Phase IIa Study Exploring the Safety and Efficacy of Convalescent Plasma From Recovered COVID-19 Donors Collected by Plasmapheresis as Treatment for Hospitalized Subjects With COVID-19 Infection
Phase: PHASE2
Conditions: COVID-19
Sponsor: Hackensack Meridian Health

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Phase IIa Study Exploring the Safety and Efficacy of Convalescent Plasma from Recovered 
COVID-19 Donors Collected by Plasmapheresis as Treatment for Hospitalized Subjects with 
COVID-19 Infection 
 
Principal Investigator: 
Michele Donato, MD FACP CPE 
 
Sub-Investigators: 
Scott Rowley, MD FACP 
Martin Gutierrez, MD 
Sean Sadikot, MD 
Robert Korngold, PhD 
Kar Chow, MD 
Andre Goy, MD, MS 
Andrew Pecora, MD 
David Siegel, MD 
Alfred Gillio, MD 
Sukhdeep Kaur, MD 
Hyung Suh, MD 
Rani Sebti, MD 
Cristina Cicogna, MD 
Phyllis McKiernan, APN 
Melissa Baker, APN 
Michele Boonstra, APN 
Tatyana Feldman, MD 
Noa Biran, MD 
Andrew Ip, MD, MS 
Jamie Koprivnikar, MD 
James McCloskey, MD 
Lori Leslie, MD 
Kaushal Parikh, MD 
Sam Singer, MD 
Danielle Schillen, APN 
Gurbakhash Kaur, MD 
Brett Lewis, MD PhD 
David Perlin, PhD 
 
Danit Arad, MD 
Elizabeth Tam, MD 
 
Keith Rose, MD 
Ronald Go, MD  
Abdulla Al-Khan, MD  
Bindu Balani, MD  
 
Joseph Underwood, MD 
Rena Feinman, MD 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
ABBREVIATIONS ................................................................................................................................. 5 
1.1 General principals of passive antibody therapy ............................................................................... 11 
1.2 Experience with the use of convalescent plasma to treat coronavirus infections .......................... 12 
1.3 Overview of safety ........................................................................................................................... 12 
2. Study Objectives.......................................................................................................................... 14 
2.1 Primary objectives ............................................................................................................................ 14 
2.2 Secondary objectives ....................................................................................................................... 14 
2.3 Exploratory objectives ...................................................................................................................... 14 
2.4 Safety endpoints .............................................................................................................................. 14 
3. Eligibility and Exclusion Criteria .................................................................................................... 14 
3.1 Donor ............................................................................................................................................... 14 
3.2 Recipient .......................................................................................................................................... 15 
4. Investigational Plan ...................................................................................................................... 15 
4.1 Overall study design ......................................................................................................................... 15 
4.2 Number of subjects .......................................................................................................................... 16 
4.3 Overall study duration ..................................................................................................................... 16 
5. Treatment Plan ............................................................................................................................ 16 
5.1 Donor procedures and evaluation ................................................................................................... 16 
5.2 Patient (recipient) procedures and evaluation (see Appendix B) .................................................... 18 
5.3 Withdrawal criteria .......................................................................................................................... 20 
5.4 Study Completion ............................................................................................................................. 20 
6. Conduct of study assessment and procedures ............................................................................... 21 
6.1 Administration of informed consent form ...................................................................................... 21 
6.2 Prior and concomitant medications ................................................................................................. 21 
6.3 Safety assessments .......................................................................................................................... 21 
7. Safety Monitoring and Reporting .................................................................................................. 23 
7.1 Adverse events ................................................................................................................................. 23 
7.2 Serious adverse events ..................................................................................................................... 24 
7.3 Data Safety Monitoring Board (DSMB) ............................................................................................ 25 

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8. Statistical Analysis ........................................................................................................................ 26 
8.2 Track 3: Mortality ............................................................................................................................ 28 
8.3 Analysis plan ..................................................................................................................................... 28 
9. Regulatory consideration .............................................................................................................. 31 
9.1 Good Clinical Practice ....................................................................................................................... 31 
9.2 Institutional Review Board (IRB) Review.......................................................................................... 31 
9.3 Ongoing Information for IRB Committee ......................................................................................... 31 
9.4 Investigator Responsibilities ............................................................................................................ 31 
9.5 Subject information and informed consent ..................................................................................... 32 
9.6 Confidentiality .................................................................................................................................. 32 
9.7 Retention of records ........................................................................................................................ 32 
10. Data handling and recordkeeping ............................................................................................... 34 
10.1 Data/documents ............................................................................................................................ 34 
10.2 Data management.......................................................................................................................... 34 
REFERENCES .................................................................................................................................... 37 

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ABBREVIATIONS 
ADR: Adverse Drug Reaction 
ADE: Antibody-mediated enhancement of infection 
AE: Adverse Event/Adverse Experience 
CDC: United States Centers for Disease Control and Prevention 
CFR: Code of Federal Regulations 
CLIA: Clinical Laboratory Improvement Amendment of 1988 
COI: Conflict of Interest 
COVID-19: Coronavirus Disease from SARS-CoV2 
CRF: Case Report Form 
DMC: Data Management Center 
DSMB: Data and Safety Monitoring Board 
EUA: Emergency Use Authorization 
FDA: Food and Drug Administration 
GCP: Good Clinical Practice 
HBV: Hepatitis B virus 
HCIP: Human Coronavirus Immune Plasma 
HCV: Hepatitis C virus 
HIV: Human immunodeficiency virus 
HTLV: Human T-cell lymphotropic virus 
IB: Investigator’s Brochure 
ICF: Informed Consent (Informed Consent Form) 
ICH: International Conference on Harmonization 
ICU: Intensive Care Unit 
IEC : Independent ethics committee 
IND: Investigational New Drug Application 
IRB: Institutional review board 
ISBT: International Society of Blood Transfusion 

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ISM: Independent Safety Monitor 
IWRS : Interactive web response system 
MERS: Middle East Respiratory Syndrome 
OP: Oropharyngeal 
RT-PCR: Reverse Transcriptase Polymerase chain reaction 
PK: Pharmacokinetic 
PPE: Personal Protective Equipment 
SAE: Serious adverse event 
SARS: Severe Acute Respiratory Syndrome 
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2 
TACO: Transfusion-associated circulatory overload 
T. cruzi: Trypanosoma cruzi 
TRALI: Transfusion-related acute lung injury 
UP: Unanticipated Problem 
UPnonAE: Unanticipated Problem that is not an Adverse Event 
ZIKV: Zika virus 

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PROTOCOL SUMMARY 
Phase IIa Study Exploring the Safety and Efficacy of Convalescent Plasma from Recovered COVID-19 
Donors Collected by Plasmapheresis as Treatment for Hospitalized Subjects with COVID-19 Infection 
Background 
SARS-CoV-2 
 
The novel coronavirus, SARS-CoV-2, is currently causing a worldwide pandemic with over 700,000 cases 
as of March 29th, 2020. There is currently no therapy for SARS-CoV-2, and the need for therapeutic 
options is urgent. The virus appears to cause multiorgan failure through several mechanisms, including a 
severe inflammatory response leading to acute respiratory distress syndrome.1 
Convalescent plasma for novel viruses 
Passive antibody therapy has been used for prior virus epidemics.2-6 Reports from outbreaks of severe 
acute respiratory syndrome (SARS) from coronavirus (SARS-CoV-1) showed that convalescent plasma 
from recovered patients contains neutralizing antibodies.7 In the 2013 Ebola epidemic, there was a 
significant increase in survival (72% vs 56%) for patients receiving convalescent whole blood compared 
to those who did not.8 The proposed mechanism of action by which passive antibody therapy works, is 
thought to be viral neutralization but may also include antibody-dependent cellular cytotoxicity. 
Study Objectives 
Primary Objectives 
• 
Primary objective for patients hospitalized for COVID-19 but not intubated, is to evaluate the 
efficacy of convalescent plasma in reducing rates of mechanical ventilation 
• 
Primary objective for patients with COVID-19 already intubated is to evaluate the efficacy of 
convalescent plasma in reducing mortality from COVID-19 related causes at day 30 
• 
To evaluate the safety of convalescent plasma 
Secondary objectives 
• 
Duration of hospitalization 
• 
Duration of mechanical ventilation 
• 
Time to symptoms resolution 
• 
Overall survival 
• 
Rate of virologic clearance by nasopharyngeal swab at day 10, 30, 60 
• 
Evaluation of donor parameters including nasopharyngeal swab positivity and titers levels 
• 
Evaluation of the impact of donor titers level (1:64, 1:128, and greater) on efficacy and safety 
• 
Recipient Anti-SARS-CoV2 titer assessment on days 0 (pre-infusion),3,10,30, 60 
Exploratory Objectives 
These are to be performed at Hackensack Meridian Health Center for Discovery and Innovation 

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• 
Plasma product analysis for cytokines, mannose-binding lectin (MBL), procalcitonin (PCT), C- 
reactive protein (CRP), Human neutrophil lipocalin (HNL), Annexin V, Surfactant protein D (SP- 
D), as well as microRNAs 
• 
Recipient cytokines and chemokines levels on days 0 (pre-infusion), 3,10,30,60 (optional) 
• 
Host genomics on day 0 (optional) 
Safety endpoints 
• 
Rates of adverse events associated with convalescent plasma infusion 
• 
Safety assessment will be performed on infusion days 0 (post infusion), 3, 10, 30, and 60 days 
 
 
Inclusion Criteria 
Donor (see Appendix A) 
• 
Age 18-60 
• 
A history of a positive nasopharyngeal swab for COVID-19 or a history of positive titer test. 
• 
At least 14 days from resolution of COVID-19-associated symptoms including fevers 
• 
One negative nasopharyngeal swabs for COVID-19 RNA 
• 
Covid-19 neutralizing antibody >1:64 
• 
Adequate venous access for apheresis 
• 
Meets donor eligibility criteria in accordance to Hackensack University Medical Center (HUMC) 
Collection Facility at the John Theurer Cancer Center (JTCC) if collecting at the JTCC, and all 
regulatory agencies as describes in SOP 800 01 (Appendix A) 
• 
Required testing of the donor and product must be performed in accordance to FDA regulations 
(21 CFR 610.40), and the donation must be found suitable (21 CFR 630.30) 
Recipient 
 
Recipients age >18 years old, are assigned to one of two clinical tracks, track 2 or 3, based on COVID-19 
disease severity. Onset of first symptoms < 9 days. 
 
Track 2 
• 
Hospitalized, moderate symptoms requiring medical care for COVID-19 infection 
• 
Symptoms may include fever, dyspnea, dehydration among others 
• 
Hypoxemia may be present but is not a requirement 
Track 3 
• 
Requiring mechanical ventilation for the care of COVID-19 infection 
• 
Requiring non-invasive positive pressure ventilation (NIPPV), such as continuous airway pressure 
(CPAP),bi-level positive airway pressure (BiPAP) or high flow nasal canula (HFNC). 
Recipient exclusion criteria 

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• 
History of severe transfusion reaction to plasma products 
• 
Infusion of immune globulin within the previous 30 days 
• 
AST or ALT > 10 x upper limit of normal 
• 
Requirement for vasopressors 
• 
COVID-19-associated acute kidney injury requiring dialysis 
• 
DNR status 
Treatment Plan 
Plasma collection 
Collection of plasma will be performed on eligible and suitable donors meeting regulatory requirements 
(Appendix A). 
SARS-CoV-2 convalescent plasma consisting of 1 unit of approximately 400-500 mL or 2 units of 
approximately 200 mL will be collected by apheresis from a volunteer donor who recovered from 
COVID-19 infection and was found to have a titer of neutralizing antibody >1:64. 
 
Donors may be referred to an outside licensed Blood Center for plasmapheresis. 
Plasma infusion 
Fresh or cryopreserved plasma will be infused one time to patients in Track 2 (hospitalized but not 
mechanically ventilated) or in Track 3 (mechanically ventilated, invasively or non-invasively). 
Statistical Analysis 
 
For each track, we have considered a multistage sequential design based on the sequential conditional 
probability ratio test which is more efficient than the Simon’s 2-stage design and has the flexibility for 
unplanned analyses should they become necessary due to slow accrual and/or competing therapies.17-18 
Track 2 Mechanical ventilation 
 
The phase II trial design for Track 2 is as follows. The first stage analysis will be after 12 patients, if 6 or 
more of them require mechanical ventilation, we conclude that the therapy is not worth pursuing; and if 
0 out of 12 patients requires mechanical ventilation, early evidence for efficacy is established. The 
maximum discordance probability is 0.00059, which indicates that if 6 or more of the first 12 patients 
require mechanical ventilation to the therapy, there is very slim (less than 0.059%) chance that the 
mechanical ventilation rate would be less than 30% should the study continue to enroll all 36 patients. 
On the other hand, if 0 of the first 12 patients requires mechanical ventilation, it is certain that the trial 
will meet its goal even if we enroll all 36 patients. This statistical design would have 80% probability to 
accept the therapy for further trials if the true mechanical ventilation rate is indeed 15% and 10% 
probability to reject the null hypothesis if the true mechanical ventilation rate is indeed 30%. 
Track 3 Mortality 
The phase II trial design for Track 3 is as follows. The first stage analysis will be after 6 patients, if 5 or 
more of them pass away, we conclude that the therapy is not worth pursuing; and if 0 out of 6 patients 
die, early evidence for efficacy is established. The maximum discordance probability is 0.00091, which 

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indicates that if 5 or more of the first 6 patients pass away to the therapy, there is very slim (less than 
0.091%) chance that the mortality rate would be less than 49% should the study continue to enroll all 19 
patients. On the other hand, if 0 of the first 6 patients is alive, it is certain that the trial will meet its goal 
even if we enroll all 19 patients. This statistical design would have 80% probability to accept the therapy 
for further trials if the true mortality rate is indeed 25% and 10% probability to reject the null hypothesis 
if the true mortality rate is indeed 49%. 
Study site 
This is a single institution study conducted at Hackensack University Medical Center (HUMC)/John 
Theurer Cancer Center at HUMC, Hackensack, NJ. The exploratory laboratory tests will be performed at 
the Hackensack Meridian Health Center for Discovery and Innovation (CDI) 

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PROTOCOL 
Phase IIa Study Exploring the Safety and Efficacy of Convalescent Plasma from Recovered COVID-19 
Donors Collected by Plasmapheresis as Treatment for Hospitalized Subjects with COVID-19 Infection 
1. Introduction 
1.1 General principals of passive antibody therapy 
There is currently no proven effective therapy for coronavirus disease (COVID-19) caused by Severe 
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Donor convalescent plasma has been 
successfully used for treatment of other viral infections, and thus may provide an option for the 
treatment of COVID-19 and could be rapidly available from people who have recovered from the disease 
and can donate plasma. 
Passive antibody therapy involves the administration of antibodies against an infectious agent to an 
afflicted individual for the purpose of treating their disease. In contrast, active vaccination requires the 
induction of an immune response, which takes time to develop and varies depending on the recipient. 
Some immunocompromised patients fail to achieve an adequate immune response. Thus, passive 
antibody administration may in some instances represent the only way of providing immediate 
immunity to susceptible persons, and more predictable immunity in immunocompromised patients. It 
also offers the potential for immediate benefit in hospitalized and ICU patients who are critically ill. 
 
Passive antibody was first described in the 1890s, and was the only way to treat certain infectious 
diseases prior to the development of antimicrobial therapy in the 1940s.2-6 Experience from prior 
outbreaks with other coronaviruses such as SARS-CoV-1 shows that convalescent plasma contains 
neutralizing antibodies to the relevant virus.7 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 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.8 
 
The only antibody therapy currently available for immediate use in SARS-CoV-2 is found in human 
convalescent plasma. As more individuals contract COVID-19 and recover, the number of potential 
donors will continue to increase. 
 
A general principle of passive antibody therapy is that it is more effective when used early in the 
treatment of disease. Antibody therapy 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.4 As an example, passive antibody 
therapy for pneumococcal pneumonia was most effective when administered shortly after the onset of 
symptoms and there was no benefit if antibody administration was delayed past the third day of 
disease.2 

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For passive antibody therapy to be effective, enough antibody must be administered. When given to a 
susceptible person, this antibody will circulate in the blood, reach tissues and provide protection against 
infection. Depending on the antibody amount and composition, the protection conferred by the 
transferred immunoglobulin can last from weeks to months. Therefore, the use of a larger amount of 
plasma collected by apheresis may be preferable to plasma separated from a unit of whole blood. 
 
 
1.2 Experience with the use of convalescent plasma to treat coronavirus infections 
In recent times there have been 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.9 Patients treated before day 14 had improved prognosis defined by 
discharge from hospital before day 22, consistent with the notion that earlier administration is more 
likely to be effective. In addition, those who were PCR positive and seronegative for coronavirus at the 
time of therapy had improved outcomes. 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 fresh convalescent plasma, resulting in a reduction in plasma virus titer and each survived.10 
Three patients with MERS in South Korea were treated with convalescent plasma, but only two of the 
recipients had neutralizing antibody in their plasma.11 The latter study highlights a challenge in using 
convalescent plasma, namely, that some who recover from viral disease may not have high titers of 
neutralizing antibody.12 Consistent with this point, an analysis of 99 samples of convalescent sera from 
patients with SARS showed that 87 had neutralizing antibody with a geometric mean titer of 1:61.7 This 
suggests that antibody declines with time or that few patients make high titer responses. 
 
It is also possible that other types of non-neutralizing antibodies are made that contribute to protection 
and recovery as described for other viral diseases.13 
 
Convalescent plasma has been reported in a case series of patients with SARS-CoV-2.20 Patients received 
transfusion with 400-500 mL of fresh convalescent plasma with a SARS-CoV-2–specific antibody binding 
titer greater than 1:1000 and a neutralization titer greater than 40 that had been obtained from 5 
patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 
days after admission. All 5 patients were receiving mechanical ventilation at the time of treatment and 
all had received antiviral agents and methylprednisolone. ARDS resolved in 4 patients at 12 days after 
transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of 
the 5 patients, 3 have been discharged from the hospital, and 2 are in stable condition at 37 days after 
transfusion. Since this is the only available data for SARS-CoV2 available, the infusion of a larger volume 
(400-500mL) of fresh plasma would be supported. 
 
 
1.3 Overview of safety 
Historical and current anecdotal data on use of convalescent plasma suggest that it is safe in coronavirus 
infection. The theoretical risk involves the phenomenon of antibody-dependent enhancement of 
infection (ADE). For coronaviruses, several mechanisms for ADE have been described and there is the 

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theoretical concern that antibodies to one type of coronavirus could enhance infection to another viral 
strain.14 Since the proposed use of convalescent plasma in the COVID-19 epidemic would rely on 
preparations with high titers of neutralizing antibody against the specific virus, SARS2-CoV-2, ADE may 
be unlikely. The available evidence from the use of convalescent plasma in patients with SARS1 and 
MERS,15 and the case series evidence of its use in patients with COVID-1920 suggests it is safe. 
 
Another theoretical risk is that antibody administration to those exposed to SARS-CoV-2 may avoid 
disease but modify the immune response such that those individuals mount attenuated immune 
responses, which would leave them vulnerable to subsequent re-infection. In this regard, passive 
antibody administration before vaccination with respiratory syncytial virus was reported to attenuate 
humoral but not cellular immunity.16 This concern will be investigated as part of this clinical trial by 
measuring immune responses in those exposed and treated with convalescent plasma to prevent 
disease. If the concern proved real, these individuals could be vaccinated against COVID-19 when a 
vaccine becomes available. The antibodies used in this study will be derived from serum obtained from 
convalescent patients and will be subjected to testing protocols used by blood banks and transfusion 
services. However, as is the case with any biological product, there is a very small risk of allergy or 
anaphylaxis, transfusion related acute lung injury (TRALI), and transfusion associated circulatory 
overload (TACO) or passive transfer of potential unknown infectious agents. Most adverse effects are 
mild and transient including headaches, flushing, fever, chills, fatigue, nausea, diarrhea, blood pressure 
changes and tachycardia. Late adverse events are rare. 

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2. Study Objectives 
2.1 Primary objectives 
• 
Primary objective for patients hospitalized for COVID-19 but not intubated, is to evaluate 
the efficacy of convalescent plasma in reducing rates of progression to mechanical 
ventilation. 
• 
Primary objective for patients with COVID-19 already intubated is to evaluate the efficacy 
of convalescent plasma in reducing mortality at day 30. 
• 
To evaluate the safety of convalescent plasma 
2.2 Secondary objectives 
• 
Duration of hospitalization 
• 
Time to symptoms resolution 
• 
Duration of mechanical ventilation 
• 
Overall survival 
• 
Rate of virologic clearance by nasopharyngeal swab at day 10, 30, 60 
• 
SARS-CoV-2 PCR positivity (RT-PCR) in blood at days 0 (pre-infusion), 3, 10, 30, 60  
• 
Evaluation of the impact of donor titers levels (1:64, 1:128, and greater) on the primary 
objectives described in 2.1. 
• 
Evaluation of donor parameters including nasopharyngeal swab positivity and titers 
levels 
• 
Recipient anti-SARS-CoV2 titers assessment on days 0 (pre-infusion), 3, 10, 30, 60 
2.3 Exploratory objectives 
These are to be performed at Hackensack Meridian Health Center for Discovery and Innovation 
• 
Plasma product analysis for cytokines, mannose-binding lectin (MBL), procalcitonin 
(PCT), C-reactive protein (CRP), Human neutrophil lipocalin (HNL), Annexin V, Surfactant 
protein D (SP-D), as well as microRNAs 
• 
Recipient cytokines and chemokines levels on days 0 (pre-infusion), 3,10,30,60 
(optional) 
• 
Host genomics on day 0 (optional) 
2.4 Safety endpoints 
• 
Rates of adverse events associated with convalescent plasma infusion will be 
determined as defined in section 6.3. 
• 
Safety assessment will be performed on post infusion day 0,3,10, 30, and 60 days.  
 
 
3. Eligibility and Exclusion Criteria 
3.1 Donor 
• 
Age 18-60 
• 
A history of a positive nasopharyngeal swab for COVID-19 or a history of positive titer 
test.  

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• 
At least 14 days from resolution of COVID-19-associated symptoms including fevers 
• 
One negative nasopharyngeal swabs for COVID-19 RNA 
• 
Covid-19 neutralizing antibody >1:64 
• 
Adequate venous access for apheresis 
• 
Meets donor eligibility criteria in accordance to regulatory requirements and 
Hackensack Meridian Health SOP 800 01 “COVID-19 Convalescent Plasma Procurement” 
(Appendix A). 
• 
Required testing of the donor and product must be performed in accordance to FDA 
regulation 21 CFR 610.40, and the donation must be found suitable (21 CFR 630.30) (See 
Appendix A) 
3.2 Recipient 
Recipients must be >18 years old, and have a documented infection with SARS-CoV-2 and 
belong to either Track 2 or Track 3. Onset of first symptoms < 9 days. 
 
3.2.1 Track 2 
• 
Hospitalized, moderate symptoms requiring medical care for COVID-19 infection  
• 
Symptoms may include fever, dyspnea, dehydration and others 
• 
Hypoxemia may be present but is not a requirement 
3.2.2 Track 3 
• 
Patients mechanically ventilated for COVID-19 infection  
• 
Requiring non-invasive positive pressure ventilation (NIPPV), such as continuous 
airway pressure (CPAP), bi-level positive airway pressure (BiPAP) or high flow 
nasal canula (HFNC).  
• 
3.2.3 Recipient exclusion criteria 
• 
History of severe transfusion reaction to plasma products  
• 
Infusion of immune globulin within the previous 30 days  
• 
AST or ALT > 10 times upper limit of normal  
• 
Requirement for vasopressors  
• 
COVID-19-associated acute kidney injury requiring dialysis  
• 
DNR status 
 
 
4. Investigational Plan 
4.1 Overall study design 
• 
This is a single arm phase IIa study of convalescent plasma for the treatment of 
individuals hospitalized with COVID-19 infection. 
• 
Subjects will be considered as having completed the study after 60 (+/- 3) days, unless 
consent withdrawal or death occurs first. 

