A Randomised Clinical Trial of Azithromycin Versus Standard Care in Ambulatory COVID-19 – The ATOMIC2 Trial

Background: The antibacterial, anti-inflammatory and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-moderate disease are lacking. We assessed whether azithromycin is effective in reducing hospitalisation in patients with mild-moderate COVID-19.  Methods:  This open-label, randomised superiority clinical trial at 19 centres in the United Kingdom enrolled adults, ≥18 years, presenting to hospitals with clinically-diagnosed highly-probable or confirmed COVID-19 infection, with <14 days symptoms, considered suitable for initial ambulatory management. Patients were randomised (1:1) to azithromycin (500 mg daily orally for 14 days) or to standard care without macrolides. The primary outcome was the difference in proportion of participants with death or hospital admission from any cause over the 28 days from randomisation, assessed according to intention-to-treat (ITT). Trial registration: ClinicalTrials.gov, NCT04381962, Study closed.  Findings: 298 participants were enrolled from 3 rd  June 2020 to 29 th  January 2021. The primary outcome was assessed in 292 participants. The primary endpoint was not significantly different between the azithromycin and control groups (Adjusted OR 0·91 [95% CI 0·43-1·92], p=0·80). Rates of respiratory failure, progression to pneumonia, all-cause mortality, and adverse events, including serious cardiovascular events, were not significantly different between groups.  Interpretation: In patients with mild-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospitalisation or death. Our findings do not support the use of azithromycin in patients with mild-moderate COVID-19.  Trial Registration: This trial was registered with ClinicalTrials.gov (NCT04381962) and EudraCT (2020-001740-26). Funding: NIHR Oxford BRC, University of Oxford and Pfizer Inc. Declaration of Interests: TSCH has received grants from Pfizer Inc., grants from University of Oxford, grants from the Wellcome Trust, grants from The Guardians of the Beit Fellowship, and grants from the NIHR Oxford Biomedical Research Centre during the conduct of the study; and personal fees from Astra Zeneca, personal fees from TEVA, personal fees from Peer Voice outside the submitted work. MJ has received grants from the University of Oxford and NIHR Oxford Biomedical Research Centre. DR has undertaken paid consultancy for GSK outside the submitted work. IDP reports personal fees from AstraZeneca, Boehringer Ingelheim, Aerocrine, Almirall, Novartis, GlaxoSmithKline, Genentech, Regeneron, Teva, Chiesi, Sanofi, Circassia, Knopp, and grants from NIHR outside the submitted work. JU has received honoraria for preparation of educational materials and has served on an advisory board for Gilead Sciences and ViiV Healthcare outside of the submitted work. LC, RK, AW, JLC, VSB, JB, SJD, JM, PM, RG, TB, GJ, FC, DC, SE, DL and SM declare they have no competing interests. Ethics Approval Statement: The trial protocol was reviewed and approved by the UK Medicines and Healthcare products Regulatory Agency and an independent ethical committee (London – Brent Research Ethics Committee, Research Ethics Committee reference number 20/HRA/2105).