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

Abstract

BackgroundThe 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.MethodsThis 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.Findings298 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.InterpretationIn 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.FundingNIHR Oxford BRC, University of Oxford and Pfizer Inc.Research in contextEvidence before this studyWe searched MEDLINE and the Cochrane Central register of Controlled Trials (CENTRAL) with the terms (“azithromycin”) AND (“COVID” OR “COVID-19”) AND (“clinical trials”), until March 25, 2021, with no language restrictions. We identified 42 studies, among which there were four completed randomised trials of azithromycin (with or without hydroxychloroquine) in hospitalised patients with severe disease, and three completed randomised trials of azithromycin in mild COVID-19 in primary care. The four trials in hospitalised patients randomised 8,988 participants to azithromycin or standard care or hydroxychloroquine and found no evidence of a difference in mortality, duration of hospital stay or peak disease severity. Of the three trials in primary care, these randomised participants with early disease to 3 or 5 days of therapy, of which only one assessed azithromycin as standalone therapy. This large, adaptive platform trial in the UK randomised 540 participants in primary care to 3 days treatment with azithromycin versus 875 to standard care alone and found no meaningful difference in time to first reported recovery, or of rates of hospitalisation (3% versus 3%) and there were no deaths. We did not identify any randomised trials in patients with COVID-19 managed in ambulatory care.Added value of this studyThe ATOMIC2 trial was uniquely-designed to assess azithromycin as a standalone therapy in those with mild-moderately COVID-19 presenting to emergency care, but assessed as appropriate for initial ambulatory management without hospital admission. ATOMIC2 also uniquely assessed high-dose, long-duration treatment to investigate the efficacy of putative anti-inflammatory effects. We found that azithromycin 500 mg daily for 14 days did not reduce the proportion of participants who died or required hospital admission from any cause over the 28 days from randomisation.Implications of all the available evidenceOur findings, taken together with existing data, suggest there is no evidence that azithromycin reduces hospitalisation, respiratory failure or death compared with standard care, either in early disease in the community, or those hospitalised with severe disease, or in those with moderate disease managed on an ambulatory pathway.

Efficacy and safety of azithromycin in Covid‐19 patients: A systematic review and meta‐analysis of randomized clinical trials

“…Four studies were identified using the search strategy, 7–9 and two additional studies were identified at a later stage using e‐mail alerts 36,37 . One additional trial, the ATOMIC2 trial, was included when it was published in April 2021 38 …”

“…All studies reported the results based on pre‐specified protocols, and all were prospectively registered at one of the clinical trials registry platforms. Four trials were conducted in hospital settings, and three (Q‐PROTECT, ATOMIC2 and PRINCIPLE trials) were conducted in community settings 36–38 . Only two studies 39 , 40 included patients with severe Covid‐19.…”

“…Five studies 38–42 reported the estimates for mortality ( n = 8754). Two of the studies conducted in the community settings did not report any deaths and were not included in the analysis.…”

“…The length of hospital stay was reported in five studies. Three studies reported the mean and the standard deviation, 38,41,42 and two reported the median and IQR. 39,40 The pooled raw difference in medians from the random-effects model did not reveal a statistically significant difference in the median LOS between patients who received AZM and patients who received the SOC (Δ = 1.11, 95% CI −2.08 to 4.31, p = 0.49), and results did not change when the fixedeffects model was used (Figure 3).…”

“…Four trials were conducted in hospital settings, and three (Q-PROTECT, ATOMIC2 and PRINCIPLE trials) were conducted in community settings. [36][37][38] Only two studies 39,40 included patients with severe Covid-19.…”