The Use of Convalescent Plasma for Patients Hospitalized With COVID-19 Disease
Phase: PHASE2
Conditions: Coronavirus Infection, Coronavirus, COVID
Sponsor: Henry Ford Health System

Convalescent Plasma for Treatment of Patients Hospitalized with COVID-19 
Respiratory Disease: A Randomized Controlled Trial 
 
ClinicalTrials.gov Identifier: NCT04385199 
Protocol May 4, 2020 
 
 

 
 
Convalescent Plasma for Treatment of COVID-19 Study Protocol 
 
Principal Investigators: 
 
Geneva Tatem, MD 
Fellowship Program Director, Pulmonary and Critical Care Medicine 
Associate Division Head 
Associate Clinical Professor of Medicine 
Wayne State University School of Medicine 
Detroit, MI 
 
Ileana Lopez-Plaza, MD 
Division Head, Transfusion Medicine 
Department of Pathology, Henry Ford Hospital 
Associate Clinical Professor of Medicine 
Wayne State University School of Medicine 
 
Jeffrey Jennings, MD 
Associate Fellowship Program Director for Research 
Pulmonary and Critical Care Medicine Fellowship Program 
Henry Ford Hospital 
 
Mayur Ramesh, MD 
Division of Transplant Infectious Diseases and Immunotherapy 
Henry Ford Hospital 
 
1. STUDY AIM, BACKGROUND, AND DESIGN ABSTRACT  
 
Background 
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
causing coronavirus disease 2019 (COVID-19) is rapidly spreading, with few therapeutic 
options.  There are currently 1.3 million confirmed cases worldwide as of April 6, 2020.  
There are currently no vaccines or specific therapeutics against COVID-19.  Novel 
antiviral therapies such as remdesivir are currently under investigation, and the efficacy 
has yet to be established. 

The use of convalescent plasma has been previously recommended as empiric 
treatment for Ebola in 2014, and there has been suggestion that transfusion of 
convalescent plasma was effective in H1N1 influenza. (1) Single transfusion of 
convalescent plasma was associated with reduced cytokine levels, reduced respiratory 
tract viral load, and reduced mortality.    
We hypothesize that use of convalescent plasma transfusion could be beneficial in 
patients infected with SARS-CoV-2.   
This is a pilot study to assess tolerability and efficacy of transfusion of convalescent 
plasma in critically ill patients with respiratory failure due to SARS-CoV-2. 
 
Specific Aims: 
1. To evaluate the clinical improvement in patients with COVID-19 after receiving 
convalescent plasma 
Rationale for the Project: 
1. The current pandemic of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) causing COVID-19 has affected over 1.3 million people 
worldwide.  Cases continue to rise due to the rapid transmission of the 
coronavirus responsible for disease.  As this is a novel coronavirus, the 
population has no immunity to this virus. Currently there are no vaccines or drugs 
that are proven beneficial in prevention or treatment of COVID-19, but many are 
under development or investigation.  
2. Human convalescent serum has been used as passive antibody therapy to 
provide immediate immunity for patients and has been used in previous 
outbreaks with other coronaviruses such as SARS-CoV-1, responsible for Middle 
Eastern Respiratory Syndrome (MERS) as well as Influenza A H1N1 2009 (1). 
3. The anticipated mechanism for passive antibody therapy in COVID-19 is viral 
neutralization. 
4. Viremia peaks in the first week of infection in most viral illnesses and patients 
develop primary immune response by days 10-14 followed by virus clearance. In 
COVID-19 disease, many patients become critically ill due to the vigorous 
immune response, resulting in the cytokine release syndrome, pneumonia, and 
renal failure. 
5. Currently, the only individuals in the population with antibodies to SARS-CoV-2 
are those who are previously confirmed to have COVID-19 and have clinically 
recovered.  
6. Passive immunity for patients with COVID-19 could be achieved by transfusion of 
convalescent plasma obtained from those individuals previously confirmed to 
have COVID-19, have clinically recovered, and have sufficient neutralizing 
antibodies. 

