Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
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Abstract
Background
Azithromycin 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.
Methods
In 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 ).
Findings
Between 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 1·00; 95% confidence interval [CI] 0·90-1·12; p=0·99). 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 1·03; 95% CI 0·97-1·10; p=0·29). 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 0·97; 95% CI 0·89-1·07; p=0·54).
Interpretation
In 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.
Funding
UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056).
Article activity feed
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SciScore for 10.1101/2020.12.10.20245944: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The trial is conducted in accordance with the principles of the International Conference on Harmonisation–Good Clinical Practice guidelines and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee (ref: 20/EE/0101).
Consent: Written informed consent was obtained from all patients, or a legal representative if they were too unwell or unable to provide consent.Randomization Eligible and consenting patients were assigned to either usual standard of care or usual standard of care plus azithromycin or one of the other available RECOVERY treatment arms using web-based simple (unstratified) … SciScore for 10.1101/2020.12.10.20245944: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The trial is conducted in accordance with the principles of the International Conference on Harmonisation–Good Clinical Practice guidelines and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee (ref: 20/EE/0101).
Consent: Written informed consent was obtained from all patients, or a legal representative if they were too unwell or unable to provide consent.Randomization Eligible and consenting patients were assigned to either usual standard of care or usual standard of care plus azithromycin or one of the other available RECOVERY treatment arms using web-based simple (unstratified) randomisation with allocation concealed until after randomisation (appendix pp 23-25). Blinding Consequently, on 27 November 2020, the steering committee, blinded to the results, closed recruitment to the azithromycin comparison as sufficient patients had been enrolled. Power Analysis As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that sufficient patients should be enrolled to provide at least 90% power at a two-sided p-value of 0.01 to detect a clinically relevant proportional reduction in the primary outcome of 20% between the two groups. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our trial has some limitations: Detailed information on laboratory markers of inflammatory status, co-existent bacterial infection, or use of non-macrolide antibiotics was not collected, nor was information on radiological or physiological outcomes. This initial report is based on complete follow-up for the primary outcome in 73% of patients (and partial follow-up for the remaining 27%). However, collection of outcome information both through case report forms and linkage to routine NHS records is ongoing and, based on previous reports from this trial, will deliver complete follow-up information for over 99% of patients by early January 2021. However, additional follow-up is unlikely to change the conclusion that azithromycin has no meaningful benefit for hospitalised patients with COVID-19. Three other randomised controlled trials have assessed the efficacy of azithromycin for the treatment of COVID-19 in hospitalised patients, all of which additionally treated patients with hydroxychloroquine.15-17 The COALITION I and COALITION II trials found that allocation of hospitalized patients with COVID-19 to azithromycin and hydroxychloroquine, was not associated with any improvement in mortality, duration of hospital stay, or clinical status as assessed using an ordinal outcome scale.15,16 A small trial in Iran that randomised patients to hydroxychloroquine and lopinavir-ritonavir with or without azithromycin also found no significant difference in mortality or intensive care unit...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04381936 Recruiting Randomised Evaluation of COVID-19 Therapy Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.12.10.20245944: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement The trial is conducted in accordance with the principles of the International Conference on Harmonisation–Good Clinical Practice guidelines and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee (ref: 20/EE/0101). Randomization 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). Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key …
SciScore for 10.1101/2020.12.10.20245944: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement The trial is conducted in accordance with the principles of the International Conference on Harmonisation–Good Clinical Practice guidelines and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee (ref: 20/EE/0101). Randomization 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). Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
Our trial has some limitations: Detailed information on laboratory markers of inflammatory status, co-existent bacterial infection, or use of non-macrolide antibiotics was not collected, nor was information on radiological or physiological outcomes. This initial report is based on complete follow-up for the primary outcome in 73% of patients (and partial follow-up for the remaining 27%). However, collection of outcome information both through case report forms and linkage to routine NHS records is ongoing and, based on previous reports from this trial, will deliver complete follow-up information for over 99% of patients by early January 2021. However, additional follow- up is unlikely to change the conclusion that azithromycin has no meaningful benefit for hospitalised patients with COVID-19. Three other randomised controlled trials have assessed the efficacy of azithromycin for the treatment of COVID-19 in hospitalised patients, all of which additionally treated patients with hydroxychloroquine.15-17 The COALITION I and COALITION II trials found that allocation hydroxychloroquine, was not associated with any improvement in mortality, duration of hospital stay, or clinical status as assessed using an ordinal outcome scale.15,16 A small trial in Iran that randomised patients to hydroxychloroquine and lopinavir-ritonavir with or without azithromycin also found no significant difference in mortality or intensive care unit admission, but suggested a reduction in duration of hospi...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04381936 Recruiting Randomised Evaluation of COVID-19 Therapy Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
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