Treatment of Severe Coronavirus Disease 2019 (COVID-19) With Convalescent Plasma Collected From Individuals With Documented Infection and Recovery From COVID-19 (SARS-CoV-2)
Phase: PHASE2
Conditions: Covid-19
Sponsor: Inova Health Care Services

Version 4.0 
Serial #0002 
1 
06/19/2020 
Study Protocol and Statistical Analysis Plan 
1 
NCT #: 04502472 
2 
Document date: 6/19/2020 
3 

Version 4.0 
Serial #0002 
2 
06/19/2020 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
 
14 
 
15 
 
16 
 
17 
 
18 
 
19 
 
20 
 
21 
 
22 
 
23 
 
24 
 
25 
 
26 
 
27 
 
28 
 
29 
 
30 
 
31 
 
32 
 
33 
 
34 
 
35 
 
36 
 
37 
 
38 
 
39 
 
40 
 
41 
 
42 
 
43 
 
44 
 
45 
Study Proposal 
46 

Version 4.0 
Serial #0002 
3 
06/19/2020 
 
1 
Study Title: Open-label Treatment of severe Coronavirus Disease 2019 (COVID-19) with 
2 
convalescent plasma collected from individuals with documented infection and recovery from 
3 
COVID-19 (SARS-CoV-2) 
4 
 
5 
Investigators:  
 
6 
Principal Investigator: 
7 
A. Whitney Brown, MD 
8 
Grace B. Sese, MD 
9 
 
10 
Co-Investigators:  
11 
Margaret Fregoso, NP 
12 
Lauren Marinak, NP 
13 
Nichole Sisserson, PA 
14 
Jessica Chun, NP 
15 
Melissa Bowen, RN  
16 
Oksana Shlobin, MD  
17 
Christopher King, MD 
18 
Kareem Ahmad, MD 
19 
Shambhu Aryal, MD 
20 
Vik Khangoora, MD  
21 
Steven Nathan, MD 
22 
Rebecca Levorson, MD 
23 
Andrew Nuibe, MD  
24 
Lucy Nam, MD 
25 
Jeremy Graf, MD 
26 
Shari Maletsky-Smith, MD  
27 
Stephen Weinroth, MD 
28 
Cindy Lee, MD 
29 
Terri Craddock, BS MLS (ASCP)H, HP  
30 
 
31 
 
32 
 
33 
 
34 
Name/Address of Institution: 
 
35 
Inova Health System  
36 
Inova Fairfax Hospital 
37 
3300 Gallows Rd 
38 
Fall Church, VA 22042 
39 
 
40 
 
 
41 

Version 4.0 
Serial #0002 
4 
06/19/2020 
Study Hypothesis:   
1 
We hypothesize that use of convalescent plasma donated from individuals recovered from Coronavirus 
2 
Disease 2019 (COVID-19) will help expedite recovery of individuals with active, severe COVID-19 
3 
infection. 
4 
 
5 
Study Background:  
6 
Plasma obtained from convalesced (recovered from virus) individuals may be an effective treatment or 
7 
prevention of viral disease through the transfer of passive immunity in the form of neutralizing 
8 
antibodies1.   
9 
Convalescent plasma therapy can be considered as a candidate intervention in the setting of an expanding 
10 
viral epidemic of public health concern for which vaccines and approved antiviral drugs are unavailable2. 
11 
It has been used to treat patients with Machupo virus (Bolivian hemorrhagic fever), Junin virus 
12 
(Argentinian hemorrhagic fever), Lassa fever, and most recently, Ebola virus, West Nile encephalitis, 
13 
SARS and Middle East respiratory syndrome (MERS)3-8. During the 2009 H1N1 (H1N1pdm09) virus 
14 
epidemic, a prospective cohort study by Hung and colleagues showed a significant reduction in the 
15 
relative risk of mortality (odds ratio 0·20 [95% CI 0·06–0·69], p=0·01) for patients treated with  
16 
convalescent plasma5. During the Ebola epidemic in West Africa, investigational use of convalescent 
17 
plasma demonstrated that it can be successfully collected from donors with recent infection, and used 
18 
safely and effectively for treatment in affected individuals7. In 2014, World Health Organization (WHO) 
19 
recommended the use of convalescent plasma collected from patients who had recovered from Ebola virus 
20 
as an empirical treatment during the outbreak8. In 2015, a protocol for the use of convalescent plasma was 
21 
utilized in the treatment of Middle East respiratory syndrome coronavirus6.  
22 
 
