential "stress hormone" during sepsis). 
Moreover, other trials are taking the same approach. For example, the Johns Hopkins study 
entitled “Convalescent Plasma to Stem Coronavirus: A Randomized, blinded Phase 2 Study 
Comparing the Efficacy and Safety Human Coronavirus Immune Plasma (HCIP) vs. control (SARS-
CoV-2 non-immune plasma) among Adults Exposed to COVID-19” is using a blinded standard 
plasma comparator. 
 
Plasma Donors:   
 
Consent/Screening (Visit 1) 
Mechanism for identifying donors  
 
 Mechanism for recruitment will include advertising in the local community where recent 
outbreaks have occurred. Flyers might be placed on the bulletin boards in the Stony 
Brook HSC. Potential donors will also be identified through a sister study occurring at 
Stony Brook. This study is examining the presence or absence of antibodies in multiple 
groups of patients, including those with a known diagnosis of COVID-19.  
 Individuals who agree to participate to donate plasma will do so under full informed 
consent; consent will be a modified version of a standard donation consent form i.e. 
content specific to the trial will be included along with the intended use for the donated 
plasma. 
 Individuals who agree to participate will undergo pre-donation screening as below prior 
to their first plasma donation unless they have been symptom free for at least 28 days in 
which case, per FDA Guidelines, a negative PCR test is not required. In addition, FDA 
guidelines only require repeat of the transmittable- disease-test (TDT) markers within 30 
days prior to donation.  
 
Eligibility for plasma donors:  
 
As per the current FDA guidelines, COVID-19 convalescent plasma must only be collected from 
recovered individuals if they are eligible to donate blood. Required testing must be performed 
and the donation must be found suitable. Additional considerations for donor eligibility should 
be addressed, as follows (as per FDA Guidance March 24, 2020, and Revised FDA Guidance April 
3, 2020 and April 13, 2020. Of note the revised FDA guidance allows exceptions/modifications 
to some of the routine donor selection criteria, see below.  ): 
I. 
Past diagnosis of COVID19 by either:  
a. Positive PCR test (FDA Emergency Use Authorization (EUA) laboratory test), or 

14 
 
b. Presence of antibodies (positive serology) as detected by an FDA approved 
laboratory test (see below).  
II. 
Complete resolution of symptoms for at least 14 days prior to donation (still requires 
negative PCR test to allow donation). We will follow FDA’s April 8, 2020 guidance for 
COVID-19 plasma donors that allows plasma donations from individuals without a 
negative PCR test who have been fully recovered for at least 28 days. 
III. 
Donors negative for HLA antibodies. Human Leukocyte Antigen (HLA) testing (5 ml 
tube) will be obtained by venipuncture in all donors. 
IV. 
Negative results for COVID-19 either from one or more nasopharyngeal swab specimens 
or by a molecular diagnostic test from blood for plasma donors who have been 
symptom free between 14 and 27 days per new FDA guidance. A partial list of available 
tests can be accessed at https://www.fda.gov/medical-devices/emergency-situations-
medical-devices/emergency-use-authorizations. 
V. 
Defined SARS-CoV-2 neutralizing antibody titers, optimally greater than 1:320 (but 
allowed as low as 1:80 per new FDA guidance if higher titer plasma not available), using 
the conditionally FDA approved Chembio assay (see Package Label), defined as an IgG reader 
value approximately >300.  Subjects will be informed whether their results meet criteria to be 
eligible for plasma donation, or if a retest is recommended if it is suboptimal, or if testing is 
negative for antibodies to COVID-19. These results are documented in the individuals EMR 
under their screening visit note. . If available, a drop of blood will also be tested on a 
“research only” plate for antibodies to the spike protein (FDA approved plate we are 
using measures antibodies to the NP portion of the virus) and these “research only”, not 
FDA approved test results will not be shared with the subject.  In addition, per FDA’s 
request (April 13, 2020 Guidelines), whenever feasible, we will collect 1-2 ml of plasma 
to be frozen and later measured for neutralizing anti-COVID antibody levels once this 
assay is up and running at Stony Brook. FDA states “When measurement of neutralizing 
antibody titers is not available, consider storing a retention sample from the 
convalescent plasma donation for determining antibody titers at a later date.” 
VI. 
Standard infectious disease marker testing, also known as TDTs, e.g. HIV, Hep BV, Hep CV, 
West Nile virus, HTLV-I/II, T. cruzi , syphilis /T. Pallidum and Babesia, will be performed on 
blood obtained during the screening visit and sent to the routine clinical laboratory that 
routinely does these tests on coded samples for the Blood Bank. This routine screening 
must be negative prior to moving on to a donation visit. Any positive results from these 
markers will be shared with the subject as per standard donor protocols. 
VII. 
Type and screen (5 ml) will also be obtained in potential donors to be screened for ABO 
and Rh determinations and for the presence of unexpected antibodies. Individuals with 
antibodies in this screen will not be eligible to donate plasma.  
VIII. 
Complete blood count (CBC), approximately 4 mL, will also be obtained to confirm 
adequate hemoglobin level per standard Blood Bank donor requirements. For repeat 
donation visits, the Blood Bank will check the adequacy of hemoglobin with their point 
of care test using a finger stick per their routine process used in all individuals prior to 
blood product donation 
IX. 
Serum protein electrophoresis pattern and protein composition (6 ml venipuncture) per 
FDA guidance/Code of Federal Regulations. 

