Convalescent plasma for hospitalized patients with COVID-19 and the effect of plasma antibodies: a randomized controlled, open-label trial

  1. The CONCOR-1 Study Group
  2. CONCOR-1 writing committee
  3. Philippe Bégin
  4. Jeannie Callum
  5. Erin Jamula
  6. Richard Cook
  7. Nancy M. Heddle
  8. Alan Tinmouth
  9. Michelle P. Zeller
  10. Guillaume Beaudoin-Bussières
  11. Luiz Amorim
  12. Renée Bazin
  13. Kent Cadogan Loftsgard
  14. Richard Carl
  15. Michaël Chassé
  16. Melissa M. Cushing
  17. Nick Daneman
  18. Dana V. Devine
  19. Jeannot Dumaresq
  20. Dean A. Fergusson
  21. Caroline Gabe
  22. Marshall J. Glesby
  23. Na Li
  24. Yang Liu
  25. Allison McGeer
  26. Nancy Robitaille
  27. Bruce S. Sachais
  28. Damon C. Scales
  29. Lisa Schwartz
  30. Nadine Shehata
  31. Alexis F. Turgeon
  32. Heidi Wood
  33. Ryan Zarychanski
  34. Andrés Finzi
  35. Donald M. Arnold
  36. for The CONCOR-1 Study Group

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Abstract

The efficacy of convalescent plasma for COVID-19 is unclear. While most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content may influence patient outcomes.

We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 days of respiratory symptom onset. Patients were allocated 2:1 to 500 mL of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 days. The effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression.

The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. 940 patients were randomized and 921 patients were included in the intent-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) in the convalescent plasma arm and 86/307 (28.0%) in the standard of care arm; relative risk (RR) 1.16 (95% confidence interval (CI) 0.94-1.43; p=0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% vs. 26.4%; RR=1.27, 95% CI 1.02-1.57, p=0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standard log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (OR=0.74; 0.57-0.95 and OR=0.66; 0.50-0.87, respectively), while IgG against the full transmembrane Spike protein increased it (OR=1.53, 95% CI 1.14-2.05).

Convalescent plasma did not reduce the risk of intubation or death at 30 days among hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavourable antibody profiles may be associated with worse clinical outcomes compared to standard care.

Trial registration

CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1); NCT04348656 ; https://www.clinicaltrials.gov/ct2/show/NCT04348656

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  1. ScreenIT

    SciScore for 10.1101/2021.06.29.21259427: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The study was approved by Clinical Trials Ontario (Research Ethics Board of Record: Sunnybrook Health Sciences Centre), project #2159; the Quebec Ministry of Health and Social Services multicenter ethics review (REB of Record: Comité d’éthique de la recherche du CHU Sainte-Justine), project #MP-21-2020-2863; the Weil Cornell Medicine General Institutional Review Board, protocol number 20-04021981; as well as the Comissão Nacional de Ética em Pesquisa, approval 4.305.792.
    Consent: Consent was obtained from all donors and participants (or their legally authorized representative).
    Sex as a biological variablenot detected.
    RandomizationTrial Design and Oversight: CONCOR-1 was an investigator-initiated, multi-center, open-label, randomized controlled trial conducted at 72 hospital sites in Canada, the United States, and Brazil.11 Eligible patients were randomly assigned to receive either convalescent plasma or standard of care.
    Blindingnot detected.
    Power AnalysisWith a 2:1 randomization ratio, 1200 patients (800 in the convalescent plasma group, and 400 in the standard of care group) were needed to provide 80% power to detect a relative risk reduction of 25% with convalescent plasma for the primary outcome with a 30% event rate under standard of care, based on a two-sided test at the 5% significance level.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    In addition, a sample from each plasma donation was tested at reference laboratories after the transfusion for: (1) anti-RBD antibodies (IgM, IgA and IgG) by enzyme-linked immunosorbent assay (ELISA);13, 14 (2) viral neutralization by the plaque-reduction neutralization test using live virus;15, 16 (3) IgG antibodies binding to the full-length trimeric transmembrane SARS-CoV-2 Spike protein expressed on 293T cells by flow cytometry;17 and, (4) Fc-mediated function by an antibody-dependent cellular cytotoxicity (ADCC) assay against the full Spike protein expressed on CEM.
    anti-RBD
    suggested: None
    IgM, IgA
    suggested: None
    IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    In addition, a sample from each plasma donation was tested at reference laboratories after the transfusion for: (1) anti-RBD antibodies (IgM, IgA and IgG) by enzyme-linked immunosorbent assay (ELISA);13, 14 (2) viral neutralization by the plaque-reduction neutralization test using live virus;15, 16 (3) IgG antibodies binding to the full-length trimeric transmembrane SARS-CoV-2 Spike protein expressed on 293T cells by flow cytometry;17 and, (4) Fc-mediated function by an antibody-dependent cellular cytotoxicity (ADCC) assay against the full Spike protein expressed on CEM.
    293T
    suggested: CCLV Cat# CCLV-RIE 1018, RRID:CVCL_0063)
    Software and Algorithms
    SentencesResources
    Randomization and Intervention: Patients were randomized in a 2:1 ratio to receive convalescent plasma or standard of care using a secure, concealed, computer-generated, web-accessed randomization sequence (REDCap).
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    20 The results from CONCOR-1 were subsequently included in a meta-analysis based on the May 20th 2021 update of the Cochrane systematic review8 and known randomised trials published since comparing convalescent plasma to placebo or standard care in patients with COVID-19.
    Cochrane systematic
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The open-label design represents a limitation of this study as knowledge of the treatment group could influence the decision to intubate, report adverse events, or administer other treatments. The antibody profile of the recipient was unavailable at the time of this analysis. In future work we will investigate the value of convalescent plasma in patients without a detectable humoral immune response. In addition, other antibody isotypes (IgM and IgA) and IgG subclasses should be evaluated in future studies to determine their effect on clinical outcomes. In summary, the CONCOR-1 trial did not demonstrate a difference in the frequency of intubation or death at 30 days with convalescent plasma or standard of care in hospitalized patients with COVID-19 respiratory illness. The antibody content had a significant effect-modifying role for the impact of convalescent plasma on the primary outcome. The lack of benefit and the potential concern of harm cautions against the unrestricted use of convalescent plasma for hospitalized patients with COVID-19.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04348656TerminatedCONvalescent Plasma for Hospitalized Adults With COVID-19 Re…
    NCT04355767CompletedConvalescent Plasma in Outpatients With COVID-19

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.06.29.21259427v1 on medRxiv