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

22 Pages Posted: 15 Apr 2021

See all articles by Timothy SC Hinks

Timothy SC Hinks

University of Oxford - Respiratory Medicine Unit

Lucy Cureton

University of Oxford

Ruth Knight

University of Oxford

Ariel Wang

University of Oxford

Jennifer L. Cane

University of Oxford - Nuffield Department of Clinical Medicine

Vicki S. Barber

University of Oxford

Joanna Black

University of Oxford

Susan J. Dutton

University of Oxford

James Melhorn

Cardiff University - University Hospital Llandough

Maisha F. Jabeen

University of Oxford

Phil Moss

St. George's Hospital Medical School - Emergency Department

Rajendar Garlapati

East Lancashire Hospitals NHS Trust

Tanya Baron

Oxford University Hospitals NHS Foundation Trust - Emergency Department

Graham Johnson

Independent

Fleur Cantle

King's College Hospital; King’s College Hospital, Department of Emergency Medicine

David Clarke

Royal Berkshire NHS Foundation Trust

Samer Elkhodair

University College Hospital

Jonathan Underwood

Cardiff and Vale University Health Board - Department of Infectious Diseases

Daniel Lasserson

University of Oxford - Oxford University Hospitals

Ian Pavord

University of Oxford - National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC)

Sophie B. Morgan

University of Oxford

Duncan Richards

University of Oxford

More...

Abstract

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).

Keywords: COVID-19; Coronavirus; SAR-CoV-2; Azithromycin; Macrolide; Randomised controlled trial; Respiratory failure; Mortality; Trial

Suggested Citation

Hinks, Timothy SC and Cureton, Lucy and Knight, Ruth and Wang, Ariel and Cane, Jennifer L. and Barber, Vicki S. and Black, Joanna and Dutton, Susan J. and Melhorn, James and Jabeen, Maisha F. and Moss, Phil and Garlapati, Rajendar and Baron, Tanya and Johnson, Graham and Cantle, Fleur and Clarke, David and Elkhodair, Samer and Underwood, Jonathan and Lasserson, Daniel and Pavord, Ian and Morgan, Sophie B. and Richards, Duncan, A Randomised Clinical Trial of Azithromycin Versus Standard Care in Ambulatory COVID-19 – The ATOMIC2 Trial. Available at SSRN: https://ssrn.com/abstract=3827019 or http://dx.doi.org/10.2139/ssrn.3827019

Timothy SC Hinks (Contact Author)

University of Oxford - Respiratory Medicine Unit ( email )

Oxfordshire
United Kingdom

Lucy Cureton

University of Oxford

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Ruth Knight

University of Oxford

Ariel Wang

University of Oxford

Jennifer L. Cane

University of Oxford - Nuffield Department of Clinical Medicine ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Vicki S. Barber

University of Oxford

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Joanna Black

University of Oxford

Susan J. Dutton

University of Oxford

Mansfield Road
Oxford, OX1 4AU
United Kingdom

James Melhorn

Cardiff University - University Hospital Llandough

Llandough
United Kingdom

Maisha F. Jabeen

University of Oxford

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Phil Moss

St. George's Hospital Medical School - Emergency Department ( email )

Cranmer Terrace
Tooting, SW17 0RE
United Kingdom

Rajendar Garlapati

East Lancashire Hospitals NHS Trust

East Lancashire
United Kingdom

Tanya Baron

Oxford University Hospitals NHS Foundation Trust - Emergency Department ( email )

Headley Way
Headington
Oxford, OX3 9DU
United Kingdom

Graham Johnson

Independent

Fleur Cantle

King's College Hospital ( email )

Denmark Hill
London, Brixton SE5 9RS
United Kingdom

King’s College Hospital, Department of Emergency Medicine ( email )

David Clarke

Royal Berkshire NHS Foundation Trust

Reading, RG1 5AN
United Kingdom

Samer Elkhodair

University College Hospital

Ibadan
Nigeria

Jonathan Underwood

Cardiff and Vale University Health Board - Department of Infectious Diseases

Fairwater Road
South Glamorgan, CF5 2LD
United Kingdom

Daniel Lasserson

University of Oxford - Oxford University Hospitals

Oxford
United Kingdom

Ian Pavord

University of Oxford - National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) ( email )

Oxford
United Kingdom

Sophie B. Morgan

University of Oxford

Mansfield Road
Oxford, OX1 4AU
United Kingdom

Duncan Richards

University of Oxford

Mansfield Road
Oxford, OX1 4AU
United Kingdom

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