Convalescent Plasma in the Early Treatment of High-Risk Patients With SARS-CoV-2 (COVID-19) Infection
Phase: PHASE2
Conditions: Covid19
Sponsor: Joseph M. Flynn, D.O., MPH

 
 
1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol 
 
NCT04513158 
 
Amendment 1.0, Version 31 AUG 2020 
 
 
 

Norton Healthcare 
IND # 23679 Convalescent Plasma in the Early Treatment of High Risk Patients with 
SARS-CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
 
2
Convalescent Plasma in the Early Treatment of High-Risk Patients with SARS-CoV-2 
(COVID-19) Infection 
 
PROTOCOL Amendment 1.0 (Version 31 AUG 2020) 
 
 
  
 
Protocol Number 
 
 
20-N0124 
 
IND Number 
 
 
23679 
 
Principal Investigator: 
 
 
Joseph M. Flynn, D.O., MPH 
 
 
 
Norton Healthcare 
 
 
 
3000 Olympia Park 
 
 
 
Louisville, KY 40241 
 
 
 
Cell: 614-204-2696 
 
 
 
Joseph.flynn@nortonhealthcare.org 
 
Norton Co-Investigators: 
 
 
Don Stevens, MD 
 
 
 
Paul Schulz, MD 
 
 
 
Joseph Maly, MD 
 
 
 
Khuda Dad Khan, MD 
 
Nurse Coordinator  
 
Marti Gardner, MSN, APRN, CCRC 
 
 
Therapy: 
 
COVID-19 Convalescent Plasma Infusion   
 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
3
SCHEMA 
Treatment Plan 
High Risk Patient Selection 
Must have the Following 
 
 Diagnosis of SARS-CoV-2 infection 
via RT-PCR or FDA approved 
testing. 
 
Patients must also have the 
following indications for 
enrollment:  
 
D-Dimer >  500  ng/ml FEU OR 
 
IL-6>  5  pg/mL  
 
With any of the following 
 
Lymphocytes < 0.8 103/ul  
OR 
 
LDH > 700  U/L  
 
OR 
 
CK > 170 U/L   
 
 OR 
 
CRP > 1.0 mg/dl  
 
OR 
 
Ferritin > 1000 ng/ml 
 
AND one of the following: 
Age over 60 years 
Underlying Active Malignancy 
Cardiovascular Disease 
Active Tobacco Use 
History of Pulmonary Volume 
Reduction Surgery 
Hypertension 
 
1 unit (Approximately 200 mL) of Convalescent 
Plasma over 60 minutes  
 
 
 
 
 
 
 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
4
Table of Contents 
Contents 
1.0 
OBJECTIVES ................................................................................................ 5 
2.0 
BACKGROUND AND RATIONALE ......................................................... 5 
3.0  
RATIONALE FOR STUDY SCHEDULE .................................................. 8 
4.0  
PATIENT SELECTION ............................................................................... 8 
5.0 
DONOR INFORMATION ......................................................................... 10 
7.0 
PROCEDURES FOR PATIENT ENTRY ON STUDY .......................... 11 
8.0 
DOSE MODIFICATION FOR OBESE PATIENTS ............................... 13 
9.0 
CRITERIA FOR RESPONSE ASSESSMENT ........................................ 13 
10.0  MONITORING OF PATIENTS ................................................................ 13 
11.0  STATISTICAL CONSIDERATIONS ....................................................... 14 
12.0  DATA REPORTING / REGULATORY REQUIREMENTS ................. 15 
13.0  ADVERSE EVENTS AND REPORTING REQUIREMENTS .............. 15 
14.0   REFERENCES ............................................................................................ 18 
15.0  TABLE 1: DEFINING CHARACTERISTICS OF SEVERE COVID-19 
DISEASE ................................................................................................................ 21 
16.0   APPENDICES .............................................................................................. 21 
 
 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
5
1.0 
OBJECTIVES 
 
1.1 
Primary Objectives:  
 
To determine the therapeutic efficacy (response rate) of convalescent plasma infusion in 
patients at high risk for mortality when infected by SARS-CoV-2 (COVID-19). The primary 
endpoint will be determined as prevention of progression to severe or life threatening COVID-
19 during the current hospitalization. The primary endpoint will be assessed at discharge and 
by evaluating if the patient experienced the following data elements:  respiratory rate >30/min, 
Blood oxygen saturation <93%, partial pressure of arterial oxygen to fraction of inspired 
oxygen ration <300, or received a medical diagnosis of respiratory failure, septic shock or 
multiple organ dysfunction/failure.  This will be captured from the daily physical exam/clinical 
assessment done as part of routine care. See table 1. 
 
1.2  
Secondary Objectives  
 
1.2.1 To determine the immunologic effects of convalescent plasma infusion as measured by 
serial SARS-CoV-2 Ag levels through RT-PCR. This will be measured by CoV PCR 
collected at enrollment, day 7 and discharge. 
 
1.2.2 To measure normalization of laboratory parameters for risk as referenced in Appendix 
2. Lab values outlined in appendix 2 will be documented every 3 days while the patient 
is hospitalized and we will evaluate labs from the time of convalescent plasma infusion 
to the time that lab value returns to within the institution’s normal range. 
2.0 
BACKGROUND AND RATIONALE 
 
The morbidity and mortality of the SARS-CoV-2 (COVID-19) pandemic has been well established.  
Approaches to COVID-19 has focused on preventing mass spread and treating those with critical 
disease, while providing supportive care to mild, moderate or severe disease.  The FDA has provided 
guidelines for the treatment of patients with convalescent plasma and this has been restricted to patients 
with severe or critical disease.  As our understanding of the epidemiology of this syndrome continues to 
expand, it has become clearer that given the extremely poor outcome for those requiring mechanical 
ventilation and those within a few discreet categories, a therapeutic approach focused around prevention 
of the transition to critical status is a key to ameliorate the poor outcomes experienced to date. 
 
2.1  
SARS-CoV-2 Infection (COVID-19)   
 
The impact of the severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2) pandemic and more 
specifically the associated syndrome [COVID-19], has been rapid and extreme.  As of June 1, 2020 
estimates for worldwide spread suggests almost 6.3 million confirmed cases, 375,000 deaths and 1.8 
million confirmed cases in the United States (GISANDDATA.maps.arcgis.com).  Data continues to 
suggest that those at greatest risk for poor outcome include the elderly and those with comorbid 
illness((1)(2)(3)).  In fact, Zhou reports in a retrospective multivariate analysis the odds of dying in the 
hospital related to COVID-19 was highest with increased age, Sequential Organ Failure Assessment 
(SOFA) score and concomitant markers of inflammation.(4)  A report of 72,314 patients in China reports 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
6
the case fatality rate (CFR) of those over 80 years of age is 14.8%, as compared to the overall CFR of 
2.3%.  (5) In fact, 61.5% of those with critical disease died. (6) 
 
There is an increasing understanding of the temporal seroconversion rate in patients infected by SARS-
CoV-2 virus.   Zhao and colleagues reported that among 173 patients tested median seroconversion time 
for IgM and IgG occurred on day 12 and day 14 respectively.(7) The relationship of this conversion 
timeline and the best timing of plasma procurement is still to be determined. Though this data allows 
that between day 14 and 21 seem optimal for plasma procurement, much of the timeliness is sure to be 
clarified in large multicenter trials.  
 
Most recently, the United States Food and Drug Administration has published guidelines on the 
emergent use of convalescent plasma in the treatment of the COVID-19 patient.(8)   It was made clear 
that patients with severe disease as measured by a laboratory confirmed COVID-19 infection, severe or 
immediately life threatening COVID-19 clinical presentation, with severe being consistent with 
presence of dyspnea, tachypnea (respiratory frequency >30/min), blood oxygen saturation < 93%, partial 
pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, and/or lung infiltrates > 50% 
within 24 to 48 hours may be eligible to receive convalescent plasma through an emergent IND protocol.  
In this definition, life threatening disease is defined as the presence of respiratory failure, septic shock 
or multiple organ dysfunction.(8) 
 
2.2  
Rationale for Convalescent Plasma Infusion in COVID-19 
 
Currently, there are no specific therapeutic agents for COVID-19 and the principal approach to the 
infected patient is supportive in nature.  Several therapies are under investigation including 
Hydroxychloroquine, Remdesivir and others, but the efficacy of these agents are not fully 
understood.(9–11)  Over the last several years, convalescent plasma has been utilized in the treatment 
of severe acute respiratory illness related to an array of viral infections, including corona viruses. 
(12)(13–17)  This “passive antibody” therapy incorporates the infusion of antibodies against specific 
antigen, in this case, the SARS-CoV-2 virus through the use of convalescent plasma.  To date, this is 
the only means to provide immediate immunity to infected individuals and differs from the impact of 
vaccination. (17)(18)  The use of convalescent plasma was first considered as possible treatment during 
outbreaks for SARS, Avian influenza and Ebola virus in the early part of this century.(13,19)  In a study 
of 80 patients with SARS, the use of convalescent plasma was associated with a higher rate of hospital 
discharge as compared with patients who did not receive convalescent plasma.(14)  Accordingly, these 
findings encouraged the theory that the use of convalescent plasma transfusion could be beneficial in 
patients infected with SARS-CoV-2.(20)   Recently, there has been preliminary data in the use of 
convalescent plasma in the treatment of 5 critically ill patients infected with SARS-CoV-2.(21)    Shen 
and colleagues report that all 5 patients were moribund and receiving mechanical ventilation.  Further, 
3 of the 5 patients were ultimately able to be discharged and 2 patients remained clinically stabilized.   
All patients had laboratory-confirmed covid-19 and displayed acute respiratory distress syndrome 
(ARDS and exhibited significant end organ dysfunction in the form of rapid clinical deterioration and 
the requirement for high levels of medical and ventilator support.(21)(22)  In the work by Shen, the ABO 
blood types of the patients were determined as is standard for compatibility of donor.  Each recipient 
received two consecutive transfusions of 200 to 250 mL of ABO-compatible convalescent plasma for a 
total of 400 mL.  This occurred on the same day it was obtained from the donor.  The Chinese team of 
Duan and colleagues have also published data on the use of convalescent plasma therapy in patients with 
COVID-19. (23)  (24)  They described the benefits in their study group of 10 patients where several 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
7
parameters such as c-reactive protein, lymphocyte count and viral load all showed improvement within 
seven days of infusion of plasma.  Importantly, they reported no severe adverse effects.  These results 
from 10 severely ill patients demonstrated that one dose of 200 mL convalescent plasma was very well 
tolerated and led to disappearance of clinical symptoms in 3 days and viremia in 7 days.  Further, the 
authors suggest that treatment earlier in the disease course seemed to result in improved responsiveness. 
 
Given this historical data of significant improvement in respiratory failure secondary to viral infection, 
coupled with the new case series of COVID-19 patients benefitting from convalescent plasma infusions 
the idea of utilization of this modality earlier in the clinical course is compelling and warrants further 
expansion of this safe and readily available therapy. 
 
2.3 
Patient Characteristics for High Risk of Mortality 
There are a number of reports of the constellation of clinical parameters that are associated with 
worse outcome when individuals are infected with SARS-CoV-2. (1)  As noted by Ruan and 
colleagues, age has a profound impact on risk of death (P<0.001) as does presence of comorbid illness 
(p=0.0069).(25)  This was confirmed by several authors.(26) (27)(1)(6) This is especially true of 
cardiovascular diseases which are associated with significantly increased risk of death when they are 
infected with SARS-CoV-2 (p < 0.001) and cancer which makes sense when one considers the 
underlying lymphopenic milieu seen in a number of hematological malignancies and their associated 
therapies.(2,28)(1)(29)  In the Washington experience, Comorbidities were identified in 18 cases with 
chronic kidney disease and congestive heart failure being the most common diseases suggesting a poor 
outcome.(30)   
Broadly, there are several markers of inflammation that portend to a worse prognosis as well.  These 
include presence of lymphopenia, cardiac troponin, C-reactive protein, Interleukin-6 (IL-6) and 
thrombocytopenia.(25)(4,26,31,32) Markers of inflammation tended to demonstrate significantly higher 
levels in those with severe disease or those who go on to severe disease than in those with mild disease.  
Gao etal reported several key findings.  C-reactive protein (CRP), D-Dimer, IL-6 were all significantly 
higher in the severe patient populations than in those with mild disease.  Specifically, they showed the 
level of CRP was significantly higher in the severe group than in the mild group, D-Dimer level was 
higher in the severe group versus the mild group and IL-6 tended to be elevated in the severe group.  In 
fact, testing the combination of IL-6 and D-Dimer added to the sensitivity and specificity for predicting 
severity of disease.  When combining IL-6 with D-Dimer by parallel testing, the sensitivity and 
specificity were 66.7% and 96.4%, respectively.  The specificity was reported at 96.4% when IL-6 and 
D-Dimer were combined by tandem testing. (33)  Others confirmed these findings, yet it is still unclear 
whether these solely represent the physiological response to disease or may serve as a target for 
treatment.(4) 
Much has been proposed in relation to outcomes of COVID-19 infections in patients with cancer.  There 
continues to be some conflicting results.  Liu and colleagues found no increased mortality in 78 patients 
studied with cancer and SARS-CoV-2 infections.(31)  Though in reporting on 1590 patients, Liang 
concludes that those with an underlying malignancy had a worse outcome.  In fact, patients who 
underwent chemotherapy or surgery in the month prior had a higher risk of clinically severe events than 
did those not receiving chemotherapy or surgery.(34)  A case fatality rate of 5.6% in patients with cancer 
was reported by Wu and colleagues.(1)  

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
8
A common feature of COVID-19 is the presence of absolute lymphopenia. (35)  This tends to 
predominate within the T cell subsets of both CD4 and CD8.  Often, one may find a corresponding 
increase in the B cell subpopulation.  Lymphopenia has been clearly shown to be associated with a worse 
outcome.(26)  In fact, CD4+T and CD8+T cells decreased in nearly all the patients studied and were 
especially low in severe cases (177.5 and 89.0 × 106/L) compared with moderate cases (381.5 and 254.0 
× 106/L).   Bhatraju etal described lymphopenia occurring in around 75% of patients on admission to 
the ICU in the Seattle experience, where median lymphocyte count was 720 per cubic millimeter.(10)  
Dr. Tan and colleagues conclude that “lymphopenia is an effective and reliable indicator of the severity 
and hospitalization in COVID-19 patients”.(36) They go on to provide several theories as to the origin 
of lymphopenia, including proinflammatory effect, direct impact on lymphatic organs and presence of 
ACE2, a target of SARS-CoV-2, on the lymphocytes. 
As noted, there are several studies that assign increased mortality related to COVID-19 amongst those 
who present with comorbid illnesses.  However, the most poignant data seems to suggest the presence 
of heart disease is particularly associated with poor outcome. (37)  One meta-analysis described patients 
with previous cardiovascular diseases were at greater risk of developing into advanced disease.(38)  
Personal history of hypertension in several studies seem particularly associated with worse 
outcomes.(4)(1)    SARS-CoV-2 is thought to directly impact cardiac tissue via attachment to ACE2 
receptors in the myocardium which results in cellular damage.  ACE2 presence in the lungs and 
myocardium likely results in those two organ systems being disproportionately impacted resulting in 
untoward results. (39)  Further, those with underlying cardiovascular disease have less reserve and this 
constellation results in SARS-CoV-2 infection with underlying cardiovascular disease at profound risk 
of mortality.   Recognizing this risk and establishing clinical approach to protect this particularly 
vulnerable group is prudent. 
It is quite interesting that patients who are active tobacco users tended to fare worse as well. (40)  
There are several theories but Emami suggests it is related to regulation of the ACE2 in patients who 
smoke tobacco compared to those who do not.    
 
COVID-19 has had a catastrophic impact on patients and society as a whole.  While herculean efforts 
have been undertaken to mitigate the spread of the infection, it seems that asymptomatic and mildly 
symptomatic patients have added to the impact globally.  It is clear that patients who present in a 
critical state do quite poorly and many or most will die.  The purpose of this study is to employ a safe 
therapeutic modality that can readily be accessed and use it earlier in the clinical course in high risk 
patients and those whose clinical picture portends to worse outcome.  If able to stop this progression to 
critical status, it will likely provide us with the best opportunity to truly impact the morbidity and 
mortality of COVID-19. 
3.0 RATIONALE FOR STUDY SCHEDULE  
 
Duan and colleagues have reported excellent outcomes with the use of 200 mL convalescent plasma in 
the treatment of COVID-19.(24)  This is administered as one unit of plasma (approximately 200 mL) 
over 30 to 60 minutes. 
 
4.0 PATIENT SELECTION 
 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
9
4.1  
Eligibility Criteria 
 
4.1.1 Diagnosis of SARS-CoV-2 infection via RT-PCR or FDA approved testing. 
 
4.1.2 Patients must also have the following indications for enrollment:  
i. 
D-Dimer >  500  ng/ml FEU OR 
ii. 
IL-6>  5  pg/mL 
 
With any of the following 
iii. 
Lymphocytes < 0.8 103/ul  
OR 
iv. 
LDH > 700  U/L  
 
OR 
v. 
CK > 170 U/L   
 
OR 
vi. 
CRP > 1.0 mg/dl  
 
OR 
vii. 
Ferritin > 1000 ng/ml 
 
AND one of the following: 
viii. 
Age over 60 years 
ix. 
Underlying Active Malignancy 
x. 
Cardiovascular Disease 
xi. 
Active Tobacco Use 
xii. 
History of Pulmonary Volume Reduction Surgery 
xiii. 
Hypertension 
 
4.1.3 Prior Treatment: Patients are still eligible for this trial if active antimicrobial agents are 
in use.  Patients are also eligible if they had been treated on COVID-19 clinical trial in 
the course of their disease. 
 
4.1.4 Age ≥ 18 years. 
 
4.1.5 The effects of allogeneic plasma infusion on the developing fetus is unknown.  For this 
reason women who are pregnant are not eligible to participate.  
 
4.1.6 Agrees to required laboratory data collected which will include the baseline organ 
function and regular ongoing assessments done as part of routine care.    
 
4.1.7 Ability to understand and the willingness to sign a written informed consent document 
or ability to have consent provided by Legally Authorized Representative. 
 
4.2 Exclusion Criteria: 
 
4.2.1  
Patients who do not meet above inclusion criteria are not eligible. 
4.2.2  
Patients may not be receiving any other investigational agents. 
4.2.3 
History of allergic reactions attributed to previous transfusion history. 
4.2.4 
Respiratory rate >30/min 
4.2.5 
Blood oxygen saturation <93% 
4.2.6 
Partial pressure of arterial oxygen to fraction of inspired oxygen ration <300 
4.2.7 
Diagnosis of respiratory failure, septic shock or multiple organ dysfunction/failure 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
10
 
4.3  
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
5.0 
DONOR INFORMATION 
 
5.1 
Eligible donors must have evidence of COVID-19 documented by  
 
5.1.1. A laboratory test either by diagnostic test at the time of illness OR a positive serological 
test for SARS-CoV-2 antibodies after recovery, if diagnostic testing was not performed at the 
time COVID-19 was suspected. AND 
 
5.1.2. Complete resolution of symptoms at least 14 days prior to donation. 
5.2 
Male donors, or female donors who have not been pregnant, or female donors who have been 
tested since their most recent pregnancy and results interpreted as negative for HLA 
antibodies.  
5.3  
Those who are identified as a potential donor will be referred to Kentucky Blood Center, a 
FDA registered (#1070402) and licensed blood establishment, and must adhere to standards as 
described for all potential donors per federal regulations. Convalescent plasma is collected, 
processed, and provided in accordance with Kentucky Blood Center SOP 11-02-005 
Convalescent Plasma (Appendix 1). 
5.4 
ABO compatible with the patient. 
 
5.5 
If SARS-CoV-2 neutralizing antibody titers are available: 
5.4.1 Neutralizing antibody titers of at least 1:160 is preferred. 
5.4.2 A titer of 1:80 may be considered acceptable if an alternative matched unit is not 
available. 
5.4.3 If a measurement of neutralizing antibody titers is not available, a retention sample from 
the convalescent plasma donation will be retained for determining antibody titers at a later date. 
 
6.0 
Treatment Plan 
6.1 
Convalescent Plasma Therapy  
6.1.1.  Convalescent Plasma Infusion Workflow 
 
 Eligibility criteria reviewed and patient is eligible. 
 Informed Consent from Patient or Legally Authorized Representative obtained 
 Patient Registered with Kentucky Blood Center per protocol. 
 Patient is Typed and Crossed per Institution protocols. 
 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
11
Convalescent plasma will be labeled as per FDA guidance for the use of convalescent plasma 
in the treatment of COVID-19 patients.  One unit (approximately 200mL) of convalescent 
plasma will be infused over 1 hour per standard institution protocols for the safe administration 
of blood products.  Acetaminophen and Diphenhydramine are allowed as premedications 
consistent with institution standard practices.  
 
Patients will be monitored in accordance with pre-established institutional guidelines. 
 
6.2 
Supportive Care for Clinical Deterioration While on This Study 
 
Due to the possibility of clinical worsening in the interim after infusion, full supportive 
measures should be undertaken.  This includes ventilator support, adequate volume expansion 
and pressure support.  Antimicrobials are allowed in accordance with institution standard 
procedures. 
 
6.3 
Other Supportive Care 
 Acetaminophen prior to plasma infusion is allowed. 
 Diphenhydramine prior to or after plasma infusion is allowed in accordance with 
institutional procedural standards.  
 Patients should receive full supportive care, including further transfusions of blood and 
blood products, antibiotics, antiemetics, etc., when appropriate.   
 