23 
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a 
24 
pandemic by WHO on 3/11/2020.  On 3/27/20, there were almost 530,000 cases confirmed in the world, 
25 
with over 23,700 deaths in 202 countries affected9.  According to WHO, management of COVID-19 has 
26 
mainly focused on infection prevention, case detection and monitoring, and supportive care9.  However, 
27 
no specific anti-SARS-CoV-2 treatment is recommended because of the absence of evidence. During the 
28 
last week of March, the United States has reported more cases than any other country, thus becoming a 
29 
new epicenter of the disease. Due to the gravity and urgency of the COVID-19 pandemic, formal 
30 
multicenter clinical trials for feasibility and medical effectiveness for collection and use of convalescent 
31 
plasma are not immediately feasible10-11.  
32 
Now we have validated FDA Emergency Use Authorization (EUA) approved serological assays to 
33 
specifically detect SARS-CoV-2 antibodies, however, the quantitative result is still in the investigational 
34 
state and quantification of neutralizing antibodies are not available, yet.  Until it becomes available, IgG 
35 
Index may soon be more widely available and standardized.12 We currently lack validated serological 
36 
assays to specifically detect SARS-CoV-2 antibodies, however, technology is rapidly evolving and 
37 
quantification of neutralizing antibodies may soon be more widely available and standardized12. Even in 
38 
the absence of that technology in hand, convalescent plasma from recovered individuals may provide 
39 
therapeutic benefit nonetheless, as neutralizing antibodies will inevitably be present in plasma. Indeed, 
40 
there are a few centers around the world with investigational protocols for convalescent plasma infusion 
41 
as a treatment for COVID-19 at the present time13-15. Therefore, under close supervision by the Food and 
42 
Drug Administration (FDA) in the context of an Investigational New Drug application (IND) pathway16, 
43 
the collection and investigational use of convalescent plasma in accordance with the safety and quality 
44 
criteria of established regulatory standards is proposed for Inova Health Systems. 
45 

Version 4.0 
Serial #0002 
5 
06/19/2020 
Safety Considerations:  
1 
1) Clinical use of convalescent plasma in this setting is regarded as investigational  
2 
 
as the safety and efficacy of convalescent plasma are unproven in the setting of this novel 
3 
pandemic. Collection and clinical use of this product will be managed as an experimental therapy 
4 
 
consistent with ethical safeguards (informed consent of donors and recipients, FDA approval 
5 
 
through IND pathway, institutional approval, and special labeling).  
6 
 
7 
2) Procedures will maximize safety of both plasma donors and recipients. 
8 
a. Standard blood donation protocols and screening will be followed (Donor History 
9 
Questionnaire, Appendix E)  
10 
b. Potential donors will be assessed by physician or nurse practitioner to assure clinical 
11 
stability and full recovery (confirmed by nucleic acid amplification technology (NAT)) 
12 
prior to donation  
13 
c. Plasma collections must be separated by ≥ 28 days, eligibility must be re-evaluated at each 
14 
collection, and total volume collected will be based on estimated donor blood volume in 
15 
accordance to guidelines for healthy donors   
16 
d. As with other plasma therapies, ABO compatibility will be assured 
17 
 
18 
 
19 
e. Potential risks to convalescent plasma recipients will be discussed in the informed consent 
20 
process and monitored for closely in the hospital setting: 
21 
i. risk of unintended transmission of relevant transfusion transmitted diseases from 
22 
donor  
23 
ii. risks of transfusion related reactions 
24 
iii. theoretical risk of immune enhancement due to transferred antibodies that could 
25 
exacerbate the disease 
26 
 
27 
 
28 
 
29 
 
30 
 
31 
 
32 
 
33 
 
34 
 
35 
 
36 
 
37 

Version 4.0 
Serial #0002 
6 
06/19/2020 
Plasma Collection and Storage: Collection, storage, and preparation of plasma will be performed by the 
1 
Inova Blood Center Staff. The plasma product is to be handled like a regular or licensed FFP/FP24, with 
2 
special labeling.  Convalescent plasma will be stored at the Inova Blood Donor Services Facility, the 
3 
largest hospital based donor center in the country. It is a well-established and regulated BSL2 facility 
4 
which is CLIA/CAP certified in full compliance with regulatory guidelines including AABB, FDA, with 
5 
use of good manufacturing practices.  
6 
The Inova Blood Center Staff are routinely engaged in automated plasma collection and preparation in 
7 
accordance with American Association of Blood Banks (AABB) and FDA guidelines 21 CFR Part 640 
8 
Standard Operating Procedures17. For automated plasma collection instruments, the allowable volume of 
9 
collection is predetermined based on a set of parameters as approved by FDA. 
10 
 
