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    Clinical Trial Results:
    A multi-centre open-label two-arm randomised superiority clinical trial of Azithromycin versus usual care In Ambulatory COVID-19 (ATOMIC2)

    Summary
    EudraCT number
    		 2020-001740-26
    Trial protocol
    		 GB  
    Global end of trial date
    20 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jun 2022
    First version publication date
    17 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ATOMIC2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04381962
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IRAS: 282892
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Clinical Trials and Research Governance, Boundary Brook House, Oxford, United Kingdom, OX3 7GB
    Public contact
    OCTRU, University of Oxford, +44 1865223469, ariel.wang@ndorms.ox.ac.uk
    Scientific contact
    OCTRU, University of Oxford, +44 1865223469, ariel.wang@ndorms.ox.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Can a course of antibiotics reduce the number of people with COVID-19 symptoms who go to hospital but who doctors decide do not need to be admitted from getting worse? (There is where worse is considered being admitted to hospital or dying). Another more scientific way of describing this is: Does giving patients who have a clinical diagnosis of COVID-19 who go to hospital with their symptoms, but who doctors decide to not need to be admitted and and are sent home, does giving these patients 14 days of an antibiotic called Azithromycin result in reducing the number of patients who then either die or get admitted to hospital, from any cause, in the period of 28 days from randomisation.
    Protection of trial subjects
    Azithromycin has a very well-known safety profile.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 298
    Worldwide total number of subjects
    298
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    266
    From 65 to 84 years
    29
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 3rd June 2020 to 29th January 2021, 1192 patients were screened, of whom 649 were ineligible, 84 declined consent, 161 were excluded for other reasons and 298 were enrolled in the trial. Three participants withdrew consent and requested removal of all data collected so are not presented in baseline data. 295 participants data was presented.

    Pre-assignment
    Screening details
    		 Eligible participants were adults, ≥18 years of age assessed in an acute hospital with a clinical diagnosis of highly-probable or confirmed COVID-19 infection made by the attending clinical team, with onset of first symptoms within the last 14 days, and assessed by the attending clinical team as appropriate for initial ambulatory management.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    ATOMIC2 is an open label study without blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Azithromycin
    Arm description
    		 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. Azithromycin Capsule: Azithromycin 500 mg OD PO 14 days
    Arm type
    		 Intervention

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Azithromycin 2*250 mg orally once daily for 14 days. The first dose will be within 4 hours of randomisation.

    Arm title
    		 Standard care
    Arm description
    		 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.
    Arm type
    		 Usual Standard Care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Azithromycin Standard care
    Started
    148
    150
    Completed
    147
    148
    Not completed
    1
    2
         Consent withdrawn by subject
    1
    2
    Period 2
    Period 2 title
    Overall trial - Primary outcome
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    ATOMIC2 is an open-label study without blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Azithromycin
    Arm description
    		 -
    Arm type
    		 Intervention

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Azithromycin 2*250 mg orally once daily for 14 days. The first dose will be within 4 hours of randomisation.

    Arm title
    		 Standard care
    Arm description
    		 -
    Arm type
    		 Usual Standard Care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Azithromycin Standard care
    Started
    147
    148
    Completed
    145
    147
    Not completed
    2
    1
         Consent withdrawn by subject
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Azithromycin
    Reporting group description
    		 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. Azithromycin Capsule: Azithromycin 500 mg OD PO 14 days

    Reporting group title
    Standard care
    Reporting group description
    		 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.

