Convalescent Plasma for Treatment of COVID-19 Patients With Pneumonia

Study Overview
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Brief Summary
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This is a single arm phase II trial to assess efficacy and confirm safety of infusions of anti-SARS-CoV-2 convalescent plasma in hospitalized patients with acute respiratory symptoms,with or without confirmed interstitial COVID-19 pneumonia by chest Xray or CT. A total of 29 eligible subjects will be enrolled to receive anti-SARS-CoV-2 plasma.Outcomes will be compared to hospitalized controls with confirmed COVID-19 disease through retrospective chart review.

Detailed Description
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There are no proven treatments for coronavirus disease (COVID-19) and associated pneumonia caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Recent experience in China suggests that convalescent immune plasma(CIP)may be an effective treatment for COVID-19. In the pandemic situation where there are no vaccines for COVID-19, specific antibodies in convalescent plasma induced by infection may provide passive protective immunity. Passive antibody therapy was the first immunotherapy dating back to the 1890's for the treatment of infectious diseases before the development of antibiotics 1940's. Experience from prior outbreaks with other coronaviruses, such as SARS-CoV-1 shows that such convalescent plasma contains neutralizing antibodies to the relevant virus. In SARS-CoV-2, passive antibody therapy from CIP probably provided protection by viral neutralization. CIP was also used in the 2013 Ebola epidemic. A small non-randomized study in Sierra Leone revealed a significant increase in survival for who received CIP4. CIP administration is the only approach that provides immediate immunity to patients who have been exposed or who have active disease. This approach is immediately available from individuals who have recovered, are viral free,and can donate immune plasma (IP) containing high titer neutralizing antibodies. Passive antibody therapy can be given to a patient recently exposed or a patient who is developing an infection with COVID-19 by obtaining plasma units from immune individuals by standard plasmapheresis using FDA-approved blood banking procedures, cross matching the unit(s) to the recipients and infusing the unit(s) using standard transfusion procedures for blood products. Based on the safety and long-term experience with plasma infusions, plasma exchanges, and other procedures involving plasma or plasma product, this protocol was designed as a phase II single arm trial that involves the administration of antibodies to a given agent to a susceptible individual for the purpose of preventing or treating an infectious disease due to that agent. The only antibody formulation that is available for emergent use is that found in convalescent plasma. As more individuals contract COVID-19 and recover, the number of potential donors will increase. The principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease. When used for therapy, antibody is most effective when administered shortly after the onset of symptoms. The reason for temporal variation in efficacy is not well understood but could reflect that passive antibody works by neutralizing the initial inoculum, which is likely to be much smaller than that of established disease. Alternatively, antibodies may dampen the early inflammatory response leaving the infected individual asymptomatic. For example, antibody therapy for pneumococcal pneumonia was most effective when given shortly after the onset of symptoms and was of no benefit if antibody therapy was delayed beyond the third day of disease. For passive antibody therapy to be effective, a sufficient amount of antibody must be infused. The antibody will circulate in the blood, reach tissues,and provide protection against infection. Depending on the type of antibody, amount, and composition, the half-life can vary from weeks to months. It is under these circumstances, the investigators plan to treat patients who are sick enough to be hospitalized before the onset of overwhelming disease involving a systemic inflammatory response, sepsis, and/or ARDS.

Official Title
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Efficacy and Safety of High-Titer Anti-SARS-CoV-2 (COVID19) Convalescent Plasma for Hospitalized Patients With Infection Due to COVID-19 to Decrease Complications: A Phase II Trial

Conditions
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Corona Virus Infection, SARS-CoV 2, SARS Pneumonia, Pneumonia

