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.

A Phase II Study on the Use of Convalescent Plasma for the Treatment of Severe COVID-19- A Propensity Score-Matched Control Analysis

“…In the study by Altuntas et al, a higher rate of mechanical ventilation support was observed in patients receiving CP 20 days after diagnosis compared to three interval groups (< 5, 6-10, and 11-15 days, p = 0.001) [23]. We failed to find a significant effect of the time to CP infusion, regarding all primary and secondary outcomes, in accordance with a recently published randomized trial where no significant difference was observed in mortality or disease deterioration in early (< 7 days of symptom onset) vs. late CP administration [43].…”

“…In most clinical trials, one to two units from one or different donors have been proposed for treatment. In some studies, only CP with arbitrarily defined high titers were used, resulting in significant reduction in the risk of death or disease progression [28,29,43].…”

“…The data regarding the efficacy of CP in COVID-19 are gradually increasing, including small case series [25,34,36], observational studies [27,32,33,42,55], matched controlled studies [21,23,30,[37][38][39][40][41][44][45][46][47]56] and a few randomized controlled trials [22,24,26,28,29,35,43], with no definite conclusions. In the observational study by Salazar et al of 25 patients with severe and life threatening disease, the infusion of CP resulted in the improvement of disease severity in 76% of patients [33].…”

Effect of time and titer in convalescent plasma therapy for COVID-19

“…During the screening phase of these manuscripts, 15 were excluded: three studies did not report mortality data or compared mortality rate with national registries (Bradfute et al, 2020;Dulipsingh et al, 2020;Perotti et al, 2020); for two studies, we were unable to assess our inclusion criteria (Anakli et al, 2021;Skrip et al, 2020); seven had no comparative group (Dulipsingh et al, 2020;Gonzá lez et al, 2020;Jaiswal et al, 2021;Madariaga et al, 2020;Olivares-Gazca et al, 2020;Tremblay et al, 2020;Valentini et al, 2020); and three studies made use of plasma from non-convalescent, generic donors (De-Simone et al, 2021;Faqihi et al, 2020;Kamran et al, 2021). Of the 25 studies included for the quantitative meta-analysis, 10 were RCTs (Agarwal et al, 2020;AlQahtani et al, 2020;Avendano-Sola et al, 2020;Balcells et al, 2021;Gharbharan et al, 2020;Horby et al, 2021;Li et al, 2020a;Libster et al, 2021;Rasheed et al, 2020;Simonovich et al, 2020), while the other 15 were non-randomized studies with different designs (Abolghasemi et al, 2020;Alsharidah et al, 2021;Altuntas et al, 2021;Budhiraja et al, 2021;Donato et al, 2021;Duan et al, 2020;Hegerova et al, 2020;Joyner et al, 2021;Liu et al, 2020;Omrani et al, 2021;Salazar et al, 2020a;Shenoy et al...…”

“…Of the 25 studies included for the quantitative meta-analysis, 10 were RCTs (Agarwal et al, 2020;AlQahtani et al, 2020;Avendano-Sola et al, 2020;Balcells et al, 2021;Gharbharan et al, 2020;Horby et al, 2021;Li et al, 2020a;Libster et al, 2021;Rasheed et al, 2020;Simonovich et al, 2020), while the other 15 were non-randomized studies with different designs (Abolghasemi et al, 2020;Alsharidah et al, 2021;Altuntas et al, 2021;Budhiraja et al, 2021;Donato et al, 2021;Duan et al, 2020;Hegerova et al, 2020;Joyner et al, 2021;Liu et al, 2020;Omrani et al, 2021;Salazar et al, 2020a;Shenoy et al, 2021;Xia et al, 2020;Yoon et al, 2021;Zeng et al, 2020), as detailed in Table S1. Two studies did not have a control group; nonetheless, one provided the relative mortality data upon multiple comparisons between patients receiving high vs. low titer plasma and between early (%3 days from hospitalization) and late treatment (Joyner et al, 2021), or comparing the effects of immediate plasma treatment toward plasma treatment only upon patient deterioration (deferred treatment) (Balcells et al, 2021), and they were thus both included. Similarly, Salazar et al provided multiple comparisons considering treatment time and plasma titer, all compared with a matched control group without treatment (Salazar et al, 2020a) and other three studies contained subgroup data for comparing early and late treatment, based on the severity of enrolled patients (Alsharidah et al, 2021;Donato et al, 2021;Horby et al, 2021).…”