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A multi-centre open-label two-arm randomised superiority clinical trial of azithromycin versus usual care in ambulatory COVID-19: study protocol for the ATOMIC2 trial

  • Hinks, Timothy S. C.1
  • Barber, Vicki S.2
  • Black, Joanna2
  • Dutton, Susan J.2
  • Jabeen, Maisha1
  • Melhorn, James3
  • Rahman, Najib M1
  • Richards, Duncan2
  • Lasserson, Daniel4, 5
  • Pavord, Ian D.1
  • Bafadhel, Mona1
  • 1 University of Oxford, Oxfordshire, OX3 9DU, UK , Oxfordshire (United Kingdom)
  • 2 University of Oxford, Oxford, UK , Oxford (United Kingdom)
  • 3 University Hospital Llandough, Cardiff, CF64 2XX, UK , Cardiff (United Kingdom)
  • 4 Oxford University, Oxford, UK , Oxford (United Kingdom)
  • 5 University of Warwick, Coventry, CV4 7AL, UK , Coventry (United Kingdom)
Published Article
Springer (Biomed Central Ltd.)
Publication Date
Aug 17, 2020
DOI: 10.1186/s13063-020-04593-8
Springer Nature


BackgroundAzithromycin is an orally active synthetic macrolide antibiotic with a wide range of anti-bacterial, anti-inflammatory and antiviral properties. It is a safe, inexpensive, generic licenced drug available worldwide and manufactured to scale and is a potential candidate therapy for pandemic coronavirus disease 2019 (COVID-19). Azithromycin was widely used to treat severe SARS-CoV and MERS-CoV, but to date, no randomised data are available in any coronavirus infections.Other ongoing trials are exploring short courses of azithromycin either in early disease, within the first 7 days of symptoms, when azithromycin’s antiviral properties may be important, or late in disease when anti-bacterial properties may reduce the risk of secondary bacterial infection. However, the molecule’s anti-inflammatory properties, including suppression of pulmonary macrophage-derived pro-inflammatory cytokines such as interleukins-1β, -6, -8, and -18 and cytokines G-CSF and GM-CSF may provide a distinct therapeutic benefit if given in as a prolonged course during the period of progression from moderate to severe disease.MethodsATOMIC2 is a phase II/III, multi-centre, prospective, open-label, two-arm randomised superiority clinical trial of azithromycin versus standard care for adults presenting to hospital with COVID-19 symptoms who are not admitted at initial presentation. We will enrol adults, ≥ 18 years of age assessed in acute hospitals in the UK with clinical diagnosis of COVID-19 infection where management on an ambulatory care pathway is deemed appropriate. Participants will be randomised in a 1:1 ratio to usual care or to azithromycin 500 mg orally daily for 14 days with telephone follow-up at days 14 and 28. The primary objective is to compare the proportion with either death or respiratory failure requiring invasive or non-invasive mechanical ventilation over 28 days from randomisation. Secondary objectives include mortality/respiratory failure in those with a PCR-confirmed diagnosis; all-cause mortality; progression to pneumonia; progression to severe pneumonia; peak severity of illness and mechanistic analysis of blood and nasal biomarkers.DiscussionThis trial will determine the clinical utility of azithromycin in patients with moderately severe, clinically diagnosed COVID-19 and could be rapidly applicable worldwide.Trial NCT04381962. Registered on 11 May 2020. EudraCT identifier 2020-001740-26. Opened for accrual on 29 May 2020.

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