Intervention / Treatment
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* Drug: High-Titer Anti-SARS-CoV-2 (COVID 19) Convalescent Plasma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be 18 years of age or older Patients hospitalized with COVID-19 respiratory symptoms within 72 hours of admission to afloor bed (non-ICU bed) and confirmation via SARS-CoV-2 RT-PCR testing. Patient and/or surrogate is willing and able to provide written informed consent and comply with all protocol requirements. Patients with hematologic malignancies or solid tumors are eligible. Patients with autoimmune disorders are eligible. Patients with immunodeficiency and organ or stem cell transplant recipients are eligible. Patients who have received or are receiving hydroxychloroquine or chloroquine are eligible (but will be taken off the drug) Prior use of IVIG is allowed but the investigator should consider the potential for a hypercoagulable state. Exclusion Criteria: Patients requiring mechanical ventilation or >6 liters per minute nasal cannula oxygen Patients on other anti-COVID-19 trials being treated with tocilizumab (anti-IL-6 receptor), Siltuximab (anti-IL-2), Remdesivir, or other pharmacological trials that may be initiated hereafter. A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the individual at a substantially increased risk of thrombosis (e.g., cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically significant monoclonal gammopathy). Contraindication to transfusion or history of prior reactions to transfusion blood products. Medical conditions for which receipt of 500-600 mL of intravenous fluid may be dangerous to the subject (e.g., decompensated congestive heart failure).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single arm phase II trial to assess preliminary efficacy and confirm safety of infusions of antiSARS-CoV-2 convalescent plasma in hospitalized patients with acute respiratory symptoms with or without confirmed interstitial COVID-19 pneumonia by CXR or chest CT. A total of 29 eligible subjects will be enrolled to receive high titer anti-SARS-CoV-2 plasma. Participants will be compared to a historical control group via retrospective chart review.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study participants<br>A total of 29 eligible subjects will be enrolled to receive high titer anti-SARS-CoV-2 plasma. Participants will be compared to a historical control group via retrospective chart review. | Drug: High-Titer Anti-SARS-CoV-2 (COVID 19) Convalescent Plasma<br>* Pathogen reduced SARS-CoV-2 convalescent plasma (1-2 units;  200 mL each for a total of 200-400mls) given preferably in one day, but allowable to be given over 2 days if clinical circumstances delay infusions in 1 day), with titer to be determined after the unit has been infused.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Transferred to Intensive Care Unit (ICU) | Will be done by comparing the admission rate to the ICU between patients who received convalescent plasma and a control group who did not enroll in the study, or receive another experimental therapy. | Days 0 - 60 | 
| 28 Day Mortality | Will be done by comparing the 28 day mortality rate between enrolled subjects and the control group. | Days 0 - 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events | Will be collected from time of enrollment until completion of the study. The adverse events will be evaluated by CTCAE V5.0 and MedDRA. | Days 0 - 60 | 
| Duration of SARS-CoV-2 Positivity | Respiratory tract swabs will be collected on days, 0, 7, 14, and 21 and will be tested for SARS-CoV-2. The outcome measurement is determining the duration from date of infection until date of first documented negative PCR test, which was assed up to 21 days | Days 0 - 21 | 
| Serum of Plasma Antibody Titer to SARS-CoV-2 | Serum or plasma will be collected and analyzed for SARS-CoV-2 antibody. | Day 28 | 
| Cellular and Humoral Immune Response | Blood will be collected and analyzed for for Spike IgG levels. | Day 28 | 
| Supplemental Oxygen Free Days | All days where a supplemental oxygen is needed will be recorded as a concomitant medication and will be subtracted from total days the participant is alive and enrolled in the study up to day 28 to determine the supplemental oxygen free days. | Days 0-28 | 
| Ventilator Free Days | All days where a ventilator is needed will be recorded as a concomitant procedure and will be subtracted from total days the participant is alive and enrolled in the study up to day 28 to determine the ventilator free days. | Days 0 - 28 | 
| ICU Free Days | All days where the participant is admitted to the ICU will be recorded and subtracted from total days the participant is alive and enrolled in the study up to day 28 to determine the ICU free days. | Days 0 - 28 | 
| Sequential Organ Failure Assessment Score Improvement | Throughout the study, participants were evaluated by study physician using the sequential organ failure assessment score. This outcome measurement is looking for the number of participants who's score improved over the duration of the study. | days 0-28 | 
| Number of Participants Who Needed for Vasopressors | Concomitant medications will be recorded throughout the patients participation in the study and vasopressors will be recorded, if they are needed. | Days 0 - 60 | 
| Number of Participants Who Needed Renal Replacement Therapy | Renal function will be assessed throughout the patients participation in the study. If renal replacement therapy is needed, it will be captured as a concomitant procedure. | Days 0 - 60 | 
| Number of Participants Who Needed Extracorporeal Membrane Oxygenation (ECMO) | Respiratory function will be assessed throughout the patients participation in the study. If ECMO is needed, it will be captured as a concomitant procedure. | Days 0 - 60 | 
| Hospital Length of Stay (LOS) | Will be calculated from the date the patient entered the hospital until they were discharged. | Days 0-60 | 
| ICU LOS | Will be calculated from the date the patient entered the ICU until they were discharged from the ICU. | days 0 - 60 | 
| Number of Participants Who Had a Grade 3 or 4 Adverse Events (AEs) | All adverse events will be recorded and evaluated by CTCAE v.5.0. All grade 3 and 4 AEs will be calculated to determine safety of convalescent plasma. | Adverse events were collected from day 0 to 7 days post infusion. |