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

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ClinicalTrials.gov Identifier: NCT04381962
Recruitment Status : Not yet recruiting
First Posted : May 11, 2020
Last Update Posted : May 11, 2020
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
University of Oxford

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.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Azithromycin Capsule Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
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
Official Title: A Multi-centre Open-label Two-arm Randomised Superiority Clinical Trial of Azithromycin Versus Usual Care In Ambulatory COVID-19 (ATOMIC2)
Estimated Study Start Date : May 13, 2020
Estimated Primary Completion Date : September 13, 2020
Estimated Study Completion Date : October 13, 2020

Resource links provided by the National Library of Medicine


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.



Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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)

  3. 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.

  4. 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.

  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.

  6. 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.


Other Outcome Measures:
  1. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04381962


Contacts
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Contact: Lucy Cureton 01865 227 374 atomic2@ndorms.ox.ac.uk
Contact: Timothy SC Hinks, MD PhD +44 (0)1865 220885 timothy.hinks@ndm.ox.ac.uk

Sponsors and Collaborators
University of Oxford
Pfizer
Investigators
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Study Chair: Paul Little, MD PhD University of Southampton
Additional Information:
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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT04381962    
Other Study ID Numbers: ATOMIC2
2020-001740-26 ( EudraCT Number )
282892 ( Other Identifier: IRAS )
20/HRA/2105 ( Other Identifier: London-Brent Research Ethics Committee )
First Posted: May 11, 2020    Key Record Dates
Last Update Posted: May 11, 2020
Last Verified: May 2020

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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
Keywords provided by University of Oxford:
SARS-CoV-2
Coronavirus
COVID-19
Azithromycin
Respiratory failure
Mortality
Trial
Additional relevant MeSH terms:
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Azithromycin
Anti-Bacterial Agents
Anti-Infective Agents