7. A case series of 5 critically ill patients in Wuhan, China treated with convalescent 
plaza demonstrated improvements in viral load, increased neutralizing antibody 
titers following plasma transfusion, and improvement in respiratory failure. (2)  
 
Significance: 
Establishing passive immunity for critically ill patients with COVID-19 could interrupt the 
exaggerated immune response from severe viremia responsible for precipitating the 
cytokine release syndrome that leads to pneumonia and severe hypoxia seen in 
COVID-19 disease. 
 
 
2. SUBJECT POPULATION AND ELIGIBILITY 
 
Methods 
Study Subjects 
Patients with laboratory confirmed COVID-19 diagnosed using qualitative reverse 
transcriptase-polymerase chain reaction (qRT-PCR) who are hospitalized with severe 
COVID-19 respiratory disease. 
Inclusion criteria: 
 
• Age >= 18 
 
With one or more of the following: 
• Dyspnea 
• RR >30 
• O2 saturation <= 93%  
• PaO2/FiO2 < 300 mmHg 
• Bilateral airspace opacities on CXR >50% within 24 to 48 hours 
 
Exclusion criteria: 
• 
Participation in any other clinical trial for COVID-19 
• 
Patients who are incarcerated 
• 
Concurrent treatment with other agents with actual or possible direct acting 
antiviral activity against SARS-CoV-2 < 24 hours prior to study drug infusion; 
excluding steroids and/or hydroxychloroquine or other standard treatment 
• 
Negative rRT-PCR from nasopharyngeal swab or respiratory secretions within 48 
hours prior to eligibility assessment 
• 
History of allergic reaction to blood or plasma products 

• 
Known IgA deficiency 
• 
Acute myocardial infarction within past 30 days 
• 
Acute stroke within past 30 days 
• 
VV-ECMO or VA-ECMO 
 
Donor Subjects 
 
• Must have confirmed prior diagnosis of COVID-19 confirmed via laboratory 
testing 
• Must have complete resolution of symptoms at least 14 days prior to donation 
• Confirmed negative testing for COVID-19 from one or more nasopharyngeal 
swab specimens or molecular diagnostic test from blood prior to donation 
• Female donors must be HLA antibody negative 
• Have blood collected at designated blood center 
 
Informed Consent: 
Study Subjects 
Informed consent will be obtained by the research coordinator after explanation of the 
study procedure, as well as potential risks and benefits. 
Donor Subjects 
Informed consent will be obtained by the research coordinator after explanation of study 
procedure, as well as potential risks and benefits. Included will be consent for serologic 
testing and rT-PCR for SARS-CoV-2. 
 
3. STUDY PROCEDURES 
 
Project Design and Protocol: 
Open label randomized controlled study with 2:1 enrollment of patients with hypoxemic 
respiratory failure receiving transfusion of convalescent plasma from donors recovered 
from COVID-19. 
Subjects meeting inclusion criteria will be screened for eligibility and upon consent 
randomized to either the treatment arm or control arm in 2:1 (treatment : control) 
allocation. 
Those randomized to the treatment arm will receive transfusion of one 200mL unit of 
ABO matched convalescent plasma in addition to standard therapy for COVID-19 
according to current treatment guidelines per our health system standard of care. 
Those randomized to the control arm will receive standard therapy for COVID-19 
according to current treatment guidelines per our health system standard of care. 

Data for all enrolled patients will be recorded and will include baseline characteristics, 
laboratory and clinical data,  
 
