Abstract
Background Dimethyl fumarate (DMF) is an anti-inflammatory drug that has been proposed as a treatment for patients hospitalised 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 for COVID-19. In this initial assessment of DMF, performed at 27 UK hospitals, eligible and consenting adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale, assessed using a proportional odds model. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).
Findings Between 2 March 2021 and 18 November 2021, 713 patients were enrolled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients were receiving corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.85-1.46; p=0.42). There was no significant effect of DMF on any secondary outcome. As expected, DMF caused flushing and gastrointestinal symptoms, each in around 6% of patients, but no new adverse effects were identified.
Interpretation In adults hospitalised with COVID-19, DMF was not associated with an improvement in clinical outcomes.
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. In this initial assessment of DMF, performed at 27 UK hospitals, eligible and consenting adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale, assessed using a proportional odds model. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).
Findings Between 2 March 2021 and 18 November 2021, 713 patients were enrolled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients were receiving corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.85-1.46; p=0.42). There was no significant effect of DMF on any secondary outcome. As expected, DMF caused flushing and gastrointestinal symptoms, each in around 6% of patients, but no new adverse effects were identified.
Interpretation In adults hospitalised with COVID-19, DMF was not associated with an improvement in clinical outcomes.
| Original language | English |
|---|---|
| Article number | 924 |
| Number of pages | 13 |
| Journal | Nature Communications |
| Volume | 15 |
| Early online date | 31 Jan 2024 |
| DOIs | |
| Publication status | Published - 31 Jan 2024 |
Bibliographical note
FundingUK Research and Innovation (Medical Research Council) and National
Institute for Health and Care Research (Grant ref: MC_PC_19056).
Acknowledgements
Above all, we would like to thank the patients who participated in this trial.
We would also like to thank the many doctors, nurses, pharmacists, other
allied health professionals, and research administrators at NHS 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 (SAIL) at 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 (UKRI) and NIHR
(MC_PC_19056), the Wellcome Trust (Grant Ref: 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_0002/14). 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 Limited. Regeneron Pharmaceuticals supported the trial through provision of casirivimab and imdevimab. The views expressed in this publication are those of the authors and
not necessarily those of the NHS, the NIHR, or the UK 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. The sponsor was not involved in study
design, data collection and analysis or manuscript writing.
Data Availability Statement
Data availabilityThe protocol, consent form, statistical analysis plan, definition &
derivation of clinical characteristics & outcomes, training materials,
regulatory documents, and other relevant study materials are available
online at www.recoverytrial.net. As described in the protocol, the trial
Steering Committee will facilitate the use of the study data and
approval will not be unreasonably withheld. Deidentified participant
data will be made available to bona fide researchers registered with an
appropriate institution within 3 months of publication. However, the
Steering Committee will need to be satisfied that any proposed publication is of high quality, honours the commitments made to the study
participants in the consent documentation and ethical approvals, and
is compliant with relevant legal and regulatory requirements (e.g.
relating to data protection and privacy). The Steering Committee will
have the right to review and comment on any draft manuscripts prior
to publication. Data will be made available in line with the policy and
procedures described at: https://www.ndph.ox.ac.uk/data-access.
Those wishing to request access should apply for access via the
Infectious Diseases Data Observatory (https://www.iddo.org/covid19/
data-sharing/accessing-data), or complete the form at https://www.
ndph.ox.ac.uk/files/about/data_access_enquiry_form_13_6_2019.docx
and e-mail to: data.access@ndph.ox.ac.uk.
Supplementary information
The online version contains supplementary material available at https://doi.org/10.1038/s41467-023-43644-x