Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial

Abstract

Background: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection.

Methods: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600).

Discussion: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification.

Trial registration: Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.

Keywords: COVID-19; Convalescent plasma; Coronavirus; Randomized controlled trial; SARS-CoV-2.

Fig. 1

Trial overview

Fig. 2

Possible mechanisms of action of passively transferred antibodies in COVID-19. These include viral neutralization, complement-mediated antibody-dependent virolysis, antibody-dependent enhancement of immune response, antibody-mediated presentation of antigen, and antibody-dependent cell cytotoxicity. Of these, only viral neutralization is measured by neutralization assays currently used to qualify convalescent plasma

Fig. 3

Flow chart for AE and SAE reporting in the trial

Fig. 4

Organizational chart for the CONCOR-1 trial

Fig. 5

Expected distribution of transfused plasma potency. The distribution of mean antibody titre in transfused convalescent plasma units was projected by performing a simulation in which plasma units from different donors were paired randomly. The simulation is based on the titres of 1150 plasma units currently in inventory at one of the blood suppliers (Héma-Québec). Titers were originally established with an in-house ELISA but have been translated in equivalent d/co units from the ORTHO VITRIOS IgG assay