15 
 
X. 
Must meet all usual donation criteria for apheresis, e.g. weight, hemoglobin, which are 
part of routine screening and the routine donor questionnaire. Revised FDA Guidance 
now allows exceptions/modifications to some of the routine donor selection criteria, 
April 2, 2020 FDA STATEMENT Coronavirus (COVID-19) Update: FDA Provides Updated 
Guidance to Address the Urgent Need for Blood During the Pandemic: 
a. For male donors who would have been deferred for having sex with another 
man: the FDA has changed the recommended deferral period from 12 months to 
3 months. 
b. For female donors who would have been deferred for having sex with a man 
who had sex with another man: the FDA has changed the recommended deferral 
period from 12 months to 3 months. 
c. For those with recent tattoos and piercings: the agency FDA has changed the 
recommended deferral period from 12 months to 3 months. 
d. For those who have traveled to malaria-endemic areas (and are residents of 
malaria non-endemic countries): the FDA has changed the recommended 
deferral period from 12 months to 3 months. In addition, the guidance provides 
notice of an alternate procedure that permits the collection of blood and blood 
components from such donors without a deferral period, provided the blood 
components are pathogen-reduced using an FDA-approved pathogen reduction 
device. 
e. For those who spent time in certain European countries or on military bases in 
Europe who were previously considered to have been exposed to a potential risk 
of transmission of Creutzfeldt-Jakob Disease or Variant Creutzfeldt-Jakob 
Disease, the FDA is eliminating the recommended deferrals and is 
recommending allowing reentry of these donors. 
f. Of note, none of the above changes impact the need for negative transmittable 
disease testing as already included in the protocol. 
XI. 
At least 18 years of age 
XII. 
For all of the above testing of donors, i.e. Type and Screen, HLA , infectious markers 
testing, antibody testing, serum protein electrophoresis, we will remove up to 50 ml via 
venipuncture.   
Following selection of an appropriate donor as above, potential donors will have their plasma 
collected (between approximately 500-1000 mLs, maximum 10.5 ml/kg per routine practice 
including blood sampling/testing) via an approved device by qualified Apheresis technical staff. 
Additional donation(s) can take place weekly but only if repeat antibody testing reveals return 
of high IgG antibody levels.  Routine blood bank required transmissible disease testing (TDT) is 
required at least every 30 days. Collections will take place at Stony Brook Hospital’s licensed 
and accredited pheresis/blood bank unit on Level 5. If there is a shortage of plasma from our 
plasma collection process, we will allow the use of acquired convalescent plasma from other 
licensed sites/vendors, e.g. the American Red Cross, New York Blood Center.  Convalescent 
plasma being collected from these sites must conform per Federal Regulations (FDA) to the 

16 
 
same guidance we are using for our plasma collections at Stony Brook, so it should be as safe 
and effective as the plasma we collect at Stony Brook. 
Donation Visit plan (Visit 2) 
Collecting and Processing 
Prior to donation, the donor will need to complete several increasingly stringent levels of 
review. They must complete a standard donor history questionnaire at the screening visit and 
prior to any plasma donation. At the time of presentation at the blood center (i.e. see Visit 2 
below), a determination of resolved infection will have already been made, and blood bank 
personnel will confirm that the subject feels well per their usual interview process.  
 
 Standard apheresis plasma collection will be performed per routine standard operating 
procedure at the certified and licensed collection facility (Stony Brook Hospital). 
 Target collection volume: at least 500 ml but maximum 10.5 ml/kg per American 
Association of Blood Bank guidelines including blood sampling; this will allow for 
splitting (separation) into daughter units 
 The plasma will be processed per routine practice; it may be frozen and thawed per 
standard blood bank protocol prior to dispensing to a recipient. 
 The plasma will be maintained in quarantine at the hospital’s Blood Bank until it needs 
to be dispensed. 
 
Control arm plasma 
 
The control arm plasma follows identical collection and processing procedures, but will 
have been collected from community blood donors with no overt history of COVID-19 infection 
and ideally a low IgG anti-CoV-2 antibody level defined as less than 25 on the CHEMBIO point of 
care assay (see below). 
Antibody Assay 
 
The antibody assay we will use was developed at Chembio Diagnostic Systems Inc. 
Chembio is a publicly traded company (Nasdaq:CEMI) on Long Island, NY that already markets 
several approved point of care assays including HIV, Zika, and Ebola. .  Chembio has developed 
an assay that appears to rapidly detect antibodies (quantitative IgM and IgG) to SARS-CoV-2 
using either a drop of whole blood (e.g. from a finger stick), plasma or serum. The assay is run 
on the company’s portable point of care analyzer in approximately 15 minutes.  Per the product 
label (conditionally approved by FDA, Appendix H) a value of IgG ≥25 to NP antigen indicates a 
higher likelihood of PCR positive COVID-19 infection, with many patients showing values of 
>300; values these high correspond with a serial dilution of 1:320 or greater as shown in the 
Table and Figure below.   
CONFIDENTIAL FIGURE REDACTED 

17 
 
 
 
CONFIDENTIAL FIGURE REDACTED 
 
While the Chembio assay measures antibody to the Nucleocapsid Protein (NP), it is important 
to note that individuals with COVID-19 infection and high antibodies to NP, also tend to have 
high antibodies to Spike Protein (SP), see Figure below. These preliminary data suggest that 
convalescent serum high in IgG to NP (per the assay) will also have antibodies to spike. To 
confirm these data, if feasible (e.g. plates available), a drop of plasma or blood will also be 
tested on a “research only” plate for antibodies to the spike protein.   
 
CONFIDENTIAL FIGURE REDACTED 
5. Data Collection From Plasma Recipients: 
 Data collection will include routine demographics (age, sex, race/ethnicity), history of present 
illness (e.g. onset of symptoms, signs, testing results for COVID-19, chest x-ray or CT findings 
from clinically ordered testing), past medical history to include comorbidities, hospital course, 
and outcomes such as death, duration/occurrence of mechanical ventilation, supplemental 
oxygen, ICU admission and duration, and length hospital stay. IgM and IgG antibody levels will 
be monitored over time for at least the first 100 patients, starting prior to randomization and 
through 14+ days if still hospitalized. Clinical symptoms such as average daily temperature and 
oxygen levels will also be collected. Most of these data will be abstracted from the electronic 
medical record, but patients will be actively monitored for safety. Follow-up clinical data are 
collected at 14, 21, 28 and 90 days from the EMR and telephone calls. Subjects will not be asked 
to return for visits after discharge.  We will also assess patient quality of life at 90 days after 
treatment using the SF-36 (telephone call), as well as the location of the patient (discharge 
location, in hospital, death). Many of our outcomes are based on time. We plan to use the time 
of randomization the start time for most of these outcomes. Time from onset of symptoms, 
admission to the hospital, and study entry are likely to be important covariates. If these factors 
are unbalanced, we will account for this in the planned analyses below. Data will be transcribed 
into a dedicated study REDCap database, and then exported for statistical analyses.  
 
