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

Abstract

Background: Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.

Methods: In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals 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 per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.

Findings: Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87-1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98-1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87-1·03; p=0·24).

Interpretation: In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication.

Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile *Number recruited overall during the period that participants could be recruited into the azithromycin comparison. †Some patients were included in both of the below groups. ‡2506 (97%) of those allocated to azithromycin and 5054 (98%) of those allocated to usual care had a complete follow-up at time of analysis. §3993 patients were additionally randomly assigned to convalescent plasma versus REGN-COV2 versus control (1320 [51·1%] patients allocated to azithromycin versus 2673 [51·6%] patients allocated usual care) and 975 patients were additionally randomly assigned to aspirin versus usual care (323 [12·5%] patients allocated to azithromycin versus 652 [12·6%] patients allocated usual care). ¶Includes 198 (7·7%) of 2582 patients in the azithromycin group and 450 (8·7%) of 5181 patients in the usual care group allocated to tocilizumab.

Figure 2

Effect of allocation to azithromycin on 28-day mortality

Figure 3

Effect of allocation to azithromycin on 28-day mortality by 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 95% CIs. The ethnicity, days since onset, and use of corticosteroids subgroups exclude those with missing data, but these patients are included in the overall summary diamond. Information on use of corticosteroids was collected from June 18, 2020, onwards following announcement of the results of the dexamethasone comparison from the RECOVERY trial. *Includes patients receiving non-invasive ventilation.