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

Abdullah Abdullah, Mohammad Ahmad, David Alderdice, John Alexander, Peter D.G. Alexander, Syed Ali, Kerry Allen, Julie Anderson, Samantha Anderson, Wendy Anderson, Mark Baker, Richard Barlow, Clare Brady, Andrew Brown, Duncan Browne, Amy Burns, Mark Campbell, Sharon Carr, Emma Chambers, Katie ChapmanPatricia Clark, Emma Collins, David Comer, David Cooper, Victoria Craig, Nicola Cunningham, David Curran, Simon Davies, Elizabeth Dawson, Conor Doherty, Eilish Donnelly, Ronan Donnelly, Damian Downey, Maire Drain, Jennifer Evans, John Evans, Jenny Ferguson, Stephen Fowler, William Gallagher, Chris Gordon, Rebecca Gosling, David Grant, David Green, Sandra Griffiths, Mohammed Hameed, Thomas Harrison, Dominic Hart, Emma Heron, Richard Hewitt, Stephen Hughes, Ahmed Ibrahim, Amanda Jackson, Gillian Johnson, Mark Johnson, Janet Johnston, Amy Jones, Louise Jones, Samantha Jones, Sophie Jones, Tim Jones, Breffni Keegan, David Kelly, Dominic Kelly, Emma Kelly, Martin Kelly, Michael Kelly, Stephen Kelly, A. Kerr, Waleed Khan, Deborah J. Kinnear, Satish Kumar, Simon Lee, Dermot Linden, Edward Malone, Andrew Marshall, Paul McCourt, John McDermott, Fred McElwaine, Lorcan McGarvey, Clodagh McGettigan, Brendan McGrath, Stephen McMahon, Terence McManus, Helen McNally, Jonathan Millar, Aoife Molloy, David A.J. Moore, Laura Moore, Patrick Morgan, Paul Morris, Clare Murray, Lisa Murray, Tracey Murray, Quang Nguyen, Fiona North, Anne M. Nugent, Ciaran O'Gorman, Sarah Orr, Robert Patterson, James Quinn, Martin Regan, A. Rehman, Andrew Reid, Jennifer Reid, Matthew Rice, Jane Ritchie, Emma Robinson, Matthew Robinson, John Rogers, Stephen Rowan, Kathryn Ryan, M. Saad, Anne Scott, Stephen Scott, Syed Shah, Christopher Shaw, Richard Simms, Thomas Simpson, Kathryn Simpson, Brendan Sloan, Catherine Smith, Christopher Smith, Oliver Smith, Rachel Smith, Richard Smith, Sally Smith, Stephanie Smith, Susan Smith, John Smith, Shiva Sreenivasan, Andrew Stevenson, Christopher Stewart, Wei Teen Tan, Julie Taylor, Samantha Taylor, Victoria Taylor, Catherine Thompson, Laura Thompson, Luke Thompson, Marianne Tinkler, Elizabeth Walsh, James Walters, Michael Walton, Ran Wang, Christopher Ward, Hannah Ward, Nicola Ward, Thomas Ward, J. G.R. Watson, Robert Watson, Deborah Webster, Ian Webster, Christopher White, Jonathan White, Gina Williams, James Williams, John Williams, Mark Williams, Robin Williams, James D. Williamson, Alison Wilson, Anna Wilson, David Wilson, Mark Wilson, Jing Zhang, Xiaobei Zhao, RECOVERY Collaborative Group

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Abstract

Background: We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1–2 inhibitor, for the treatment of patients admitted to hospital with 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 with COVID-19 in the UK. 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 done, which 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) and is ongoing.

Findings: Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 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% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (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 0·77–0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight 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 in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72–0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes. 

Interpretation: In patients hospitalised with 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.

Original languageEnglish
Pages (from-to)359-368
Number of pages10
JournalThe Lancet
Volume400
Issue number10349
DOIs
Publication statusPublished - 30 Jul 2022

Bibliographical note

Funding Information:
Above all, we thank the thousands of patients who participated in this trial. We also thank the many doctors, nurses, pharmacists, other allied health professionals, and research administrators at National Health Service hospital organisations across the whole of the UK, supported by staff at the National Institute of Health Research (NIHR) Clinical Research Network, NHS DigiTrials, Public Health England, Department of Health & Social Care, the Intensive Care National Audit & Research Centre, Public Health Scotland, National Records Service of Scotland, the Secure Anonymised Information Linkage at the University of Swansea, and the NHS in England, Scotland, Wales, and Northern Ireland. The RECOVERY trial is supported by grants to the University of Oxford from UK Research and Innovation and NIHR (MC_PC_19056), the Wellcome Trust (grant reference 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator, and by core funding provided by the NIHR Oxford Biomedical Research Centre, the Wellcome Trust, the Bill and Melinda Gates Foundation, the Foreign, Commonwealth and Development Office, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. TJ is supported by a grant from UK Medical Research Council (MC_UU_00002/14). WSL is supported by core funding provided by NIHR Nottingham Biomedical Research Centre. Tocilizumab was provided free of charge for this trial by Roche Products. Regeneron Pharmaceuticals supported the trial through provision of casirivimab and imdevimab. Baricitinib was provided from routine NHS stock. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Funding Information:
Above all, we thank the thousands of patients who participated in this trial. We also thank the many doctors, nurses, pharmacists, other allied health professionals, and research administrators at National Health Service hospital organisations across the whole of the UK, supported by staff at the National Institute of Health Research (NIHR) Clinical Research Network, NHS DigiTrials, Public Health England, Department of Health & Social Care, the Intensive Care National Audit & Research Centre, Public Health Scotland, National Records Service of Scotland, the Secure Anonymised Information Linkage at the University of Swansea, and the NHS in England, Scotland, Wales, and Northern Ireland. The RECOVERY trial is supported by grants to the University of Oxford from UK Research and Innovation and NIHR (MC_PC_19056), the Wellcome Trust (grant reference 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator, and by core funding provided by the NIHR Oxford Biomedical Research Centre, the Wellcome Trust, the Bill and Melinda Gates Foundation, the Foreign, Commonwealth and Development Office, Health Data Research UK, the Medical Research Council Population Health Research Unit, the NIHR Health Protection Unit in Emerging and Zoonotic Infections, and NIHR Clinical Trials Unit Support Funding. TJ is supported by a grant from UK Medical Research Council (MC_UU_00002/14). WSL is supported by core funding provided by NIHR Nottingham Biomedical Research Centre. Tocilizumab was provided free of charge for this trial by Roche Products. Regeneron Pharmaceuticals supported the trial through provision of casirivimab and imdevimab. Baricitinib was provided from routine NHS stock. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

ASJC Scopus subject areas

  • General Medicine

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