11 

Version 4.0 
Serial #0002 
7 
06/19/2020 
All established safeguards for prevention of relevant transfusion transmitted diseases for standard blood 
1 
donation will be followed. Infectious disease testing includes EIA(enzyme immunoassay): HTLV 1 and 2; 
2 
Syphilis; HIV 1, 2 and group O, Hepatitis B, Hepatitis C, Trypanosoma cruzi. Nucleic acid tests (NAT) 
3 
are performed for: HIV 1 and 2, Hepatitis B, Hepatitis C, West Nile Virus and Zika. Other tests include 
4 
antibody screen and ABO-Rh, all in accordance with FDA regulatory standards. In addition, Babesia was 
5 
recently identified by FDA as a relevant transfusion transmitted disease. Therefore, Babesia testing will be 
6 
implemented as soon as feasible no later than May 31, 2020 by Inova Blood Center. 
7 
Convalescent plasma will be collected from a single donor connected to an apheresis equipment (TRIMA 
8 
by Terumo-BCT) using an anticoagulant: ACD-; frozen within 8 hours; volume: 200 – 600ml and may be 
9 
separated into 200 ml aliquots and stored: < -18°C with a shelf-life of 365 days.  
10 
Plasma units will be labeled in the standard manner with ABO typing but will also include the following 
11 
statement, “Caution: New Drug--Limited by Federal (or United States) law to investigational use." (21 
12 
CFR 312.6 (a)). 
13 
 
14 
 
15 
 
16 
 
17 
 
18 
 
19 
 
20 
 
21 
 
22 
 
23 
 
24 
 
 
25 

Version 4.0 
Serial #0002 
8 
06/19/2020 
Structure of Study:  
1 
 
2 
Phase 1:  
3 
Phase 1 will be recruitment and enrollment of plasma donors.   
4 
 
5 
Phase 2:  
6 
Phase 2 will be continued recruitment and enrollment of plasma donors, with the addition of recruitment 
7 
and enrollment of plasma recipients. 
8 
 
9 
 
10 
Study Participants:  
11 
 
12 
PLASMA DONORS:  
13 
  
14 
Inclusion Criteria for Convalescent Plasma Donors:  
15 
Outpatients 18 years old and older who have recovered from COVID-19:  
16 
 Have proof of Original Positive SARS-CoV-2 NAT nasopharyngeal (NP) test result  
17 
 Complete resolution of symptoms at least 14 days prior to donation  
18 
 Negative SARS-CoV-2 NAT nasopharyngeal (NP) specimen at screening visit 
19 
 Able to meet standard criteria for blood donation  
20 
 Clinically stable based on provider assessment  
21 
Recruitment Population: Self- referrals from community with local advertisement tools utilized. Patients 
22 
captured in Inova COVID-19 Research Team database of patients diagnosed with COVID-19 in the Inova 
23 
Health System (emergency department/hospital setting as well as outpatient clinics/urgent care facilities 
24 
within Inova)   
25 
Target Donor Recruitment: 100-150 individuals 
26 
 
27 
Exclusion criteria:  
28 
Inability to complete or contraindication to donation based on Donor History Questionnaire (DHQ), FDA 
29 
approved standard blood donation form  
30 
Hb<13.0 g/dL for males 
31 
Hb<12.5 g/dL for females  
32 
History of 3 more pregnancies unless HLA antibody testing is performed and deemed acceptable by 
33 
director of blood donor services (to reduce risks of transfusion Related Acute Lung Injury in recipients) 
34 
The presence of any transfusion transmitted diseases is based on history or test results from blood sample 
35 
collected from the donor at time of plasma collection in accordance to standard practice. 
36 
Female subjects who are pregnant by self-report. 
37 
Receipt of pooled immunoglobulin in past 30 days 
38 
 
39 
Schedule of Events for DONOR:  
40 
1) Phone call or email for pre-screening  ≥ 14 days post confirmed COVID-19 infection to inquire 
41 
about clinical status and interest in study participation;  consent will be made available to patient 
42 
electronically or mailed upon request for their review  
43 
2) Screening visit   
44 

Version 4.0 
Serial #0002 
9 
06/19/2020 
 
1 
In person screening visit can be waived if donors have documentation of a repeat SARS-CoV-2 
2 
NAT nasopharyngeal test from an outside source that is negative. In this situation, consent form 
3 
can be reviewed over the phone and signed electronically.  
4 
 