 
Study Subjects 
1. Patients admitted to HFHS with confirmed COVID-19 will be reviewed daily  
2. Critically ill patients meeting the inclusion criteria for study subjects will be 
approached for informed consent.  
3. The treating physician will be notified of potential for study enrollment 
4. Potential study subjects will have consent form given to them in the room by 
bedside nurse. Research personnel will have a discussion with the patient 
through ICU phone explaining the benefits and risks of participation, as well as 
inform them that participation will not affect their standard care.  
5. Upon agreement to participate, consent form will be signed with a copy provided 
to the patient or their representative. 
6. Once enrolled the patient history and laboratory data will be reviewed and 
collected. Baseline data review will include: 
a. CBC 
b. Electrolyte panel 
c. Crp 
d. IL-6 (if available) 
e. D-dimer 
f. LDH 
g. ABG 
h. PaO2/FiO2 ratio or 
i. SaO2/FiO2 ratio if ABG unavailable 
j. Ventilator settings (if mechanically ventilated) 
7. HLA antibody testing and blood typing will occur. 
8. Study consent form and hospital transfusion consent will be sent to the HFHS 
blood bank along with a request form for a single 200 mL unit of ABO matched 
convalescent plasma.  All blood will be screened, tested, and plasma banked 
according to current blood bank standards per FDA regulations. 
9. The HFHS blood bank will allocate the unit of ABO matched convalescent 
plasma from the blood collection center (Versiti) or HFHS blood bank.  
10. In the event that the HFHS blood bank cannot allocate an ABO matched 
convalescent plasma unit, they will be provided plasma through the expanded 
access program.  
11. The blood bank will inform the study subject’s care team when convalescent 
plasma is available and ready for transfusion.  
12. Provider will place an order for plasma transfusion in the EMR. 

13. Subjects will be given oral medication to prevent fever and allergic reactions. 
Acetaminophen 325mg orally, Diphenhydramine 25mg orally, and Famotidine 
20mg orally will be given to subjects to take 30 minutes prior to transfusion.   
14. The unit of ABO matched convalescent plasma will be delivered to the patient 
bedside. 
15. The 200mL unit of plasma will be verified for ABO compatibility by bedside nurse 
according to standard practice and will be transfused by bedside nurse over 3 
hours. Transfusion of donor plasma will be performed according to current Tier 1 
Nursing Protocol for Blood and Blood Product Transfusion (found at 
https://henryford.policystat.com/policy/6696852/latest/). 
16. The recipient will be monitored for transfusion reactions, and infusion 
immediately discontinued if any signs or symptoms of transfusion reaction. Any 
transfusion reaction will be reported to transfusion medicine.  
17. Clinical and laboratory data will be collected at baseline, 30 minutes after 
convalescent plasma transfusion, and study days 1,3,5,7,14 and 28. This data 
will include: 
a. CBC 
b. Electrolyte panel 
c. Crp 
d. D-dimer 
e. LDH 
f. Ventilator settings (if mechanically ventilated) 
g. Chest x-ray and ABG will be performed on day 3 after plasma transfusion. 
h. Chest x-ray will also be performed on day 28. 
Donor Subjects 
1. Eligible candidates for convalescent plasma donation will be approached for 
testing.  
2. Upon agreement to participate, informed consent form will be signed with a copy 
provided to the donor or their representative. 
3. Confirmation of negative testing for COVID-19 from a nasopharyngeal swab 
specimen via RT-PCR or molecular diagnostic blood test will be performed. 
4. Donor subjects meeting plasma donation criteria will have plasma collected by 
apheresis at a designated blood collection center for this study.  
5. Collected plasma will be frozen and stored in the blood bank after being tested 
and screened according to current blood bank standards per FDA regulations.  
 
Co-Interventions 
The primary clinical team will have independent control of all treatment management, 
and outside of plasma transfusion will not be influenced nor impacted by the 
investigational team. 

Data regarding co-interventions will be collected on the data forms.  
Outcome Measures: 
Primary Outcomes: 
Improvement in oxygenation as documented by PaO2/FiO2 or Sa/FiO2 (if ABG 
was unavailable at enrollment) 72 hours after infusion 
 
 
Secondary Outcomes: 
I. 
Clinical recovery 
i. Improvement in SOFA/mSOFA score at days 1,3,5,7,14, and 28 
after plasma transfusion 
ii. Avoidance of intubation (within 7 days of plasma infusion for those 
not intubated at time of enrollment) 
iii. Ventilation days  
iv. ICU length of stay 
v. Hospital length of stay 
vi. Mortality at 28 days 
 
II. 
Laboratory recovery 
i. Crp measured on days 1,3,5,7,14, and 28 
ii. IL6 measured 72 hours after plasma transfusion 
iii. Improvement of airspace opacities on chest radiograph done 72 
hours after plasma transfusion 
iv. Improvement of airspace opacities on chest radiograph done on 
day 28 
 
