Convalescent Plasma in the Treatment of COVID 19
Phase: PHASE2
Conditions: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), COVID, Coronavirus
Sponsor: Trinity Health Of New England

 
 
 
 
Convalescent plasma in the Treatment of COVID 19 
Principal Investigator:  Latha Dulipsingh, MD 
NCT04343261 
 
 
PROTOCOL 
Version 4 
4/23/2020 

IRB Revision: July 2017
Version 4 4/23/2020
                   Convalescent plasma in the treatment of COVID 19
   Latha Dulipsingh, Kendra Williams, Rebecca Crowell, Syed Hussain and Danyal Ibrahim
Principal Investigator (PI): Latha Dulipsingh, MD
Collaboraborators:
NEW YORK BLOOD CENTER
Christopher Hiller, MD
BOSTON HEART DIAGNOSTICS
Ernst Schaefer, MD
Margaret Differderfer, PhD
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Table of Contents:
Study Schema
1.0
Background
2.0
Rationale and Specific Aims
3.0
Inclusion/Exclusion Criteria
4.0
Enrollment/Randomization
5.0
Study Procedures
6.0
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others
7.0
Statistical Considerations
8.0
Privacy/Confidentiality Issues
9.0
Follow-up and Record Retention
10.0    References
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1.0
Background
The epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-
19 originated in Wuhan, China in Dec 2019 and has rapidly spread worldwide.  On March 
11th 2020, WHO declared this a pandemic, and as of March 30th, 737,929 people in 177 
countries have been affected with a total of 34,800 deaths.  As of March 30th 2020, the 
United States has reported 143,055 positive cases and 2513 deaths. 
 
At Trinity Health of New England we have 234 patients who are positive for COVID-19 
with 56 patients who are hospitalized and in critical condition.  Currently there are no 
approved treatment options for COVID-19 and there are trials underway for antiviral 
medications such as Remdesivir.  
In 2014, the use of convalescent plasma collected from patients who had recovered 
from Ebola virus disease was recommended by WHO as an empirical treatment during 
outbreaks.  The use of convalescent plasma for the treatment viral infections such as 
SARS, H5N1 avian influenza and H1N1 influenza have suggested that transfusion of 
convalescent plasma was effective. Shen C et al published a case series of 5 critically ill 
patients with COVID-19 and Acute Respiratory Distress Syndrome (ARDS) who were 
treated with convalescent plasma containing neutralizing antibody and detected an 
improvement in the patients’ clinical status.  Research has shown that IgM and IgG 
antiviral antibodies can be detected in the serum samples of infected patients. After 
infection with COVID-19, the virus antigen stimulates the immune system to produce 
antibodies that can be detected in the blood.  Among these antibodies, IgM antibodies 
appears early and are mostly positive after 3-5 days of onset.  IgM titers then decrease 
while the IgG antibody potency starts to rise rapidly. During the recovery phase, the 
titer of the IgG antibody may increase four times or more compared to the acute phase.
The purpose of this prospective interventional study is to gain clinical experience using 
convalescent plasma transfusion administered to critically ill patients with COVID-19.
2.0
Rationale and Specific Aims
 
To study the efficacy of plasma from patients recovered from COVID-19 infection 
with a high neutralizing antibody titer (NAT) as treatment for individuals who are 
critically ill with COVID-19.

Determine if the antibodies from convalescent plasma will suppress virus load in 
critically ill patients with COVID-19.
Primary Outcomes:

Mortality within 28 days

Viral load on days 0, 3, 5 and 7
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
Serum antibody titers on days 0, 3, 5 and 7
Secondary Outcomes:

Changes of body temperature

Days on Ventilator post transfusion

Length of stay

PAO2/FIO2
Safety end-points include but not limited to 

Transfusion related acute lung injury

Transfusion associated circulatory overload

Allergic/anaphylactic reactions 
Other less common risks include: 

Transmission of infections

Febrile non-hemolytic transfusion reactions

RBC allo-immunization

Hemolytic transfusion reactions.
3.0
Inclusion/Exclusion Criteria
INCLUSION CRITERIA FOR OBTAINING CONVALESCENT PLASMA

Male donors

Female donors negative for HLA antibodies

Age > 18 yrs and < 90 yrs

Prior diagnosis of COVID-19 documented by a confirmed laboratory test within 
the last 45 days.  