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• 
Interim analysis will be permitted as described in the statistical section 8. 
• 
The final analysis will be conducted once the last subject completes the day 60 visit or 
withdraws from the study. 
4.2 Number of subjects 
• 
 Up to 36 patients in track 2, and 19 patients in track 3 as described in the statistical 
section 8.   
4.3 Overall study duration 
• 
The study begins when the first subject (this will likely be a donor) signs the informed 
consent. The study will end once the last enrolled subject completes the study (likely a 
recipient). 
• 
The expected duration of the study is approximately 12 months. 
 
 
5. Treatment Plan 
5.1 Donor procedures and evaluation 
 
All activities pertaining to donor recruitment, enrollment, collection, product handling and 
processing will take place at Hackensack University Medical Center (HUMC) and John Theurer 
Cancer Center at HUMC. This facility is FDA-registered and AABB accredited, attesting to robust 
quality oversight of all operations. All donor-related procedures pertaining to this study are 
detailed in our SOP 800 01 “COVID-19 Convalescent Plasma Procurement” in Appendix A. 
5.1.1 Donor recruitment and screening (see Appendix A) 
• 
Mechanism for recruitment will include advertising in the local community where recent 
outbreaks have occurred. 
• 
Individuals who agree to participate will do so under full informed consent. 
• 
Individuals who agree to participate will undergo pre-donation screening by a clinical 
health care provider (visit 1). 
• 
Only those individuals who satisfy all criteria for collection as determined through 
medical evaluation and laboratory testing described in Appendix A will proceed to a 
second visit (visit 2) during which the collection will take place. Visit 2 will occur within 
seven days of visit 1. 
1. Visit 1: 
a. History and physical examination if collecting at JTCC 
b. Donor health questionnaire 
c. Nasopharyngeal swab for COVID-19 
d. Blood for SARS-CoV-2 neutralizing antibody 
e. Blood tests as described in SOP 800.01 section “Donor Evaluation and 
Eligibility” subsection L (Appendix A), for collections at the JTCC 
2. Visit 2: 
a. Donor health questionnaire 
b. Blood tests as described in SOP 800.01 section “Donor Evaluation and 
Eligibility” subsection L (Appendix A) 

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c. Apheresis procedure as described in section 5.1.2 and Appendix A if 
collecting at the JTCC. 
 
 
 
5.1.2 Donor plasma collection (see Appendix A) 
• 
The plasma collection will be performed by apheresis at the John Theurer Cancer Center 
(JTCC) Collection Facility at HUMC as per “COVID-19 Convalescent Plasma Procurement” 
SOP (Appendix A) or the donor will be referred to an outside licensed Blood Center for 
plasmapheresis. 
• 
The JTCC houses a FACT accredited Collection Facility, NJ Blood Bank license 10317, FDA 
(BMT FEI) Registration 3004726780. 
• 
The plasma collection will be performed using either the Trima Accel® System by 
Terumo BCT (Appendix A SOP 800 01). 
• 
As per routine practice, samples will be collected at the time of donation for testing for 
transfusion-transmissible infections (all donors), ABO and red cell antibodies (all donors) 
and HLA antibodies (female donors), in accordance with FDA regulation 21 CFR 610.40, 
and the donation must be found suitable (21 CFR 630.30). 
• 
Target collection volume: 500mL in a single collection bag or two collection bags of 
200mL. The Trima Accel® system considers the total blood volume and will make 
recommendations to the volume that can be removed safely. Therefore, the collection 
goal will be either 500mL or the machine recommended maximum volume, whichever is 
smallest. 
• 
Labeling will be in accordance with FDA regulations 21CFR 606.121. 
• 
The plasma will be maintained in quarantine pending laboratory test results (i.e. 
infectious screening, ABO and RhD status, Red cell and HLA antibodies). 
• 
If laboratory testing is acceptable (i.e. negative infectious and antibody screening), the 
products will be appropriately labeled and distributed to hospital blood bank for 
storage. 
• 
In the event of an abnormal test result, the product will be discarded, and the donor will 
be notified by the blood center as is standard practice. 
• 
Donors may donate plasma every > 7 days. The donor screening 
procedure described in section 5.1.1 “ visit 2” will need to be repeated 
for each subsequent donation on the day of plasmapheresis, with the 
addition of blood for SARS-CoV-2 neutralizing antibody 

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5.1.3 Product handling 
Product handling including labeling, testing, transportation, distribution and record keeping 
including chain of custody recording will be performed in accordance with regulations and 
HUMC SOP 800.01 “COVID-19 Convalescent Plasma Procurement” (Appendix A). 
 
5.2 Patient (recipient) procedures and evaluation (see Appendix B) 
5.2.1 Day -1 to 0 (pre-infusion) 
• 
Screening 
• 
Informed consent must be obtained before performing study related activities (can be 
from healthcare proxy if subject unable to provide consent due to medical status) 
• 
Baseline Evaluation (at screening) 
1. Demographics (age, sex ethnicity, race)  
2. Medical history   
a. Onset of COVID-19 symptoms   
b. Date of positive test   
c. Acute and chronic medical conditions, medications, allergies.   
d. Any medical condition arising after consent should be recorded 
as an AE  
3. COVID-19 symptom screen (fevers, cough, shortness of breath and 
others)  
4. Vital signs  
5. Physical examination as last reported in the medical records on current 
day  
6. Documentation of positive nasopharyngeal COVID-19 testing within 10 
days (RT-PCR) prior to infusion. If not, repeat.   
7. Blood typing, CBC, comprehensive metabolic panel  
8. Serological testing: anti-SARS CoV-2 titers   
9. Blood SARS-CoV-2 PCR (RT-PCR)   
10. Determination of eligibility as per inclusion/exclusion criteria  
11. Exploratory blood test (optional) if recipient consents  
5.2.2 Day 0 (infusion day) 
• 
Study plasma administration 
1. A single unit of fresh plasma will be transfused at an approximate rate 
of 50 mL per hour x 30 minutes, then the rate may be increased up to 
250 mL per hour until completion.   
a. Alternatively, recipients may receive 200 mL to 400 mL of 
cryopreserved plasma collected at an outside Blood Center. The 

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cryopreserved plasma will be administered as per standard 
institutional SOP for fresh frozen plasma infusion. 
2. If possible, 10mL of plasma will be collected for research from the 
infusion line and sent to the CDI 
3. The infusion may be slowed or stopped as per investigator’s decision for 
minor transfusion reactions only. The transfusion will be discontinued 
for any transfusion reactions other than minor allergic reactions.   
4. An investigation will be initiated when there are signs of a systemic 
transfusion reaction.  
5. Premedication 30 – 60 minutes prior to the infusion will include 100 mg 
hydrocortisone IV, acetaminophen 650 mg PO, and diphenhydramine 25 
mg IV. Diphenhydramine 25 mg IV and hydrocortisone 100 mg IV may 
be repeated as needed for an infusion reaction at the discretion of the 
investigator.   
6. Time at start and end of infusion will be recorded    
7. Vitals signs should be monitored following Hackensack Meridian Health 
Blood and Blood Product Administration SOP guidelines:  
a. Temperature, pulse, respirations, and blood pressure pre- 
infusion (within 30 minutes), 15 minutes after the start, every 
hour during, if a transfusion reaction is suspected or if there is 
any change in patient condition, post transfusion (5-15 minutes 
post) 
• 
COVID-19 symptom screen (fevers, cough, shortness of breath) 
• 
Assessment of clinical status 
1. ICU and mechanical ventilation (invasive or non-invasive) status 
2. Oxygen % requirement 
3. Severe end-organ dysfunction 
• 
New medical conditions, concomitant medication, AE evaluation 
• 
Physical examination, may use as recorded in the medical record from the same day 
• 
CBC, blood chemistry  
• 
Serological testing: anti-SARS CoV-2 titers   
• 
Blood for SARS-CoV-2 PCR (RT-PCR) 
• 
Exploratory blood test for genomics, cytokines/chemokines to be sent to the CDI 
(optional) 
5.2.3 Post infusion day +3, +10 (+/- 48 hours for day 10) 
• 
Vital signs 
• 
COVID-19 symptom screen (fevers, cough, shortness of breath) 
• 
Assessment of clinical status (composite outcome of disease severity) 
• 
New medical conditions, AE evaluation 
• 
Physical examination, may use physical examination from the medical record from the 
same day 

