A randomised clinical trial of azithromycin versus standard care in ambulatory COVID-19 - the ATOMIC2 trial

Hinks, T. S.; Cureton, L.; Knight, R.; Wang, A.; Cane, J. L.; Barber, V. S.; Black, J.; Dutton, S. J.; Melhorn, J.; Jabeen, M.; Moss, P.; Garlapati, R.; Baron, T.; Johnson, G.; Cantle, F.; Clarke, D.; Elkhodair, S.; Underwood, J.; Lasserson, D.; Pavord, I. D.; Morgan, S. B.; Richards, D.

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 3rd June 2020 to 29th 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. Funding NIHR Oxford BRC, University of Oxford and Pfizer Inc.