Currently negative for COVID-19 by test

Complete resolution of symptoms at least 14 days prior to donation

Defined SARS-CoV-2 neutralizing antibody titers (optimally greater than 1:40)

Defined SARS –CoV IgG antibody titer > 1: 320
 
EXCLUSION CRITERIA FOR OBTAINING CONVALESCENT PLASMA

No gender exclusion

Age < 18 yrs and > 90 yrs

No positive diagnosis of COVID-19 within the last 45 days. Symptomatic with 
COVID-19

H/o HIV

H/o Hepatitis B or C
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
Temp > 99.5

Pregnancy or  6 weeks post-partum

Female Hb/HCT: < 12.5 gm/dL /38%

Male Hb/HCT: < 13 gm/dL /39%

H/o prior blood donation within the last 6 months

Weight < 50 Kg
INCLUSION CRITERIA FOR RECEIVING CONVALESCENT PLASMA

All genders

Age > 18 yrs and < 90 yrs

Must have laboratory confirmed COVID-19

Must provide informed consent

Must have severe or immediately life-threatening COVID-19,
 Severe disease is defined as:

dyspnea,

respiratory frequency ≥ 30/min,

blood oxygen saturation ≤ 93%,

partial pressure of arterial oxygen to fraction of inspired 
oxygen ratio < 300

lung infiltrates > 50% within 24 to 48 hours
             Life-threatening disease is defined as:

respiratory failure,

septic shock

multiple organ dysfunction or failure
EXCLUSION CRITERIA FOR RECEIVING CONVALESCENT PLASMA

No gender exclusion

Age < 18 yrs and > 90 yrs

COVID-19 negative
4.0
Enrollment/Randomization
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We propose to conduct a prospective study on patients admitted with COVID-19 to 
Trinity Health Of New England Hospitals (Saint Francis Hospital and Medical Center, 
Mount Sinai Rehab Hospital, Saint Mary’s, Mercy Medical Center, Johnson Memorial.   
There will no randomization.  Subjects will be enrolled if the satisfy the inclusion and 
exclusion criteria 
5.0
Study Procedures
Obtaining convalescent plasma
COVID-19 convalescent plasma will only be collected from recovered individuals if they 
are eligible to donate blood.   Subjects are eligible to participate if they are over the age 
of 18 years and below the age of 90 years and were diagnosed with COVID-19 and 
confirmed by lab tests within the last 45 days.  Eligible subjects who meet inclusion 
criteria will be contacted by the Study Team by telephone.  See telephone script.  Once 
informed consent is obtained, subjects will be screened with a medical history screening 
and will be tested to make sure they are currently COVID-19 NEGATIVE.  This will be 
done with a nasal swab and in some subjects with both the nasal swab and salivary 
sample.  The salivary sample will be compared with results of the nasal swab in order to 
have it validated at Boston Heart Diagnostics.  They will then have have blood drawn to 
measure serum SARS-CoV-2 specific antibody titers,neutralizing antibody titers (when 
kit is available) and viral load.   Blood will be collected and stored  so we can measure 
SARS-CoV-2– specific antibody(IgM and IgG) binding titers and a neutralization titers.  
We will be patnering with Boston Heart Diagnostics for these tests.
We hope to screen and collect plasma from 300 subjects. 
The subject will then be sent to the New York Blood Center (NYBC)  where plasma is 
obtained according to  NYBC Standard Operating Procedures (SOP) for plasma collection 
by apheresis methods.  Plasma is frozen within 24 hours of collection per NYBC 
SOPs.  Plasma will be labeled:   Caution: New Drug--Limited by Federal (or United 
States) law to investigational use along with the IND number. It is then stored for up to 
one year, and thawed when needed. Plasma will be stored at Saint Francis Hospital local 
lab.  The subject’s plasma samples will be assigned an unique number and de-identified.  
Duty of Privacy and Confidentiality has been outlined in the Master Blood Services 
Agreement and the Affiliate Participation Agreement.
Risks to subjects may include side effects from intravenous needle insertion site. This 
includes skin irritation, pain, swelling, bleeding, bruising and infection.  Other symptoms 
include light-headedness, dizziness, nausea after drinking.
Treating patients with convalescent plasma
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Once we have availability of the convalescent plasma from the NYBC patients are 
eligible to participate if they are over the age of 18 years and below the age of 90 years 
and are critically ill with COVID-19, meet inclusion criteria and are not responding to 
supportive care.  We will study the use of  Convalescent Plasma on 45 eligible recipients.
Eligible subjects or legally authorized representative (LAR) will be asked for consent by 
the treating physician.  Once informed consent is obtained, subjects will have ABO blood 
types determined for compatibility with the convalescent plasma donor and will receive 
two consecutive convalescent plasma infusions of 200 -250 ml each.  Total transfusion 
time can last 2-4 hours.
Viral load after convalescent plasma treatment will be measured on day 0 prior to 
administering the convalescent plasma and then on days 3, 5, and 7.  In addition 
antibody titers will be measured on day 0 prior to administering the convalescent 
plasma and thereafter on days 3, 5 and 7.
Blood  will be sent off to Boston Heart Research labs for antibody titers using DIAZYME 
DZ-LITE SARS-CoV-2 IgM CLIA KIT.  They will also measure the viral load
Risks to subjects may include side effects from intravenous injection like skin irritation, 
pain, swelling, bleeding or bruising. Serious risks include: 