    Reporting group values
    		 Azithromycin Standard care Total
    Number of subjects
    		 148 150 298
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 134 129 263
        From 65-84 years
    		 13 16 29
        85 years and over
    		 0 3 3
        Not reported
    		 1 2 3
    Age continuous
    adults, ≥18 years of age
    Units: years
        arithmetic mean (standard deviation)
    		 45.5 ( 14.2 ) 46.3 ( 15.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 71 72 143
        Male
    		 76 76 152
        Not reported
    		 1 2 3
    Ethnicity
    Units: Subjects
        White
    		 103 98 201
        Mixed
    		 0 4 4
        Asian/Asian British
    		 23 24 47
        Black/Black British
    		 6 5 11
        Other Ethnic Group
    		 15 17 32
        Not recorded
    		 1 2 3
    Hypertension
    Units: Subjects
        Yes
    		 25 27 52
        No
    		 122 121 243
        Not reported
    		 1 2 3
    Diabetes
    Units: Subjects
        Yes
    		 11 14 25
        No
    		 136 134 270
        Not reported
    		 1 2 3
    Smoking
    Units: Subjects
        Never smoked
    		 81 76 157
        Ex-smoker
    		 25 26 51
        Current smoker
    		 16 17 33
        Ex-smoker & current vaper
    		 3 4 7
        Never smoked & current vaper
    		 0 1 1
        Not recorded
    		 23 26 49
    Residence
    Units: Subjects
        Non- residential care
    		 132 137 269
        Residential care
    		 7 3 10
        No fixed address
    		 5 4 9
        Not reported
    		 4 6 10
    Living alone
    Units: Subjects
        Yes
    		 17 13 30
        No
    		 108 110 218
        Not recorded
    		 23 27 50
    Work status
    Units: Subjects
        Retired
    		 15 23 38
        Working
    		 101 95 196
        Houseperson
    		 22 21 43
        Not reported
    		 10 11 21
    Occupation
    Units: Subjects
        Not healthcare related
    		 77 69 146
        Healthcare worker
    		 20 23 43
        Laboratory worker
    		 1 1 2
        Not reported
    		 50 57 107
    Have asthma
    Units: Subjects
        Yes
    		 26 27 53
        No
    		 121 121 242
        Not reported
    		 1 2 3
    History of previous myocardial infarction
    Units: Subjects
        Yes
    		 5 7 12
        No
    		 142 141 283
        Not reported
    		 1 2 3
    Currently undergoing any cancer treatment
    Units: Subjects
        Yes
    		 1 0 1
        No
    		 146 148 294
        Not reported
    		 1 2 3
    Have chronic pulmonary disease
    Units: Subjects
        Yes
    		 7 5 12
        No
    		 140 143 283
        Not reported
    		 1 2 3
    The severity scale score
    Units: Subjects
        Ambulatory, no limitation of activities
    		 61 66 127
        Limitation of simple activities
    		 85 81 166
        Hospitalised, mild disease, no oxygen therapy
    		 1 1 2
        Not reported
    		 1 2 3
    Pneumonia
    Pneumonia is defined as 'consolidation on a chest X-ray', if a chest X-ray was not taken it is assumed there was no pneumonia.
    Units: Subjects
        Yes
    		 28 34 62
        No
    		 119 114 233
        Not reported
    		 1 2 3
    Swab results
    SWAB test results are only available for those who had a Covid-19 swab at randomisation
    Units: Subjects
        Positive
    		 76 76 152
        Negative
    		 41 38 79
        Failed Assay
    		 0 3 3
        Not available
    		 31 33 64
    COVID-19 COS Score of clinical symptoms
    COVID-19 COS Score of clinical symptoms is a total score of six common and important clinical symptoms, including fever, cough, fatigue, shortness of breath, diarrhoea, and body pain, each of which can be scored as 0 (no), 1 (mild), 2 (moderate), or 3 (significant). COS scores range from 0 to 18, with higher scores indicating patient has more significant Covid symptoms.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 6.4 ( 3.6 ) 7.0 ( 3.9 ) -
    COVID-19 COS PLUS Score of clinical symptoms
    An amended version COVID-19 COS PLUS with 2 extra clinical symptoms that also considered as having clinical importance: changes to sense of smell and loss of taste. COS Plus scores range from 0 to 24. Higher scores indicating patient has more significant Covid symptoms.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 7.7 ( 4.6 ) 8.9 ( 5.2 ) -
    The Charlson Comorbidity Index
    The Charlson Comorbidity Index assigns a numerical value or “weight” from 1,2,3 or 6 to nineteen specific chronic illnesses. The final score (range 0-42) is simply the sum of weighted values with higher scores indicating more comorbidities.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 1.1 ( 1.5 ) 1.2 ( 1.8 ) -
    Duration of symptoms (days)
    Units: Days
        arithmetic mean (standard deviation)
    		 5.8 ( 3.5 ) 6.3 ( 3.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Azithromycin
    Reporting group description
    		 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. Azithromycin Capsule: Azithromycin 500 mg OD PO 14 days

