Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial

  1. Florence Ader
  2. Maude Bouscambert-Duchamp
  3. Maya Hites
  4. Nathan Peiffer-Smadja
  5. Julien Poissy
  6. Drifa Belhadi
  7. Alpha Diallo
  8. Christelle Delmas
  9. Juliette Saillard
  10. Aline Dechanet
  11. Claire Fougerou
  12. Minh-Patrick Lê
  13. Gilles Peytavin
  14. Noémie Mercier
  15. Priyanka Velou
  16. Sarah Tubiana
  17. Xavier Lescure
  18. Emmanuel Faure
  19. Saad Nseir
  20. Jean-Christophe Richard
  21. Florent Wallet
  22. François Goehringer
  23. Benjamin Lefèvre
  24. Antoine Kimmoun
  25. François Raffi
  26. Benjamin Gaborit
  27. Jean Reignier
  28. Jean-Philippe Lanoix
  29. Claire Andrejak
  30. Yoann Zerbib
  31. Firouzé Bani-Sadr
  32. Bruno Mourvilliers
  33. François Danion
  34. Yvon Ruch
  35. Raphaël Clere-Jehl
  36. Vincent Le Moing
  37. Kada Klouche
  38. Karine Lacombe
  39. Guillaume Martin-Blondel
  40. Fanny Vardon-Bounes
  41. André Cabié
  42. Jean-Marie Turmel
  43. Lionel Piroth
  44. Mathieu Blot
  45. Élisabeth Botelho-Nevers
  46. Amandine Gagneux-Brunon
  47. Guillaume Thiery
  48. François Bénézit
  49. Rostane Gaci
  50. Joy Mootien
  51. Sébastien Gallien
  52. Denis Garot
  53. Kevin Bouiller
  54. Loïc Epelboin
  55. Stéphane Jauréguiberry
  56. Alexandre Gaymard
  57. Gil Verschelden
  58. Sandra Braz
  59. Joao Miguel Ferreira Ribeiro
  60. Michael Joannidis
  61. Thérèse Staub
  62. Antoine Altdorfer
  63. Richard Greil
  64. Alexander Egle
  65. Jérémie Guedj
  66. Marion Noret
  67. Roberto Roncon-Albuquerque
  68. Jose-Artur Paiva
  69. Bruno Lina
  70. Dominique Costagliola
  71. Yazdan Yazdanpanah
  72. Charles Burdet
  73. France Mentré

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Abstract

Background

The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring.

Methods

In this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948 ; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-β-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.

Findings

Between March 22 nd , 2020 and January 21 st , 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420).

At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29).

Interpretation

Remdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15.

Funding

European Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER “European Regional Development Fund”, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.

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  1. Version published to 10.1101/2022.03.30.22273206v2 on medRxiv
  2. ScreenIT

    SciScore for 10.1101/2022.03.30.22273206: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744), and is sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France); it was conducted in accordance with the Declaration of Helsinki.
    Consent: Written informed consent was obtained from all included participants (or their legal representatives if unable to consent).
    Sex as a biological variableWomen of childbearing potential must agree to use at least one primary form of contraception for the duration of the study.
    RandomizationStudy design: DisCoVeRy is a phase 3, open-label, adaptive, multicentre, randomised, controlled, superiority trial for evaluating the efficacy and safety of repurposed drugs in adults hospitalised for COVID-19 (1).
    BlindingVirological methods: Systematic determination of the normalized viral load blinded to treatment arm was performed on NPS specimens by RNA extraction on the EMAG® platform (bioMerieux, Marcy-l’Étoile, France) following manufacturer’s instructions.
    Power AnalysisSample size calculation: The sample size was determined assuming the following scenario under SoC for each item of the ordinal scale at day 15: 1, 42%; 2, 38%; 3, 8%; 4, 7%; 5, 2%; 6, 1%; 7, 2%.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All analyses were performed using SAS v9.4 (SAS Institute, Cary, NC, USA).
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    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 trial has some limitations. It was open, and not placebo-controlled. Indeed, several treatments were concomitantly evaluated at the beginning of the trial, and blinding was thus impossible due to the different modes of administration (intravenous, subcutaneous or oral) of the different treatment arms. This might have introduced bias in the follow up and management of patients, and in the evaluation of endpoints whose assessment contains elements of subjectivity: decision to begin corticosteroids in patients management or to begin mechanical ventilation might have been influenced by the knowledge of the treatment arm, even unconsciously. This risk of bias is however mitigated for the viral load, which was analysed blindly from treatment arm. Next, viral load assessment was not available for 18% of participants (nearly half at baseline). However, the proportions of participants with available viral loads at each sampling time were similar in both experimental groups, suggesting that NP sampling was not guided by the allocated treatment. Finally, plasma concentrations of the prodrug remdesivir and GS-441524 were assessed in only 10% of participants and the concentrations of its intracellular active metabolite were not measured. Although the trial was not designed as a pharmacokinetic study, it provides currently lacking data on remdesivir exposure in patients hospitalised with COVID-19.

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

    IdentifierStatusTitle
    NCT04315948RecruitingTrial of Treatments for COVID-19 in Hospitalized Adults

    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.

  3. Version published to 10.1101/2022.03.30.22273206v1 on medRxiv