 
Data Collection: 
1. Baseline characteristics: 
a. Demographics: Age (years), Gender, Height, Weight, Race/Ethnicity  
b. Comorbidities   
c. Preadmission Medications 
 
2. Laboratory evaluation: 
a. CBC, electrolytes, creatinine clearance, LDH, ferritin, CPK, manually 
calculated SOFA or mSOFA score 
 
3. Clinical evaluation (daily measurements at  9pm) 
1. COVID-19 therapy (hydroxychloroquine, solumedrol, etc.) 
2. FiO2 

3. SaO2 
4. P/F Ratio  
5. S/F Ratio (if ABG unavailable) 
6. Notation of prone positioning 
7. Volume status 
8. SOFA or mSOFA score (manually calculated) 
 
4. Radiographic imaging 
a. CT or chest radiograph reports will be collected and temporally related to 
point of admission to study. Subsequent chest x ray imaging will be done 
3 days after plasma transfusion and on day 28.  
 
Necessary laboratory work and/or imaging needed for study completion will be 
performed during hospitalization. If patient is discharged prior to study completion, it will 
be performed at the enrolling HFHS site.  
 
 
Data Analysis: 
 
This is a pilot study to assess safety, tolerability and efficacy of transfusion of 
convalescent plasma to gain information on safety and possible effect sizes for efficacy. 
 
Thirty patients will be enrolled using a 2:1 (treatment:control) randomization strategy, for 
20 patients in the treatment arm and 10 patients in the control arm. 
 
Descriptive statistics will be presented. 
Randomization: 
Study subjects will be randomized into the treatment or the control arm using a 2:1 
overall ratio. 
 
4. ANTICIPATED RISKS  
 
Patients will be followed for 28 days during which time all adverse events (AE) and 
significant adverse events (SAE) will be recorded and reported. 
Likely  
• Not applicable 
Less Likely – Blood transfusion reactions 
• Fever (1%) 

• Mild allergic reaction (1%) 
• Transfusion related volume overload / excess fluid in lungs (1%) 
Rare but Serious – Blood transfusion reactions 
• Transfusion related acute lung injury also known as “TRALI” (< 0.8%) 
• Hemolysis or low blood count due to red blood cell destruction (0.1%) 
• HIV (1 in 2 million) 
• Hepatitis B (1 in 800,000) 
 
 
 
In the event of an acute transfusion reaction the transfusion will be stopped immediately 
and must be reported to the blood bank and the investigator team. Study subjects will 
be monitored for 24 hours post-transfusion related for the development of 
signs/symptoms after the transfusion of the convalescent plasma.  The standard of 
practice described in the Tier 1 Nursing Protocol for Blood and Blood Product 
Transfusion will be followed.  
A safety monitoring board will review all events and will have authority to stop the trial if 
deemed necessary. 
5. ANTICIPATED BENEFITS 
 
Clinical improvement with reduced oxygen requirements, radiographic improvement, 
and decreased ICU LOS. 
6. RENUMERATION/COMPENSATION 
 
No compensation is available for participation in this study. 
 
7. COSTS 
 
There is no cost for participation in this study. 
 
8. ALTERNATIVES 
 
Subjects do not have to participate in this study. If they choose not to participate, they 
will continue to receive current standard therapy for COVID-19. 
 
9. CONSENT PROCESS AND DOCUMENTATION 
 

1. Potential study subjects will have consent form given to them in the room by 
bedside nurse. Research personnel will have a discussion with the patient 
through ICU phone explaining the benefits and risks of participation, as well as 
inform them that participation will not affect their standard care.  
2. Upon agreement to participate, consent form will be signed with a copy provided 
to the patient or their representative. 
 
 
10.  WITHDRAWAL OF SUBJECTS 
 
Subjects will be withdrawn from the study if a suitable ABO matched plasma unit cannot 
be obtained.  
 
11. PRIVACY AND CONFIDENTIALITY  
 
Name and MRN of subjects will be collected to ensure that all laboratory specimens and 
results are attained and recorded properly.  Once all of the data is collected, all patient 
identifiers will be removed/de-identified and each subject assigned a numeric identifier. 
An electronic data base with de-identified data will be kept by the PI, in a password 
protected database on an HFHS computer. The data will only be accessible behind the 
HFHS firewall. The data will be kept at least 1 year post study completion to allow for 
adequate data review and publication. 
 
