RECOVERY Trial

The Randomised Evaluation of COVID-19 therapy (RECOVERY) Trial is a large-enrollment clinical trial of possible treatments for people in the United Kingdom admitted to hospital with severe COVID-19 infection.[1][2][3] As of 17 June 2020, the trial included six proposed interventions: five repurposed drugs and convalescent plasma.[1]

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Treatments

The following treatments are allocated at random to hospitalized people with severe COVID-19 infection:[1]

The Lopinavir-Ritonavir and Hydroxychloroquine arms were closed to new entrants after being shown to be ineffective[4][5] Dexamethasone was closed to new adult entries after positive results.

Design

The RECOVERY Trial is a large-scale, randomized controlled trial.[1][6] When people who have been hospitalised with COVID-19 are enrolled in the trial, they are automatically randomized to receive one (or none) of the trial treatments. The primary objective of the trial is to "provide reliable estimates of the effect of study treatments on all-cause mortality at 28 days after first randomisation."[1][6] It is an "open label" study: people receiving the treatment and the attending clinicians both know which treatment is being administered.[1]

It is a multi-arm adaptive clinical trial. New treatments can be added into the trial as it progresses, and other treatment "arms" closed to new enrolment when results have been produced. [3]

The trial protocol was developed to minimize the administrative load on hospital staff who at the time (March 2020[7]) were facing the prospect of overwhelming numbers of COVID-19 admissions.[8]

Operations

The trial is run by the Nuffield Departments of Population Health and of Medicine at the University of Oxford, and led by Professor Peter Horby. It involves many thousands of health professionals at 175 NHS hospitals in the UK.[5][7]

The trial began in March 2020 and has an estimated duration through June 2021.[6] As of June 2020, the trial had enrolled more than 11,800 COVID-19 participants admitted to hospitals in the UK.[4]

Results

Hydroxychloroquine

On 5 June 2020, the trial determined that there was no clinical benefit from use of hydroxychloroquine in people hospitalized with COVID-19.[5] Patients treated with hydroxychloroquine saw a 25.7% 28-day mortality compared to a 23.5% 28-day mortality in those treated with standard care. The trial also showed that hydroxychloroquine was correlated with longer hospital stays and progression to invasive ventilation, but not with cardiac arrhythmia. The results are available on medRxiv. [9]

Dexamethasone
Mortality rates over 28 days for 1007 COVID-19 patients on mechanical ventilation at time of randomisation: 324 patients who received dexamethasone (red) compared to 683 who received standard hospital care (black)[10]

On 22 June 2020, preliminary results were published in a preprint showing that low-dose dexamethasone treatment reduced the death rate by one third in hospitalized people needing ventilators due to severe COVID-19 infection, and by one fifth in people treated with oxygen therapy. There was no benefit (and the possibility of harm) among people who did not require oxygen.[10] The preliminary report was subsequently published in The New England Journal of Medicine.[11]

Impacts

Six days previously, these results had been announced in a news release.[12] A UK Therapeutic Alert was issued the same day, and all the Chief Medical Officers in the United Kingdom exceptionally recommended an immediate change of UK-wide clinical practice, in advance of publication of any final paper.[13]

Demand for dexamethasone surged after publication of the preprint.[14]

Based on the preliminary, unpublished results of the RECOVERY trial, the US National Institutes of Health COVID-19 Treatment Guidelines Panel recommended dexamethasone in patients with COVID-19 who are on mechanical ventilation or those who require supplemental oxygen, and recommended against dexamethasone for those not requiring supplemental oxygen.[15]