Transfusion related acute lung injury

Transfusion associated circulatory overload

Allergic/anaphylactic reactions 
Other less common risks include: 

Transmission of infections

Febrile non-hemolytic transfusion reactions

RBC allo-immunization

Hemolytic transfusion reactions.
6.0
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others

Using the Full unanticipated problem and Adverse event report all AE, 
unanticipated AE and SAE will be reported to the IRB  and the FDA. .  The PI and 
study team will follow regulatory requirements related to the reporting of 
unexpected serious adverse drug reactions to the regulatory authority and the IRB.   

In each  safety report, the study team will identify all IND safety reports 
previously submitted to FDA concerning a similar suspected adverse reaction, 
and will analyze the significance of the suspected adverse reaction in light of 
previous, similar reports or any other relevant information.

In the case of Unexpected fatal or life-threatening suspected adverse reaction the 
PI and study team will notify FDA of any unexpected fatal or life-threatening 
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suspected adverse reaction as soon as possible but in no case later than 5 
calendar days after the PI’s initial receipt of the information.
As defined in 21 CFR 312.32(a):
Adverse event - means any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction - An 
adverse event or suspected adverse reaction is considered "life-threatening" if, in 
the view of either the investigator or sponsor, its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
Serious adverse event or serious suspected adverse reaction - An adverse event or 
suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Suspected adverse reaction - means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of 
IND safety reporting, "reasonable possibility" means there is evidence to suggest a 
causal relationship between the drug and the adverse event. Suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
Unexpected adverse event or unexpected suspected adverse reaction - An adverse event or 
suspected adverse reaction is considered "unexpected" if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
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virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation.  
STUDY PERIOD FOR DONOR
Eligibility
Day
-14 to 0
Visit 1
Visit 2
Re-test  Visit
 (as needed) 
Informed Consent
X
Demographics 
and History
X
COVID-19 
Symptom screen
X
COVID-19 test for 
eligibility
X
X
Antibody titer
X
X
Viral load
x
X
Blood stored for 
future testing
X
Adverse Event 
Monitoring
X
X
NYBCvisit to 
donate plasma
X
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STUDY PERIOD FOR RECIPIENT
Eligibility
Day
-14 to 0
0
3
5
7
14
28
Informed 
Consent
X
Convalescent 
Plasma 
Infusion
X
Vital Signs
X
X
X
X
X
X
X
Physical 
Examination
X
X
X
X
X
X
Medications
X
X
X
X
X
X
X
Co-morbid 
illnesses
X
Adverse 
Event 
Monitoring
X
X
X
X
X
X
Laboratory Testing
CBC and 
CMP
X
X
X
X
X
X
COVID-19 
test
X
Viral Load
X
X
X
X
Antibody 
titers
X
X
X
X
Cytokine 
Panel
X
X
X
X
CxR*
X
EKG *
ECHO *

