1

Sponsor: National Heart, Lung, and Blood Institute (NHLBI) Investigational Product: SARS-CoV-2 Convalescent Plasma

(COVID-19 Convalescent Plasma) Study Name: Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) (C3PO) A multicenter, two arm, randomized, single-blind clinical trial to determine if receiving one dose of convalescent plasma (CP) for mild COVID-19 illness prevents illness progression.

INVESTIGATOR’S BROCHURE Edition Number: 1.0 Release Date: 10 June 2020 Replaces Previous Editions Number: N/A Date: N/A

2

Table of Contents 1. Summary …………………………………………………………………. 3

2. Introduction …………………………………………………………………. 4

3. Physical, Chemical, and Pharmaceutical Properties …………………………. 5

3.1 Donor Qualifications …………………………………………………. 5

3.2 Convalescent Plasma Preparation …………………………………. 5

3.3 Convalescent Plasma Labels …………………………………………. 6

3.4 Convalescent Plasma Administration …………………………………. 8

3.5 Biohazard Information …………………………………………. 8

4. Nonclinical Studies …………………………………………………………. 9

5. Effects in Humans …………………………………………………………. 9

5.1 Use in COVID-19 …………………………………………………. 9

5.2 Use in SARS-CoV-1 …………………………………………………. 12

5.3 Use in H1N1 Influenza …………………………………………. 12

6. Risks and Benefits …………………………………………………………. 13

6.1 Benefits …………………………………………………………. 13

6.2 Risks …………………………………………………………………. 13

7. Summary of Data and Guidance for the Investigator …………………………. 14

References

3

1. Summary This information brochure is for use with the C3PO clinical trial under IND 20722. The information in this document is being provided to participating treating physicians along with the protocol and consent form to assist in protecting subjects who enroll in this trial. This clinical trial will test the efficacy of COVID-19 convalescent plasma (CP) versus a placebo for preventing the progression of early, mild-moderate COVID-19 to more severe illness in patients who are managed as outpatients but who have high risk for more severe illness. After providing informed consent, subjects who enroll in the trial will receive a transfusion of ABO compatible CP obtained from an individual who has recovered from documented infection with SARS-CoV-2 or an infusion of saline that contains multivitamins for color. Safety information will include all adverse events on the day of infusion and any serious events for 30 days after the infusion. The efficacy of CP for preventing progression of disease will be based on progression of symptoms or illness that prompts subjects to seek urgent or emergent medical care or that results in death. Other information collected will include a symptom inventory, total hospital days, mortality and antibody levels. Vitalant will provide CP collected by apheresis for this trial. Collection of plasma follows the guidelines from AABB, the FDA, and Vitalant or as contained in the COVID-19 Convalescent Plasma Collection Protocol. Vitalant uses standard operating procedures at the plasma collection centers. CP for this trial will have documented titers of anti-SARS-CoV-2 antibodies. These antibodies may be able to modify the course of the infection and decrease progression to more severe disease.

4

2. Introduction COVID-19 is a respiratory disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). As of June 9, 2020, over 7.2 million persons worldwide have been diagnosed with COVID-19 and approximately 409,000 persons have died from this disease. In the United States alone, as of June 9, 2020, there have been approximately 1.977 million cases and 111,876 deaths. [https://coronavirus.jhu.edu/map.html, accessed 9 June 2020] The majority (80%) of COVID-19 cases are mild and characterized by fever, myalgia, fatigue or dry cough. However, approximately 15-20% of cases are severe and characterized by dyspnea and hypoxia. About 5% of all cases progress into critical illness, characterized by hypoxemic respiratory failure, shock, and end-organ failure. Among the 5% who develop severe disease, as many as 50% die. [Grasselli et al. 2020; Richardson et al. 2020] The time between illness onset and progression to severe disease is variable with many reports indicating progression from mild-moderate illness to severe illness or mechanical ventilation with a mode of 9 days. [Argenziano et al. 2020] Older age and comorbidities such as hypertension, diabetes, chronic lung disease, coronary heart disease, and immunosuppression increase the risk for developing severe COVID-19 illness and mortality [Richardson et al. 2020]. At present there is no specific therapy for preventing the progression of COVID-19 from mild to severe disease. Patients who are recovering from COVID-19 develop antibodies that can bind to and neutralize the infectious viral particles. These antibodies develop over 2-3 weeks after infection [Long et al. 2020]. Convalescent plasma (CP) is the liquid portion of blood donated by patients who have recovered from an illness. CP from people who have recovered from COVID-19 contains antibodies that can bind and neutralize SARS-CoV-2 virus [Budhai et al. 2020]. Transfusion of CP to treat infectious disease has been used since the 1890s [Casadevall and Pirofski 2020]. More recently, transfusion of CP has been used to treat SARS-CoV-1, the 2013 African Ebola epidemic, and H1N1 influenza. One open-label, randomized trial that stopped early when the local epidemic resolved reported that transfusion of CP for severe COVID-19 reduced levels of virus and increased the proportion of patients showing clinical improvement at some time points [Li et al. 2020].

5

3. Physical, Chemical, and Pharmaceutical Properties The product to be administered is COVID-19 Convalescent Plasma. This product is human plasma, collected from patients who have recovered from a documented infection with the novel coronavirus, SARS-Co V-2 who have been screened for blood borne pathogens, according to standard FDA criteria to be qualified as plasma/blood donors. 3.1 Donor Qualifications COVID-19 convalescent plasma is collected from recovered individuals according to the FDA document: “Investigational COVID-19 Convalescent Plasma – Guidance for Industry (May 1, 2020)” (https://www.fda.gov/media/136798/download, Accessed 6/9/2020) “Donor Eligibility

a.COVID-19 convalescent plasma must only be collected from individuals who meet all donor eligibility requirements (21 CFR 630.10 and 21 CFR 630.15). Note the additional donor eligibility requirements for the collection of plasma by plasmapheresis in 21 CFR 630.15(b). Donation testing for relevant transfusion-transmitted infections must be performed (21 CFR 610.40) and the donation must be found suitable (21 CFR 630.30).

b.COVID-19 convalescent plasma is collected from individuals who meet the following

qualifications: i. Evidence of COVID-19 documented by a laboratory test either by:

1. A diagnostic test (e.g., nasopharyngeal swab) at the time of illness OR 2. A positive serological test for SARS-CoV-2 antibodies after recovery, if prior

diagnostic testing was not performed at the time COVID-19 was suspected.

ii. Complete resolution of symptoms at least 14 days before the donation. A negative result for COVID-19 by a diagnostic test is not necessary to qualify the donor.

iii. 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.

iv. SARS-CoV-2 neutralizing antibody titers of at least 1:160.”

3.2 Convalescent Plasma Preparation The manufacturing process used and the expiration date on the label for COVID-19 convalescent plasma is the same as for other plasma products that are of the same type. COVID-19 Convalescent Plasma, Fresh Frozen, is frozen within 8 hours after collection, stored at -18ºC or colder, and labeled with an expiration date one year from the date of collection. The plasma will be maintained in quarantine at the blood center pending laboratory test results (i.e. infectious screening, ABO and RhD status, Red cell and HLA antibodies, positive binding antibody detected with the Ortho Vitros CoV2T assay). When all release criteria for the CP are verified, the CP units are released to inventory and may be distributed to a hospital blood bank for storage or may be stored at the Blood Center until an order is received from the hospital. In the event of

6

an abnormal test result, the product is discarded and the donor will be notified by the blood center following standard policies and procedures. 3.3 Convalescent Plasma Labels The containers for the COVID-19 convalescent plasma are labeled as “E9747XXX Apheresis CONVALESCENT PLASMA|ACD-A/XX/<=-18C|COVID-19”. The IND label (“CAUTION- New drug …”) is on a tie-tag. In the short term, you will see labels as outlined below for products collected in your geographic area. However, as we expand the convalescent plasma program, you may see any or all of the labels as products are moved across the country. Each convalescent plasma unit will have two labels:

1) A tie tag as shown below:

2) One of the standard labels in the format you are accustomed to seeing: a) From Vitalant centers on eProgesa (BECS system) – legacy Blood Centers of the Pacific, BloodSource, Bonfils Blood Center, Inland Northwest Blood Center, Lifeblood, LifeShare Community Blood Services, and United Blood Services.

7

b) Legacy Central Blood Bank and LifeSource:

c) Legacy Community Blood Services

8

3.4 Convalescent Plasma Administration The subject must provide and properly document informed consent. Treating clinicians or their designee must read through the protocol and appropriately direct the use of the CP. The clinician or designee must check the label to verify that the information on the label as it relates to the transfusion to the intended patient is correct. Do not use CP if there is evidence of container breakage or of thawing during storage. Frozen CP must be thawed in a water bath at 30-37ºC or in an FDA-cleared device. If a water bath is used, thaw the component in a protective plastic overwrap using gentle agitation. Plasma must be ABO compatible with the recipient’s red cells. Follow individual institutional guidelines for determining the recipient’s blood type and for ensuring compatibility of the CP unit. For this trial, there is no change in institutional practices for ABO typing, matching, and confirmation. Administer one unit (~200 ml) of ABO compatible COVID-19 CP according to standard hospital procedures. For this trial, there is no change in institutional practices for ABO typing, matching, and confirmation. Administer CP through a peripheral or central venous catheter according to standard institutional medical and nursing practices for the administration of plasma. Follow individual institutional guidelines for the administration of plasma, including the use of any premedication, such as acetaminophen and diphenhydramine. The duration of infusion should be 30 minutes to 2 hours (rate of 100 ml/hr to 500 mL/hr). 3.5 Biohazard Information CP is a blood-derived product capable of transmitting infectious agents. Use universal precautions. No test method can provide total assurance that Hepatitis B Virus, Hepatitis C Virus, Human Immunodeficiency Virus, or Other Infectious Agents are absent. CP, like all biological products, should be handled at the Bio-Safety Level 2 as recommended by the CDC/NHI Manual “Biosafety In Microbiological And Biomedical Laboratories, From Potentially Infectious Human Serum Or Blood Specimens”.

9

4. Nonclinical Studies There are no preclinical models testing CP for COVID-19 illness. 5. Effects in Humans 5.1 Use in COVID-19 Several programs have reported experience with CP in COVID-19, primarily in patients with severe or life-threatening illness. Shen et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Mar 27;323(16):1582–9. doi: 10.1001/jama.2020.4783. PMID: 32219428; PMCID: PMC7101507. This uncontrolled case series described clinical outcomes before and after CP transfusion in 5 critically ill patients (age 36-65 years; 2 women) with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) at the Shenzhen Third People's Hospital in Shenzhen, China. Patients met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment, PAO2/ FIO2 < 300 and mechanical ventilation. CP was obtained from 5 patients who recovered from COVID- 19. CP had a SARS-CoV-2–specific antibody (IgG) binding titer greater than 1:1000 and a neutralization titer greater than 40. CP was administered. between 10 and 22 days after admission. After CP transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and PAO2/ FIO2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads decreased and became negative within 12 days after the transfusion, and SARS-CoV-2–specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion. Zhang et al. Treatment With Convalescent Plasma for Critically Ill Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Chest. 2020 Mar 31:S0012-3692(20)30571-7. doi: 10.1016/j.chest.2020.03.039. PMID: 32243945; PMCID: PMC7195335. This uncontrolled case series describes 4 critically ill patients with COVID-19 (69F, 55M, 73M, 31F) treated with up to 8 transfusions of CP. There were no reported transfusion-related adverse events. Ye et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020 Apr 15:10.1002/jmv.25882. doi: 10.1002/jmv.25882. PMID: 32293713; PMCID: PMC7262027.

10

This uncontrolled case series describes 6 patients (69M, 75F. 56M, 63F, 28F, 57M) with COVID-19 treated with one or two cycles of 200 ml CP. Included were patients with abnormalities in chest CT, patients worsening after standard treatment, patients with persistent positive SARS-CoV-2 in throat swab and/or critically ill patients. Transfusion of CP ranged from 21-45 days after symptom onset. All patients were reported to improve after CP transfusion with no adverse reactions to CP. Duan et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9490-9496. doi: 10.1073/pnas.2004168117. Epub 2020 Apr 6. PMID: 32253318; PMCID: PMC7196837. This uncontrolled case series reported the safety of administering one 200 ml dose of CP to 10 severe COVID-19 patients (age 34-78, male). Inclusions were at least one of respiratory distress with rate>30 /min, oxygen saturation < 93% at rest, and/or PaO2/FiO2 ratio <300 mmHg. CP had neutralizing antibody titers of at least 1:640. CP transfusion was a median 16.5 days (IQR 11.0-19.3) after symptom onset. All symptoms in the 10 patients disappeared or improved within 1-3 days after CP transfusion. Adverse events reported included an “evanescent facial red spot” on one patient. All patients had an increase in serum neutralizing antibody titers after CP transfusion. Joyner M et al. Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients. medRxiv [Preprint]. 2020 May 14:2020.05.12.20099879. doi: 10.1101/2020.05.12.20099879. PMID: 32511566; PMCID: PMC7274247. This report describes the safety profile from the first 5000 patients treated with 200-500 ml CP under the FDA-initiated expanded access program. CP was transfused into 3,153 men, 1,824 women and 23 persons in other gender/sex categories with diverse racial representation including Asian (6%), American Indian or Alaskan Native (<1%), Black (18%), White (49%), Native Hawaiian or Pacific Islander (<1%) and Multi-racial (<1%). Median age was 62 years (range, 18 – 97 years). 4,051 (81%) patients had severe or life-threatening COVID-19 (3,316 were in ICU) and 949 (19%) were judged to have a high risk of progressing to severe or life-threatening COVID-19.