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• 
COVID-19 testing (RT-PCR) from nasopharyngeal or ET secretions if intubated on day 10 
• 
Serological testing: anti-SARS CoV-2 titers if possible. 
• 
Blood for SARS-CoV-2 PCR (RT-PCR) 
• 
Exploratory blood test for genomics, cytokines/chemokines to be sent to the CDI 
(optional) 
  
 
5.2.4 Day +30 and +60 ,+/- 3 days (can be remote) 
• 
COVID-19 symptom screen (fevers, cough, shortness of breath) 
• 
Stool for microbiome and viral content if possible 
• 
COVID-19 testing (RT-PCR) from nasopharyngeal sampling 
• 
New medical conditions, AE evaluation 
• 
Serological testing: anti-SARS CoV-2 titers if possible. 
• 
SARS-CoV-2 PCR (RT-PCR) in blood 
• 
Exploratory blood test for genomics, cytokines/chemokines to be sent to the CDI 
(optional)  
5.3 Withdrawal criteria 
 
5.3.1 A subject must be withdrawn from study treatment for the following reasons 
• 
Subject has experienced an unacceptable toxicity precluding the completion of plasma 
infusion.   
• 
The study is terminated by the local health authority, or IRB. 
 
5.3.2 If a subject is withdrawn from study treatment 
• 
The reason(s) for withdrawal must be documented in the subject's medical record and 
in the CRF.  
• 
The end of treatment (EOT) visit should be performed.  
• 
Subjects must be followed for safety until the time of the follow-up visit or until study 
treatment–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest.  
• 
If the subject discontinues study treatment and actively withdraws consent for 
collection of follow-up data (safety follow-up or disease assessment), then no additional 
data collection should occur; however, subjects will have the option of withdrawing 
consent for study treatment but continuing in the follow-up period of the study.  
5.4 Study Completion 
5.4.1 A subject will be considered as completing the study if he or she meets any the following 
criteria: 
• 
Subject completes the day 60 visit 
• 
Subject dies, and a date of death is available 
• 
Subject is known to have died; however, the date of death cannot be obtained (every 
effort must be made to obtain the date of death) 

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• 
Subject has discontinued study treatment and has withdrawn consent for collection of 
further follow-up data 
 
6. Conduct of study assessment and procedures 
6.1 Administration of informed consent form 
Valid informed consent must be obtained from the study subjects, donor and recipient, before 
conducting any study-specific procedures pertaining to donor or recipient, using an ICF 
approved by the local IRB/IEC that contains all elements required by ICH E6 and describes the 
nature, scope, and possible consequences of the study in a form understandable to the study 
subject. Local and institutional guidelines for ICF content and administration must be followed; 
the original signed ICF must be retained by the investigator, and a copy of the signed ICF must 
be provided to the study subject. The informed consent process for each subject must be 
documented in writing within the subject source documentation. Rescreening of potential 
subjects is permitted. Recipient consent need not be obtained for a donor to consent and 
initiate treatment. 
6.2 Prior and concomitant medications 
The medication record will be maintained after signing the ICF to document concomitant 
medications. 
6.3 Safety assessments 
6.3.1 Adverse events 
Adverse events for both donors and recipients will be monitored from the time the 
subjects sign the ICF. Subjects will be instructed to report all AEs during the study and 
will be assessed for the occurrence of AEs throughout the study. In order to avoid bias in 
eliciting AEs, subjects will be asked general, nonleading questions such as "How are you 
feeling?" All AEs (serious and nonserious) must be recorded on the source documents 
and CRFs regardless of the assumption of a causal relationship with study treatment. 
The definition, reporting, and recording requirements for AEs are described in Section 8. 
6.3.2 Physical examinations 
The targeted physical examinations will be symptom-directed evaluations conducted by 
the investigator or a medically qualified designee. Since subjects (recipients) are highly 
contagious, a physical examination recorded by a clinician (APN, MD, DO), in the medical 
record on visit day, will be acceptable. 
 
6.3.3 Performance status 
ECOG performance status (table 1) or Karnofsky performance status (table 2) will be 
assessed. Performance status must be assessed by a medically qualified individual and 
recorded in the CRF. 

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Table 1. ECOG Performance Status Grades: 
 
Grad 
e 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 
 
Table 2. Karnofsky Performance Status Grades: 
 
Grade 
Performance Status 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self; unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance but can care for most of their personal needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although death not imminent. 
20 
Very sick; hospital admission necessary; active supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead. 
 
 
6.3.4 Infection monitoring 

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Monitoring for infection other than COVID-19 will be performed on recipient days 
0,3,10,30,60. 
 
7. 
Safety Monitoring and Reporting 
7.1 
Adverse events 
7.1.1 Definitions 
For the purposes of this Protocol, an AE is defined as any untoward medical occurrence 
associated with the donation or use of a convalescent plasma for COVID-19 whether or 
not considered related, that occurs after a subject provides informed consent. Abnormal 
laboratory values or test results occurring after informed consent constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically meaningful, or require 
therapy (eg, hematologic abnormality that requires transfusion). 
7.1.2 Reporting 
• 
Adverse events that begin or worsen after initiation of plasma donation or 
infusion should be recorded on the Adverse Events Form of the CRF. Monitoring 
for the occurrence of new AEs should be continued for 1 days after the plasma 
donation and at least 60 days after the plasma infusion. Adverse events 
(including laboratory abnormalities that constitute AEs) should be described 
using a diagnosis whenever possible rather than by individual underlying signs 
and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate AE. 
• 
If an adverse event meets the criteria for an SAE (eg, resulted in hospitalization, 
a life-threatening event, or death), the specific event(s) should be reported as 
an SAE(s). 
• 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 5. If an 
event is not classified by CTCAE, the severity of the AE will be graded according 
to the scale below to estimate the grade of severity: 
 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
Grade 2 Moderate; minimal, local, or noninvasive 
intervention indicated; limiting age-appropriate 
activities of daily living. 
Grade 3 Severe 
or 
medically 
significant 
but 
not 
immediately life-threatening; hospitalization or 
prolongation      of      hospitalization      indicated; 
disabling; limiting self-care activities of daily living. 

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Grade 4 Life-threatening consequences, urgent 
intervention indicated. 
Grade 5 Death due to AE 
 
 
• 
The occurrence of AEs should be sought by nondirective questioning of the 
subject during the screening process after signing the ICF and at each visit 
during the study. This will apply for the donor where a post donation phone call 
will be placed. For the recipient, occurrence of AEs will be sought on days 0, 3, 
10, 30, 60. Adverse events may also be detected when they are volunteered by 
the subject during the screening process or between visits, or through physical 
examination, laboratory test, or other assessments. To the extent possible, each 
AE should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1 to 5)  
2. Whether there is at least a reasonable possibility that the AE is related 
to the study treatment: suspected (yes) or not suspected (no)  
3. The start and end dates, unless unresolved at final follow-up  
4. The action taken about study treatment  
5. The event outcome (eg, not recovered/not resolved, 
recovered/resolved, recovering/resolving, recovered/resolved with 
sequelae, fatal, unknown)  
6. The seriousness, as per SAE definition provided in section 7.2  
• 
Unlike routine safety assessments, SAEs are monitored continuously and have 
special reporting requirements described in section 7.2.2. 
• 
All AEs should be treated appropriately. If an AE is treated with a concomitant 
medication or nondrug therapy, this action should be recorded on the Adverse 
Event Form and the treatment should be specified on the Prior/Concomitant 
Medications or Procedures and Non-Drug Therapy Form in the CRF. 
• 
Once an AE is detected, it should be followed until it has resolved or until it is 
judged to be permanent; assessment should be made at each visit (or more 
frequently if necessary) of any changes in severity, the suspected relationship to 
the study drug, the interventions required to treat the event, and the outcome. 
• 
When the severity of an AE changes over time for a reporting period (eg, 
between visits), each change in severity will be reported as a separate AE until 
the event resolves. 
7.2 Serious adverse events 
7.2.1 Definitions 
A SAE is defined as an event that meets at least 1 of the following criteria 
• 
Is fatal or life-threatening 

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• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is a result of: 
1. A routine treatment or monitoring of the studied indication not 
associated with any deterioration in condition  
2. An elective or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since 
signing the ICF  
3. A treatment on an emergency outpatient basis for an event not fulfilling 
any of the definitions of a SAE and not resulting in hospital admission  
4. Any social reasons and respite care, in the absence of any deterioration 
in the subject's general condition  
• 
Results in persistent or significant disability, incapacity, or a substantial 
disruption of a person's ability to conduct normal life functions 
 
Constitutes a congenital anomaly or birth defect 
• 
Is considered to be an important medical event or a medically significant event 
that may not result in death, be immediately life-threatening, or require 
hospitalization but may be considered serious when, based upon appropriate 
medical judgment, the event may jeopardize the subject or may require medical 
or surgical intervention to prevent 1 of the outcomes listed above. 
7.2.2 Reporting 
• 
Information about all SAEs is collected and recorded on the Adverse Event Form 
of the CRF. The investigator must assess and record the causal relationship of 
each SAE to the treatment. SEA must be reported in compliance with 
institutional IRB/DSMD requirements. 
• 
Investigational site personnel must report any new information regarding the 
SAE within 24 hours of becoming aware of the information in the same manner 
that the initial SAE Report Form was sent. Follow-up information is recorded on 
an amended or new SAE Report Form, with an indication that it is follow-up to 
the previously reported SAE and the date of the original report. The follow-up 
report should include information that was not provided on the previous SAE 
Report Form, such as the outcome of the event (eg, resolved or ongoing), 
treatment provided, action taken with study drug because of the SAE (eg, dose 
reduced, interrupted, or discontinued), or subject disposition (eg, continued or 
withdrew from study participation). Each recurrence, complication, or 
progression of the original event should be reported as follow-up to that event, 
regardless of when it occurs. 
7.3 Data Safety Monitoring Board (DSMB) 
This study will be approved and monitored by the HackensackUMC DSMB. The DSMB is 
responsible for the monitoring of investigator initiated research studies to ensure the safety of 
participants, the integrity of the data, and the appropriate termination of studies in the event 

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that undue risks have been uncovered, or it appears that trials cannot be conducted 
successfully. The DSMB provides multidisciplinary, independent oversight of research studies 
conducted by HackensackUMC staff and or affiliates. The DSMB can require protocol 
modifications related to participant safety and to recommend suspension of termination to the 
IRB and institutional official of any research protocols that fall within its jurisdiction. The DSMB 
may request that HackensackUMC’s Corporate Compliance Department conduct periodic audits 
to assure that data are being collected and recorded according to the protocol. 
 
The investigator is required to submit monthly monitoring reports which include current 
enrollment data, adverse event summary data and any other data requested by the DSMB. The 
DSMB will meet monthly to review the trial progress, adverse event data, and any relevant 
information such as significant amendments or reviews from IRB submitted by the principal 
investigator. If significant concerns are raised by the DSMB, the concerns will be forwarded to 
the PI as well as recommendations made to the IRB, and Institutional Official. 
Recommendations may include modifying, suspending, or terminating the protocol. 
 
 
 
8. Statistical Analysis 
Patients are clinically divided into Track 2 or Track 3. For each track, we have considered a multistage 
sequential design based on the sequential conditional probability ratio test which is more efficient than 
the Simon’s 2-stage design and has the flexibility for unplanned analyses should they become necessary 
due to slow accrual and/or competing therapies.17-18 
The statistical design is based on the following hypotheses: 
For Track 2, the null hypothesis is that the Mechanical Ventilation Rate is at least 30% and the 
alternative hypothesis is that the Mechanical Ventilation Rate is less than or equal to 15%. 
For Track 3, the null hypothesis is that the Mortality Rate is at least 49% and the alternative hypothesis 
is that the Mortality Rate is less than or equal to 25%. 
The design in each track has a type I error rate at 0.10 with statistical power at least 0.80. For Track 2, this 
statistical design would have 80% probability to accept the therapy for further trials if the true mechanical 
ventilation rate is indeed 15% and 10% probability to reject the null hypothesis if the true mechanical 
ventilation rate is indeed 30%. For Track 3, the statistical design would have 80% probability to accept the 
therapy for further trials if the true mortality rate is indeed 25% and 10% probability to reject the null 
hypothesis if the true mortality rate is indeed 49%. 
For each of the tracks, if a decision for rejecting or accepting the null hypothesis is made based on the 
interim data at any stage, then the probability that such a decision would be reversed is negligible (less 
than 0.1%, the maximum discordant probability) should the trial continue to the end and include all 
patients. This probability is calculated using the SCPRT method and software.18 This methodology takes 
the usual fixed sample/single stage design and makes it a multiple-stage design while still retaining the 
type I and II error. The sample size is calculated with the typical fixed sample test of a proportion. The 
SCPRT method just makes it multi-stage to allow evaluation of early evidence. While retaining the rigor of 

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the original fixed sample design. Interim analysis will therefore be performed after each Stage described 
in Tables 3 and 4. For Track 2 after 12, 24 and 36 patients, and for Track 3 after 6, 12 and 19 patients. 
 
8.1 Track 2: Mechanical ventilation 
The phase II trial design for Track 2 is as follows. The first stage analysis will be after 12 patients, 
if 6 or more of them require use of mechanical ventilation, we conclude that the therapy is not 
worth pursuing, and this will be reported to the DSMB for further guidance. If 0 out of 12 
patients requires mechanical ventilation, early evidence for efficacy is established and accrual 
continues. 
The maximum discordance probability is 0.00059, which indicates that if 6 or more of the first 
12 patients require mechanical ventilation to the therapy, there is very slim (less than 0.059%) 
chance that the mechanical ventilation rate would be less than 30% should the study continue 
to enroll all 36 patients. On the other hand, if 0 of the first 12 patients requires mechanical 
ventilation, the trial will certainly meet its goal even if we enroll all 36 patients (which is 
allowed). 
This statistical design would have 80% probability to accept the therapy for further trials if the 
true mechanical ventilation rate is indeed 15% and 10% probability to reject the null hypothesis 
if the true mechanical ventilation rate is indeed 30%. 
Table 3. Study design of Track 2 
 
Stage 
Cumulative sample size 
Not Promising if number of 
MVent ≥ 
Promising if number of 
MVent ≤ 
1 
12 
6 
0 
2 
24 
8 
1 
3 
36 
8 
7 
*Number of patients requiring mechanical ventilation 

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8.2 Track 3: Mortality 
The phase II trial design for Track 3 is as follows. The first stage analysis will be after 6 patients, if 
5 or more of them pass away, we conclude that the therapy is not worth pursuing, and this will 
be reported to the DSMB for further guidance.  If 0 out of 6 patients passed away, early 
evidence for efficacy is established and accrual continues. 
The maximum discordance probability is 0.00091, which indicates that if 5 or more of the first 6 
patients pass away after the therapy, there is very slim (less than 0.091%) chance that the 
mortality rate would be less than 49% should the study continue to enroll all 19 patients. On the 
other hand, if 0 of the first 6 patients die, the trial will certainly meet its goal even if we enroll all 
19 patients (which is allowed). 
This statistical design would have 80% probability to accept the therapy for further trials if the 
true mortality rate is indeed 25% and 10% probability to reject the null hypothesis if the true 
mortality rate is indeed 49%. 
Table 4. Study design of Track 3 
 