 
 
12. DATA AND SAFETY MONITORING PLAN 
 
Assuring patient safety is an essential component of this protocol. Each participating 
investigator has primary responsibility for the safety of the individual participants under 
his or her care. After 5 patients have been enrolled in the study, and for each 5 patients 
thereafter, safety data will be reviewed by the data safety monitoring committee ( 
committee consisting of panel of  at least 2 physicians unrelated to the study but with 
expertise in the field of this research) to evaluate the study related  data and look at any 
adverse events that have been reported and assess the severity of the events on case 
by case bases. Study data will be monitored every week for accuracy and patient safety 
stand point. Any issues found during the safety data monitoring will be conveyed to the 
IRB by the study coordinator after that report has been reviewed by the study lead 
investigator. Risk to the patient is removed by stopping study intervention (plasma 
infusion) and providing necessary supportive care according to existing clinical 
guidelines. 
The Investigators will determine daily if any adverse events occur during the period from 
enrollment through study day 28 or hospital discharge, whichever occurs first and will 
determine if such adverse events are reportable. 

The following adverse events will be considered reportable and thus collected in the 
adverse event case report forms: 
 
• Serious adverse events 
• Non-serious adverse events that are considered by the investigator to be 
related to study procedures or of uncertain relationship (Appendix A) 
• Study-specific clinical outcomes (Primary and Secondary Outcomes and 
Assessments During the Study), including serious adverse events such as 
organ failures and death, are systematically recorded in the case report 
forms and are exempt from adverse event reporting unless the 
investigator deems the event to be related to the administration of study 
drug (plasma infusion) or the conduct of study procedures (or of uncertain 
relationship) as outlined in Appendix A.  
After randomization, adverse events must be evaluated by the investigator. If the 
adverse event is judged to be reportable, as outlined above, then the investigator will 
report to the IRB their assessment of the potential relatedness of each adverse event to 
the study drug or protocol procedure IRB specified process. Investigators will assess if 
there is a reasonable possibility that the study procedure caused the event, based on 
the criteria outlined in Appendix A. Investigators will also consider if the event is 
unexpected.  Unexpected adverse events are events not listed in the anticipated risk of 
the study intervention. Investigators will also determine if adverse events are 
unanticipated given the patient’s clinical course, previous medical conditions, and 
concomitant medications.   
 
If a patient's treatment is discontinued as a result of an adverse event, study site 
personnel must report the circumstances and data leading to discontinuation of 
treatment in the adverse event case report forms.   
 
 

 
APPENDIX A: Adverse Event Reporting and Unanticipated Events 
 
Investigators will report all rare but serious adverse events immediately to transfusion 
medicine. The transfusion-related adverse event will be investigated and treated 
according to transfusion medicine protocols, including investigation for blood product 
ABO incompatibility.  
As noted before, investigators will report all adverse events that are serious and study 
drug/intervention or study procedure related (or of uncertain relatedness) to the IRB 
within 24 hours.   
The study Medical Monitor will work collaboratively with the reporting investigator to 
determine if a serious adverse event has a reasonable possibility of having been 
caused by the study drug or study procedure, as outlined below. The Medical Monitor 
will also determine if the event is unexpected for the study treatment. An adverse event  
is considered “unexpected” if it is not listed in the study protocol anticipated risks 
(section 4). If a determination is made that a serious adverse event has a reasonable 
possibility of having been caused by a study procedure or the study drug, it will be 
classified as a suspected adverse reaction. If the suspected adverse reaction is 
unexpected, it will be classified as a serious unexpected suspected adverse reaction 
(SUSAR).  
The investigator/ coordinator will report all unexpected deaths, serious and treatment 
related adverse events, and SUSARs to the DSMB and IRB within 7 days after receipt 
of the report from the study group. A written report will be sent to the DSMB and the IRB 
within 15 calendar days. The DSMB will also review all adverse events and clinical 
outcomes during scheduled interim analyses. The investigator will distribute the written 
summary of the DSMB’s periodic review of adverse events to the IRB in accordance   
guidelines for safety review and guidance for study continuance. 
The DSMB will inform the Investigator regarding study termination in the event of clear 
harm (worsening of clinical status, need for increased interventions beyond standard of 
care for minimal transfusion reaction) to multiple study subjects. 
 