Within 4 hours of completion of the CP transfusion, 36 serious adverse events (SAEs) were reported (0.7% of transfusions). Of the SAEs, 15 deaths were reported (0.3% of all transfusions) and 4 of those deaths were judged as related to CP transfusion (possibly, n=3; probably, n=1; definitely, n=0). Of 21 non-death SAEs reported, with 7 reports of transfusion- associated circulatory overload (TACO), 11 reports of transfusion-related acute lung injury (TRALI), and 3 reports of severe allergic transfusion reaction. All incidences of TACO and TRALI were judged as related (possibly, n=9; probably, n=7; definitely, n=2). Over the first 7 days after CP transfusion, a total of 602 mortalities were observed. In summary, the experience from the first 5000 patients with COVID-19 transfused with convalescent plasma provides no signal of toxicity beyond what is expected from plasma use in severely ill patients.

11

Salazar et al. Treatment of COVID-19 Patients with Convalescent Plasma. Am J Pathol. 2020 May 27:S0002-9440(20)30257-1. doi: 10.1016/j.ajpath.2020.05.014. Epub ahead of print. PMID: 32473109; PMCID: PMC7251400. This uncontrolled case series reported the safety of administering one 300 ml dose of CP to 25 severe or life-threatening COVID-19 patients (age 19-77 years, 11 male). Severe illness was defined as one or more of: shortness of breath (dyspnea), respiratory rate ≥ 30/min, blood oxygen saturation ≤ 93%, PaO2/FiO2 ratio < 300 mmHg, and/or pulmonary infiltrates > 50% within 24 to 48 hours. Life-threatening disease was defined as one or more of the following: respiratory failure, septic shock, and/or multiple organ dysfunction or failure. CP had anti-SARS-CoV-2 binding titers of 0 to 1350. CP transfusion was a median of 10 days (IQR, 7.5 to 12.5) after symptom onset. No adverse events attributed to plasma transfusion occurred within 24 hours after transfusion. One patient developed a morbilliform rash consistent with an exanthematous drug eruption one day post-transfusion. That rash lasted for several days. Two patients developed deep-vein thrombosis 4 and 8 days after CP. One patient developed deep-vein thrombosis and pulmonary embolus 4 days after CP. At 7 days after CP transfusion, 9 patients (36%) improved on the WHO ordinal scale, 13 patients (52%) had no change and 3 patients (12%) worsened. At 14 days after CP transfusion, 19 patients (76%) improved, 3 patients (12%) were unchanged and 3 patients (12%) worsened. Li L et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020 Jun 3. doi: 10.1001/jama.2020.10044. PMID: 32492084. This open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, enrolled 103 (median age 70 years, IQR 62-78, 60 male) patients with pneumonia confirmed by chest imaging and clinical symptoms meeting the definitions of severe or life-threatening COVID-19. The trial stopped early because the epidemic subsided in the region. Subjects were assigned to receive 200 ml CP or no CP. CP subjects were enrolled a median of 27 days (IQR 22-39) and control subjects were enrolled a median of 30 days (IQR 19-38) after symptom onset. The primary outcome of time to clinical improvement within 28 days of randomization did not differ between groups (HR 1.40, 95% CI 0.79-2.49). The proportion with clinical improvement in CP group versus control was 9.6% vs 9.8% at 7 days, 32.7% vs. 17.6% at 14 days, and 51.9% vs. 43.1% at 28 days. The 28-day mortality was 15.7% in the CP group vs 24.0% in the control group; OR, 0.65 (95%CI 0.29- 1.46, P = 0.30). Among patients with severe disease, no patients died in the CP group, while 2 patients (9.1%) died in the control group. Among patients with life-threatening disease, 8 patients (28.6%) died in the CP group, while 10 patients (35.7%) died in the control group. The rates of negative SARS-CoV-2 viral PCR in the CP group were higher than that of the control group at 24 hours (44.7% vs 15.0%, P = 0.003), at 48 hours (68.1% vs 32.5%, P =0 .001 and at 72 hours (87.2% vs 37.5%, P < .001) .

