Standard or Convalescent Plasma in Patients With Recent Onset of COVID-19 Respiratory Failure

Study Overview
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Brief Summary
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To date no specific treatment has been proven to be effective for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) infection. It is possible that convalescent plasma that contains antibodies to SARS-Cov-2 might be effective against the progression of infection. Promising results have been shown by preliminary data from China cases. The investigators planned to compare effectiveness of adding COVID-19 convalescent plasma to standard therapy protocol (STP) versus adding plasma donated in pre-COVID era versus STP alone in patient with COVID-19 within 5 days from the onset of respiratory distress. STP at enrolment is the best evidence based therapy approved for treatment of COVID patients by regional Health system emergency committee.

Detailed Description
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500-700 ml of Plasma will be collected by apheresis from COVID recovered donors showing the presence of neutralizing antibodies to SARS-Cov-2 (anti-SARS-Cov-2). All plasma will be screened for transmissible diseases according to italian law (Hepatitis B Virus,Hepatitis C Virus, Human Immunodeficiency Virus 1-2, Syphilis) plus adjunctive screening for Hepatitis A Virus and Hepatitis E Virus-RNA and Parvovirus B19-DNA as requested from Italian National Blood Authority. Apheresis will be divided in two/three units (170-300 ml each), virus inactivated with Riboflavin and ultraviolet light illumination technology and immediately frozen and stored separately from other plasma bags. Enrolled patients will be stratified according to severity of respiratory failure and randomized in three arms: 1) Standard Therapy Protocol (STP), 2) Standard Therapy Protocol + 170-350 ml standard Plasma (SP) on day 1-3-5 after randomization, 3) Standard Therapy Protocol + 170-350 ml COVID-19 Convalescent Plasma on day 1-3-5 after randomization. The three therapeutic units of COVID-19 Convalescent plasma will be chosen in order to minimize variations among patients in the total amount of infused SARS-Cov-2 antibodies.

Official Title
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Effectiveness of Adding Standard Plasma or COVID-19 Convalescent Plasma to Standard Treatment, Versus Standard Treatment Alone, in Patients With Recent Onset of COVID-19 Respiratory Failure. A Randomized, Three-arms, Phase 2 Trial

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Standard Therapy Protocol (STP)
* Other: STP + Standard Plasma (SP)
* Other: STP + COVID-19 Convalescent Plasma (CP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed SARS-Cov-2 diagnosis by RT-PCR on nasopharyngeal swab or on bronchoalveolar lavage Respiratory failure onset or progression within 5 days Signed Informed Consent Exclusion Criteria: Pregnancy Previous severe reactions to plasma transfusion Unavailability of blood group compatible COVID-19 convalescent plasma

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: Three arms randomized trial, partially blinded
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard therapy protocol (STP)<br>STP is defined as the best evidence based therapy approved for treatment of COVID-19 patients by Regional Health System emergency committee. STP could be updated during the trial. | Drug: Standard Therapy Protocol (STP)<br>* Standard Therapy Protocol according to the best evidence treatment recommended by the Regional Health System emergency committee<br>|
| Experimental: STP + Standard Plasma (SP)<br>STP + 3 units on day 1-3-5 of Standard Plasma collected in pre-COVID era (January-September 2019) | Drug: Standard Therapy Protocol (STP)<br>* Standard Therapy Protocol according to the best evidence treatment recommended by the Regional Health System emergency committee<br>Other: STP + Standard Plasma (SP)<br>* Transfusion of three Standard Plasma Units (SP) on day 1,3,5 in addition to STP<br>|
| Experimental: STP + COVID-19 Convalescent Plasma (CP)<br>STP + 3 units on day 1-3-5 of COVID-19 Convalescent Plasma containing neutralizing SARS-Cov-2 antibodies | Drug: Standard Therapy Protocol (STP)<br>* Standard Therapy Protocol according to the best evidence treatment recommended by the Regional Health System emergency committee<br>Other: STP + COVID-19 Convalescent Plasma (CP)<br>* Transfusion of three SARS-Cov-2 neutralizing antibodies positive Plasma Units (CP) on day 1,3,5 in addition to STP<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30-days survival | Proportion of patients alive 30 days after randomization | 30 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator free survival | Cumulative incidence of mechanical ventilation or death | 30 days after randomization | 
| 6-months survival | Probability of being alive at 6 months after randomization | 6 months after randomization | 
| Incidence of complications | Proportion of patients developing any serious medical or procedure related complications | Within 12 months | 
| Days in intensive care units (ICU) | Proportion of days spent in ICU on the total length of hospital stay | From date of randomization until the date of discharge or date of death from any cause, whichever came first, assessed up to 12 months | 
| Positivity for Immunoglobulin G to SARS-Cov-2 | Proportion of patients showing seroconversion to Immunoglobulin G (IgG) anti-SARS-Cov-2 | On day 0, 2, 4, 6,10,14, 21, 28 after randomization and at date of discharge or death from any cause, whichever came first, assessed up to 12 months | 
| Clearance of viral load | Proportion of patients showing viral clearance by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) on plasma and respiratory tract samples | On day 0, 2, 4, 6,10,14, 21, 28 after randomization and at date of discharge or death from any cause, whichever came first, assessed up to 12 months | 
| Sequential Organ Failure Assessment (SOFA) score | Variations in SOFA Score (range 0-24; higher score mean a worse outcome) | On day 0, 2, 4, 6, 10, 14, 28 after randomization and at date of discharge or death from any cause, whichever came first, assessed up to 12 months | 
| Any variation from Standard Therapy Protocol | Proportion of patients needing introduction of new drug or discontinuation of drug from standard therapy protocol | From date of randomization until the date of discharge or date of death from any cause, whichever came first, assessed daily up to 2 months |