6. Statistical Methods 
 
  
All analyses will be presented by treatment group. Descriptive summaries of all 
outcomes and covariates will be presented. All analyses will be conducted as an intent to treat 

18 
 
approach, which includes all randomized subjects.  All statistical analyses will use a two-sided 
Type 1 error rate of 0.05 and 95% confidence intervals.   
We are currently uncertain of the size of the observational group (i.e., those who 
qualified for the study but did not have a donor match at the time, and remained in the 
observational group). If the sample size is large enough, we will include this observational group 
as a third study arm. Alternatively, we may add these individuals to the plasma control group if 
and only if all outcomes and covariates are equivalent. This could be done in the form of a 
sensitivity analysis. Any analyses specifically referencing 2 groups below will be revised to three 
groups if appropriate (e.g., t-tests will be revised to ANOVA).  
Randomization:  
 
  
Patients will be randomized in a 4:1 plasma to placebo ratio using permuted block 
randomization. Randomization will be stratified by non-intubated vs. intubated patients. The 
total number of target patients is 500, with 400 in the plasma treatment group and 100 in the 
placebo control group.  Our target enrollment ratio is 2 to 1 for the randomization strata to 
promote inclusion of more patients with less severe disease who may benefit more from 
convalescent plasma. Randomization lists will be generated using SAS software, and 
implemented using an interactive web response randomization tool in REDCap.  
Primary Outcome and Power Analysis:  
 
  
The primary outcome in this study is total number of ventilator-free days from 
randomization to day 28 (ICU ROX, NEJM 2020). We are defining ventilator free days as the 
total number of calendar days or proportions of calendar days of (assisted breathing per 
definition earlier) during the first 28 days after randomization.  All study participants who never 
require intubation will be assigned a time of 28 days. All patients who die by day 28 will be 
considered to have a time of 0 ventilator-free days.  Ventilator free days will be compared by 
study group using a Wilcoxon rank sum test. We believe that an average difference of 2.5 
ventilator-free days (SD 6) is a clinically meaningful difference between groups, but the 
measure of variance is truly unknown for this population. We have calculated the sample size 
based on this moderate effect size of 0.42, but we have also added an 18% inflation to allow for 
a possible interim analysis (if requested by the DSMC) and to account for a range of uncertainty 
in the standard deviation of days. We have also built in a 7% buffer to allow for possible study 
withdrawals, even though this is expected to be minimal. Using a 90% power and alpha of 
0.05%, the final study size needed is 500 participants, with 400 plasma treatment patients and 
100 placebo patients. We will also stratify this analysis by our randomization strata (intubated 
vs. non-intubated).   The change (improvement) in WHO Ordinal Scale will be calculated daily 
for all randomized patients prior to discharge (or day 28, whichever is earlier), with 

19 
 
improvement defined as patients with a ≥2 point improvement to be consistent with previous 
trials.  The worst (highest amount of support) on any given 24 hour period will be used, with 24 
hour periods starting at the time the plasma infusion begins (or time of randomization if no 
plasma received). This will be analyzed as the proportion in each arm with a ≥2 point 
improvement, and analyzed in both the ITT (all randomized) as well as Per Protocol 
(randomized and receiving 2 units of assigned plasma) populations. The time to a ≥2 point 
improvement will also be determined in both arms using survival analysis, again both in the ITT 
as well as Per Protocol populations.  
 
Secondary Outcomes:  
 
  
Death:  As a secondary outcome, we will examine all-cause mortality through 90 days 
post randomization in two ways: as a dichotomous variable (yes/no), and as a time to event 
(number of days from treatment/placebo to death). Chi-square tests, multivariable logistic 
regression, and cox proportional hazards models (with Kaplan Meier survival curves) may be 
used for these analyses.  
WHO Ordinal Scale:  Many clinical trials related to COVID-19 use the WHO Ordinal Scale 
as either a primary or secondary endpoint.  This is promulgated by the World Health 
Organization (https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf).  It is a 9 point 
scale, however, since our trial focuses on hospitalized patients we will collapse Scores 0, 1, and 
2 (all outpatients) into 1 single score. So 1= no longer hospitalized (i.e., discharged)2= 
hospitalized, not on oxygen, 3= hospitalized, on nasal cannula or face mask, 4= hospitalized, 
high flow nasal cannula or bipap, 5= hospitalized, intubated, 6= hospitalized, ECMO, 7= dead.  
This will be calculated daily (prior to discharge) for all randomized patients.   
Immune response: The trajectories of whole blood or plasma IgM and IgG will be plotted 
over time and compared in the treatment group vs. the placebo group for all patients with this 
data. The first sample will be taken prior to administration of the treatment/placebo, and 
repeated samples will be taken after the intervention through hospital discharge.  Average 
antibody levels at each time point will be compared using t-tests.   
Resolution of Clinical Symptoms:  Temperature will be monitored for all patients per 
routine hospital policy. Average daily scores (during the first 7 days while in hospital, after 
randomization) will be recorded. Time to temperature normalization will be compared between 
the two groups using log-rank tests (with Kaplan-Meier curves).   

