Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

BackgroundDimethyl fumarate (DMF) is an anti-inflammatory drug that has been proposed as a treatment for patients hospitalised with COVID-19 MethodsThis randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised for COVID-19. In this initial assessment of DMF, performed at 27 UK hospitals, eligible and consenting adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale, assessed using a proportional odds model. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 2 March 2021 and 18 November 2021, 713 patients were enrolled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients were receiving corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.85-1.46; p=0.42). There was no significant effect of DMF on any secondary outcome. As expected, DMF caused flushing and gastrointestinal symptoms, each in around 6% of patients, but no new adverse effects were identified. InterpretationIn adults hospitalised with COVID-19, DMF was not associated with an improvement in clinical outcomes. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

BackgroundREGEN-COV is a combination of 2 monoclonal antibodies (casirivimab and imdevimab) that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike protein. We aimed to evaluate the efficacy and safety of REGEN-COV in patients admitted to hospital with COVID-19. MethodsIn this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus a single dose of REGEN-COV 8g (casirivimab 4g and imdevimab 4g) by intravenous infusion (REGEN-COV group). The primary outcome was 28-day mortality assessed first among patients without detectable antibodies to SARS-CoV-2 at randomisation (seronegative) and then in the overall population. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 18 September 2020 and 22 May 2021, 9785 patients were randomly allocated to receive usual care plus REGEN-COV or usual care alone, including 3153 (32%) seronegative patients, 5272 (54%) seropositive patients and 1360 (14%) patients with unknown baseline antibody status. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to REGEN-COV and 451 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio 0{middle dot}80; 95% CI 0{middle dot}70-0{middle dot}91; p=0{middle dot}0010). In an analysis involving all randomised patients (regardless of baseline antibody status), 944 (20%) of 4839 patients allocated to REGEN-COV and 1026 (21%) of 4946 patients allocated to usual care died within 28 days (rate ratio 0{middle dot}94; 95% CI 0{middle dot}86-1{middle dot}03; p=0{middle dot}17). The proportional effect of REGEN-COV on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity = 0{middle dot}001). InterpretationIn patients hospitalised with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab (REGEN-COV) reduced 28-day mortality among patients who were seronegative at baseline. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).

Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

BackgroundAzithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We evaluated the efficacy and safety of azithromycin in hospitalised patients with COVID-19. MethodsIn this randomised, controlled, open-label, adaptive platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once daily by mouth or intravenously for 10 days or until discharge (or one of the other treatment arms). Patients were twice as likely to be randomised to usual care as to any of the active treatment groups. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). FindingsBetween 7 April and 27 November 2020, 2582 patients were randomly allocated to receive azithromycin and 5182 patients to receive usual care alone. Overall, 496 (19%) patients allocated to azithromycin and 997 (19%) patients allocated to usual care died within 28 days (rate ratio 1{middle dot}00; 95% confidence interval [CI] 0{middle dot}90-1{middle dot}12; p=0{middle dot}99). Consistent results were seen in all pre-specified subgroups of patients. There was no difference in duration of hospitalisation (median 12 days vs. 13 days) or the proportion of patients discharged from hospital alive within 28 days (60% vs. 59%; rate ratio 1{middle dot}03; 95% CI 0{middle dot}97-1{middle dot}10; p=0{middle dot}29). Among those not on invasive mechanical ventilation at baseline, there was no difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0{middle dot}97; 95% CI 0{middle dot}89-1{middle dot}07; p=0{middle dot}54). InterpretationIn patients hospitalised with COVID-19, azithromycin did not provide any clinical benefit. Azithromycin use in patients hospitalised with COVID-19 should be restricted to patients where there is a clear antimicrobial indication. FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).