The Lopinavir-Ritonavir and Hydroxychloroquine arms were closed to new entrants after being shown to be ineffective Dexamethasone was closed to new adult entries after positive results.
Design
The RECOVERY Trial is a large-scale, randomized controlled trial. When people who have been hospitalised with COVID-19 are enrolled in the trial, they are automatically randomized to receive one 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." It is an "open label" study: people receiving the treatment and the attending clinicians both know which treatment is being administered. 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. The trial protocol was developed to minimize the administrative load on hospital staff who at the time were facing the prospect of overwhelming numbers of COVID-19 admissions.
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. The trial began in March 2020 and has an estimated duration through June 2021. As of June 2020, the trial had enrolled more than 11,800 COVID-19 participants admitted to hospitals in the UK.
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. 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.
Dexamethasone
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 among people who did not require oxygen. The preliminary report was subsequently published in The New England Journal of Medicine.
Impacts
Six days previously, these results had been announced in a news release. 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. Demand for dexamethasone surged after publication of the preprint. Based on the preliminary, unpublished results of the RECOVERY trial, the US National Institutes of HealthCOVID-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.
Limitations of dexamethasone result
John Fletcher, research editor at the BMJ, notes that there are "limitations and causes of concern" in the dexamethasone results.
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.
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. The trial observed a 22% increase in mortality in these patients, though this observation may still be due to chance.
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."
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., the results have not been published.
