Early Convalescent Plasma for High-Risk Outpatients with Covid-19

Abstract

Background Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19. Methods In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause. Results A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, −6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups. Conclusions The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767 .)

COVID-19 convalescent plasma and randomized clinical trials: explaining conflicting outcomes and finding signals of efficacy

“…CCP therapy requires matching on blood type, ordering the CCP, which may or may not be available on site, and setting up the transfusion. This inherent delay from randomization to infusion means that RCTs may build in a disadvantage for the CCP study arm, where controls may have received treatment earlier in the disease course (as, for example, in the CP3O trial (23). ABO-compatible CCP units may be not readily available at the local blood bank and recruited patients may have to wait for a compatible unit of CCP.…”

“…This finding has implication for RCTs that use nationally sourced (centralized) CCP, since the attempt to standardize the therapeutic units centrally could inadvertently reduce CCP efficacy if hospitals use CCP obtained from distant loci. For example, in the C3PO RCT, which was conducted in 21 USA states, 95% of the donor CCP was collected in either Chicago or Denver: since only 4 of the 48 centers were in Illinois or Colorado, most CCP usage had to be from remote sources (23). By contrast, the NCT04359810 RCT in New York and Brazil used CCP locally sourced in New York, whose efficacy against P.1 was tested to ensure efficacy at the other recruiting center in Brazil (11).…”

Vaccination of COVID-19 Convalescent Plasma Donors Increases Binding and Neutralizing Antibodies Against SARS-CoV-2 Variants

“…However, based on further findings from observational studies, the beneficial effects of CCP were limited to units with high titers of neutralizing antibodies (nAbs) administered early after infection, and efficacy was not confirmed by recent large randomized trials 3 . For example, the Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) study showed no significant beneficial effect in mildly symptomatic treated patients compared to controls 4 , with similar findings in the CONCOR-1 study in hospitalized patients 5 ; both were halted early for futility.…”

Update on and Future Directions for Use of Anti–SARS-CoV-2 Antibodies: National Institutes of Health Summit on Treatment and Prevention of COVID-19

“…These studies suggested that CP acts like a conventional antiviral, so benefit may be seen only when CP is administered early in the disease course with donor units containing potent, high-titer antibodies. Disappointingly, however, the C3PO (Convalescent Plasma in Outpatients With COVID-19) trial (ClinicalTrials.gov: NCT04355767) in recently diagnosed outpatients failed to show benefit ( 23 ).…”