5 
Location: Inova Health System Facility   
6 
Infection control procedures will be utilized for the protection of both the donor and research 
7 
staff.  
8 
Donor screening visit will occur in their private vehicles.  
9 
Staff will come to donor’s vehicle dressed in personal protective equipment to include gown, 
10 
gloves, goggles/face shield, and mask. 
11 
Study visit procedures include:  
12 
 Consent form reviewed and signed (electronic will be used unless not logistically 
13 
feasible) 
14 
 Medical history and concomitant medications reviewed 
15 
 Donor temperature will be checked  
16 
 Visual inspection will be performed by physician or nurse practitioner  
17 
 SARS-CoV-2 NAT test performed (nasopharyngeal (NP) swab)  
18 
 Optional duplicate SARS-CoV-2 NAT test performed (NP swab) for assessment of 
19 
presence of replicable virus   
20 
 If donors have documentation of a repeat SARS-CoV-2 NAT nasopharyngeal test 
21 
from an outside source that is negative, this test result will be accepted in lieu of 
22 
repeating the SARS-CoV-2 NAT nasopharyngeal test at screening visit  
23 
 If phlebotomy is feasible and safe:  
24 
o Blood draw of two tubes (1 serum and 1 EDTA) of blood for SARS-CoV-2 
25 
antibody testing  
26 
o Blood draw of up to four additional tubes for COVID-19 Inova Biobank 
27 
specimen (optional) In cases of extreme urgency for recipient plasma 
28 
infusion, there may be an option of drawing an additional four tubes for 
29 
transfusion transmissible disease testing at screening visit to expedite 
30 
readiness of plasma for use (normally this blood is drawn at time of plasma 
31 
donation and may take an additional 1-2 days) 
32 
 
33 
*If SARS-CoV-2 NAT nasopharyngeal test  is positive at screening visit, potential donor will not 
34 
be allowed to donate plasma and will be given the option to return for a repeat screening SARS-
35 
CoV-2 NAT nasopharyngeal test after 7 or more days.   
36 
 Once a negative SARS-CoV-2 NAT nasopharyngeal test has been confirmed,  
37 
plasma donation appointment can be scheduled 
38 

Version 4.0 
Serial #0002 
10 
06/19/2020 
** If timely antibody testing should become available at a future date that allows prospective 
1 
evaluation of antibody profiles, donors may be asked to postpone plasma donation and return for 
2 
repeat antibody testing prior to donation in order to enhance the presence of IgG in the plasma. 
3 
*** If SARS-CoV-2 antibody testing becomes more standardized in the future, may be able to 
4 
forgo NAT nasal swab test if documented SARS-CoV-2 infection was >28 days prior to screening 
5 
visit.  
6 
 
7 
3) Plasma Donation  
8 
 Location: Inova Blood Donor Services Facility May occur same day as screening visit after 
9 
confirmed negative NAT test result, or on a subsequent day. 
10 
 Completion of donor history questionnaire (in accordance to standard practice for blood 
11 
donation). Plasma collection performed by blood donor services staff member according to 
12 
standard protocol using automated apheresis machine (TRIMA by Terumo-BCT)) 
13 
 Plasma is collected in an aseptic manner into a closed sterile system  
14 
 Duration of procedure is approximately 1.5 hours  
15 
 Total collection volume dependent on individual donor characteristics  and includes:  
16 
  
17 
o Whole blood sample collected into the sample diversion pouch and aliquoted into:  
18 
 3 purple top tubes and 1 red top tube for routine transfusion transmitted 
19 
disease testing 
20 
o Additional  two tubes for SARS-CoV-2 antibody testing (if not already 
21 
collected at screening visit or if initial screen failure with positive NAT 
22 
nasal swab test in which case may be repeated)  
23 
o Optional tubes  for COVID-19 Inova Biobank specimen  (if not already 
24 
collected at screening visit) to permit retrospective determination of the 
25 
characteristics of an effective product and dosage regimen 
26 
  (if not already collected at screening visit)  
27 
o Up to 1000mL of plasma may be collected in one donation as calculated by the 
28 
automated collection machine based on patient characteristics (gender, weight, 
29 
height, point of care complete blood count test results)  
30 
 Due to secondary binding of calcium by citrate anticoagulant used in the extracorporeal 
31 
circuit to prevent clotting during plasma collection, calcium carbonate 2000mg total (four 
32 
Tums tablets) will be given to each patient per protocol.  
33 
 Replacement fluid will be administered to donors during collection based on calculated 
34 
volume by TRIMA instrument during automated plasma collection 
35 
 Monitoring occurs per protocol for standard plasma donation  
36 
 
37 
4) Follow-Up Phone Call or Email (1-7 days post-donation) 
38 
Script for Phone Call or Email to Donors:  
39 

Version 4.0 
Serial #0002 
11 
06/19/2020 
1) How have you been feeling since your plasma donation?  
1 
2) Do you have any new health concerns?  
2 
3) Do you have any questions for the study team regarding your participation in the study?  
3 
4) Would you be interested in donating plasma again in 28 days if you are eligible?  
4 
 
5 
Repeat plasma collections are optional and must be separated by ≥ 28 days.  Eligibility must be re-
6 
evaluated at each collection, and total volume collected each time will be based on assessment at that time 
7 
in accordance to guidelines for healthy donors.   
8 
COVID-19 Convalescent Plasma (CCP) collected as part of this clinical trial will be prioritized for use in 
9 
recipients enrolled in this clinical trial.  In the event that the need arises for CCP in patient(s) outside of 
10 
the clinical trial and the Blood Bank has a donor match of CCP collected under the clinical trial, the Blood 
11 
Bank will try to accommodate the request, in the best interest of patient care. 
12 
 
 
13 

Version 4.0 
Serial #0002 
12 
06/19/2020 
BIOBANKING:  
1 
 
2 
Collection and retention of blood specimens from both donors and recipients (pre- and post-treatment) 
3 
will be performed to permit retrospective determination of the characteristics of an effective product and 
4 
dosage regimen, and the characteristics of patients most likely to benefit18.  
5 
Data and blood specimen will be banked for future use pursuant to the IRB Approved Inova COVID-19 
6 
Biobanking Protocol. We will follow the guidelines and procedures for specimen storage and access as 
7 
described in the IRB approved Inova COVID-19 Biobanking Protocol. 
8 
Specimens will be stored at the Office of Research at Inova Biobank with standard certifications in place. 
9 
 
 
10 

Version 4.0 
Serial #0002 
13 
06/19/2020 
PLASMA RECIPIENTS: 
1 
 
2 
Inclusion Criteria for Recipients of COVID-19 Convalescent Plasma: 
3 
 
4 
Patients in the Inova Health System with confirmed COVID-19 by PCR testing  
5 
Age ≥ 13 years 
6 
Currently hospitalized with COVID-19 infection with severe or life-threatening clinical syndrome22 as 
7 
follows: 
8 
Severe COVID-19:  (three or more of the following)  
9 
 Dyspnea  
10 
 Respiratory rate ≥ 30/min 
11 
 Blood oxygen saturation (SpO2) ≤ 94% on room air  
12 
 Partial pressure of arterial oxygen to fraction of inspired oxygen (P:F) ratio < 300 
13 
 Pulmonary infiltrates > 50% of lung parenchyma within 24 to 48 hours 
14 
Life-threatening disease is defined as: (one of the following)  
15 
 Respiratory failure 
16 
 Septic shock, and/or 
17 
 Multiple organ dysfunction or failure 
18 
Patient must provide informed consent or have health care power of attorney/next of kin provide consent 
19 
if he/she cannot. 
20 
 
21 
Exclusion Criteria:  
22 
Contraindication to receive plasma as deemed by the treating physician  
23 
Severe hypercoagulable state (documented in medical chart or by treating physician assessment)  
24 
Absolute IgA deficiency  
25 
Prior history of Transfusion Related Acute Lung Injury (TRALI) 
26 
Inability to tolerate plasma volume due to severe systolic or diastolic heart failure despite slower infusion 
27 
and diuretic administration 
28 
Positive pregnancy test (HCG) 
29 
 
30 
Recipient Screening Labs   
31 
Blood Type  
32 
Total immunoglobulin (Ig) levels: IgG, IgA, IgM 
33 
Coagulation tests to include PT/INR and PTT 
34 
Complete blood count and differential  
35 
 
36 
Pre-Treatment Testing:  
37 
Optional Blood draw for Inova COVID-19 Biobank (up to four tubes each) prior to each dose of plasma 
38 
Target Recipient Recruitment: 150-200 individuals 
39 
 
40 
Primary Endpoints:    
41 
1) Change in clinical status as captured by 7-point ordinal scale score (being utilized in Gilead Sciences 
42 
remdesivir trial19, 20) at time of plasma infusion (day 0) compared to day 7:  
43 
 
1. Death 
44 
2. Hospitalized, requiring mechanical ventilation or ECMO 
45 

Version 4.0 
Serial #0002 
14 
06/19/2020 
3. Hospitalized, requiring non-invasive ventilation or high flow oxygen 
1 
4. Hospitalized, requiring supplemental oxygen 
2 
5. Hospitalized, not requiring supplemental oxygen--requiring ongoing medical care 
3 
(COVID-19 related or otherwise) 
4 
6. Hospitalized, not requiring supplemental oxygen-not requiring ongoing medical care 
5 
(COVID-19 related or otherwise). 
6 
7. Not Hospitalized  
7 
2) Adverse events related to plasma infusion (within 6 hours of infusion) to include23:  
8 
a) Transfusion-related events 
9 
i. Transfusion Associated Circulatory Overload  
10 
ii. Transfusion-Related Lung Injury 
11 
iii. Allergic Reaction/Anaphylaxis  
12 
iv. Transmission of transfusion transmitted diseases 
13 
v. Febrile Transfusion Non-hemolytic Transfusion Reaction  
14 
 