12

Transfusion-related adverse events after CP transfusion occurred in 2 patients. One developed chills and rashes within 2 hours of transfusion but recovered fully after treatment with dexamethasone and promethazine. The second patients, who had life-threatening COVID-19, presented with shortness of breath, cyanosis, and severe dyspnea within 6 hours of transfusion. The patient was given dexamethasone, aminophylline, and other supportive care immediately and gradually improved after 2 hours. This was determined to be possible severe transfusion- associated dyspnea. 5.2 Use in SARS-CoV-1 Cheng et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005 Jan;24(1):44-6. doi: 10.1007/s10096-004-1271-9. PMID: 15616839; PMCID: PMC7088355. This case series describes open-label treatment of 80 patients (median age 45 years, range, 21–82 years, 43 females and 37 males) with SARS in Hong Kong with a mean (SD) 279.3 (127.1) ml (range, 160–640 ml) of CP. Included were patients whose condition continued to deteriorate, as defined by SaO2<90% on 0.5 FiO2. Each dose comprised 200–400 ml (4–5 ml/kg) of ABO-compatible CP at the discretion of the attending clinicians and according to CP availability. CP was obtained from patients who had recovered from SARS and were seropositive for coronavirus (titer range, 160–2,560). CP transfusion occurred 7–30 days after the onset of symptoms. Of 80 patients, 33 (41%) had a good clinical outcome defined as discharge by day 22 following the onset of SARS symptoms. Poor outcome was defined as death before day 22 or hospitalization beyond 22 days. Patients given CP before day 14 after symptom onset had a better outcome than those given plasma after day 14. The mortality rates in the two groups were 6.3% and 21.9%, respectively. The mortality rate was 12.5% among all 80 patients given CP compared to the overall SARS-related mortality rate in Hong Kong of 17% (299/1755) during the SARS epidemic from 6 March to 24 May 2003. Among patients with a good outcome, 61% were PCR positive and seronegative for coronavirus at the time of CP infusion as compared with 21% in the group with a poor outcome. Among 30 patients who were PCR positive and seronegative for coronavirus at the time of CP therapy, more had a better outcome than those who were already seropositive (66.7% vs 20%). No immediate adverse effects were observed with CP infusion. There was no correlation between clinical outcome and either the volume of CP infused or the coronavirus antibody titers of the donors. 5.3 Use in H1N1 Influenza Hung et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011 Feb 15;52(4):447-56. doi: 10.1093/cid/ciq106. Epub 2011 Jan 19. PMID: 21248066. A prospective cohort study reported treatments and outcomes for 93 patients aged >18 years

13

with severe H1N1 2009 infection requiring intensive care in Hong Kong. A total of 20 patients (median age 48, IQR 37-55.8, 11 males, 9 females) who had clinical deterioration despite optimal antiviral treatment within 7 days of symptom onset were treated with 500 mL CP with a neutralizing H1N1 2009 antibody titer of >1:160, collected from patients recovering from H1N1 2009 infection. CP was infused on day 2 (median; IQR, day 1–2.5) of ICU admission. Mortality in the treatment group was significantly lower than in the nontreatment group (20.0% vs 54.8%; P = 0.01). Multivariate analysis showed that plasma treatment reduced mortality (OR= 0.20; 95%CI, 0.06-0.69; P = 0.011). Viral loads measured on day 3, 5, and 7 after ICU admission were lower in the CP group than in the control group. There were no adverse events (AEs) attributed to the convalescent plasma. 6. Risks and Benefits 6.1 Benefits Benefits of CP in patients with COVID-19 are unknown. It is possible that neutralizing antibodies in CP will more rapidly decrease viral burden, reduce the duration and severity of illness, reduce complications, and improve outcomes. 6.2 Risks Hazards that pertain to transfusion of any plasma are reported in Circular of Information for Human Blood and Blood Components (2017) [28] Immunologic Complications, Immediate

