Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial

Abstract

Background: Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.

Methods and findings: The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32-2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54-17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19-2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion.

Conclusions: In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration.

Trial registration: NCT04375098.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: -S.M. is a consultant for Foundation Medicine and Roche; he also has received research funding from Bristol-Myers Squibb and Foundation Medicine. - C.C is the Head of Cancer Research Department at Instituto Oncológico Fundación Arturo López Pérez (FALP) and declares that FALP has received funding from "Confederación de la producción y el Comercio (CPC)" to develop research based on Convalescent Plasma from COVID-19 recovered patients to treat patients with active COVID-19 infection. None of the authors from FALP has received any payment for their participation in this publication nor for participating in the trial in their investigator roles.

Figures

Fig 1. Study flow diagram.

Patient enrollment and treatment assignment. SAE, serious adverse event.

Fig 2. Time from enrollment to key secondary outcomes.

(A) Time from enrollment to severe respiratory failure development (PaO2/FiO2 < 200) in the early plasma and deferred plasma groups. (B) Time from enrollment to death in the early plasma and deferred plasma groups.

Fig 3. SARS-CoV-2 real-time PCR in nasopharyngeal samples.

(A) Each column represents the real-time PCR results obtained in patients from the early plasma group and deferred plasma group. Above the columns, the number of samples is indicated. The proportion of positive PCR is represented in white, negative PCR in black, and an indeterminate result (CT ≥ 35) dotted. (B) Changes in real-time PCR CT for patients from the early plasma group and for the subset of patients from the deferred plasma group that did not receive plasma before day 3 or day 7. Results are expressed as the ratio between CT values from day 0 (D0) to day 3 (D3) and D0 to day 7 (D7). Filled circles represent each patient from the early plasma group, and open circles represent patients from the deferred plasma group. Above the scatter plots, the number of available samples is indicated; lines represent the medians. CP, convalescent plasma; CT, cycle threshold.

Fig 4. The humoral immune response induced by SARS-CoV-2.

(A) IgG seropositivity (optical density [OD] ratio ≥ 1.1) analysis by sampling day: D0, day of enrollment; D3, the third day after enrollment; D7, 7 days after enrollment. Dashed columns represent the patients who received convalescent plasma (CP) at enrollment (n = 26 samples available on day 0, n = 26 on day 3, and n = 23 on day 7); white columns represent the patients from the deferred plasma group who did not receive plasma (n = 20 samples available on day 0, n = 20 on day 3, and n = 12 on day 7). Above each column, the percentage of seropositivity is indicated. (B) IgG seroconversion was considered to have occurred if a patient had a negative sample at 1:100 dilution at baseline but increased to any positive dilution after 72 hours or 7 days, or if a 4-fold increase in endpoint dilution titer from baseline was reached. Dashed columns represent patients who received CP; white columns represent patients from the deferred plasma group who did not receive plasma. Above each column, the percentage of seroconversion is indicated. (C) Neutralizing antibody (NAb) titer measured by 50% inhibitory dose (ID50) quantified at D0. The total number of patients reaching every dilution titer interval is indicated above each column. *ID50 titer ≤ 1:159 or no neutralization observed. (D) NAb titers showed by days since COVID-19 symptom onset. Each column represents the number of days after onset of symptoms; above each column are the number of individuals. Summary statistics above represent the number of individuals with NAb titers ≥ 1:160 from 2 groups: those enrolled in the first 5 days since symptom onset and those enrolled 6 or 7 days since symptom onset. *ID50 titer ≤ 1:159 or no neutralization observed.