15 
Secondary Endpoints:   
16 
3) Change in 7-point ordinal scale score (being utilized in Gilead Sciences remdesivir trial) from time 
17 
of plasma infusion (day 0-prior to first infusion) to days 14, 21, and 2819,-20. 
18 
4) SOFA score at days 0, 7, 14, 21, 2821 
19 
5) Time to discontinuation of supplemental oxygen 
20 
6) Duration of hospitalization  
21 
7) Time to liberation from mechanical ventilation (for patients on a ventilator) 
22 
8) Need for mechanical ventilation (For those not on the ventilator) 
23 
9) All-cause Mortality [at 28 days] 
24 
o  
25 
 
26 
 
27 
10) All other adverse and serious adverse events will be recorded as well (see adverse events section to 
28 
follow). 
29 
11) Change in standard of care inflammatory markers (ferritin, LDH, CRP, D-dimer) where available 
30 
from day 0 to days 7, 14, 21, 28.  
31 

Version 4.0 
Serial #0002 
15 
06/19/2020 
Exploratory Endpoints:  
1 
12) Association between antibody levels and donor characteristics/clinical course  
2 
13) Association between clinical response in recipients and antibody levels in the donors  
3 
 
4 
Dosing:  
5 
 One dose of 200-300mL (standard collection bag volume) of convalescent plasma will be infused 
6 
over approximately one hour intravenously with standard vital sign monitoring per unit protocol 
7 
and standard of care for plasma infusion.   
8 
 
Up to two additional doses of 200 mL of convalescent plasma may be administered within 14 days of initial 
9 
dose at 1-7 day intervals according to disease severity and tolerance of the infusions. Where possible, 
10 
plasma from distinct donors will be used for additional doses. 
11 
 To reduce probability of allergic reaction, pre-medication with diphenhydramine 25mg orally or 
12 
intravenously will be given within 2 hours before each dose of plasma, unless there is a 
13 
contraindication noted by treating physician. 
14 
 Slower infusion time of  two hours with optional dose of 20mg intravenous furosemide after first 
15 
hour can be considered for patients at risk for transfusion-associated circulatory overload   
16 
 Infusion can be slowed for patient comfort at any time.  
17 
Safety: Patients will be monitored closely during plasma infusion per Inova nursing policy titled 
18 
“Transfusion/Infusion of Blood Components” Version 01.01.Patients will remain in the hospital for a minimum 
19 
of 24 hours post-infusion with vital signs performed per standard of care with frequency based on the 
20 
treating hospital unit. Patients will be discharged from hospital according to standard of care any time 
21 
after completion of 24 hour observation period post-infusion dosing.  
22 
 
23 
If oxygenation worsens post-infusion, treating physician will perform assessment as to the presence of a 
24 
transfusion related reaction, increase oxygen delivery, and obtain portable chest film if deemed clinically 
25 
appropriate. Treating physician will notify the study doctor and staff if there is an adverse reaction. 
26 
Possible anticipated infusion related reactions could include:  
27 
1) Transfusion Associated Circulatory  Overload – dose of intravenous furosemide may be 
28 
considered  
29 
2) Transfusion-Related Lung Injury- supportive care as directed by treating physician 
30 
3) Allergic Reaction/Anaphylaxis – additional dose of diphenhydramine, dose of intravenous or oral 
31 
corticosteroids or intramuscular epinephrine could be considered  
32 
4) Transmission of transfusion transmitted diseases – supportive care or targeted treatment if 
33 
infection identified  
34 
5) Febrile Transfusion Non-hemolytic Transfusion Reaction – supportive care  
35 
 
36 
These adverse events, if present, will be recorded by clinical research team. 
37 
 
38 
Post-Treatment Blood Draws:  
39 
Optional blood draws (up to four tubes) may be drawn on days 7, 14, 21, and 28 (+/2 days) following each 
40 
dose of convalescent plasma where feasible for Biobanking. 
41 
 
42 
 If patient is discharged prior to 7 days post-dosing, then follow-up phone call or email assessments 
43 
will be made by study staff at 7 days, 14 days, 21, and 28 days (+/2 days) following the original dose.  
44 

Version 4.0 
Serial #0002 
16 
06/19/2020 
 
 
1 
Script for Phone Call(s) or Email(s) to Recipients (if applicable):  
2 
1) Are you in a home environment (your home or family member’s home)?  
3 
2) If not, are you in a nursing or rehabilitation facility?  
4 
3) Are you using oxygen?  
5 
4) Have you required an urgent care or emergency room visit for any reason since your 
6 
discharge?  
7 
5) Have you required re-hospitalization for any reason since your discharge?  
8 
 
9 
Trial Methods 
10 
Convalescent plasma will be made available to patients hospitalized in the Inova Heath System. 
11 
 
12 
Patient outcome monitoring and reporting will include indicators of safety and efficacy. Case Report 
13 
Forms will be used to capture essential data.  
14 
 
15 
Statistical Plan 
16 
Study parameters (e.g., clinical status scale, death, hospitalization, etc.) will be described using traditional 
17 
descriptive statistics (median [IQR], frequency and percent). Data will be assessed for ‘missingness’ with 
18 
parameters exceeding 10% missing explored for imputation (e.g., multiple imputation, last value carried 
19 
forward, etc.). Departures from normality will be assessed via Shapiro-Wilkes test with data 
20 
transformations explored as needed. All analyses will be conducted using SAS (version 9.4, Cary, NC) 
21 
with p<0.05, two-tailed considered statistically significant.  
22 
 
23 
Primary efficacy endpoints: 
24 
1. Gilead 7-point scale – For each time point (day 0 vs. 7), summary clinical status scores will be 
25 
calculated. Changes in scores will be subsequently assessed via a generalized linear mixed model 
26 
with clinical status assessed at day 0 vs. 7. A statistically significant increase of ± 2 points in β 
27 
from day 0 to day 7 will be considered as evidence of efficacy. A mixed model allows for 
28 
examination and inclusion of the variance-covariance matrix into the model as a result of expected 
29 
within-subject serial correlation as a result of repeated assessments over time. 
30 
2. Plasma transfusion related adverse events will be scored as 1+ vs. 0 and will be assessed via Chi-
31 
Square test with a hypothesized distribution of expected AE (using the higher incidence estimate): 
32 
i. Transfusion Associated Circulatory Overload: 1:1,566 to 1:68 plasma units 
33 
transfused  
34 
ii. Transfusion-Related Lung Injury: 1:1,200 to 1:190,000  
35 
iii. Allergic Reaction/Anaphylaxis: 1-3% 
36 
iv. Febrile Transfusion Non-hemolytic Transfusion Reaction: 0.1-1% 
37 
 
38 
Secondary endpoints:  
39 
1. Change in 7-point ordinal scale score and SOFA score over time will be assessed via individual 
40 
growth models (IGM). Times will be day0, 14, 21, and 28 
41 
2. Mortality will be assessed via Chi-Square test with a hypothesized current mortality rate of 1-5% 
42 
(age adjusted). 
43 
3.  Need for mechanical ventilation for those not ventilator at time of plasma infusion will be 
44 
assessed via Chi-Square test with a currently available published estimates. 
45 
 
46 

Version 4.0 
Serial #0002 
17 
06/19/2020 
4. Time to discontinuation of supplemental oxygen, time to liberation from mechanical ventilation, 
1 
duration of hospitalization will be summarized as median (IQR) or rates and compared to currently 
2 
available published estimates. 
3 
 
4 
 
5 
ADVERSE EVENTS AND TOXICITY MANAGEMENT 
6 
 
7 
Definitions of Adverse Events and Serious Adverse Events 
8 
Adverse Events (AE) 
9 
An AE is any untoward medical occurrence in a clinical study subject administered an investigational 
10 
product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be 
11 
any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of an 
12 
investigational product, whether or not considered related to the investigational product. AEs may also 
13 
include pretreatment or posttreatment complications that occur as a result of protocol specified procedures 
14 
or special situations. 
15 
Serious Adverse Events (SAE)  
16 
A SAE is defined as an event that, at any dose, results in the following: 
17 
1) Death 
18 
2) Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an event 
19 
in which the subject was at risk of death at the time of the event; it does not refer to an event that 
20 
hypothetically might have caused death if it were more severe.) 
21 
3) In-patient hospitalization or prolongation of existing hospitalization 
22 
4) Persistent or significant disability/incapacity 
23 
5) A congenital anomaly/birth defect 
24 
6) A medically important event or reaction: such events may not be immediately 
25 
7) Life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
26 
intervention to prevent one of the other outcomes constituting SAEs. Medical and scientific 
27 
judgment must be exercised to determine whether such an event is a reportable under expedited 
28 
reporting rules. Examples of medically important events include intensive treatment in an 
29 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
30 
not result in hospitalization; and development of drug dependency or drug abuse. 
31 
 
32 
Data Storage and Records Retention Information about study subjects will be kept confidential and 
33 
managed according to the requirements of the Health Insurance Portability and Accountability Act of 
34 
1996 (HIPAA).  Data will be stored in a secure electronic database during and after the study and will not 
35 
be shared with unauthorized persons. Subjects will be de-identified in the database. Each subject will have 
36 
a unique identification number that will be maintained in a separate database. The principal investigator, 
37 
co-investigators, and authorized clinical research personnel will have access to the data to perform the 
38 
retrospective chart review to verify COVID-19 test result(s) and details of the index COVID-19 
39 
hospitalization (with regards to blood transfusion and blood type), if applicable. For the protection and 
40 
privacy of the patients, no identifying information will be released.  
41 
  
 
42 

Version 4.0 
Serial #0002 
18 
06/19/2020 
Data will be retained and possibly used in the future for further analysis. All identifiers will be removed. 
1 
 