6.4 Duration of Therapy 
 
Patients should be considered enrolled in this clinical trial until discharge from the hospital or 
the following: 
 Unacceptable adverse event(s), 
 Patient decides to withdraw from the study, or 
 General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
6.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 6.4 apply.  The 
reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
6.6 
Correlative Studies 
 
6.6.1  Baseline and longitudinal laboratory assessment (Appendix 2). Appendix 2 contains data 
elements that will be collected at both baseline and every three days while the patient is 
hospitalized.  
7.0 
PROCEDURES FOR PATIENT ENTRY ON STUDY 
 
7.1 
Informed Consent 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
12
 
The patient or legal surrogate must be aware of the nature of his/her disease and willingly 
consent after being informed of the procedure to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, side effects, risks, and discomforts.  Human protection 
committee approval of this protocol and a consent form is required. 
 
Whenever possible, the clinician or other delegated staff will obtain informed consent in 
person. In the event PPE preservation is needed, we will use the process outlined below. 
 
Consent Process for Hospitalized COVID-19 Positive Patients in Isolation 
 
 
Once a potential subject is identified, the PI will speak with the treating clinician.  The 
clinician will tell the patient that they may be eligible for a trial and that someone from the 
research team would be calling them.  
 
Someone from the study team will speak with the patient to introduce the study and assess their 
initial interest (via phone call/facetime/zoom if the patient has access). 
 
If patient is interested in learning more about the study, the study team would email the consent 
form to the patients’ nurse to print out and take to the patient to read the next time she/he enters 
the room. 
 
Research staff (delegated to conduct consent) will have another discussion with the patient via 
phone (or facetime/zoom) to review the consent form, answer the patient’s questions and 
obtain verbal consent.   
 
If the patient has a phone with a camera in their hospital room, they can print their name, sign 
and date the subject lines of the consent document, take a picture of the signed page and email 
it to the research staff.   
 
If the patient does not have a phone camera in their room to take a picture of the signed consent 
document, a witness (unit nurse ideally) would need to be present in the room or on a three 
way phone call to attest that the consent was reviewed with the patient, the patient had an 
opportunity to ask questions and they agree to consent to participate in the study. 
 
Due to isolation precautions, the consent will remain with the patient and not be removed from 
the room.  Upon patient discharge the consent form will be destroyed. 
 
The witness will sign a copy that has not been taken in the room, take a picture or scan a copy 
of the signature page and send via email to the research staff. 
 
The independent witness will document in EPIC his/her participation in the consent process.  
 
The research team should document the consent process in EPIC, sign as the person obtaining 
consent and upload a copy of the signed consent under the media tab.    
 
The research team should document the entire consent discussion in EPIC including questions 
that the patient asked and how understanding was assessed.  
 
When the patient is discharged, the research staff can mail a partially signed ICF document to 
the home of the patient when they are discharged home.    
 
Consent process for hospitalized COVID-19 positive patients in isolation – When LAR is needed 
 
 If a patient is on the ventilator and unable to provide consent, the patients’ LAR can consent on 
their behalf following the LAR consenting process.   

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
13
 If the LAR is not able to meet with the research team for the consent discussion due to their 
own quarantine or visitors being prohibited.  The research team will have the option to email 
the consent to the LAR for their review.   
 The research team will review the document with the LAR over the phone, answer all 
questions and assess understanding prior to obtaining signature.   
 The LAR can sign and return the signed page by taking a photo or scanning and then emailing 
to the research team.  Due to isolation precautions, the consent will remain with the LAR and 
not be returned.  If, due to technology limitations, it is not possible for the LAR to receive the 
consent via email, print, sign electronically, or take an image of the consent form, the LAR 
may provide consent with a witness signing the consent. 
 The research team will then sign as the person conducting consent send a signed copy to the 
LAR.   
 The research staff will document the entire LAR consent process in EPIC  
 The site will request a waiver of authorization from the IRB until the patient is able to sign the 
consent and authorization for themselves. 
 
7.2 
Eligibility Checklist 
The Investigator and study personnel are required to complete the eligibility checklist and 
ensure that there is adequate source documentation regarding eligibility.  In the event that there 
is no written confirmation that a patient meets a criterion, the Investigator must document 
eligibility in patient’s chart.  
 
8.0 
DOSE MODIFICATION FOR OBESE PATIENTS 
 
There is standard dose of 1 unit (approximately 200 mL) convalescent plasma for all patients. 
9.0 
CRITERIA FOR RESPONSE ASSESSMENT 
 
All patients will be evaluated for response based on clinical outcomes and laboratory 
improvement.   
 
Clinical assessment is done daily. Laboratory evaluation is done every three days.  
10.0 MONITORING OF PATIENTS 
 
Baseline evaluations are to be conducted the day of planned plasma infusion.  At the discretion 
of the treating team, convalescent plasma may be held. 
 
The recipient will be monitored for transfusion reaction in accordance with Norton 
Healthcare’s policy which includes: 
 
 Take vital signs (temp, pulse, blood pressure) prior to, 15 minutes after initiating and at 
the completion of the transfusion. 
 RN, LPN, APRN, PA must remain with the patient unit the 15 min vital signs are 
performed and asses the patient periodically during the transfusion.  

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
14
 Follow Norton Healthcare policy for Transfusion Reaction Protocol.  Transfusion 
reactions will be reported per institutional policy.   
 
Physical examination/clinical assessment will be done each day while on study. 
 
Imaging will be completed at the discretion of the treatment team in response to clinical needs. 
 
Laboratory testing as listed in Appendix 1 should be repeated every three days as part of 
clinical care.  The frequency of overall testing should be at the discretion of the treating team. 
 
Physical examination and laboratory recording should continue until patient no longer actively 
followed per section 6.4 and 6.5. 
 
11.0 STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design / Endpoints  
 
This study uses a standard descriptive statistics for outcomes.   
 
To determine the therapeutic efficacy (response rate) of convalescent plasma infusion in 
patients at high risk for mortality when infected by SARS-CoV-2 (COVID-19). The primary 
endpoint will be determined as prevention of progression to severe or life threatening COVID-
19 during the current hospitalization. The primary endpoint will be assessed at discharge and 
by evaluating if the patient experienced the following data elements:  respiratory rate >30/min, 
Blood oxygen saturation <93%, partial pressure of arterial oxygen to fraction of inspired 
oxygen ration <300, or received a medical diagnosis of respiratory failure, septic shock or 
multiple organ dysfunction/failure.  This will be captured from the daily physical exam/clinical 
assessment done as part of routine care. See table 1. 
 
The secondary objectives are to: 
 
 Determine the immunologic effects of convalescent plasma infusion as measured by 
serial SARS-CoV-2 Ag levels through RT-PCR. This will be measured by CoV PCR 
collected at enrollment, day 7 and discharge. 
 To measure normalization of laboratory parameters for risk as referenced in Appendix 
2. Lab values outlined in appendix 2 will be documented every 3 days while the patient 
is hospitalized and we will evaluate labs from the time of convalescent plasma infusion 
to the time that lab value returns to within the institution’s normal range. 
 
11.2 
Sample Size and Accrual Rate  
 
The maximum projected accrual is 100 patients.  Patients who succumb to COVID-19 or 
associated comorbid illness will be clearly identified.  Patients who die as a result of the 
convalescent plasma infusion, though likely rare, will result in mandatory study suspension 
until review undertaken. 
 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
15
Summary statistics will be calculated: mean and standard deviation for continuous variables; 
frequency for categorical variables. No inferential statistical tests of hypotheses are planned.  
For exploratory purposes, standard statistical method will be used. For repeated measures over 
time, individual as well as group profile plots will be generated to visualize the data.  
12.0 DATA REPORTING / REGULATORY REQUIREMENTS 
 
All IRB and FDA reporting requirements will be followed per applicable FDA regulations. 
 