Stage 
Cumulative sample size 
Not Promising if number of 
deaths ≥ 
Promising if number of 
deaths≤ 
1 
6 
5 
0 
2 
12 
7 
1 
3 
19 
7 
6 
 
8.3 Analysis plan 
8.3.1 Primary endpoints 
 
The primary endpoint of the phase II study is to determine mechanical ventilation rate 
at 7 days from starting treatment in hospitalized COVID-19 patients (Track 2), and 
mortality rate at 30 days from starting treatment for patients with COVID-19 (Track 3) 
receiving new therapies. The above-mentioned rates (response rates) will be computed 
and reported with an 95% exact binomial confidence interval (CI). 
8.3.2 Secondary Endpoints 
 
Describe the rate of virologic clearance at 10 days will be calculated and reported 
with an 95% exact binomial CI. Viral clearance at a designed follow-up date is 
defined as the cycle threshold (Ct) of RT-PCT at that designed follow-up date ≥ 
40. 
 
Time to symptom resolution (Track 2 and 3) 
Kaplan-Meier analysis will be used to describe time to symptom resolution (Track 
1 to 2), the median time with 95% CI will be reported. 
The time to symptom resolution is defined as the time in days from new therapy 
initiation to the first documented symptom resolution as assessed by local site. 

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Patients whose symptom are not resolved, who are dead, or lost follow-up on the 
designed follow-up date will be censored on that date. 
 
Duration of hospitalization (Tracks 2 to 3) 
Kaplan-Meier analysis will be used to describe the duration of hospitalization 
(Track 2 to 3), the median time with 95% CI will be reported. 
The duration of hospitalization is defined as the time in days from the first day of 
hospitalized to the date of discharge or death. Patients who are not discharged, 
are alive and still in the hospital on the date of closing follow-up, or lost follow- 
up on the date of closing follow-up will be considered censored on that date. 
 
Duration of Mechanical Ventilation (Track 3) 
Kaplan-Meier analysis will be used to describe the duration of mechanical 
ventilation for all evaluable patients (Track 3), the median time with 95% CI will 
be reported. 
The duration of mechanical ventilation is defined as the time in days from the first 
day of using mechanical ventilation to the last day of using mechanical 
ventilation. All evaluable patients will be included and no censoring for this 
analysis. 
 
Overall Survival (OS) (Tracks 2 to 3) 
Overall survival will be defined as the time in days from study entry to death. 
Patients who are alive on the date of closing follow-up will be censored on that 
date. All events of death will be included, regardless of whether the event 
occurred while the subject was still taking new therapies, or after the subject 
discontinued study therapy. If a subject has not died, then the data will be 
censored according to the following rule: if the subject was lost to follow-up, then 
data will be censored at the last study visit, or the last contact date, or the date 
the subject was last known to be alive, whichever is later; if the subject was not 
lost to follow-up, then data will be censored at the last study visit or the last 
contact date, whichever is later. OS will be estimated by Kaplan-Meier 
methodology, and median OS with 95% CI will be reported. 
 
Safety Assessments (Tracks 2 to 3) 
Overall safety monitoring will be performed throughout the study for each track. 
The safety of study therapy of patients with COVID-19 will be accessed by 
evaluating new therapies exposure, adverse events, serious adverse events, and 
death. And adverse events will be evaluated according to the NCI Common 
Terminology for Adverse Events (CTCAE) as described in section 7. 
 
Baseline Characteristics (Tracks 2 to 3) 
For each track, the baseline summary statistics and analyses will be based on 
characteristics prior to the initiation of new therapies. Frequency and 
percentages for categorical variables and mean (SD) or median (IQR interquartile 
range) for the continuous variables based on the normalization of the data. 

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8.3.3 Exploratory 
 
Descriptive statistics will be used to characterize the genomic expression 
profiling, immunologic profiling, quantitative viral load, and anti-SAS-CoV-2 titer 
assessment during the study therapy as well as several follow-up time points. 
Frequency and percentages for categorical variables and mean (SD) or median 
(IQR interquartile range) for the continuous variables based on the normalization 
of the data. 
 
Univariate test will be performed in terms of identifying the association between 
baseline genomic expression profiling and the severity of patients’ disease 
(severe disease vs. non-severe disease), Chi-square test or Fisher’s exact test for 
categorical variables, and t-test or its non-parametric version for the continuous 
variables based on the normalized of the data. These analyses will most likely be 
in a pairwise fashion given the moderate sample size. 
 
P-value less than 0.05 will be considered significant. All statistical analyses will be 
performed using RStudio (Version 0.99.902) and SAS (Version 9.4). 

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9. Regulatory consideration 
9.1 Good Clinical Practice 
The study will be conducted according to the International Conference on Harmonization (ICH), 
Good Clinical Practice (GCP), the Declaration of Helsinki, Institutional Review Boards (IRB) and in 
accordance with the U.S. Code of Federal Regulations on Protection of Human Rights (21 CFR 
50). 
9.2 Institutional Review Board (IRB) Review 
• 
The final study protocol and consent form (and any other appropriate 
documents as applicable) will be approved by the Institutional Review Board 
(IRB) at Hackensack Meridian Health. Approval will be received in writing before 
initiation of the study. 
• 
Any changes to the study design will be formally documented in protocol 
amendments and will be approved by the IRB prior to implementation. 
• 
Any amendment to this protocol must also be approved by the IRB and FDA. 
The written signed approval from the IRB should specifically reference the 
investigator name, protocol number, study title and amendment number(s) that 
is applicable. Amendments that are administrative in nature do not require IRB 
approval but will be submitted to the IRB for information purposes. 
• 
The investigator must keep a record of all communication with the IRB and, if 
applicable, between a Coordinating investigator and the IRB. This statement 
also applies to any communication between the investigator (or Coordinating 
investigator, if applicable) and regulatory authorities. 
• 
Any advertisements used to recruit subjects for the study must be reviewed by 
[sponsor] and the IRB prior to use. 
9.3 Ongoing Information for IRB Committee 
As required by legislation and local regulatory requirements, the investigator must submit to the 
IRB: 
 
Information on serious or unexpected adverse events as soon as possible 
 
Annual reports on the progress of the study 
 
Deviations from the protocol or anything that may involve added risk to subjects 
 
9.4 Investigator Responsibilities 
• 
Investigator responsibilities are set out in the ICH Guideline for Good Clinical 
Practice and in the local regulations. 
• 
The investigator should ensure that all persons assisting with the study are 
adequately informed about the protocol, amendments, study treatments, as 
well as study-related duties and functions. 
• 
The investigator should maintain a list of Sub-Investigators and other 
appropriately qualified persons to whom he or she has delegated significant 
study-related duties. The investigator is responsible for keeping a record of all 

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subjects who sign an informed consent document and are screened for entry 
into the study. Subjects who fail screening must have the reason(s) recorded in 
the subject’s source documents. 
• 
The investigator, or a designated member of the investigator’s staff, must be 
available during monitoring visits to review data, resolve queries and allow 
direct access to subject records (eg, medical records, office charts, hospital 
charts, and study-related charts) for source data verification. The investigator 
must ensure timely and accurate completion of CRFs and queries. 
9.5 Subject information and informed consent 
• 
The investigator must obtain informed consent of a subject and/or a subject’s 
legal representative prior to any study related procedures. 
• 
Documentation that informed consent occurred prior to the study subject’s 
entry into the study and of the informed consent process should be recorded in 
the study subject’s source documents including the date. The original informed 
consent document signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, 
must be maintained in the investigator’s study files and a copy given to the 
study subject. 
• 
In addition, if a protocol is amended and it impacts on the content of the 
informed consent, the informed consent document must be revised. Study 
subjects participating in the study when the amended protocol is implemented 
must be re-consented with the revised version of the informed consent 
document. The revised informed consent document signed and dated by the 
study subject and by the person consenting the study subject must be 
maintained in the investigator’s study files and a copy given to the study 
subject. 
9.6 Confidentiality 
• 
The patient charts, collected data, and all analysis of the data will adhere to 
HIPAA & institutional patient confidentiality requirements. 
• 
More specifically, a coding system will be used for which a unique identifier 
(study ID number) will be assigned to each patient name and contact details. 
Only the study number will be included in the data collection tool, data analysis 
software and potential publications. The list with the direct identifiers (for the 
purposes of linking data and keeping track of patients) will be stored separately 
in a secure server at each site. 
• 
Analytical datasets will be stored on secure servers that also limit access to the 
investigator team. Should results of the study be published or reported, 
individual names or other identifying information will not be used. 
9.7 Retention of records 
Records will be retained in accordance with regulatory, organizational and sponsor 
requirements, but no less than six (6) years following the completion of the research. 

