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

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

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.

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.

Only the two experimental arms are masked. COVID-19 convalescent plasma (CP) and standard plasma (SP) will be masked and delivered to the wards in identical bags; a tag printed as "PLASMA TRIAL" will cover the actual name of the product

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.

STP + 3 units on day 1-3-5 of COVID-19 Convalescent Plasma containing neutralizing SARS-Cov-2 antibodies

Standard Therapy Protocol according to the best evidence treatment recommended by the Regional Health System emergency committee

Transfusion of three SARS-Cov-2 neutralizing antibodies positive Plasma Units (CP) on day 1,3,5 in addition to STP

From date of randomization until the date of discharge or date of death from any cause, whichever came first, assessed up to 12 months

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

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

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

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

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

All Individual Participant Data requests should be submitted to the corresponding author for consideration. Access to deidentified participant data may be granted following review, after the publication of major results