Convalescent Plasma for Treatment of COVID-19

Study Overview
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Brief Summary
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Convalescent plasma has been shown to be safe and effective for treatment of several diseases. Preliminary data indicate that it is safe for treatment of COVID-19. We found that viremia upon admission identifies patients at 7 fold increased risk of admission to intensive care and 8 fold increased risk of death. CP treatment appeared to result in rapid viral clearance in a small case series. CP appeared to be well tolerated in a phase I study in which patients only received one dose of CP and a phase II study in which CP was given until viremia disappeared (unpublished data). Randomised controlled studies assessing the efficacy of CP are lacking and thus the efficacy of CP is unknown. Preliminary data indicate that treatment should be given early, prior to development of severe illness. Detection of viremia upon admission identifies a group at high risk of severe disease and death that has the most to benefit from CP. Phase II study data indicates that treatment should be given until SARS-CoV-2 is no longer detected in serum and the donor antibody neutralization titres should be ≥1/640. A randomised controlled trial in which viremic patients are treated with CP with the equivalent of an antibody titre ≥1/640 is thus required to determine if CP can be an effective COVID-19 treatment.

Official Title
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Convalescent Plasma for Treatment of COVID-19: An Open Randomised Controlled Trial

Conditions
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Covid19

Intervention / Treatment
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* Biological: SARS-CoV-2 convalescent plasma
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 18 Admitted to a study hospital Active COVID-19 defined as symptoms + SARS CoV-2 identified from upper or lower airway samples and blood Negative pregnancy test taken before inclusion and use of an acceptable effective method of contraception until treatment discontinuation if the participant is a woman of childbearing potential Written informed consent after meeting with a study physician and ability and willingness to complete follow up Exclusion Criteria: No matching plasma donor (Exact matching in the ABO system is required) Unavailability of plasma Estimated glomerular filtration rate <30 (kidney failure stage III or more) Pregnancy (urinary-hcg) Breast feeding Inability to give informed consent

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomised 2:1 to treatment with convalescent plasma and standard of care only. Randomisation is by random permutated blocks using Redcap or equivalent.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Convalescent plasma treatment<br>Participants will receive 200 ml convalescent plasma daily until SARS-CoV-2 is no longer detectable in the blood up to a maximum of 10 CP infusions. If steroid therapy has not already been initiated, betamethasone 3 mg daily will be given concomitantly with steroid therapy or longer if clinically indicated but for a maximum of 10 days. | Biological: SARS-CoV-2 convalescent plasma<br>* Participants will receive 200 ml convalescent plasma daily until SARS-CoV-2 is no longer detectable in the blood up to a maximum of 10 CP infusions. CP will be given as a slow infusion over 2 hours. CP neutralization titre of ≥ 1/640 or an ELISA reactivity against the Spike protein of SARS-CoV-2 by the Euroimmun commercial assay >9 is desired. New antibody tests are under development and can be used instead if equivalence to neutralization or Euroimmun ELISA is demonstrated.<br>|
| Active Comparator: Control<br>Standard of care for COVID-19 patients. | Other: Standard of care<br>* Standard of care as determined by hospital practices for COVID-19 patients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COVID-19 related mortality within 28 days | Death of a study participant within 28 days. | Measured 28 days after inclusion into the study. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COVID-19 related mortality within 60 days | Death of a study participant within 60 days. | Measured 60 days after inclusion into the study. | 
| Requirement of invasive ventilation or Pao2/FiO2 ≤ 70 for ≥ 12 hours in the case of patients not eligible for intensive care | The need for mechanical ventilation and date when this was initiated For patients not eligible for intensive care: each day when PaO2/FiO2 ratio was less than 70 for ≥ 12 hours. PaO2 and FiO2 will be estimated from SO2% and O2 flow in nasal cannula, face mask or face mask with reservoir based on EPIC II data. A ratio of 70 is approximately equal to 90% SO2 with 8-9 L of Oxygen flow using a face mask with a reservoir. | Until discharged from the hospital, up to 2 months | 
| Adverse events | Possible adverse events will be elicited using a modification and Swedish translation (appendix 6) of Common Terminology Criteria for Adverse Events v5.0 and they will be continuously reported to the sponsor. Adverse events related to convalescent plasma therapy shall be followed to assess reversibility. | The reporting period for AEs starts at inclusion and ends at the final follow-up visit 2 months after inclusion. | 
| Dose of plasma needed to clear viremia | Measured as doses of convalescent plasma administered (1-10 infusions, 200ml). | 28 days | 
| Time to clearance of viremia | Blood samples for detection of SARS-CoV-2 in the blood will be taken prior to treatment start, daily during treatment and until two consecutive negative results are obtained. | Until discharged from the hospital, up to 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19 convalescent plasma treatment, SARS-CoV-2 infection, Viremia