Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial

Abstract

Importance: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19.

Objective: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen.

Design, setting, and participants: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation.

Interventions: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline).

Main outcomes and measures: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8.

Results: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06).

Conclusions and relevance: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use.

Trial registration: ClinicalTrials.gov Identifier: NCT04364737.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Philley reported receiving personal fees from INSMED as an advisory board member, consultant, researcher, and member of the speaker’s bureau, fees from participating in trials as an investigator from Regeneron, Redhill, AN2, Electromed, and Zambon; fees from the France Foundation speaker's bureau, and fees from the RMEI educational bureau outside the submitted work. Dr Devine reported serving as an investigator for the REGENERON studies. Dr Santin reported receiving grants from Puma, Immunomedics, Gilead, and Synthon; grants and personal fees from Merck; grants from Boehringer-Ingelheim and Genentech, grants and personal fees from Tesaro; and grants and personal fees from Eisai. Dr Chandran reported receiving fees from Biovaxys Technology Corp as a science advisory board member, consulting fees from Axon Advisors Consulting, and fees from Integrum Scientific LLC as a science advisory board member outside the submitted work; in addition, Dr Lai reported receiving consultant fees from Celdara Medical and grants from the Mapp Biopharmaceutical Collaboration and Integrated BioTherapeutics Collaboration outside the submitted work; in addition, Dr Lai had a patent for SARS-CoV2 laboratory diagnostic test pending and a patent for antibodies targeting SARS-CoV2 pending. Dr Shenoi having a spouse who worked for Merck Pharmaceuticals 1997-2007 and retains company stock in his retirement account. No other disclosures were reported.

Figures

Figure 1.. Patient Screening, Enrollment, and Treatment Assignment

Figure 2.. Primary and Secondary Outcomes by Treatment Group

Distribution of clinical status assessed on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement 14 and 28 days after randomization. ECMO indicates extracorporeal membrane oxygenation; HFNC, high-flow nasal cannula; MV, mechanical ventilation; NIV, noninvasive ventilation; PO2/FIO2, ratio of partial pressure of oxygen (PO2) to fraction of inspired oxygen (FIO2).

Figure 3.. Posterior Distributions of Cumulative Odds Ratio (OR) for World Health Organization (WHO) Scores and OR for Mortality 14 and 28 Days After Randomization

Posterior distribution of cumulative OR and OR estimates from bayesian models adjusted for sites, baseline risk, baseline WHO score, age, sex, and days since symptom onset to randomization (0-3, 4-7, or >7 days). Sites were combined within networks (New York University, Albert Einstein College of Medicine, Montefiore Medical Center, Yale University School of Medicine, University of Miami Miller School of Medicine, University of Texas Health Science Center at Houston, University of Texas Health Science Center at Tyler, Johns Hopkins University, and Medical College of Wisconsin Froedtert Hospital). The dashed curves represent the prior distribution assumptions for the ORs, and the solid curves represent the estimated posterior probability distributions of the ORs: P(ORs). The area under each solid curve totals 1, and the area to the left of the dashed orange line represents P(OR

Figure 4.. Clinical Outcomes among Patients Treated With COVID-19 Convalescent Plasma and Placebo 14 Days After Randomization by Remdesivir/Corticosteroid Use

Distribution of clinical status assessed on the 11-point WHO Ordinal Scale for Clinical Improvement 14 days after randomization by remdesivir and/or corticosteroid use shown by cumulative OR (curves) and WHO scores (stacked bars). In the top panel, the dashed curves represent the prior distribution assumptions for the ORs, and the solid curves represent the estimated posterior probability distributions of the ORs: P(ORs). The area under each solid curve totals 1, and the area to the left of the dashed orange line represents P(OR2/FIO2, ratio of partial pressure of oxygen (PO2) to fraction of inspired oxygen (FIO2).