*Only if clinically indicated
7.0
Statistical Considerations
The analysis will focus on two primary comparison groups. Within the intervention 
group, viral load and antibody titers overall and at 0, 3, 5, and 7 will be compared by 
patient survival, patient demographics, and clinical profile. Viral load and antibody 
response at each time point will be graphed.  A secondary analysis will compare in-
patient mortality between the intervention group and a matched control group of 
COVID-19 inpatients cared for prior to the intervention. Descriptive statistics and 
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comparisons will include patient demographics, comorbidities, medications, laboratory 
values, APACHE score, and other clinical variables. Variables pertaining to hospital stay 
will include admission dates, date of onset of COVID-19 symptoms, length of stay and 
days in the ICU.  Continuous variables will be compared using the Wilcoxon rank-sum 
test or t-test; categorical variables will be compared using χ² tests or Fisher’s exact test. 
Outcomes will be considered statistically significant at a p-value < 0.05. 
8.0
Privacy/Confidentiality Issues
Discuss the methods for ensuring participant privacy, and the methods for protecting All 
data collected will be stored in the hard drive of a password-protected and encrypted 
computer at Saint Francis Hospital and Medical Center.  The subjects’ research folder 
and medical records for both the donor and the recipient of the plasma will be kept in a 
locked file cabinet in the co-investigators’ office at the Research Department at Saint 
Francis Hospital and Medical Center and will only be accessible by study staff.  The study 
database will contain only de- identified data points.  A study identifier, linked to the 
database through a key code, will be kept separate from the data set, stored in a 
password protected and encrypted database accessible only to the Primary 
Investigator.  The study identifier will be used only to verify and confirm the accuracy of 
the data collected from the medical record. This study identifier will be kept separate 
and hidden from the database, and also maintained on a password protected and 
encrypted database in files accessible only to the Primary Investigator.
9.0
Follow-up and Record Retention
All records will be maintained for 3 years after study completion.
10.0     References
1. Huang C, Wang Y, Li X, et al.  Clinical features of   Wuhan, China.Lancet.2020;395 
(10223):497-506. 
2. WHO. Novel coronavirus (COVID-19) situation. 
UpdatedMarch24,2020.https://experience. arcgis.com/experience/ 
685d0ace521648f8a5beeeee1b9125cd
3. Chen L, Xiong J, Bao L, Shi Y.  Convalescent plasma as a potential therapy for COVID-
19.Lancet InfectDis.2020;S 1473-3099(20)30141-9. 
4. Shen C; Wang Z, Zhao F, et al.  Treatment of 5 Critically Ill Patients With COVID-19 
With Convalescent Plasma; JAMA Published online on March 27th 2020
5. Kraft CS, Hewlett AL, Koepsell S, et al; Nebraska Biocontainment Unit and the Emory 
Serious Communicable Diseases Unit. The use of TKM-
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100802andconvalescentplasmain2 patients with Ebola virus disease in the United 
States.ClinInfectDis.2015;61(4):496-502. 
6. vanGriensven J, Edwards T, deLamballerie X, et al; Ebola-Tx Consortium.  Evaluation of 
convalescent plasma for Ebola virus disease in Guinea.  NEnglJMed.2016;374(1):33-42. 
7. Florescu DF, Kalil AC, Hewlett AL, et al.   Administration of brincidofovir and 
convalescent plasma in a patient with Ebola virus disease.  Clin InfectDis.2015;61(6):969-
973. 
8. Zhou B, Guan Y.  Treatment with convalescent plasma for influenza A  (H5N1) 
infection.  NEnglJMed. 2007;357(14):1450-1451. 
9. HungI F, To KK, Lee CK, et al.  Convalescent plasma treatment reduced mortality in 
patients with severe pandemic influenza A (H1N1)2009 virus infection.  
ClinInfectDis.2011;52(4):447-456. 
10. Burnouf T, Radosevich M.  Treatment of severe acute respiratory syndrome with 
convalescent plasma.  HongKongMedJ.2003;9(4):309. 
11. Cheng Y, Wong R, Soo YO, et al.  Use of convalescent plasma therapy in SARS 
patients in Hong Kong.  2005;24 (1):44-46. 
12. https://www.redcrossblood.org/donate-blood/dlp/plasma-donations-from-
recovered-covid-19-patients.html
13. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-
device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-
emergency-inds .
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