A randomized, double-blind, controlled trial of convalescent plasma in adults with severe COVID-19

O'Donnell, M.; Grinsztejn, B.; Cummings, M.; Justman, J.; Lamb, M.; Eckhardt, C.; Phillip, N.; Cheung, K.; Abrams, D.; Gupta, V.; Diniz, M. P.; Cardoso, S. W.; Rajagopalan, K.; Borden, S.; Wolf, A.; Bitan, Z.; Meyer, B.; Jacobson, S.; Kantor, A.; Mishra, N.; Hod, E.; Briese, T.; Sidi, L. C.; Wontakal, S.; Hudson, K.; Stotler, B.; Lin, W.-H.; Pilotto, J. H.; Joao, E.; Chauhan, L.; Veloso, V.; Schwartz, J.; Stone, E.; Dei Zotti, F.; La Carpia, F.; Shaz, B.; Ferrara, S.; Vizzoni, A.; Spitalnick, S.; Eisenberger, A.; Lipin, W. I.

Background: Although convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited. Objective: To evaluate the clinical efficacy and safety of convalescent plasma among adults hospitalized with severe and critical COVID-19. Design: Randomized, double-blind, controlled, multicenter, phase 2 trial conducted from April 21st to November 27th, 2020. Setting: Five hospitals in New York City (NY, USA) and Rio de Janeiro (Brazil). Participants: Hospitalized patients aged [≥]18 years with laboratory-confirmed COVID-19, infiltrates on chest imaging and oxygen saturation [≤] 94% on room air or requirement for supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Intervention: Participants were randomized 2:1 to a single transfusion of either 1 unit of convalescent or normal control plasma. Measurements: The primary outcome was clinical status at 28 days, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population (with an odds ratio (OR) >1.0 indicating improved clinical status in the convalescent plasma group). Results: Of 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to normal control plasma. At 28 days, no significant improvement in clinical status was observed in participants randomized to convalescent plasma (OR 1.50, 95% confidence interval (CI) 0.83-2.68, p=0.180). However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 [12.6%] versus 18/73 [24.6%], OR 0.44, 95% CI 0.22-0.91, p=0.034). The median titer of anti-SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80-1:320). In a subset of nasopharyngeal swab samples from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected. Serious adverse events occurred in 39/147 (27%) participants who received convalescent plasma and 26/72 (36%) participants who received control plasma. Limitations: Some participants did not receive high-titer convalescent plasma. Conclusion: In adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in 28 days clinical status. However, a significant improvement in mortality was observed, which warrants further evaluation. Registration: ClinicalTrials.gov, NCT04359810 Funding: Amazon Foundation