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

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ClinicalTrials.gov Identifier: NCT04381962
Recruitment Status : Completed
First Posted : May 11, 2020
Last Update Posted : May 6, 2021
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
University of Oxford

Tracking Information
First Submitted Date  ICMJE May 7, 2020
First Posted Date  ICMJE May 11, 2020
Last Update Posted Date May 6, 2021
Actual Study Start Date  ICMJE June 3, 2020
Actual Primary Completion Date January 29, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2020)
Proportion progressing to respiratory failure or death (all clinically-diagnosed participants) [ Time Frame: Determined at day 28 from randomisation. ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2020)
  • Proportion progressing to respiratory failure or death (SARS-CoV-2 PCR positive) [ Time Frame: Determined at day 28 from randomisation. ]
    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.
  • All cause mortality [ Time Frame: Ascertain data at 28 days after randomisation. ]
    Data on vital status (alive / dead, with date and presumed cause of death if appropriate)
  • Proportion progressing to pneumonia. [ Time Frame: Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner) ]
    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.
  • Proportion progressing to severe pneumonia [ Time Frame: Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner) ]
    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.
  • Peak severity of illness [ Time Frame: Ascertain from day 14 and day 28 telephone call and from retrospective ePR/medical notes data at 28 days after randomisation. ]
    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.
  • Safety and tolerability [ Time Frame: Emergent data collection days 0-28 and elicit proactively at day 14 and day 28 post randomisation. ]
    Serious adverse events and concomitant medications. Record at enrolment, emergently during study period and proactively elicit at day 14 and at day 28.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 7, 2020)
Mechanistic analysis of blood and nasal biomarkers if available [ Time Frame: 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. ]
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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Multicentre Open-label Two-arm Randomised Superiority Clinical Trial of Azithromycin Versus Usual Care In Ambulatory COVID19 (ATOMIC2)
Official Title  ICMJE A Multi-centre Open-label Two-arm Randomised Superiority Clinical Trial of Azithromycin Versus Usual Care In Ambulatory COVID-19 (ATOMIC2)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Open label, Two-arm, Randomised Superiority Trial
Masking: None (Open Label)
Masking Description:
This is an open-label study. However, while the study is in progress, access to tabular results by allocated treatment allocation will not be available to the research team, patients, or members of the Steering Committee (unless the DSMC advises otherwise).
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE Drug: Azithromycin Capsule
Azithromycin 500 mg OD PO 14 days
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Azithromycin Capsule
  • 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.
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 4, 2021)
298
Original Estimated Enrollment  ICMJE
 (submitted: May 7, 2020)
800
Actual Study Completion Date  ICMJE April 20, 2021
Actual Primary Completion Date January 29, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04381962
Other Study ID Numbers  ICMJE ATOMIC2
2020-001740-26 ( EudraCT Number )
282892 ( Other Identifier: IRAS )
20/HRA/2105 ( Other Identifier: London-Brent Research Ethics Committee )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Oxford
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Study Chair: Paul Little, MD PhD University of Southampton
PRS Account University of Oxford
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP