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

Study Overview
=================
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.

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

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: Azithromycin Capsule


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label, Two-arm, Randomised Superiority Trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycin<br>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<br>* Azithromycin 500 mg OD PO 14 days<br>|
| No Intervention: Usual standard care<br>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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SARS-CoV-2, Coronavirus, COVID-19, Azithromycin, Respiratory failure, Mortality, Trial