Higher dose corticosteroids in hospitalised COVID-19 patients requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial

Abstract

Background: Low dose corticosteroids (e.g., 6 mg dexamethasone) have been shown to reduce mortality for hypoxic COVID-19 patients. We have previously reported that higher dose corticosteroids cause harm in patients with clinical hypoxia but not receiving ventilatory support (the combination of non-invasive mechanical ventilation, including high-flow nasal oxygen, continuous positive airway pressure and bilevel positive airway pressure ventilation, and invasive mechanical ventilation or extra-corporeal membrane oxygenation), but the balance of efficacy and safety in patients receiving ventilatory support is uncertain.

Methods: This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) assessed multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients receiving ventilatory support were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. Recruitment closed on 31 March 2024 when funding for the trial ended. The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).

Findings: Between 25 May 2021 and 9 January 2024, 477 COVID-19 patients receiving ventilatory support were randomly allocated to receive usual care plus higher dose corticosteroids vs. usual care alone (of whom 99% received corticosteroids during the follow-up period). Of those randomised, 221 (46%) were in Asia, 245 (51%) in the UK and 11 (2%) in Africa. 143 (30%) had diabetes mellitus. Overall, 86 (35%) of 246 patients allocated to higher dose corticosteroids vs. 86 (37%) of 231 patients allocated to usual care died within 28 days (rate ratio [RR] 0.87; 95% CI 0.64-1.18; p = 0.37). There was no significant difference in the proportion of patients discharged from hospital alive within 28 days (128 [52%] in the higher dose corticosteroids group vs. 120 [52%] in the usual care group; RR 1.04, 0.81-1.33]; p = 0.78). Among those not on invasive mechanical ventilation at baseline, there was no clear reduction in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (76 [37%] of 206 vs. 93 [45%] of 205; RR 0.79 [95% CI 0.63-1.00]; p = 0.05).

Interpretation: In patients hospitalised for COVID-19 receiving ventilatory support, we found no evidence that higher dose corticosteroids reduced the risk of death compared to usual care, which included low dose corticosteroids.

Funding: UK Research and Innovation (Medical Research Council) and National Institute for Health Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).

Keywords: COVID-19; Clinical trial; Corticosteroid; Dexamethasone; Mortality.

Fig. 1

Trial profile. ITT = intention to treat. Higher dose corticosteroid unavailable and higher dose corticosteroid considered unsuitable are not mutually exclusive. Ventilatory support defined as non-invasive ventilation or invasive mechanical ventilation at randomisation. ∗ Number recruited overall during period that adult participants could be recruited into the higher dose corticosteroid comparison.

Fig. 2

Effect of allocation to higher dose corticosteroids or usual care (lower dose corticosteroids) on 28-day mortality in patients receiving ventilatory support. RR = rate ratio. Estimates are taken as 100 minus the Kaplan–Meier estimated survival percentage.

Fig. 3

Effect of allocation to higher dose corticosteroids or usual care (lower dose corticosteroids) on 28-day mortality in patients receiving ventilatory support by other baseline characteristics. Subgroup−specific rate ratio estimates are represented by squares (with areas of the squares proportional to the amount of statistical information) and the lines through them correspond to the 95% CIs. RR = rate ratio.