Hemolytic transfusion reaction Febrile nonhemolytic reaction Allergic reactions Anaphylactoid/anaphylactic reactions Transfusion-related acute lung injury (TRALI)

Immunologic Complications, Delayed

Posttransfusion purpura Nonimmunologic Complications

Transmission of infectious diseases Bacterial sepsis Transfusion-associated circulatory overload (TACO) o Hypothermia Metabolic complications

Common risks of plasma transfusions may include one or more of the following: fever, rash, hives, or headache. Other more serious risks are rare and may include the following: serious allergic reactions including anaphylaxis, bacterial infections, or viral infections like Hepatitis B, Hepatitis C and human immunodeficiency virus (HIV). The study plasma will follow FDA guidance for donor screening and testing of plasma products.

14

Transfusion-related acute lung injury (TRALI) may occur, but this risk will be minimized by using male donated plasma 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. TRALI is characterized by a clinical constellation of symptoms including dyspnea, hypotension and fever. Although the precise pathogenesis of TRALI remains unknown, it has been shown to be most often related to the transfusion of anti-HLA and anti-neutrophil antibodies from plasma from multiparous women (antibodies presumably generated during pregnancy) or donors who have received multiple blood transfusions. The risk of TRALI after plasma administration is reported as about 1 out of 65000. [Bux 2011] Each unit of plasma contains ~200 mL of volume. Depending on the total volume infused, there is the risk of volume overload in the recipient that could cause pulmonary edema. Transfusion-associated circulatory overload (TACO) has been associated with plasma infusion, with an incidence in some series of 1 in 1566 units transfused with passive reporting and 1 in 68 units transfused in active surveillance reporting [Pandey and Vyas 2012]. Subjects who may not tolerate this volume of plasma will be excluded from this study, but this condition could still occur in recipients. TACO is hydrostatic not permeability edema and more responsive to diuresis when it occurs. There are case reports of deep vein thrombosis and pulmonary emboli occurring after administration CP [Salazar et al. 2020], but the fact that pulmonary emboli may develop in 10-15% of critically ill adults makes it difficult to know if these are causally related. There is the risk of other infections that can be transmitted by blood products. The study plasma will follow FDA guidance for donor screening and testing of plasma products. Universal testing for Zika virus was implemented at the end of November 2016. The risk of transfusion associated Zika virus infection is considered low [Galel et al. 2017]. 7. Summary of Data and Guidance for the Investigator In the case of SARS-CoV-2, the anticipated mechanism of action by which CP therapy would mediate protection is viral neutralization. CP can reduce levels of SARS-CoV-2 virus [Shen et al. 2020; Li et al 2020]. However, other immunomodulatory mechanisms may also result from plasma administration. CP has the highest chance of showing efficacy if used for treatment of COVID-19 patients early in the course of disease. Early in the disease, the recipient is less likely to have developed their own antibodies, and the passive immunization from CP can increase circulating neutralizing antibodies [Duan et al. 2020]. No published data reports results of early administration of CP in mild-moderate COVID-19. The safety profile of CP is comparable to administration of plasma for other indications. Experience with 5000 CP transfusions in severe COVID-19 reports serious adverse event rate of 0.7% [Joyner et al. 2020]. Thrombotic complications have been reported in critically ill COVID-

15

19 patients who received CP, but no comparative data address whether these events occurred more often than in the general critically ill population.

16

References

1. Argenziano MG, Bruce SL, Slater CL, Tiao JR, Baldwin MR, Barr RG, Chang BP, Chau KH, Choi JJ, Gavin N, Goyal P, Mills AM, Patel AA, Romney MS, Safford MM, Schluger NW, Sengupta S, Sobieszczyk ME, Zucker JE, Asadourian PA, Bell FM, Boyd R, Cohen MF, Colquhoun MI, Colville LA, de Jonge JH, Dershowitz LB, Dey SA, Eiseman KA, Girvin ZP, Goni DT, Harb AA, Herzik N, Householder S, Karaaslan LE, Lee H, Lieberman E, Ling A, Lu R, Shou AY, Sisti AC, Snow ZE, Sperring CP, Xiong Y, Zhou HW, Natarajan K, Hripcsak G, Chen R. Characterization and clinical course of 1000 Patients with COVID-19 in New York: retrospective case series. Version 2. medRxiv [Preprint]. 2020 Apr 22:2020.04.20.20072116. doi: 10.1101/2020.04.20.20072116. Update in: BMJ. 2020 May 29;369:m1996. PMID: 32511507; PMCID: PMC7273275.

