Early Outpatient Treatment for Covid-19 with Convalescent Plasma

Abstract

Background: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain.

Methods: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion.

Results: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.

Conclusions: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

Figure 1. Enrollment, Randomization, and Follow-up.

Participants may have had more than one reason for exclusion from the trial. The modified intention-to-treat population included all the participants who underwent randomization and received a transfusion. There was 100% ascertainment of the primary-outcome events by day 28.

Figure 2. Cumulative Incidence of Coronavirus Disease 2019–Related Hospitalization.

On the left, the results of the unadjusted analysis are shown. Shading indicates the 95% confidence interval. On the right, estimates according to the adjusted targeted minimum loss–based estimation model are shown. The insets show the same data on an expanded y axis.

Figure 3. Subgroup Analyses.

Subgroup analyses suggested that participants who received a transfusion within 5 days after symptom onset had a greater reduction in the risk of hospitalization than those who received a transfusion later. These subgroup point estimates are considered to be hypothesis generating. The statistical analysis plan did not include a provision for correcting for multiplicity when conducting tests for other outcomes, so the results are reported as point estimates for relative risk and corresponding 95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity, so the intervals should not be used to infer definitive treatment effects for these outcomes. The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters.