Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial

  1. María Elvira Balcells
  2. Luis Rojas
  3. Nicole Le Corre
  4. Constanza Martínez-Valdebenito
  5. María Elena Ceballos
  6. Marcela Ferrés
  7. Mayling Chang
  8. Cecilia Vizcaya
  9. Sebastián Mondaca
  10. Álvaro Huete
  11. Ricardo Castro
  12. Mauricio Sarmiento
  13. Luis Villarroel
  14. Alejandra Pizarro
  15. Patricio Ross
  16. Jaime Santander
  17. Bárbara Lara
  18. Marcela Ferrada
  19. Sergio Vargas-Salas
  20. Carolina Beltrán-Pavez
  21. Ricardo Soto-Rifo
  22. Fernando Valiente-Echeverría
  23. Christian Caglevic
  24. Mauricio Mahave
  25. Carolina Selman
  26. Raimundo Gazitúa
  27. José Luis Briones
  28. Franz Villarroel-Espindola
  29. Carlos Balmaceda
  30. Manuel A. Espinoza
  31. Jaime Pereira
  32. Bruno Nervi

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Abstract

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 .

Article activity feed

  1. Version published to 10.1371/journal.pmed.1003415
  2. ScreenIT

    SciScore for 10.1101/2020.09.17.20196212: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Laboratory and radiology secondary outcomes were analyzed by modified-ITT, excluding a patient who withdrew consent before any intervention.
    IRB: Ethics: This study was approved by the Institutional Review Board of the Pontificia Universidad Católica de Chile.
    RandomizationThis study consisted of a randomized, controlled, open-label phase II trial done in a single Chilean medical center in Santiago, Chile.
    BlindingFor the combined analysis with portable chest X-rays, a blinded thoracic radiologist expert categorized images as “progression” vs “stable or improved”.
    Power AnalysisStatistical Analysis: Sample size was calculated with a power of 80% and a statistical significance of 5% for an absolute risk reduction of 35% in the primary outcome based on a previous report of convalescent plasma administration in the early stage of AH1N1 influenza[26].
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Also, pre-planned analyses of baseline neutralizing antibodies (NAbs) titers, and anti-SARS-CoV-2 IgG titers were determined in participants from the early plasma group and in the subset of participants from the deferred plasma group who had not yet received plasma on days 0, 3 and 7.
    anti-SARS-CoV-2 IgG
    suggested: None
    Neutralizing antibody titers assay: Anti-SARS-CoV-2 NAbs were measured in serum samples using an HIV-1 backbone expressing firefly luciferase as a reporter gene and pseudotyped with the SARS-CoV-2 Spike glycoprotein[24,25].
    Anti-SARS-CoV-2
    suggested: None
    Software and Algorithms
    SentencesResources
    Analyses were done with R version 3.6.3 and figures with GraphPad Prism version 8.4.3 software.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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:
    Our study presents some limitations. Firstly, NAbs were not determined in donor plasma before the patient’s transfusion and we could not select plasma units with the highest neutralizing activity. Secondly, although we selected a very homogeneous population, it is possible that the study was underpowered to detect a statistically significant difference. Thirdly, as an open-label study, cointerventions such as steroid use may have unintendedly influenced outcomes[35]. Such management was not standardized, although alternative drug therapies were equally distributed in both study arms. In conclusion, convalescent plasma transfusion in patients hospitalized in the early stage of COVID-19, compared to giving plasma only at clinical deterioration, did not improve clinical outcomes. Further research is needed to find the optimal use and timing of convalescent plasma in COVID-19.

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

    IdentifierStatusTitle
    NCT04375098CompletedEfficacy and Safety of Early COVID-19 Convalescent Plasma in…

    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.

    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.

  3. Version published to 10.1101/2020.09.17.20196212v1 on medRxiv