Adverse events will be reported by the treating physician or other research team members to 
the principal investigator. The sponsor/principal investigator is responsible for filing reports to 
the FDA and IRB as required. 
 
All adverse events will be reviewed by the medical monitor at Norton Healthcare.  
 
This study will be registered on clinicaltrials.gov. 
 
Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor 
investigator as described in the protocol and ordinarily would not be reported under paragraph 
21 CFR 312.32(c).  
 
13.0 ADVERSE EVENTS AND REPORTING REQUIREMENTS 
 
Serious Adverse Events and Transfusion Reactions will be collected from the time of informed 
consent until the subject is discharged or dies.  
 
The following information about the event will be documented: event, start and resolution date 
(and time if known), treatments received, and outcome.  
 
The event will be reviewed by the Sponsor/Principal Investigator to determine severity and 
causality to the convalescent plasma infusion.  
 
SAEs will be reported to the FDA and IRB as required. SAEs include those events that result 
in death, life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect, or other important medical 
event that may jeopardize the subject or may require intervention to prevent one of the 
outcomes included in this definition. 
 
ADVERSE EVENT DEFINITIONS 
 
The following definitions regarding adverse events, as defined by 21 CFR 312.32(a), will be 
used for this protocol. 
 
Adverse event - Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
16
 
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 - 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 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. 
 
Unexpected fatal or life-threatening suspected adverse reaction reports - The sponsor must 
also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon 
as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the 
information. 
 
REVIEW OF SAFETY INFORMATION 
 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
17
The sponsor investigator must promptly review all information relevant to the safety of the 
drug obtained or otherwise received by the sponsor investigator from foreign or domestic 
sources, including information derived from any clinical or epidemiological investigations, 
animal or in vitro studies, reports in the scientific literature, and unpublished scientific papers, 
as well as reports from foreign regulatory authorities and reports of foreign commercial 
marketing experience for drugs that are not marketed in the United States. 
 
IND SAFETY REPORTS 
 
The sponsor investigator must notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor investigator is providing drug under in an IND safety report 
of potential serious risks, from clinical trials or any other source, as soon as possible, but in no 
case later than 15 calendar days after the sponsor investigator determines that the information 
qualifies for reporting under paragraph 21 CFR 312.32 (c)(1)(i), (c)(1)(ii), (c)(1)(iii), or 
(c)(1)(iv) of this section. In each IND safety report, the sponsor investigator must identify all 
IND safety reports previously submitted to FDA concerning a similar suspected adverse 
reaction, and must analyze the significance of the suspected adverse reaction in light of 
previous, similar reports or any other relevant information.  
 
REPORTING REQUIREMENTS 
 
Serious and unexpected suspected adverse reaction - The sponsor investigator must report 
any suspected adverse reaction that is both serious and unexpected. The sponsor investigator 
must report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, such as: 
 
 A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome);  
 
 One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture); 
 
 An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the drug treatment group than in a 
concurrent or historical control group. 
 
If a serious and unexpected adverse event occurs for which there is evidence suggesting a 
causal relationship between the drug and the event (e.g., death from anaphylaxis), the event 
must be reported under 312.32(c)(1)(i) as a serious and unexpected suspected adverse reaction 
even if it is a component of the study endpoint (e.g., all-cause mortality). 
 
Findings from other studies - The sponsor investigator must report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical studies (other than those 
reported under paragraph 21 CFR 312.32(c)(1)(i) of this section), whether or not conducted 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
18
under an IND, and whether or not conducted by the sponsor investigator, that suggest a 
significant risk in humans exposed to the drug. Ordinarily, such a finding would result in a 
safety-related change in the protocol, informed consent, investigator brochure (excluding 
routine updates of these documents), or other aspects of the overall conduct of the clinical 
investigation. 
 
Findings from animal or in vitro testing - The sponsor investigator must report any findings 
from animal or in vitro testing, whether or not conducted by the sponsor investigator, that 
suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, 
teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected 
human exposure. Ordinarily, any such findings would result in a safety-related change in the 
protocol, informed consent, investigator brochure (excluding routine updates of these 
documents), or other aspects of the overall conduct of the clinical investigation. 
 
Increased rate of occurrence of serious suspected adverse reactions - The sponsor 
investigator must report any clinically important increase in the rate of a serious suspected 
adverse reaction over that listed in the protocol or investigator brochure. 
 
Submission of IND safety reports - The sponsor investigator must submit each IND safety 
report in a narrative format or on FDA Form 3500A or in an electronic format that FDA can 
process, review, and archive. Reports of overall findings or pooled analyses from published and 
unpublished in vitro, animal, epidemiological, or clinical studies must be submitted in a 
narrative format. Each notification to FDA must bear prominent identification of its contents, 
i.e., "IND Safety Report," and must be transmitted to the review division in the Center for Drug 
Evaluation and Research or in the Center for Biologics Evaluation and Research that has 
responsibility for review of the IND. Upon request from FDA, the sponsor investigator must 
submit to FDA any additional data or information that the agency deems necessary, as soon as 
possible, but in no case later than 15 calendar days after receiving the request. 
 
FOLLOW-UP 
 
 The sponsor investigator must promptly investigate all safety information it receives. 
 Relevant follow up information to an IND safety report must be submitted as soon as 
the information is available and must be identified as such, i.e., "Followup IND Safety 
Report." 
 If the results of a sponsor investigator’s investigation show that an adverse event not 
initially determined to be reportable under paragraph (c) of this section is so reportable, 
the sponsor investigator must report such suspected adverse reaction in an IND safety 
report as soon as possible, but in no case later than 15 calendar days after the 
determination is made. 
14.0  REFERENCES 
 