2 
 
 
3 

Version 4.0 
Serial #0002 
19 
06/19/2020 
References:  
1 
 
2 
1. Marano G, Vaglio S, Pupella S, et al. Convalescent plasma: new evidence for an old therapeutic 
3 
tool, Blood Transfus 2016; 14: 152-157. 
4 
2. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. The effectiveness of convalescent plasma 
5 
and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral 
6 
etiology: a systematic review and exploratory meta-analysis. J Infect Dis 2015; 211:80–90. 
7 
3. Maiztegui JI, Fernandez NJ, de Damilano AJ. Efficacy of immune plasma in treatment of 
8 
Argentine haemorrhagic fever and association between treatment and a late neurological 
9 
syndrome. Lancet 1979; 2:1216–1217. 
10 
4. Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with 
11 
continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect 2004; 
12 
10:676–678. 
13 
5. Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with 
14 
severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 2011; 52: 447–56. 
15 
6. Arabi Y, Balkhy H, Hajeer AH. Feasibility, safety, clinical, and laboratory effects of convalescent 
16 
plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study 
17 
protocol. Springerplus 2015; 4:709. 
18 
7. van Griensven J, Edwards T, Baize S; Ebola-Tx Consortium Efficacy of convalescent plasma in 
19 
relation to dose of Ebola virus antibodies. N Engl J Med 2016; 375:2307–2309. 
20 
8. WHO. Use of convalescent whole blood or plasma collected from patients recovered from Ebola 
21 
virus disease for transfusion, as an empirical treatment during outbreaks. 2014 
22 
http://apps.who.int/iris/rest/bitstreams/604045/retrieve (accessed 3/27/2020). 
23 
9. WHO. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) 
24 
infection is suspected 2020. https://www.who.int/docs/default-source/coronaviruse/clinical-
25 
management-of-novel-cov.pdf (accessed 3/27/20). 
26 
10. Chen L, Xiong J, Bao L, ShiY. Convalescent plasma as a potential therapy for COVID-19. Lancet 
27 
Infections Disease 2020 Feb 27. pii: S1473-3099(20)30141-9. 
28 
11. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 (COVID-19) 
29 
from publicly reported confirmed cases: estimation and application Ann Intern Med. 2020 Mar 10 
30 
doi: 10.7326/M20-0504. 
31 
12. Amanat F, Nguyen T, Chromikova V, et al. A serological assay to detect SARS-CoV-2 
32 
seroconversion in humans. BMJ Yale 2020. https://doi.org/10.1101/2020.03.17.20037713 
33 
13. https://clinicaltrials.gov/ct2/show/NCT04292340?term=NCT04292340&draw=2&rank=1 
34 
14. https://clinicaltrials.gov/ct2/show/NCT04325672?cond=covid+19+convalescent+plasma&draw=2
35 
&rank=2 
36 
15. https://clinicaltrials.gov/ct2/show/NCT04323800?cond=covid+19+convalescent+plasma&draw=2
37 
&rank=3 
38 
16. http://www.fda.gov/advisory-committees/blood-vaccines-and-other-biologics/blood-products-
39 
advisory-committee 
40 
17. WHO guidelines on good manufacturing practices for blood establishments. In: WHO Expert 
41 
committee on specifications for pharmaceutical preparations. 45 Report. Geneva, WHO 
42 
2011(WHO Technical Report Series; No. 961, Annex 4). 
43 
http://www.who.int/bloodproducts/publications/GMP_Bloodestablishments.pdf. 
44 
18. Points to consider in the preparation and transfusion of COVID-19 convalescent plasma. Epstein J 
45 
and Burnouf T. Vox Sanguinis, 2020: doi: 10.1111/vox.12939. 
46 

Version 4.0 
Serial #0002 
20 
06/19/2020 
19. Beigel JH, Tebas P, Elie-Turenne MC, et al. A randomized study of immune plasma for the 
1 
treatment of severe influenza. Lancet Respir Med 2017; 5(6):500-511. 
2 
20. Wang Y, Fan G, Horby P, et al. CAP-China Network. Comparative outcomes of adults 
3 
hospitalized with seasonal influenza A or B virus infection: Application of the 7-category ordinal 
4 
scale. 
5 
21. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related organ failure assessment) score 
6 
to describe organ dysfunction/failure. Intensive Care Med 1996; 22:707-710. 
7 
22. Woelfel R, Corman VM, Guggemos W, et al. Clinical presentation and virological assessment of 
8 
hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. BMJ 
9 
Yale 2020. https://doi.org/10.1101/2020.03.05.20030502 
10 
23. Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012;52 Suppl 1(Suppl 
11 
1):65S–79S. doi:10.1111/j.1537-2995.2012.03663. 
12 
 
13