Background Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support. Trial registrations The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Funding Medical Research Council and National Institute for Health Research (Grant ref: MC_PC_19056).

We generalize the Dunnett test to derive efficacy and futility boundaries for a flexible multi-arm multi-stage clinical trial for a normally distributed endpoint with known variance. We show that the boundaries control the familywise error rate in the strong sense. The method is applicable for any number of treatment arms, number of stages and number of patients per treatment per stage. It can be used for a wide variety of boundary types or rules derived from α-spending functions. Additionally, we show how sample size can be computed under a least favourable configuration power requirement and derive formulae for expected sample sizes.

Background Tocilizumab is a monoclonal antibody that binds to the receptor for interleukin (IL)-6, reducing inflammation, and is commonly used to treat rheumatoid arthritis. We evaluated the safety and efficacy of tocilizumab in adult patients admitted to hospital with COVID-19 with evidence of both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein [CRP] ≥75 mg/L) were eligible for randomisation to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg to 800 mg (depending on weight) given intravenously. A second dose could be given 12 to 24 hours later if the patient’s condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings Between 23 April 2020 and 24 January 2021, 4116 adults were included in the assessment of tocilizumab, including 562 (14%) patients receiving invasive mechanical ventilation, 1686 (41%) receiving non-invasive respiratory support, and 1868 (45%) receiving no respiratory support other than oxygen. Median CRP was 143 [IQR 107-204] mg/L and 3385 (82%) patients were receiving systemic corticosteroids at randomisation. Overall, 596 (29%) of the 2022 patients allocated tocilizumab and 694 (33%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·86; 95% confidence interval [CI] 0·77-0·96; p=0·007). Consistent results were seen in all pre-specified subgroups of patients. In particular, a clear mortality benefit was seen in those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital alive within 28 days (54% vs. 47%; rate ratio 1·22; 95% CI 1·12-1·34; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (33% vs. 38%; risk ratio 0·85; 95% CI 0·78-0·93; p=0·0005). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the level of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Adaptive designs for clinical trials permit alterations to a study in response to accumulating data in order to make trials more flexible, ethical, and efficient. These benefits are achieved while preserving the integrity and validity of the trial, through the pre-specification and proper adjustment for the possible alterations during the course of the trial. Despite much research in the statistical literature highlighting the potential advantages of adaptive designs over traditional fixed designs, the uptake of such methods in clinical research has been slow. One major reason for this is that different adaptations to trial designs, as well as their advantages and limitations, remain unfamiliar to large parts of the clinical community. The aim of this paper is to clarify where adaptive designs can be used to address specific questions of scientific interest; we introduce the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials ranging from early-phase dose escalation to confirmatory phase III studies.