20 
 
SF-36: 90 day quality of life (as measured by the SF 36) will be assessed by study arm 
using Wilcoxon rank sum tests.   
Adverse Events: Analysis of adverse data will primarily be descriptive based on the 
coding of events. The proportion of subjects experiencing an SAE will be compared between 
randomized arms using Fisher’s Exact Test. 
 
7. Data and Safety Monitoring Plan, Regulatory, Registration 
 
Registration:  
The trial was registered (NCT04344535) prior to subject enrollment at 
clinicaltrials.gov per Federal guidelines. 
Regulatory: 
 
The trial will be conducted under an IND. 
 
Data and Safety Monitoring: 
 
Adverse event Definitions: 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this product. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. This includes exacerbation of pre-existing conditions and intercurrent 
illnesses. This definition of “adverse event” will be applied to all study subjects beginning at the 
time of randomization. 
Serious Adverse Event 
A Serious Adverse Event (SAE) is an AE, whether considered related to the study product or not, that: 
1. Results in death during the period of protocol-defined surveillance 
2. Is life threatening: defined as an event in which the participant was at immediate 
risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death were it more severe 
3. Requires inpatient hospitalization (or prolongation of existing hospitalization): 
defined as at least an overnight stay in the hospital or emergency ward for 
treatment that would have been inappropriate if administered in the outpatient 
setting 
4. Results in a persistent or significant disability/incapacity 
 
Relationship categories for Adverse Events are as follows: 

21 
 
For purposes of reporting to IRB and the FDA, AEs will also be characterized as Related or Not-Related 
per FDA’s Guidance for Industry and Investigators, Safety Reporting Requirements for INDs and BA/BE 
Studies, December 2012 (see below). 
Related 
There is a reasonable possibility that the adverse event may be related to the 
study drug. 
Not related 
There is not a reasonable possibility that the adverse event may be related to the 
study drug.  
 
Safety-Related Recording and Reporting to Internal Safety Monitor  
The study will have an internal blinded Safety Monitor (Sharon Nachman, MD, Professor of 
Pediatrics, Associate Dean for Research, Renaissance School of Medicine). This individual will be 
responsible for reviewing safety data (below) and making recommendations to the PI on what 
data should be reported to the DSMB, IRB, and/or FDA.  
Any event that occurs during protocol-specified AE reporting periods (see Table AA), following 
plasma donation (donors) or infusion with study product (recipients), is to be considered an AE 
and should be evaluated as a potential Expedited AE, with reporting within 48 hours of 
knowledge of event to the internal safety monitor (not IRB or FDA unless it meets their 
reporting criteria- see below). The current section outlines which events which should be 
recorded on eCRFs for inclusion in the database. 
 Table AA: 
1. Within 24 hours of infusion or donation 
a. Hypotension requiring new initiation of vasopressors 
b. Rash 
c. Any other event which leads to acute stopping of IgG infusion 
d. Death 
2. Within  7 days of infusion or donation 
a. Organ failure*, grade 4 (this includes worsening of underlying comorbid conditions) 
b. Grade 4 liver, kidney or hematologic toxicity 
c. Death 
3. Within 28 days of infusion or donation 
a. Organ failure* 
b. Grade 4 liver, kidney or hematologic toxicity 
c. Death 
Grading table for adverse events 
Severity 
Defined 
Grade (0) None 
Not applicable 

