Convalescent or standard plasma versus standard of care in the treatment of COVID-19 patients with respiratory impairment: short and long-term effects. A three-arm randomized controlled clinical trial

Abstract

Background The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies. Methods To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle. Results 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57–73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61–2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63–2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively. Conclusions Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020

Exploring Study Design Foibles in Randomized Controlled Trials on Convalescent Plasma in Hospitalized COVID-19 Patients

“…A statistically significant low in the median expected absolute difference was observed in studies with a favorable outcome [21,28] compared to those with an unfavorable outcome [7,12,15,18,22,38,39,45,46] (20.0% versus 33.9%, p = 0.04).…”

“…After the exclusion of 130 records, 94 full-text articles were identified and assessed for eligibility, resulting in the selection of 48 RCTs. Finally, after the exclusion of 16 RCTs (see Supplementary Table S1 for the reasons for their exclusion), 32 RCTs [7,8,10,[12][13][14][15][16][17][18][20][21][22]25,26,28,[30][31][32]34,35,[37][38][39]41,43,[45][46][47][48][49]51] were included in the systematic review. The study selection process is summarized in the PRISMA flow diagram in Figure 1.…”

Effects of remdesivir on SARS-CoV-2 viral dynamics and mortality in viraemic patients hospitalized for COVID-19

“… 28–32 A randomized study reported no effect on clearance of viraemia with three units of convalescent plasma ( n = 60) compared with standard of care ( n = 60). 33 In contrast, one unit of convalescent plasma was administered daily until serum viral clearance at our study hospital, which may explain a difference between these studies. It is, however, important to note that results from this study were incidental findings and that the study was primarily designed to investigate the effect of remdesivir and not convalescent plasma treatment.…”

Convalescent Plasma Therapy for COVID-19: A Systematic Review and Meta-Analysis on Randomized Controlled Trials

“…For the 28-day main cohort, 34 randomized controlled trials were included [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. For the 14-day secondary cohort, 10 articles on randomized controlled trials provided the necessary data.…”

“…In total, 34 studies were included in the overall meta-analysis for the 28-day cohort [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. The effect outcome for 28-day mortality was not statistically significant [RR = 1.00, 95% C.I.…”