1.  
Wu Z, McGoogan JM. Characteristics of and Important Lessons from the Coronavirus Disease 
2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese 
Center for Disease Control and Prevention. JAMA - J Am Med Assoc. 2020;2019:4–7.  
2.  
Bonow RO, Fonarow GC, O’Gara PT, Yancy CW. Association of Coronavirus Disease 2019 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
19
(COVID-19) with Myocardial Injury and Mortality. JAMA Cardiol. 2020;Mar 27.  
3.  
Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-
Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: 
A systematic review and meta-analysis. Travel Medicine and Infectious Disease. Elsevier USA; 
2020.  
4.  
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of 
adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;  
5.  
Team TNCPERE. The Epidemiological Characteristics of an Outbreak of 2019 Novel 
Coronavirus Disease (COVID-19) - China, 2020. CCDC. 2020;2(8):113–22.  
6.  
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill 
patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 
observational study. Lancet Respir Med. 2020;2600(20):1–7.  
7.  
Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, et al. Antibody Responses to SARS-CoV-2 in 
Patients of Novel Coronavirus Disease 2019. SSRN Electron J. 2020;1–22.  
8.  
FDA website https://fda.gov.  
9.  
Jean S, Lee P, Hsueh P. Treatment options for COVID-19 : the reality and challenges. J 
Microbiol Immunol Infect [Internet]. 2020; Available from: 
https://doi.org/10.1016/j.jmii.2020.03.034 
10.  
Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Jerome KR, Nalla AK, et al. Covid-19 in 
Critically Ill Patients in the Seattle Region - Case Series. N Engl J Med [Internet]. 2020;1–11. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/32227758 
11.  
Baron SA, Devaux C, Colson P, Raoult D, Rolain J-M. Teicoplanin: an alternative drug for the 
treatment of COVID-19? Int J Antimicrob Agents [Internet]. 2020;2(xxxx):105944. Available 
from: https://doi.org/10.1016/j.ijantimicag.2020.105944 
12.  
Mair-jenkins J, Saavedra-campos M, Baillie JK, Cleary P, Khaw F, Lim WS. The Effectiveness 
of Convalescent Plasma and Hyperimmune Immunoglobulin for the Treatment of Severe Acute 
Respiratory Infections of Viral Etiology The Effectiveness of Convalescent Plasma and 
Hyperimmune Immunoglobulin for the Treatment of Severe Acute Re. 2020;  
13.  
Lim VW, Tudor Car L, Leo YS, Chen MIC, Young B. Passive immune therapy and other 
immunomodulatory agents for the treatment of severe influenza: Systematic review and meta-
analysis. Influenza Other Respi Viruses. 2020;14(2):226–36.  
14.  
Cheng Y, Wong R, Soo YOY, Wong WS, Lee CK, Ng MHL, et al. Use of convalescent plasma 
therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44–6.  
15.  
Van Griensven J, Edwards T, De Lamballerie X, Semple MG, Gallian P, Baize S, et al. 
Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med. 
2016;374(1):33–42.  
16.  
Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG, Al-Omari A, et al. Feasibility, 
safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle 
East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015;4(1):1–8.  
17.  
Zhou G, Zhao Q. Perspectives on therapeutic neutralizing antibodies against the Novel 
Coronavirus SARS-CoV-2. Int J Biol Sci. 2020;16(10):1718–23.  
18.  
Cassadevall A E. The Convalescent Sera Option for Containing COVID-19. J Clin Invest. 
2020;130(4):1545–8.  
19.  
Hung IFN, To KKW, Lee CK, Lee KL, Chan K, Yan WW, et al. Convalescent plasma 
treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus 
infection. Clin Infect Dis. 2011;52(4):447–56.  
20.  
Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. The 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
20
Lancet Infectious Diseases. 2020.  
21.  
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients with 
COVID-19 with Convalescent Plasma. JAMA - J Am Med Assoc. 2020;(29):1–8.  
22.  
Robeck J. Convalescent Plasma to Treat COVID-19. JAMA - J Am Med Assoc. 2020;Mar 
27(Published online).  
23.  
Duan K. The Feasibility of Convalescent Plasma Therapy in Severe COVID-19 Patients: A 
Pilot Study. MedRxiv2. 2020;https://do.  
24.  
Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy 
in severe COVID-19 patients. 2020;1–7.  
25.  
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID ‑ 19 
based on an analysis of data of 150 patients from Wuhan , China. Intensive Care Med [Internet]. 
2020; Available from: https://doi.org/10.1007/s00134-020-05991-x 
26.  
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunologic features in 
severe and moderate Coronavirus Disease 2019. J Clin Invest. 2020;0–30.  
27.  
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized 
Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA - J Am 
Med Assoc. 2020 Mar 17;323(11):1061–9.  
28.  
Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of Cardiac Injury With 
Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. 2020;1–8.  
29.  
Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on the 
Cardiovascular System: A Review. JAMA Cardiol. 2020;10:1–10.  
30.  
Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, et al. Characteristics and 
Outcomes of 21 Critically Ill Patients with COVID-19 in Washington State. JAMA - Journal of 
the American Medical Association. American Medical Association; 2020.  
31.  
Liu W, Tao Z-W, Lei W, Ming-Li Y, Kui L, Ling Z, et al. Analysis of factors associated with 
disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chin Med J 
(Engl). 2020;0:1.  
32.  
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 
2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.  
33.  
Gao Y, Li T, Han M, Li X, Wu D, Xu Y, et al. Diagnostic Utility of Clinical Laboratory Data 
Determinations for Patients with the Severe COVID‐19. J Med Virol. 2020;  
34.  
Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 
infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3):335–7.  
35.  
Chan JWM, Ng CK, Chan YH, Mok TYW, Lee S, Chu SYY, et al. Short term outcome and risk 
factors for adverse clinical outcomes in adults with severe acute respiratory syndrome (SARS). 
Thorax. 2003;58(8):686–9.  
36.  
Tan L, Wang Q, Zhang D, Ding J, Huang Q, Tang Y-Q, et al. Lymphopenia predicts disease 
severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 
2020;5(1):16–8.  
37.  
Zhang J jin, Dong X, Cao Y yuan, Yuan Y dong, Yang Y bin, Yan Y qin, et al. Clinical 
characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy Eur J 
Allergy Clin Immunol. 2020;  
38.  
Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, et al. Prevalence and impact of cardiovascular 
metabolic diseases on COVID-19 in China. Clinical Research in Cardiology. 2020.  
39.  
Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev 
Cardiol [Internet]. 2020; Available from: http://dx.doi.org/10.1038/s41569-020-0360-5 
40.  
Emami A, Javanmardi F, Pirbonyeh N, Akbari A. Prevalence of Underlying Diseases in 

Norton Healthcare 
Convalescent Plasma in the Early Treatment of High Risk Patients with SARS-
CoV-2 (COVID-19) Infection Protocol (Amendment 1.0 Version 31 AUG 2020) 
 
 
 
21
Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis. Arch Acad 
Emerg Med [Internet]. 2020;8(1):e35. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/32232218 
 
15.0 TABLE 1: DEFINING CHARACTERISTICS OF SEVERE COVID-19 DISEASE 
 
Respiratory Frequency >30/min 
 
Blood Oxygen Saturation < 93% 
 
Partial Pressure of Arterial Oxygen to Fraction of Inspired Oxygen Ratio <300 
 
Respiratory Failure 
 
Septic Shock 
 
Multiple Organ  Dysfunction /Failure 
 
16.0  APPENDICES 
 
15.1 
Kentucky Blood Center SOP 11-02-005 Convalescent Plasma 
15.2 
RedCap Data Collection Form 

APPENDIX 1 
 
SOP 11-02-005 
CONVALESCENT PLASMA 
 
 
KENTUCKY BLOOD CENTER 
Lexington, Kentucky 
(859) 276-2534 
 
 
 
22
I. 
PURPOSE 
To provide directions for the handling of convalescent plasma.  
II. 
SPECIAL NOTES 
A. 
Convalescent Plasma (CP) is plasma from patients who have recovered from an 
infection and used as a therapy to treat those with the same infection. Although it may 
be promising, convalescent plasma has not been shown to be effective in every disease 
studied. 
B. 
COVID-19 Convalescent Plasma (CCP) is a treatment option for COVID-19 while 
additional treatment options are evolving. It is possible convalescent plasma may 
contain antibodies to SARS-CoV-2, the virus that causes COVID-19, and may be 
effective against the infection. 
C. 
During an infectious disease outbreak or pandemic, the FDA may allow collection and 
transfusion of convalescent plasma due to the public health emergency.  
1. 
The FDA through a single patient or traditional emergency Investigational New 
Drug Applications (eINDs) usually authorize this process. It is also possible for 
the FDA to utilize additional pathways, including the expanded access pathway 
(EAP) for the eIND, to allow increased participation by health care facilities. 
2. 
COVID-19 Convalescent Plasma (CCP) is used for patients with serious or 
immediately life-threatening COVID-19 infections. 
D. 
Hospitals should ensure the following prior to requesting convalescent plasma: 
1. 
Obtain approval for treating patients with convalescent plasma. This usually 
entails obtaining an emergency Investigational New Drug Application (eIND) 
completed by the treating licensed physician through the FDA prior to 
transfusion. The eIND does not need to be yet accepted but the hospital will be 
given an eIND reference number. 
2. 
Ensure the patient meets the requirements for transfusion with the convalescent 
plasma (and/or the eIND). At a minimum: 
a. 
Must have a laboratory confirmed positive test result (e.g. COVID-19) 
b. 
Must have severe or immediately life-threatening disease (or other 
criteria) as defined by the FDA. 
E. 
KBC is not required to verify that the receiving hospital has an IND. The receiving 
hospital is responsible for ensuring that approval for treating patients with Convalescent 
Plasma is obtained. 
F. 
Collection of CP does not require any approvals.  
1. 
Kentucky Blood Center may collect donors for storage of  COVID-19 
convalescent plasma. 
2. 
An IND is only required for transfusion of the component. 
III. 
MATERIALS REQUIRED - N/A 
IV. 
EQUIPMENT REQUIRED - N/A 
V. 
DOCUMENTS REQUIRED 
A. 
Attached in MasterControl - N/A 
B. 
Linked in MasterControl 
1. 
SOP 60-01-015 - Release of Untested Products 

APPENDIX 1 
 
SOP 11-02-005 
CONVALESCENT PLASMA 
 
 
KENTUCKY BLOOD CENTER 
Lexington, Kentucky 
(859) 276-2534 
 
 
 
23
2. 
SOP 62-10-001 - Receiving Unprocessed Units Collected by KBC 
3. 
SOP 62-10-005 - Preparation of Blood Components 
4. 
SOP 62-22-001 - Fresh Frozen Plasma Preparation 
5. 
SOP 70-21-031 - Emergency Release of Product - Hospital Services 
C. 
Other - N/A 
VI. 
PROCEDURE  
A. 
BLOOD COLLECTIONS 
1. 
Collection of the product must be coordinated with KBC’s Medical Director.  
2. 
Potential donors should be identified and screened. The following is required 
for the recovered potential donor: 
a. 
Documented positive laboratory test result (e.g. Positive COVID-19 test 
result). 
b. 
Resolution of symptoms for the required timeframe post-recovery.  
1) 
For COVID-19 the timeframe requirement for resolution of 
symptoms is 14 days post recovery in order to donate. 
c. 
Documented negative laboratory test result post-infection, if within 
required timeframe. 
1) 
For COVID-19 the requirement is a negative test result if less 
than 28 days post-recovery. If the timeframe is greater than 28 
days post-recovery then no test is required. 
d. 
Eligible to donate blood. Female donors should be negative for HLA 
antibodies or never pregnant. 
 
NOTE:    If the Medical Director approved the collection of plasma 
from   
 
 
     a female donor who has been pregnant but her HLA status has  
 
     not been determined, then initiate a KBC-025 and send with        
                 the test tube samples with the normal shipment.   
e. 
ABO compatible with the patient. 
f. 
Prior infectious disease testing is performed, if desired. 
g. 
Defined neutralizing antibody titers, if testing can be conducted (e.g. 
SARS-CoV-2 neutralizing antibody titers). This may be performed at a 
later date. 
3. 
Collection will be performed at one of KBC’s fixed collection sites by plasma 
pheresis (PA). 
NOTE:   
Most of the donors selected may not have donated blood before 
and most likely never have donated plasmapheresis.  Provide 
explanations as needed of the collection process.  Encourage the 
donor to drink offered fluids (after temperature has been taken) 
and snacks during the collection procedure.   
a. 
If during the screening process the donor reveals an unexpected answer 
that would disqualify them, contact the KBC Medical Director (not the 
on call physician) before proceeding with the deferral.  

APPENDIX 1 
 
SOP 11-02-005 
CONVALESCENT PLASMA 
 
 
KENTUCKY BLOOD CENTER 
Lexington, Kentucky 
(859) 276-2534 
 
 
 
24
b. 
If the donor is deferred (or no product is collected), then notify the 
Covid-19 Plasma email group.    
4. 
The BC Manager or designee will ensure the configurations of the Trima 
(collections are performed off-line from Vista) are set as follows: 
NOTE:   
The Platelet/Plasma/RBC tubing set is capable of a jumbo 
plasma collection if the MultiPlasma tubing set is not available.  
Donors do receive saline as a replacement fluid if the 
MultiPlasma tubing set is used while the Platelet/Plasma/RBC 
tubing set does not provide an access to the use of saline as a 
replacement fluid.    
a. 
The 5 digit catalog number of the MultiPlasma tubing set, 80700 or 
82700 (as applicable) is entered in the Machine screen, as needed. 
b. 
The upper limit for As Much As Possible (AMAP) is set to 825 mL on 
the Plasma screen.  
c. 
To allow all qualified donors do the following: 
1) 
For Trima version 6, change the donors allowed on the Plasma 
screen from MALES to ALL.  
2) 
For Trima version 7, on the Procedure Priority screen add an 
AMAP procedure and change the donors allowed to ALL.  
 
d. 
See the steps to follow based on the tubing set used to collect the plasma 
product:  
 
 
1)    
If using the MultiPlasma tubing set, then collect the plasma 
product in two bags if the total volume is expected to be over 
600mL. 
 
 
2) 
If using the Platelet/Plasma/RBC tubing set then collect the 
plasma product in one bag.        
5. 
Apply the appropriate face label for the collection. For collection of COVID-19 
Convalescent Plasma see Appendix A for an example of the E9747 face label to 
be applied to the PA donation. 
6. 
Collect 4 red top and 3 purple top test tube samples.   
7. 
Blood Collections or designee will notify involved KBC departments when the 
donation has been completed.  Blood Collections will immediately send the 
product and collection test tubes to Components Laboratory for processing. 
8. 
Once CLAB has completed processing, notify QA via email to perform the 
donation review, if the product is to be emergency released for patient specific 
transfusion.  
B. 
TECHNICAL SERVICES: COMPONENTS LABORATORY (CLAB) [PART I] 
1. 
Receive the product and collection test tubes from Blood Collections, and 
process per SOP 62-10-001 Receiving Unprocessed Units Collected by KBC 
and SOP 62-10-005 Preparation of Blood Components. The process is similar to 
Fresh Frozen Plasma (FFP). 