22 
 
Severity 
Defined 
Grade (1) Mild 
No medical intervention required; may include use of over-the-counter 
medications managed by the caregiver for treatment of symptoms 
Grade (2) Moderate 
Outpatient medical intervention by a health care provider required; may 
include use of over-the-counter and/or prescription medications 
Grade (3) Severe 
Prolonged medical intervention required 
Grade (4) Life 
threatening 
Illness requiring continued hospitalization with intensive care  
Grade (5) Death 
Event resulting in fatal outcome to the participant 
 
Organ Failure/Grade 4 SAE Definitions: 
1) CNS: 
new stroke 
2) Cardiovascular:  new myocardial infarction (defined as troponin above ULN and new 
pathologic Q wave by ECG or overt clinical evidence of MI) 
3) Pulmonary:  new pulmonary embolus (note: intubation/mechanical ventilation is the 
primary endpoint for the study so per FDA guidelines does not require AE reporting for 
this endpoint) 
4) Renal:  new hemodialysis (does not include patient already on HD but given plasma on 
“off day” 
5) Liver:  new INR > 1.8 (without alternative cause, e.g. Coumadin or other drug affecting 
INR) 
6) Hematologic:  a) new platelet count <50,000,  or, b) arterial or venous thrombosis 
requiring surgical treatment or thrombolytic, e.g. TPA, treatment. 
 
Note that if a condition exists at baseline, i.e. prior to plasma infusion, e.g. platelet count is <50 
at baseline, but then increases to >50, that if it subsequently decreases to 50 this will trigger 
the AE definition. 
 
Safety-Recording and Reporting to IRB and FDA and Internal Safety Monitor 
Plasma has been administered to millions of patients and has a well-known safety profile.  In 
this study, plasma is collected, processed, stored, and administered per established FDA and 
hospital approved guidelines. It is only the quantity of antibodies in the plasma, and its “off-
label” use to treat COVID-19 infection, which differentiates it from usual “on-label” use in 
hospitalized patients, where it is used extensively. In addition, hospitalized patients with 
COVID-19 infection are usually very ill and experience a multitude of adverse events, almost all 
of them likely related to their underlying condition.  
 

23 
 
 
We will record and report to IRB and FDA AEs occurring within 28 days of plasma infusion that 
are serious, unexpected, and related to the study per FDA reporting guidelines.  
 
Adverse events (other than SAEs) which in the opinion of the principal investigator meet the 
criteria for an unanticipated problem involving risk to subjects or others (unanticipated, 
reasonably related to the research as defined above, and increase risk to subjects), and 
occurring within 28 days of plasma infusion will also be recorded and reported to the IRB and 
FDA. 
 
SUSAR: (S)AEs that occur within 28 days of plasma infusion and that are serious, unexpected, 
reasonably related to the study, and informative to the IRB or FDA as a single event per FDA’s 
Guidance for Industry and Investigators, Safety Reporting Requirements for INDs and BA/BE 
Studies, December 2012, will be reported in an expedited manner to the IRB within 5 days of 
knowledge of the event, and to the FDA no later than 15 calendar days after the sponsor 
determines that the suspected adverse reaction or other information qualifies for reporting to 
the FDA.  
 
Results of aggregate safety analysis suggesting that (S)AEs or death occur more frequently in 
the treatment group will also be reported to the IRB and FDA according to the above timelines. 
 
DSMC: 
The trial will have 3 member independent Data and Safety Monitoring Committee (DSMC) also 
known as DSMB. Per the DSMC’s Charter, the DSMC will review all deaths, infusion halts, and 
recorded AEs on a rolling basis as well as in aggregate on a monthly basis.  The DSMC will 
inform the investigators if there are concerns that warrant revision to the consent form or 
other change to study procedures. After the 100th randomized subject and the 250th 
randomized subject reach the 28-day post-randomization time point, plus allowance of up to 2 
weeks for preparation of a report to DSMC, the DSMC will review the available data for futility, 
safety, and efficacy but it will be the DSMC’s decision whether inferential/statistical testing for 
efficacy is necessary.  There will be no formal stopping rules for these analyses.  
 
The blood bank policies will be followed throughout the study and if the blood bank staff need 
to report according to their standard guidelines they will do so separate from the study group 
reporting. 
 
