Clinical trial NCT04381962: A Multicentre Open-label Two-arm Randomised Superiority Clinical Trial of Azithromycin Versus Usual Care In Ambulatory COVID19 (ATOMIC2)
Official title: A Multi-centre Open-label Two-arm Randomised Superiority Clinical Trial of Azithromycin Versus Usual Care In Ambulatory COVID-19 (ATOMIC2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: SARS-CoV-2
Coronavirus
COVID-19
Azithromycin
Respiratory failure
Mortality
Trial
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2020-05-11
Enrollment: 298
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open label, Two-arm, Randomised Superiority Trial
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion progressing to respiratory failure or death (all clinically-diagnosed participants)
timeFrame: Determined at day 28 from randomisation.
Secondary outcomes:
measure: Proportion progressing to respiratory failure or death (SARS-CoV-2 PCR positive)
timeFrame: Determined at day 28 from randomisation.
measure: All cause mortality
timeFrame: Ascertain data at 28 days after randomisation.
measure: Proportion progressing to pneumonia.
timeFrame: Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner)
measure: Proportion progressing to severe pneumonia
timeFrame: Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner)
measure: Peak severity of illness
timeFrame: Ascertain from day 14 and day 28 telephone call and from retrospective ePR/medical notes data at 28 days after randomisation.
measure: Safety and tolerability
timeFrame: Emergent data collection days 0-28 and elicit proactively at day 14 and day 28 post randomisation.
Other outcomes:
measure: Mechanistic analysis of blood and nasal biomarkers if available
timeFrame: 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.
Locations:
city: Banbury
country: United Kingdom
facility: Horton General Hospital
state: Oxfordshire
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
state: Oxfordshire
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
state: Scotland
city: Birmingham
country: United Kingdom
facility: Birmingham City Hospital
city: West Bromwich
country: United Kingdom
facility: Sandwell General Hospital
Study officials:
affiliation: University of Southampton
name: Paul Little, MD PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.