RECOVERY Trial

Mortality 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)[16]

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.[16] The preliminary report was subsequently published in The New England Journal of Medicine.[17]

Six days before the pre-print, these results had been announced in a news release.[18] 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.[19]

Demand for dexamethasone surged after publication of the preprint.[20]

Based on the preliminary, unpublished results of the RECOVERY trial, the US National Institutes of Health COVID-19 Treatment Guidelines Panel recommended dexamethasone in patients with COVID-19 who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.[21]

Other countries granted specific approval for the drug as part of standard medical care, among them Japan,[22] Taiwan[23] and South Africa.[24]

A pre-print study, which was awarded Health Data Research UK Open Access Publication of the Month for August 2020, found that the discovery would save approximately 650,000 lives globally over the course of six months.[25][26]

Mortality 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)[16]

• John Fletcher, research editor at the BMJ, noted that there were "limitations and causes of concern" in the dexamethasone results.[20]
• 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 were not known.[20]
• 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.[11][27]
• The preprint authors themselves warned that "the results are consistent with possible harm" in patients who did not require oxygen at the time of enrolment.[16] 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.[16]
• 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."[28]

The results of this initial finding have now been replicated in a systematic review by the World Health Organization's Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group.[29]

On 5 June 2020, the trial determined that there was no clinical benefit from use of hydroxychloroquine in people hospitalized with COVID-19.[7] 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.[30] The trial also showed that hydroxychloroquine was correlated with longer hospital stays and progression to invasive ventilation, but not with cardiac arrhythmia.[30]

Patients received substantial doses of hydroxychloroquine (400 mg every 12h, after two loading doses of 800 mg), higher than other trials.[31] Preprint published on July 15, 2020 stated: "the 4-aminoquinoline drugs are relatively weak antivirals ... Thus, to provide the greatest chance of providing benefit in life threatening COVID-19, the dose regimen was designed to result in rapid attainment and maintenance of plasma concentrations that were as high as safely possible."[30]

The results are available on medRxiv.[30]

The trial did not address its use as prophylaxis or in patients with less severe SARS-CoV-2 infection managed in the community. The RECOVERY trial was specifically performed in the hospital context and another study by Oxford, the COPCOV trial, has the goal of evaluating hydroxychloroquine as a prophylaxis.[32] Nor did it trial the use of HCQ in combination with azithromycin as has been suggested by some observational studies.[30]

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.[6] These results were published in The Lancet on 5 October 2020.[33]

In a news release on 14 December 2020, the chief investigators announced that they had found no benefit from azithromycin in patients hospitalised with COVID-19. 2582 patients had received azithromycin, and 5182 were randomised to usual care alone. 28-day mortality in both cohorts was 19%.[8] These preliminary results were released as a preprint on the same day.[34]

In a news release on 15 January 2021, the chief investigators announced the closure of the convalescent plasma arm of the trial. Among 1873 reported deaths from 10,405 patients, the trial reported "no significant difference in the primary endpoint of 28-day mortality (18% convalescent plasma vs. 18% usual care alone; risk ratio 1.04 [95% confidence interval 0.95-1.14]; p=0.34)". The results will be published as soon as possible.[9]