Dexamethasone significantly reduces mortality in subset of patients hospitalised with advanced COVID-19: UK RECOVERY study
26 June 2020. Related: COVID-19: investigational drugs, COVID-19.
STOP PRESS: The pre-review paper from this study is also now available online; 32 of the study participants were HIV positive. While relative rates impressively benefitted the active arm, the mortality in both arms is sobering. It shows the need for much better and more effective treatments for COVID-19. [7]
On 14 June 2020, top-line results from one arm of the UK RECOVERY study, included significant benefits from using the anti-inflammatory drug dexamethasone to treat COVID-19. [1]
In patients with the most advanced stages of COVID-19 – those either on mechanical ventilation or assisted breathing – dexamethasone reduced the relative risk of death by approximately one-third and one-fifth, respectively. No benefit was seen in people with less advanced infection who were not using oxygen support.
The results are based on 6335 participants who were randomised (1:2) to either dexamethasone (n=2104) or a control arm using standard of care (n=4321). Dexamethasone was dosed at 6 mg daily for ten days, either orally or by IV injection.
The dexamethasone arm was stopped early on 8 June 2020 after the trial steering committee decided enough participants had been recruited to show significant results based on the primary endpoint of survival at day-28 – reached by 94% of participants. The statistical basis for this decision though or the timeline and review plan for other arms are not included in study protocol online. [2]
Mortality overall correlated with severity of COVID-19: 41% in people on mechanical ventilation, 25% in those needing oxygen only and 13% in people not needing respiratory support.
Overall, dexamethasone reduced the 28-day mortality rate by 17% (RR 0.83; 95%CI: 0.74 to 0.92, p=0.0007) with a highly significant trend showing greatest benefit among those patients requiring ventilation (test for trend p<0.001).
The press release includes that dexamethasone reduced deaths by one-third in ventilated patients (RR: 0.65; 95% CI: 0.48 to 0.88, p=0.0003) and by one fifth in other patients receiving oxygen only (RR: 0.80; 95%CI: 0.67 to 0.96, p=0.0021). Also, that there was no benefit among participants who did not receive respiratory support (RR: 1.22; 95% CI: 0.86 to 1.75, p=0.14).
The study included 176 clinic sites throughout the UK and funders included the UK NIHR, Wellcome and the Bill and Melinda Gates Foundation, DFID and the MRC, with details on the study website.
comment
These results are good news. Although only the top-line , the UK government has already announced that dexamethasone is already included in the new standard of care for people hospitalised with COVID-19 and using oxygen support. [3]
This should also include other participants in the RECOVERY study who are currently randomised to monotherapy treatment using other single investigational drugs. These include lopinavir/r, azithromycin, tocilizumab and convalescent plasma.
Community participation in research has always included the principle of responding to new standards of care that change while a study is ongoing.
Dexamethasone is an inexpensive and widely used generic drug that can be accessed immediately. It is already included on the WHO list of essential medicines. This will enable wide use including in low- and middle-income countries (LMICs), although mechanical ventilation is often extremely limited in these settings and require different guidelines might [4]
The full analysis will hopefully explain the lack of benefit in people hospitalised in earlier stages who are not using oxygen, even though they should also be at a stage of immune inflammation.
The RECOVERY study was launched in March 2020 and has now randomised more than 11,500 participants to one of six investigational treatments for COVID-19 or to a control group that receives standard of care. Earlier this month, the hydroxychloroquine (HCQ) arm was stopped early after an MHRA-requested review showed no benefit. [5]
This raised concerns, including in a report from i-Base, about the duration of time participants were kept on ineffective treatment and the lack of transparency about the timeline and details of the statistical analysis plan that has still not be made publicly available. [6]
This article was first published online on 17 June 2020.
References
- University of Oxford. RECOVERY study press release. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. (16 June 2020).
http://www.ox.ac.uk/news/2020-06-16-low-cost-dexamethasone-reduces-death-one-third-hospitalised-patients-severe - RECOVERY study protocol.
https://www.recoverytrial.net/files/recovery-protocol-v6-0-2020-05-14.pdf (PDF) - UK Department of Health and Social Care press statement. World first coronavirus treatment approved for NHS use by government. (16 June 2020).
https://www.gov.uk/government/news/world-first-coronavirus-treatment-approved-for-nhs-use-by-government - WHO. WHO Model List of Essential Medicines, 21st List (2019).
https://www.who.int/medicines/publications/essentialmedicines/en - RECOVERY trial statement. Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on hydroxychloroquine. (5 June 2020).
https://www.recoverytrial.net/files/hcq-recovery-statement-050620-final-002.pdf (PDF) - Collins S. UK RECOVERY study stops hydroxychloroquine (HCQ) for COVID-19: more than 1100 deaths question ethics and safety overall. HTB early access (6 June 2020).
https://i-base.info/htb/38188 - Horby P et al for the RECOVERY Group. Effect of dexamethasone in hospitalised patients with COVID-19—preliminary report. MedRxiv pre-review preprint. (22 Jun 2020). https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1.full.pdf.(PDF)