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

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 21 ^st to November 27 ^th , 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.

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 (with an odds ratio (OR) of a 1-point improvement in the scale: 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 (n=40) 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. The significant reduction in mortality associated with convalescent plasma, however, may warrant further evaluation.

Registration

ClinicalTrials.gov, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04359810">NCT04359810</ext-link>

Funding

Amazon Foundation

Clinical Trial Registration

<ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> Identifier: <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04359810">NCT04359810</ext-link>