A Multicentre Open-label Two-arm Randomised Superiority Clinical Trial of Azithromycin Versus Usual Care In Ambulatory COVID19 (ATOMIC2) (ATOMIC2)

A Multi-centre Open-label Two-arm Randomised Superiority Clinical Trial of Azithromycin Versus Usual Care In Ambulatory COVID-19 (ATOMIC2)

A multi-centre open-label two-arm randomised superiority clinical trial of two weeks of oral Azithromycin 500mg once daily versus usual care in adult patients presenting to secondary care with clinically-diagnosed COVID-19 but assessed as appropriate for initial ambulant (outpatient) management, in preventing progression to respiratory failure or death.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Azithromycin Capsule

Detailed Description

Hypothesis: Use of Azithromycin 500 mg once daily for 14 days is effective in preventing and/or reducing the severity of lower respiratory illness of COVID-19 disease at 28 days.

Study design: Multi centre, prospective open label two-arm randomised superiority clinical trial of standard care and Azithromycin with standard care alone for those presenting to hospital with COVID-19 symptoms who are not admitted at initial presentation.

Study setting: Patients being assessed by secondary care NHS hospitals in the UK.

Participants: Adults, ≥18 years of age assessed in an acute hospital with clinical diagnosis of COVID-19 infection and where medically it is decided not to admit the patient and for the patient to be managed on an ambulatory (outpatient) care pathway at their usual residence (home or care home).

Study schedule: Enrolment on day 0. Telephone follow up at day 14 day, and day 28. If admitted between randomisation and day 28, data will be collected until hospital discharge.

Intervention: Azithromycin 500 mg orally once daily for 14 days. The first dose will be within 4 hours of randomisation. This is in addition to standard care as per local hospital advice for those patients with suspected COVID who are not admitted: i.e. symptomatic relief with rest, as-required paracetamol (where appropriate) and advice to seek further medical attention if significant worsening of breathlessness.

Comparator: Standard care as per local hospital advice for those patients with suspected COVID who are not admitted: i.e. symptomatic relief with rest, as-required paracetamol (where appropriate) and advice to seek further medical attention if significant worsening of breathlessness.

• Study Type: Interventional
• Enrollment (Actual): 298
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom, B18 7QH
    • Birmingham City Hospital
  • West Bromwich, United Kingdom, B71 4HJ
    • Sandwell General Hospital
  • Oxfordshire
    • Banbury, Oxfordshire, United Kingdom, OX3 9DU
      • Horton General Hospital
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • John Radcliffe Hospital
  • Scotland
    • Dundee, Scotland, United Kingdom, DD2 1SG
      • Ninewells Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or Female, aged at least 18 years
• Assessed by the attending clinical team as appropriate for initial ambulatory (outpatient) management
• A clinical diagnosis of highly-probable COVID-19 infection (diagnosis by the attending clinical team)
• No medical history that might, in the opinion of the attending clinician, put the patient at significant risk if he/she were to participate in the trial
• Able to understand written English (for the information and consent process) and be able to give informed consent

Exclusion Criteria:

• Known hypersensitivity to any Macrolide including Azithromycin, Ketolide antibiotic, or the excipients including an allergy to soya or peanuts.
• Known fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase-insufficiency
• Currently on a Macrolide antibiotic (Clarithromycin, Azithromycin, Erythromycin, Telithromycin, Spiramycin)
• On any SSRI (Selective Serotonin Reuptake Inhibitor)
• Elevated cardiac troponin at initial assessment suggestive of significant myocarditis (if clinically the clinical team have felt it appropriate to check the patient's troponin levels)
• Evidence of QTc prolongation: QTc>480ms
• Significant electrolyte disturbance (e.g. hypokalaemia K+<3.5 mmol/L)
• Clinically relevant bradycardia (P<50 bpm), non-sustained ventricular tachycardia or unstable severe cardiac insufficiency
• Currently on hydroxychloroquine or chloroquine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azithromycin; Azithromycin 2x250mg capsules to be taken orally once daily for 14 days. The first dose will be within 4 hours of randomisation. This is in addition to standard care as per local hospital advice for those patients with suspected COVID who are not admitted: i.e. symptomatic relief with rest, as-required paracetamol (where appropriate) and advice to seek further medical attention if significant worsening of breathlessness.	Drug: Azithromycin Capsule; Azithromycin 500 mg OD PO 14 days
No Intervention: Usual standard care; Standard care as per local hospital advice for those patients with suspected COVID who are not admitted: i.e. symptomatic relief with rest, as-required paracetamol (where appropriate) and advice to seek further medical attention if significant worsening of breathlessness.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion progressing to respiratory failure or death (all clinically-diagnosed participants)	Efficacy will be determined through differences in the proportion with either death or admission with respiratory failure requiring level 2 ventilation (NIV/CPAP/nasal high-flow) or level 3 (invasive mechanical ventilation) in the 28 days from randomisation.	Determined at day 28 from randomisation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion progressing to respiratory failure or death (SARS-CoV-2 PCR positive)	Efficacy will be determined through differences in the proportion with either death or admission with respiratory failure requiring level 2 ventilatory support (NIV/CPAP/nasal high-flow) or level 3 (invasive mechanical ventilation) in the 28 days from randomisation using a retrospective analysis of COVID-19 oropharyngeal swabs for those who had one taken at time of randomisation.	Determined at day 28 from randomisation.
All cause mortality	Data on vital status (alive / dead, with date and presumed cause of death if appropriate)	Ascertain data at 28 days after randomisation.
Proportion progressing to pneumonia.	Progression to pneumonia as diagnosed by chest x-ray (or CT thorax), with compatible clinical findings, if no pneumonia is present at time of enrolment. To be diagnosed by a medically qualified doctor and data obtained from review of case-notes and relevant radiology.	Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner)
Proportion progressing to severe pneumonia	Evolution of pneumonia, as diagnosed by chest x-ray or CT thorax, if pneumonia is present at time of enrolment. To be diagnosed by a medically qualified doctor and data obtained from review of case-notes and relevant radiology. Severe pneumonia is defined as BTS CURB-65 score of 3-5.	Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner)
Peak severity of illness	The 9-point ordinal scoring system is described in the protocol reflects the severity of respiratory illness. The maximum severity score during the entire study period will be compared.	Ascertain from day 14 and day 28 telephone call and from retrospective ePR/medical notes data at 28 days after randomisation.
Safety and tolerability	Serious adverse events and concomitant medications. Record at enrolment, emergently during study period and proactively elicit at day 14 and at day 28.	Emergent data collection days 0-28 and elicit proactively at day 14 and day 28 post randomisation.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mechanistic analysis of blood and nasal biomarkers if available	The following samples may be taken. Blood for serum, Tempus tube (whole blood RNA), EDTA tubes (PBMC), nasal brush to be placed immediately into RNA lysis buffer (for subsequent PCR and transcriptomic analysis). Includes assessment of mycoplasma prevalence for subgroup analysis.	Samples to be collected prospectively at baseline and again if patient admitted, to be taken as soon as possible and within 72 hours of admission if possible.

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Pfizer
• Investigators: Study Chair: Paul Little, MD PhD, University of Southampton

Publications and helpful links

General Publications

• Hinks TSC, Barber VS, Black J, Dutton SJ, Jabeen M, Melhorn J, Rahman NM, Richards D, Lasserson D, Pavord ID, Bafadhel M. 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. Trials. 2020 Aug 17;21(1):718. doi: 10.1186/s13063-020-04593-8.
• Hinks TSC, Cureton L, Knight R, Wang A, Cane JL, Barber VS, Black J, Dutton SJ, Melhorn J, Jabeen M, Moss P, Garlapati R, Baron T, Johnson G, Cantle F, Clarke D, Elkhodair S, Underwood J, Lasserson D, Pavord ID, Morgan S, Richards D. Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet Respir Med. 2021 Oct;9(10):1130-1140. doi: 10.1016/S2213-2600(21)00263-0. Epub 2021 Jul 9. Erratum In: Lancet Respir Med. 2021 Sep 2;:

Helpful Links

• ATOMIC2 homepage

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2020
• Primary Completion (Actual): January 29, 2021
• Study Completion (Actual): April 20, 2021

Study Registration Dates

• First Submitted: May 7, 2020
• First Submitted That Met QC Criteria: May 7, 2020
• First Posted (Actual): May 11, 2020

Study Record Updates

• Last Update Posted (Actual): May 6, 2021
• Last Update Submitted That Met QC Criteria: May 4, 2021
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Coronavirus; COVID-19; Azithromycin; Mortality; Trial; Respiratory failure
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: ATOMIC2; 2020-001740-26 (EudraCT Number); 282892 (Other Identifier: IRAS); 20/HRA/2105 (Other Identifier: London-Brent Research Ethics Committee)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No