    Reporting group title
    Standard care
    Reporting group description
    		 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.
    Reporting group title
    Azithromycin
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -

    Subject analysis set title
    Primary analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Efficacy and safety analyses were based on the intention-to-treat (ITT) population, defined as all randomised patients analysed according to their randomised allocation

    Subject analysis set title
    Secondary analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Efficacy and safety analyses were based on the intention-to-treat (ITT) population, defined as all randomised patients analysed according to their randomised allocation.

    Subject analysis set title
    Secondary analysis (ITT+ve)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    A supplementary ITT population (ITT +ve) is defined as all randomised patients with a positive COVID PCR result.

    Primary: Proportion of Participants With Hospital Admission or Death From Any Cause Within 28 Days From Randomisation

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    End point title
    		 Proportion of Participants With Hospital Admission or Death From Any Cause Within 28 Days From Randomisation
    End point description
    The primary outcome for this study is the proportion of patients progressing to death or hospitalisation from any cause, by day 28 post-randomisation. The primary objective is to compare the effect of Azithromycin in participants with a clinical diagnosis of COVID-19 in reducing the proportion with either death or hospital admission from any cause over the 28 days from randomisation.
    End point type
    Primary
    End point timeframe
    28 Days From Randomisation
    End point values
    		 Azithromycin Standard care Primary analysis
    Number of subjects analysed
    145
    147
    292
    Units: Participants
        All cause hospitalisation or death
    15
    17
    32
        Not hospitalised or died
    130
    130
    260
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Unadjusted logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.74 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.84
    Notes
    [1] - Unadjusted
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.92
    Notes
    [2] - Adjust for stratification factors: centre, hypertension, diabetes, and sex. Hypertension, diabetes and sex were adjusted for as fixed effects. Centre was included as a random effect.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Fully adjusted logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.97
    Notes
    [3] - Fully adjusted: Adjust for stratification factors and other important prognostic variables: centre, hypertension, diabetes, sex, and age ≥65 years, presence of chronic lung disease, and treatment for cancer
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Unadjusted Log Rank test
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79 [4]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - Unadjusted
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Adjusted Cox's proportional hazard
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.89 [5]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.96
    Notes
    [5] - Adjust for stratification factors: hypertension, diabetes and sex were adjusted for as fixed effects; centre was included as a random effect.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Fully adjusted Cox's proportional hazard
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 2
    Notes
    [6] - Adjust for stratification factors and other important prognostic variables: centre, hypertension, diabetes, sex, and age ≥65 years, presence of chronic lung disease, and treatment for cancer.

    Secondary: Proportion With All-cause Hospital Admission or Death (SARS-CoV-2 PCR Positive)

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    End point title
    		 Proportion With All-cause Hospital Admission or Death (SARS-CoV-2 PCR Positive)
    End point description
    Efficacy was determined through differences in the proportion with all-cause hospital admission or death 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.
    End point type
    Secondary
    End point timeframe
    Determined at day 28 from randomisation
    End point values
    		 Azithromycin Standard care Secondary analysis (ITT+ve)
    Number of subjects analysed
    75
    75
    150
    Units: Participants
        All cause hospital admission or death
    11
    11
    22
        Not hospitalised or died
    64
    64
    128
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Unadjusted logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 2.47
    Notes
    [7] - Unadjusted
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted linear regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 2.57
    Notes
    [8] - Adjust for stratification factors: centre, hypertension, diabetes, and sex. Hypertension, diabetes and sex were adjusted for as fixed effects. Centre was included as a random effect.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Adjusted logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 2.9
    Notes
    [9] - Fully adjusted: adjust for stratification factors and other important prognostic variables: centre, hypertension, diabetes, sex, and age ≥65 years, presence of chronic lung disease, and treatment for cancer.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Unadjusted Log Rank test
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78 [10]
    Method
    		 Logrank
    Confidence interval
    Notes
    [10] - Unadjusted
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Adjusted Cox's proportional hazard
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72 [11]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 2.77
    Notes
    [11] - Adjusted for stratification factors (centre, hypertension, diabetes and sex). Hypertension, diabetes and sex were adjusted for as fixed effects. Centre was included as a random effect
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Fully adjusted Cox's proportional hazard
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.57 [12]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 3.21
    Notes
    [12] - Fully adjusted: adjust for stratification factors and other important prognostic variables: centre, hypertension, diabetes, sex, and age ≥65 years, presence of chronic lung disease, and treatment for cancer.

