Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis

  1. RECOVERY Collaborative Group
  2. Peter W Horby
  3. Jonathan R Emberson
  4. Marion Mafham
  5. Mark Campbell
  6. Leon Peto
  7. Guilherme Pessoa-Amorim
  8. Enti Spata
  9. Natalie Staplin
  10. Catherine Lowe
  11. David R Chadwick
  12. Christopher Brightling
  13. Richard Stewart
  14. Paul Collini
  15. Abdul Ashish
  16. Christopher A Green
  17. Benjamin Prudon
  18. Tim Felton
  19. Anthony Kerry
  20. J Kenneth Baillie
  21. Maya H Buch
  22. Jeremy N Day
  23. Saul N Faust
  24. Thomas Jaki
  25. Katie Jeffery
  26. Edmund Juszczak
  27. Marian Knight
  28. Wei Shen Lim
  29. Alan Montgomery
  30. Andrew Mumford
  31. Kathryn Rowan
  32. Guy Thwaites
  33. Richard Haynes
  34. Martin J Landray

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Background

We evaluated the use of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, for the treatment of patients admitted to hospital because of COVID-19.

Methods

This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was conducted that included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov ( NCT04381936 ).

Findings

Between 2 February 2021 and 29 December 2021, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% receiving tocilizumab (with planned use within the next 24 hours recorded for a further 9%). Overall, 513 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77-0·98; p=0·026). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of 8 previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths) in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0.57; 95% CI 0.45-0.72). Including the results from RECOVERY into an updated meta-analysis of all 9 completed trials (involving 11,888 randomised patients and 1484 deaths) allocation to baricitinib or other JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0.80; 95% CI 0.71-0.89; p<0.001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no excess of thrombosis, or other safety outcomes.

Interpretation

In patients hospitalised for COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.

Funding

UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2022.03.02.22271623: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The trial is conducted in accordance with the principles of the International Conference on Harmonisation–Good Clinical Practice guidelines and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee (ref: 20/EE/0101).
    Consent: Written informed consent was obtained from all patients, or a legal representative if patients were too unwell or unable to provide consent.
    Sex as a biological variablenot detected.
    RandomizationStudy design and participants: The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is an investigator-initiated, individually randomised, controlled, open-label, platform trial to evaluate the effects of potential treatments in patients hospitalised with COVID-19.
    BlindingOn the advice of the Trial Steering Committee, recruitment to this comparison was closed on 29 December 2021 when over 8150 patients had been randomised and the blinded 28-day mortality rate was 12.9% (suggesting there would be at least 1050 deaths), giving at least 90% power to detect a proportional risk reduction in the primary outcome of one-fifth at 2P=0.01.
    Power AnalysisOn the advice of the Trial Steering Committee, recruitment to this comparison was closed on 29 December 2021 when over 8150 patients had been randomised and the blinded 28-day mortality rate was 12.9% (suggesting there would be at least 1050 deaths), giving at least 90% power to detect a proportional risk reduction in the primary outcome of one-fifth at 2P=0.01.

    Table 2: Resources

    No key resources detected.

    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 study has some limitations: this randomised trial is open label (i.e., participants and local hospital staff are aware of the assigned treatment), however, the outcomes are unambiguous and were ascertained without bias through linkage to routine health records. Use of tocilizumab during the follow-up period was slightly lower among those allocated to baricitinib compared with control (26% vs. 29%). Based on what we already know about the effects of tocilizumab, would, if anything, lead to a small underestimate of the effects of baricitinib. Furthermore, use of anti-viral or immunomodulatory treatments known to reduce mortality in this setting was similar in those allocated baricitinib and those allocated usual care. Information on radiological, virological or physiological outcomes was not collected. The smaller effect size observed in RECOVERY compared to earlier trials of baricitinib may simply be a chance effect. However, several other factors could have contributed. The patient population in RECOVERY may have been broader than some of the other trials, which may have been enriched for patients more likely to benefit from immunomodulatory therapy. The use of concomitant therapies has varied between the trials. For example, the ACTT-2 trial did not permit the use of dexamethasone as a treatment for COVID-19, and ACTT-2, COV-BARRIER, RUXCOVID and the study by Guimaraes and colleagues all excluded the use of an IL-6 receptor blocker.11,15,16,18 Other factors that may be d...

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

    IdentifierStatusTitle
    NCT04381936RecruitingRandomised Evaluation of COVID-19 Therapy

    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.
    • No funding statement was detected.
    • 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 10.1101/2022.03.02.22271623 on medRxiv