2. Budhai A, Wu AA, Hall L, Strauss D, Paradiso S, Alberigo J, Hillyer CD, Jett B, Tobian AAR,

Bloch EM, Sachais BS, Shaz BH. How did we rapidly implement a convalescent plasma program? Transfusion. 2020 May 25. doi: 10.1111/trf.15910. Epub ahead of print. PMID: 32449169.

3. Bux J. Antibody-mediated (immune) transfusion-related acute lung injury. Vox Sang.

2011 Jan;100(1):122-8. doi: 10.1111/j.1423-0410.2010.01392.x. PMID: 21175662.

4. Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020 Apr 1;130(4):1545-1548. doi: 10.1172/JCI138003. PMID: 32167489; PMCID: PMC7108922.

5. Cheng Y, Wong R, Soo YO, Wong WS, Lee CK, Ng MH, Chan P, Wong KC, Leung CB, Cheng

G. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005 Jan;24(1):44-6. doi: 10.1007/s10096-004-1271-9. PMID: 15616839; PMCID: PMC7088355.

6. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M,

Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9490-9496. doi: 10.1073/pnas.2004168117. Epub 2020 Apr 6. PMID: 32253318; PMCID: PMC7196837.

7. Galel SA, Williamson PC, Busch MP, Stanek D, Bakkour S, Stone M, Lu K, Jones S,

Rossmann SN, Pate LL; cobas Zika IND Study Group. First Zika-positive donations in the continental United States. Transfusion. 2017 Mar;57(3pt2):762-769. doi: 10.1111/trf.14029. Epub 2017 Feb 5. PMID: 28164310.

17

12. Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, Cereda D, Coluccello A, Foti G, Fumagalli R, Iotti G, Latronico N, Lorini L, Merler S, Natalini G, Piatti A, Ranieri MV, Scandroglio AM, Storti E, Cecconi M, Pesenti A; COVID-19 Lombardy ICU Network, Nailescu A, Corona A, Zangrillo A, Protti A, Albertin A, Forastieri Molinari A, Lombardo A, Pezzi A, Benini A, Scandroglio AM, Malara A, Castelli A, Coluccello A, Micucci A, Pesenti A, Sala A, Alborghetti A, Antonini B, Capra C, Troiano C, Roscitano C, Radrizzani D, Chiumello D, Coppini D, Guzzon D, Costantini E, Malpetti E, Zoia E, Catena E, Agosteo E, Barbara E, Beretta E, Boselli E, Storti E, Harizay F, Della Mura F, Lorini FL, Donato Sigurtà F, Marino F, Mojoli F, Rasulo F, Grasselli G, Casella G, De Filippi G, Castelli G, Aldegheri G, Gallioli G, Lotti G, Albano G, Landoni G, Marino G, Vitale G, Battista Perego G, Evasi G, Citerio G, Foti G, Natalini G, Merli G, Sforzini I, Bianciardi L, Carnevale L, Grazioli L, Cabrini L, Guatteri L, Salvi L, Dei Poli M, Galletti M, Gemma M, Ranucci M, Riccio M, Borelli M, Zambon M, Subert M, Cecconi M, Mazzoni MG, Raimondi M, Panigada M, Belliato M, Bronzini N, Latronico N, Petrucci N, Belgiorno N, Tagliabue P, Cortellazzi P, Gnesin P, Grosso P, Gritti P, Perazzo P, Severgnini P, Ruggeri P, Sebastiano P, Covello RD, Fernandez-Olmos R, Fumagalli R, Keim R, Rona R, Valsecchi R, Cattaneo S, Colombo S, Cirri S, Bonazzi S, Greco S, Muttini S, Langer T, Alaimo V, Viola U. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6;323(16):1574–81. doi: 10.1001/jama.2020.5394. Epub ahead of print. PMID: 32250385; PMCID: PMC7136855.

13. Hung IF, To KK, Lee CK, Lee KL, Chan K, Yan WW, Liu R, Watt CL, Chan WM, Lai KY, Koo

CK, Buckley T, Chow FL, Wong KK, Chan HS, Ching CK, Tang BS, Lau CC, Li IW, Liu SH, Chan KH, Lin CK, Yuen KY. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011 Feb 15;52(4):447-56. doi: 10.1093/cid/ciq106. Epub 2011 Jan 19. PMID: 21248066.