a. Unanticipated problems (UP)  
Investigators must also report Unanticipated Problems, regardless of severity, 
associated with study procedures within 24 hours. An unanticipated problem is defined 
as follows: any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected, in terms of nature, severity, or frequency, given the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 

research protocol and informed consent document; and the characteristics of the 
subject population being studied;  
• Related or possibly related to participation in the research, in this guidance document, 
possibly related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research;  
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized.  
 
b.Determining relationship of adverse events to procedures  
Investigators will be asked to grade the strength of the relationship of an adverse event 
to study procedures as follows:  
• Definitely Related: The event follows: a) A reasonable, temporal sequence from a 
study procedure; and b) Cannot be explained by the known characteristics of the 
patient’s clinical state or other therapies; and c) Evaluation of the patient’s clinical state 
indicates to the investigator that the experience is definitely related to study procedures.  
 
• Probably or Possibly Related: The event should be assessed following the same 
criteria for “Definitely Associated”. If in the investigator’s opinion at least one or more of 
the criteria are not present, then “probably” or “possibly” associated should be selected.  
 
• Probably Not Related: The event occurred while the patient was on the study but can 
reasonably be explained by the known characteristics of the patient’s clinical state or 
other therapies.  
 
• Definitely Not Related: The event is definitely produced by the patient’s clinical state or 
by other modes of therapy administered to the patient.  
 
• Uncertain Relationship: The event does not meet any of the criteria previously 
outlined.  
 
c. Clinical outcomes that may be exempt from adverse event reporting: 
Study-specific clinical outcomes of patient’s condition, as outlined as primary and 
secondary outcomes and assessments during the study are exempt from adverse event 
reporting unless the investigator deems the event to be related to the study procedures 

(or of uncertain relationship) or if the event leads to discontinuation of study procedures. 
The following are examples of events that will be considered study specific clinical 
outcomes: 
• Death not related to the study procedures  
• Cardiovascular events: need for vasoactive drugs or fluids for hypotension or 
hypotension not temporally related to study drug infusion as outlined in section 
• Respiratory events: decreased PaO2/FiO2, hypoxia, worsening acute respiratory 
distress syndrome, or respiratory failure not related to the study procedures 
• Hepatic events: hepatic injury or liver dysfunction that leads to an increase from 
baseline in the serum level of bilirubin.  
• Renal events: renal failure, renal insufficiency, or renal injury that leads to an increase 
from baseline in serum creatinine 
 
 
13. QUALIFICATIONS OF THE INVESTIGATOR(S) 
 
Dr. Tatem is board certified in Pulmonary and Critical Care Medicine and has 
been a senior staff physician at HFH for the past 12 years. She has been 
involved in educational research as well as retrospective data review for quality 
improvement projects within the critical care setting. She has been actively 
involved in care of patients with COVID-19 and collaborating with intensivists 
regarding research protocols in the PETAL network for this population. 
 
 

 
14. REFERENCES 
 
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severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 
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2. Shen C, et al. JAMA 2020;E1-E8. 
3. Arabi YM et al. Feasibility, safety, clinical, and laboratory effects of convalescent 
plasma therapy for patients with Middle East respiratory syndrome coronavirus 
infection: a study protocol.  Emerging Infect Dis. 2016;22(9):1154-1561. 
4. Zhang W, Du RH, Li B, et al. Molecular and serological investigation of 2019-
nCoV infected patients: implication of multiple shedding routes. Emerg Microb 
Infect. 2020; 9:386–389. doi: 10.1080/22221751.2020.1729071 
5. Chen WL, Lan Y, Yuan XZ, et al. Detectable 2019-nCoV viral RNA in blood is a 
strong indicator for the further clinical severity. Emerg Microb Infect. 2020; 
9:469–473.