Informed Consent:  
 
Patients must be able to provide written informed consent or a legally authorized 
representative must be able to provide written informed consent.  Individuals will be provided 
with as much time as they need to read the consent form, ask questions to the study team, and 

24 
 
confer with others.  Refusal to participate will not alter their hospital care or  post-
hospitalization management. 
 
Confidentiality of Data:  
 
A REDCAP Database, created by the trial’s data manager, will be used for data collection.  This 
Database will sit behind the firewall at Stony Brook University and will only be accessible to 
study personnel using a secure login/password protected program.  Electronic data will be 
stored on password protected computers in password-protected, Stony Brook Medicine IT 
controlled folders or encrypted folders (e.g. SB IT created BOX folders) setup by the SB 
Research IT group. Paper records will be stored in a locked file cabinet in a secure location 
within the hospital. 
 
Risks, Benefits, and Procedures to Minimize Risk to Subjects 
Risks to donors. 
Likely:  
Pain and bruising where the needles are put into the arms  
Transient lowered platelet count. Platelet counts usually return to normal levels within two to 
four weeks after collection of the plasma. 
 
Less Likely:  
Lightheadedness  
Nausea  
Citrate reaction - to prevent clotting, citrate will be used mixed in the machine as an 
“anticoagulant”. Citrate can bind to the calcium, and cause hypocalcemia. Hypocalcemia related 
symptoms include numbness and tingling of the fingertips or around the mouth. This can be 
treated with calcium including oral Tums depending on severity, or calcium pills (at least 1200 
mg daily) for 5 days.  
 
Rarely:  
Chills, fainting during the procedure 
Large amount of bleeding/bruising where the needles in the arm veins are located  
Loss of blood from a breakdown of the apheresis machine.  About 1½ cups of blood is reported 
if the machine breaks. This is unlikely to  cause any harm or require transfusion replacement.  
 
There is a small (about 1 in 1,200) risk of being hospitalized for observation of side effects from 
the procedure, (for example, lightheadedness, nausea).  
 
These volume changes risks will be minimized by continued hydration the day of the procedure 
and monitoring of pulse and blood pressure during and shortly after 

25 
 
 
Benefits to donor: 
 
Donors will not receive direct benefit from having this procedure. This study may help cure or 
stop the  progression of the recipient’s disease, which will limit further exposure of donors and 
their community to the disease under study. 
 
Risks for recipients. 
Acute risks:  
1. Volume overload: The intended plasma infusion could represent additional volume to 
already fluid overloaded patients. We acknowledge this risk and therefore exclude 
patients in whom the treating physician does not think it is safe to proceed, even with the 
countermeasures below.  Volume overload will be promptly monitored by continuous 
measurements of output related to input and other routine clinical measures. Diuretics 
will be utilized to allow removal of accumulated fluids if needed. Also, to further minimize 
risks, extended infusion for up to 4 hours per unit (8 hours for both units) will be 
considered in such patients. 
2. Acute allergic reactions to the infused plasma. These infusions will be done under hospital 
acute care monitoring. If reactions are detected, the infusion will be paused and the 
treating team will employ standard treatment including antihistamines, H2 blockers and 
small doses of hydrocortisone if needed, as well as epinephrine injections in severe cases. 
The treating team, with consultation with the Transfusion Service physician on call, will 
evaluate if and when it is safe to restart the infusion following standards of transfusion 
reactions. 
Intermediate term risks 
1. Antibody-mediated enhancement of infection (ADE): ADE can occur for several viral 
diseases and involves an enhancement of disease in the presence of certain antibodies. 
For coronaviruses, several mechanisms for ADE have been described and there is the 
theoretical concern that antibodies to one type of coronavirus could enhance infection to 
another viral strain [Wan Y, ET AL, Molecular mechanism for antibody-dependent 
enhancement of coronavirus entry. Journal of Virology. 2020; 94, (7).  However, 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, so ADE may be unlikely. The available evidence from the use of convalescent plasma in 
patients with SARS1 and MERS [8], and (9) anecdotal evidence of its use in patients with 
COVID-19, suggest it is safe. Nevertheless, caution and vigilance will be required in 