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Disposal of records will be done in such a manner that no identifying information can be 
linked to research data. 

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10. Data handling and recordkeeping 
10.1 Data/documents 
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained. 
 
The primary source documents for this study will be the subjects’ medical records. If the 
investigators maintain separate research records, both the medical record and the research 
records will be considered the source documents for the purposes of auditing the study. The 
investigator will retain a copy of source documents. The investigator will permit monitoring and 
auditing of these data, and will allow the sponsor, IRB and regulatory authorities access to the 
original source documents. The investigator is responsible for ensuring that the data collected 
are complete, accurate, and recorded in a timely manner. Source documentation (the point of 
initial recording of information) should support the data collected and entered into the study 
database/case report form and must be signed and dated by the person recording and/or 
reviewing the data. All data submitted should be reviewed by the site investigator and signed as 
required with written or electronic signature, as appropriate. Data entered into the study 
database will be collected directly from subjects during study visits or will be abstracted from 
subjects’ medical records. The subjects’ medical records must record their participation in the 
clinical trial and what medications (with doses and frequency) or other medical interventions or 
treatments were administered, as well as any AEs experienced during the trial. 
 
 
10.2 Data management 
Study data will be collected at the study site(s) and entered into the study database. Data entry 
is to be completed on an ongoing basis during the study. Clinical data will be entered into an 
electronic case report form. The data system includes password protection and internal quality 
checks to identify data that appear inconsistent, incomplete, or inaccurate. 

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APPENDIX A 
COVID-19 Convalescent Plasma Procurement SOP BMT 800 01 
• 
BMT 800 01, appendices a- k 
• 
BMT 800 01, referenced SOPs 

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APPENDIX B 
Recipient schedule of assessment 

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REFERENCES 
1. Mehta P, McAuley DF, Brown M, Sanches E, Tattersall RS, Manson JJ. COVID-19: Consider 
cytokine storm syndromes and immunosuppression. Lancet March 13, 2020. 
2. Casadevall A, and Scharff MD. "Serum Therapy" revisited: Animal models of infection and the 
development of passive antibody therapy. Antimicrob Agents Chemotherap. 1994;38(1695-702). 
3. Casadevall A, and Scharff MD. Return to the past: the case for antibody-based therapies in 
infectious diseases. Clin Infect Dis. 1995;21(150-61). 
4. Casadevall A, and Pirofski LA. Antibody-mediated regulation of cellular immunity and the 
inflammatory response. Trends Immunol. 2003;24(9):474-8. 
5. Casadevall A, Dadachova E, and Pirofski L. Passive antibody therapy for infectious diseases. 
Nature Microbiol Rev. 2004;2(695-703). 
6. Casadevall A, Pirofski, L. The Convalescent Sera Option for Containing COVID-19. Journal of 
Clinical Investigation. 2020; (1-4). 
7. Zhang JS, Chen JT, Liu YX, Zhang ZS, Gao H, Liu Y, Wang X, Ning Y, Liu YF, Gao Q, et al. A 
serological survey on neutralizing antibody titer of SARS convalescent sera. Journal of medical 
virology. 2005;77(2):147-50. 
8. Sahr F, Ansumana R, Massaquoi TA, Idriss BR, Sesay FR, Lamin JM, Baker S, Nicol S, Conton B, 
256 Johnson W, et al. Evaluation of convalescent whole blood for treating Ebola Virus Disease in 
257 Freetown, Sierra Leone. The Journal of infection. 2017;74(3):302-9. 
9. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, Chan P, Wong KC, Leung CB, and Cheng G. 
Use of convalescent plasma therapy in SARS patients in Hong Kong. European journal of clinical 
microbiology & infectious diseases: official publication of the European Society of Clinical 
Microbiology. 2005; 24(1):44-6.]. 
10. Yeh KM, Chiueh TS, Siu LK, Lin JC, Chan PK, Peng MY, Wan HL, Chen JH, Hu BS, Perng CL, et al. 
Experience of using convalescent plasma for severe acute respiratory syndrome among 
healthcare workers in a Taiwan hospital. The Journal of antimicrobial chemotherapy. 2005; 
56(5):919-22. 
11. Ko JH, Seok H, Cho SY, Ha YE, Baek JY, Kim SH, Kim YJ, Park JK, Chung CR, Kang ES, et al. 
Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus 
infection: a single centre experience. Antiviral therapy. 2018; 23(7):617-22. 
12. Arabi YM, Hajeer AH, Luke T, Raviprakash K, Balkhy H, Johani S, Al-Dawood A, Al-Qahtani S, Al- 
Omari A, Al-Hameed F, et al. Feasibility of Using Convalescent Plasma Immunotherapy for MERS- 
283 CoV Infection, Saudi Arabia. Emerging infectious diseases. 2016; 22(9):1554-61. 
13. Gunn BM, Yu WH, Karim MM, Brannan JM, Herbert AS, Wec AZ, Halfmann PJ, Fusco ML, 
Schendel SL, Gangavarapu K, et al. A Role for Fc Function in Therapeutic Monoclonal Antibody- 
Mediated Protection against Ebola Virus. Cell host & microbe. 2018; 24(2):221-33. e5. 
14. Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, Chen Y, Wu J, and Shi Z. Molecular 
mechanism for antibody-dependent enhancement of coronavirus entry. Journal of Virology. 
2020; 94(5) 
15. 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 

Confidential and Proprietary 
   Protocol v. 15-Dec-2020 
38 
 
systematic review and exploratory meta-analysis. The Journal of infectious diseases. 2015; 
211(1):80-90.) 
16. Crowe JE, Firestone C-Y, and Murphy BR. Passively acquired antibodies suppress humoral but 
not cell-mediated immunity in mice immunized with live attenuated respiratory syncytial virus 
vaccines. The Journal of Immunology. 2001; 167(7):3910-8.]. 
17. Tan, M and Xiong, X. "Continuous and group sequential conditional probability ratio tests for 
phase II clinical trials". Statistics in medicine 15, no.19 (15 Oct.1996): 2037- 
2051. doi:10.1002/(SICI)1097-0258(19961015)15:19. 
18. Tan, Ming T. and Xiong, Xiaoping. "A flexible multi-stage design for phase II oncology 
trials". Pharmaceutical statistics 10, no.4 (Jul.2011): 369-373. doi:10.1002/pst.478. 
19. Yeh KM, Chiueh TS, Siu LK, Lin JC, Chan PK, Peng MY, Wan HL, Chen JH, Hu BS, Perng CL, et al. 
Experience of using convalescent plasma for severe acute respiratory syndrome among 
healthcare workers in a Taiwan hospital. The Journal of antimicrobial chemotherapy. 2005; 
56(5):919-22. 
20. Chenguang Shen, PhD1; Zhaoqin Wang, PhD1; Fang Zhao, PhD1; et al. Treatment of 5 Critically Ill 
Patients With COVID-19 With Convalescent Plasma. JAMA. Published online March 27, 2020. 
doi:10.1001/jama.2020.4783.