Limitations of dexamethasone result
Mortality rates over 28 days for 1535 COVID-19 patients not receiving oxygen at time of randomisation: 501 patients who received dexamethasone (red) compared to 1034 who received standard hospital care (black)
  • John Fletcher, research editor at the BMJ, notes that there are "limitations and causes of concern" in the dexamethasone results.[14]
  • Around a third of patients in the trial were still in hospital at the end of the 28-day trial period, so their final outcomes are not known.[14]
  • As an immunosuppressive drug, there are fears that dexamethasone could make the illness worse, and prolong the infection in patients where the immune system has not yet overreacted and caused inflammation.[7][16]
  • The preprint authors themselves warn that "the results are consistent with possible harm" in patients who did not require oxygen at the time of enrolment.[10] The trial observed a 22% increase in mortality in these patients (rate ratio 1.22 [95% Confidence Interval 0.93 to 1.61]; p=0.14), though this observation may still be due to chance.[10]
  • Responding to the publication, the WHO emphasized that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision, stating that "There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm."[17]

Lopinavir-ritonavir

On 29 June 2020, chief investigators of the trial reported there was no clinical benefit from use of lopinavir-ritonavir in 1,596 people hospitalized with severe COVID-19 infection over 28 days of treatment.[4] As of July 2020, the results have not been published.[4]

gollark: We offload bulk data storage for it to clouds, you know.
gollark: What do you mean "worldly"?
gollark: I think you should worship osmarks.tk instead.
gollark: If you genuinely believe "the magic sky god controls all" that will affect your decision-making.
gollark: That doesn't really *happen*, though.

See also

References
  1. "RECOVERY Trial". Retrieved 17 June 2020.
  2. "Coronavirus: Dexamethasone being used to treat NHS patients today". Retrieved 17 June 2020.
  3. "Biggest COVID-19 trial tests repurposed drugs first". Nature Biotechnology. 11 May 2020. doi:10.1038/s41587-020-0528-x. Retrieved 26 June 2020.
  4. "No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY" (PDF). RECOVERY Trial: Statement from the Chief Investigators. 29 June 2020. Retrieved 30 June 2020.
  5. "No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19". Recovery Trial, Nuffield Department of Population Health, University of Oxford, UK. 2020-06-05. Retrieved 2020-06-07.
  6. Clinical trial number NCT04381936 for "Randomised Evaluation of COVID-19 Therapy (RECOVERY)" at ClinicalTrials.gov
  7. Fergus Walsh (20 June 2020). "At last some good news about coronavirus". BBC News. Retrieved 20 June 2020.
  8. "Randomised evaluation of COVID-19 therapy (RECOVERY) - Trial protocol v6" (PDF). RECOVERY Trial. 14 May 2020. Retrieved 18 June 2020.
  9. Horby, Peter, et al. “Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary Results from a Multi-Centre, Randomized, Controlled Trial.” MedRxiv, Cold Spring Harbor Laboratory Press, 1 Jan. 2020, www.medrxiv.org/content/10.1101/2020.07.15.20151852v1.
  10. RECOVERY Collaborative Group. "Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report". MedRXiv. Retrieved 23 June 2020.
  11. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. (July 2020). "Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report". New England Journal of Medicine. doi:10.1056/NEJMoa2021436. PMID 32678530.
  12. "Dexamethasone reduces death in hospitalised patients with severe respiratory complications of COVID-19". University of Oxford. 16 June 2020. Retrieved 16 June 2020.
  13. "Dexamethasone in COVID-19" (PDF). 16 June 2020. Retrieved 23 June 2020.
  14. Mahase E (June 2020). "Covid-19: Demand for dexamethasone surges as RECOVERY trial publishes preprint". BMJ. 369: m2512. doi:10.1136/bmj.m2512. PMID 32576548.
  15. "The National Institutes of Health COVID-19 Treatment Guidelines Panel Provides Recommendations for Dexamethasone in Patients with COVID-19". NIH COVID-19 Treatment Guidelines. National Institutes of Health. 25 June 2020. Retrieved 26 June 2020.
  16. Roni Caryn Rabin (24 June 2020). "Breakthrough Drug for Covid-19 May Be Risky for Mild Cases". New York Times. Retrieved 25 June 2020.
  17. "WHO Director-General's opening remarks at the media briefing on COVID-19 - 22 June 2020". World Health Organisation. Retrieved 25 June 2020.
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