APPENDIX 1 
 
SOP 11-02-005 
CONVALESCENT PLASMA 
 
 
KENTUCKY BLOOD CENTER 
Lexington, Kentucky 
(859) 276-2534 
 
 
 
25
a. 
The product code for COVID-19 plasma collected by apheresis will be 
E9747 (Apheresis CONVALESCENT PLASMA|ACD-A/XX/<=-
18C|COVID-19).  
NOTE: If this product code is thawed the product code will then be 
E9752 (Thawed Apheresis CONVALESCENT PLASMA|ACD-
A/XX/refg|COVID-19) and the expiration will be in 24 hours. 
b. 
If needed, Apheresis plasma products are split for COVID-19 
convalescent plasma. At a minimum, the products should be 200mL 
each and not less. 
c. 
Save two segments of plasma for the donation product.  Send the two 
segments to Testing Lab (TLAB) for freezing.   
2. 
If the product is for emergency release, follow the emergency release process.  
Refer to SOP 60-01-015, Release of Untested Products. 
a. 
Ensure the product has a tag designating the product as convalescent 
plasma for a patient. The tag should state the following: 
1) 
Patient’s first and last name 
2) 
Date of Birth (DOB) 
3) 
Hospital Name 
4) 
Hospital ID 
3. 
Send the plasma product, before freezing, and collection test tubes, the 
segments from the product, to Testing Laboratory (TLAB) for processing, 
including manually labeling the product, if for emergency release. 
NOTE: Seven (7) test tubes will be delivered with the product from Blood 
Collections and should go to TLAB.  
4. 
Receive the products from Testing Laboratory once manually ABO/Rh labeled 
and continue manufacturing through the freezing process per SOP 62-22-001 
Fresh Frozen Plasma Preparation. 
a. 
See step VI.D for additional CLAB manufacturing information. 
b. 
Product should have a 1 year expiration date and be stored at -18ºC or 
colder. 
C. 
TECHNICAL SERVICES: TESTING LABORATORY (TLAB) 
1. 
Receive the product from Components Laboratory and process per SOP 60-01-
015 Release of Untested Products, including manually labeling the product. 
TLAB will only receive the product if it will be emergency released. 
a. 
Reference Lab will perform a manual ABO type and antibody screen. 
b. 
TLAB and RLAB will manually ABO label the product(s).   
2. 
Receive the collection test tubes from Components Laboratory. Save and freeze 
any plasma/serum from the test tubes as needed. 
a. 
For COVID-19, seven (7) tubes should be delivered with the product. 
Serum from two (2) red top tubes should be frozen and saved for 
possible future testing. If serum tubes are not available, plasma from 
EDTA tubes may be used if necessary. 
3. 
Send the product back to Components Laboratory to finish manufacturing. 

APPENDIX 1 
 
SOP 11-02-005 
CONVALESCENT PLASMA 
 
 
KENTUCKY BLOOD CENTER 
Lexington, Kentucky 
(859) 276-2534 
 
 
 
26
4. 
Send tubes to designated testing laboratory for infectious disease testing. 
D. 
TECHNICAL SERVICES: COMPONENTS LABORATORY (CLAB) [PART II] 
1. 
Component Laboratory will freeze the product. 
a. 
If for emergency release, once freezing is completed, send product(s) to 
HS for shipment. 
b. 
If for storage, store products in the walk in freezer in a designated bin 
using the STOR process in BBCS. 
1) 
Once test results have posted, perform label verification in BBCS 
to label the convalescent plasma.   
2. 
Send the product to Hospital Services once the freezing of the plasma product is 
complete if for emergency release for patient specific transfusion. 
E. 
TECHNICAL SERVICES: HOSPITAL SERVICES (HS) 
1. 
Visually inspect the product upon receipt. The container label must contain the 
following: “Caution: New-Drug - Limited by Federal (United States) law to 
investigational use”. 
2. 
Ensure there are no blanks on the label, including the volume and anticoagulant 
section. 
3. 
If for emergency release, ship the product per SOP 70-21-031 Emergency 
Release of Product - Hospital Services.  A manual shipping document will need 
to be completed. Otherwise, ship per normal shipping procedure. 
NOTE: The product cannot be shipped until QA performs a review of the donor 
record. QA will notify when the review has been completed. 
VII. 
REFERENCE VALUES – N/A 
VIII. REFERENCES 
A. 
Food and Drug Administration (FDA) emergency Investigational New Drug (IND) 
guidelines

APPENDIX 1 
 
SOP 11-02-005 
CONVALESCENT PLASMA 
 
 
KENTUCKY BLOOD CENTER 
Lexington, Kentucky 
(859) 276-2534 
 
 
 
27
B. 
 
IX. 
APPENDIX 
A. 
Appendix A: E9747 Label - COVID-19 
 

APPENDIX 2 
Convalescent Plasma in Early Treatment of High‐Risk Patients with SARS‐CoV‐2 (COVID‐19) Infection 
RedCap Data Collection Form 
 
 
28
LAB VALUES 
Lab Name 
Result 
Units 
White blood cell count 
 
10*3/uL 
Hemoglobin 
 
g/dL 
Platelet count 
 
10*3/uL 
Absolute neutrophil count 
 
10*3/uL 
Absolute lymphocyte count 
 
10*3/uL 
Absolute eosinophil count 
 
10*3/uL 
Sodium 
 
mmol/L 
Potassium 
 
mmol/L 
Chloride 
 
mmol/L 
Bicarbonate 
 
mmol/L 
BUN 
 
mg/dL 
Creatinine 
 
mg/dL 
ALT 
 
U/L 
AST 
 
U/L 
Alkaline Phosphatase 
 
U/L 
Total Bilirubin 
 
mg/dL 
PT/INR  last tested  
 
sec 
CK  
 
U/L 
LDH 
 
U/L 
 
CRP 
 
mg/dl 
D‐Dimer 
 
ng/ml FEU 
IL–6  
 
 
 
 
 
Other Pertinent Lab results, ABGs, 
Culture Results 
 
 
Ferritin  
 
ng/mL 

APPENDIX 2 
Convalescent Plasma in Early Treatment of High‐Risk Patients with SARS‐CoV‐2 (COVID‐19) Infection 
RedCap Data Collection Form 
 
 
29
CoV PCR (indicate site and date of 
collection) 
Done prior to enrollment, at 
day 7, and on discharge 
 
 
Plasma 
 Date of plasma infusion 
 Plasma infusion start time 
 Plasma infusion end time 
 Total volume infused 
 Plasma unit number infused  
Radiological Results 
 Radiological procedure completed: (must be able to enter multiple) 
 Date Completed 
 Normal/Abnormal 
o If abnormal, describe  
 
Physical Exam (must be able to enter daily) 
Date Completed 
 HEENT – (column for body systems, Normal/Abnormal ‐‐ If abnormal, describe) 
 Neurological 
 Cardiac 
 Pulmonary 
 Abdominal 
 Skin 
 Extremities 
 
Oxygen Use (will need to be able to have multiple entries): 
 Route of Oxygen administration  
 Amount of O2 
 Start Date 
 Stop Date  
 
Respiratory Status (enter daily) 
 Highest respiratory rate in 24 hour period 
 Lowest blood oxygen saturation in a  24 period 
 
Partial Pressure of Arterial Oxygen to Fraction of Inspired Oxygen Ratio, if available 
 
 

APPENDIX 2 
Convalescent Plasma in Early Treatment of High‐Risk Patients with SARS‐CoV‐2 (COVID‐19) Infection 
RedCap Data Collection Form 
 
 
30
Concomitant medications (must be able to enter multiple) 
 Name 
 Dose 
 Frequency 
 Route 
 Indication 
 Start Date  
 End Date 
Adverse Events (must be able to enter multiple) 
 Event 
 Start Date 
 End Date 
 Serious Yes/No 
 Severity 
 Relationship to investigational product 
 
Ventilator 
Was Ventilator support ever needed during this hospitalization?  Yes/No 
 
If yes, date placed on vent, date off vent 
 
Outcomes 
 Date of symptom resolution 
 Date of hospital discharge or death 
 Did the subject complete the protocol? 
o Date of completion or withdrawal 
o If withdrawal, describe reason 
 
Additional Diagnosis after Convalescent Plasma Treatment with Date of Diagnosis 
 
Respiratory Failure 
 
 
 
 
 
 
Septic Shock 
 
 
 
 
 
 
 
Multiple Organ  Dysfunction /Failure