26 
 
monitoring for any evidence of enhanced infection within the 90-day study period follow-
up.  
2. 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. This risk is less applicable 
to our patient cohort because this is a treatment study and not a prophylactic study. 
3. Risk of administering virus to recipients if donor is not virus free:  although a possible risk, 
this will be minimized by following steps advised by the FDA as well as other trial criteria. 
This includes enrolling asymptomatic donors after a total of 14 days from beginning of 
symptoms and, in donors who have been symptom free for less than 28 days, 
documenting a negative viral PCR test (Per FDA Guidelines). The above follows FDA’s 
revised guidelines on required testing for recovered COVID plasma donors. 
4. There are theories that administration of convalescent plasma for COVID-19 may lead to 
increased risk of thrombosis and/or lung injury (Cao H. and Shi Y, Convalescent Plasma: 
possible therapy for novel coronavirus disease 2019, Transfus Med Rev, in press; Dzik S., 
Transfus Med Rev, in press). 
Long term risks:  
Theoretical risks that inflict long-term harm include infections with hepatitis, HIV, and other 
known blood- borne viruses. This will be minimized by stringent donor screening and is not 
expected to occur.  
 
Benefits to recipient. 
If this study meets its primary and secondary endpoints of safety and efficacy, recipients of 
convalescent plasma may have reduced viral load, accelerated time to recovery and hence 
fewer complications, which may ultimately increase their chances of survival.  
 
 
 

27 
 
REFERENCES: 
 
1. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, Chan P, Wong KC, Leung CB, Cheng 
G. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J  Clin 
Microbiol Infect Dis. 2005 Jan;24(1):44-6. PubMed PMID: 15616839; PubMed Central 
PMCID: PMC7088355. 
2. 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 Group.  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. 2015 Jan 1;211(1):80-90. doi: 
10.1093/infdis/jiu396. Epub 2014 Jul 16. Review. PubMed PMID: 25030060; PubMed 
Central PMCID: PMC4264590. 
3. Roback JD, Guarner J. Convalescent Plasma to Treat COVID-19: Possibilities and 
Challenges. JAMA. 2020 Mar 27. doi: 10.1001/jama.2020.4940. [Epub ahead of print] 
PubMed PMID: 32219429. 
4. Tanne JH. Covid-19: FDA approves use of convalescent plasma to treat critically ill 
patients. BMJ. 2020 Mar 26;368:m1256. doi: 10.1136/bmj.m1256. PubMed PMID: 
32217555. 
5. 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. Treatment of 5 Critically Ill Patients With COVID-19 With 
Convalescent Plasma. JAMA. 2020 Mar 27. doi: 10.1001/jama.2020.4783. [Epub ahead 
of print] PubMed PMID: 32219428. 
6. (https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-
exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-
inds) 
7. Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, Chen Y, Wu J, and Shi Z. Molecular 
mechanism for antibody-dependent enhancement of coronavirus entry. Journal of 
Virology. 2020; 94 
8. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, Makki S, 
Rooney KD, Nguyen-Van-Tam JS, and Beck CR. The effectiveness of convalescent plasma 
and hyperimmune immunoglobulin for the treatment of severe acute respiratory 
infections of viral etiology: a systematic review and exploratory meta-analysis. The 
Journal of infectious diseases. 2015; 211(1):80-90.) 
9. http://www.xinhuanet.com/english/2020-02/28/c_138828177.htm 
10. ICU -ROX Investigators and the Australian and New Zealand Intensive Care Society 
Clinical Trials Group, Mackle D, Bellomo R, Bailey M, Beasley R, Deane A, Eastwood G, 

28 
 
Finfer S, Freebairn R, King V, Linke N, Litton E, McArthur C, McGuinness S, Panwar R, 
Young P; ICU-ROX Investigators the Australian and New Zealand Intensive Care Society 
Clinical Trials Group. Conservative Oxygen Therapy during Mechanical Ventilation in the 
ICU. N Engl J Med. 2020 Mar 12;382(11):989-998. doi: 10.1056/NEJMoa1903297. Epub 
2019 Oct 14. PubMed PMID: 31613432. 
11. Dzik S; COVID-19 Convalescent Plasma: Now Is the Time for Better Science. Transfus 
Med Rev, In Press 
12. Cao H. and Shi Y, Convalescent Plasma: possible therapy for novel coronavirus disease 
2019