14. Joyner M, Wright RS, Fairweather D, Senefeld J, Bruno K, Klassen S, Carter R, Klompas A,

Wiggins C, Shepherd JR, Rea R, Whelan E, Clayburn A, Spiegel M, Johnson P, Lesser E, Baker S, Larson K, Ripoll Sanz J, Andersen K, Hodge D, Kunze K, Buras M, Vogt M, Herasevich V, Dennis J, Regimbal R, Bauer P, Blair J, van Buskirk C, Winters J, Stubbs J, Paneth N, Casadevall A. Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients. medRxiv [Preprint]. 2020 May 14:2020.05.12.20099879. doi: 10.1101/2020.05.12.20099879. PMID: 32511566; PMCID: PMC7274247.

15. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, Hu C, Tao C,

Yang R, Wang J, Yu Y, Guo Y, Wu X, Xu Z, Zeng L, Xiong N, Chen L, Wang J, Man N, Liu Y, Xu H, Deng E, Zhang X, Li C, Wang C, Su S, Zhang L, Wang J, Wu Y, Liu Z. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020 Jun 3. doi: 10.1001/jama.2020.10044. Epub ahead of print. PMID: 32492084.

16. Long QX, Liu BZ, Deng HJ, Wu GC, Deng K, Chen YK, Liao P, Qiu JF, Lin Y, Cai XF, Wang

DQ, Hu Y, Ren JH, Tang N, Xu YY, Yu LH, Mo Z, Gong F, Zhang XL, Tian WG, Hu L, Zhang

18

XX, Xiang JL, Du HX, Liu HW, Lang CH, Luo XH, Wu SB, Cui XP, Zhou Z, Zhu MM, Wang J, Xue CJ, Li XF, Wang L, Li ZJ, Wang K, Niu CC, Yang QJ, Tang XJ, Zhang Y, Liu XM, Li JJ, Zhang DC, Zhang F, Liu P, Yuan J, Li Q, Hu JL, Chen J, Huang AL. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. 2020 Apr 29. doi: 10.1038/s41591-020-0897-1. Epub ahead of print. PMID: 32350462.

17. Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012 May;52

Suppl 1(Suppl 1):65S-79S. doi: 10.1111/j.1537-2995.2012.03663.x. PMID: 22578374; PMCID: PMC3356109.

18. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW; and the Northwell COVID-19 Research Consortium, Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020 Apr 22;323(20):2052–9. doi: 10.1001/jama.2020.6775. Epub ahead of print. Erratum in: doi: 10.1001/jama.2020.7681. PMID: 32320003; PMCID: PMC7177629.

19. Salazar E, Perez KK, Ashraf M, Chen J, Castillo B, Christensen PA, Eubank T, Bernard DW,

Eagar TN, Long SW, Subedi S, Olsen RJ, Leveque C, Schwartz MR, Dey M, Chavez-East C, Rogers J, Shehabeldin A, Joseph D, Williams G, Thomas K, Masud F, Talley C, Dlouhy KG, Lopez BV, Hampton C, Lavinder J, Gollihar JD, Maranhao AC, Ippolito GC, Saavedra MO, Cantu CC, Yerramilli P, Pruitt L, Musser JM. Treatment of COVID-19 Patients with Convalescent Plasma. Am J Pathol. 2020 May 27:S0002-9440(20)30257-1. doi: 10.1016/j.ajpath.2020.05.014. Epub ahead of print. PMID: 32473109; PMCID: PMC7251400.

20. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H,

Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Mar 27;323(16):1582–9. doi: 10.1001/jama.2020.4783. Epub ahead of print. PMID: 32219428; PMCID: PMC7101507.

21. Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, Xia X, Lv T. Treatment with convalescent

plasma for COVID-19 patients in Wuhan, China. J Med Virol. 2020 Apr 15:10.1002/jmv.25882. doi: 10.1002/jmv.25882. Epub ahead of print. PMID: 32293713; PMCID: PMC7262027.

22. Zhang B, Liu S, Tan T, Huang W, Dong Y, Chen L, Chen Q, Zhang L, Zhong Q, Zhang X, Zou

Y, Zhang S. Treatment With Convalescent Plasma for Critically Ill Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Chest. 2020 Mar 31:S0012-

19

3692(20)30571-7. doi: 10.1016/j.chest.2020.03.039. Epub ahead of print. PMID: 32243945; PMCID: PMC7195335.