    Secondary: Proportion Progressing to Respiratory Failure or Death

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    End point title
    		 Proportion Progressing to Respiratory Failure or Death
    End point description
    Efficacy was 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.
    End point type
    Secondary
    End point timeframe
    Determined at day 28 from randomisation.
    End point values
    		 Azithromycin Standard care Secondary analysis
    Number of subjects analysed
    145
    147
    292
    Units: Participants
        Participants on level 2/3 ventilation or died
    2
    2
    4
        Not on level 2/3 ventilation or died
    143
    145
    288
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Fisher Exact test
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [13] - Due to the very low number of events Fisher’s exact test was used to compare the Azithromycin and control groups.

    Secondary: Proportion Progressing to Respiratory Failure or Death (SARS-CoV-2 PCR Positive)

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    End point title
    		 Proportion Progressing to Respiratory Failure or Death (SARS-CoV-2 PCR Positive)
    End point description
    Efficacy was 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.
    End point type
    Secondary
    End point timeframe
    Determined at day 28 from randomisation
    End point values
    		 Azithromycin Standard care Secondary analysis (ITT+ve)
    Number of subjects analysed
    75
    75
    150
    Units: Participants
        Participants on level 2/3 ventilation or died
    2
    2
    4
        Not on level 2/3 ventilation or died
    73
    73
    146
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Fisher Exact test
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [14] - Due to the very low number of events Fisher’s exact test was used to compare the Azithromycin and control groups.

    Secondary: All Cause Mortality

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    End point title
    		 All Cause Mortality
    End point description
    All-cause mortality was assessed and reported based on data ascertained at 28 days after randomisation. Hospitalised patients were followed up until discharge or death where possible. Data on vital status (alive / dead, with date and presumed cause of death if appropriate) was collected at day 14 and at 28 days post-randomisation.
    End point type
    Secondary
    End point timeframe
    Ascertain data at 28 days after randomisation
    End point values
    		 Azithromycin Standard care Secondary analysis
    Number of subjects analysed
    145
    147
    292
    Units: Participants
        Died
    1
    1
    2
        Alive
    144
    146
    290
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Fisher Exact test
    Comparison groups
    Standard care v Azithromycin
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [15] - Due to the very low number of events Fisher’s exact test was used to compare the Azithromycin and control groups

    Secondary: All-cause Mortality (SARS-CoV-2 PCR Positive)

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    End point title
    		 All-cause Mortality (SARS-CoV-2 PCR Positive)
    End point description
    All-cause mortality was assessed and reported based on data ascertained at 28 days after randomisation. Hospitalised patients were followed up until discharge or death where possible. Data on vital status (alive / dead, with date and presumed cause of death if appropriate) was collected at day 14 and at 28 days post-randomisation.
    End point type
    Secondary
    End point timeframe
    Ascertain data at 28 days after randomisation
    End point values
    		 Azithromycin Standard care Secondary analysis (ITT+ve)
    Number of subjects analysed
    75
    75
    150
    Units: Participants
        Died
    1
    1
    2
        Alive
    74
    74
    148
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Fisher Exact test
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [16] - Due to the very low number of events Fisher’s exact test was used to compare the Azithromycin and control groups

    Secondary: Proportion Progressing to Pneumonia

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    End point title
    		 Proportion Progressing to Pneumonia
    End point description
    Progression to pneumonia as diagnosed by chest x-ray (or CT thorax), with compatible clinical findings, if no pneumonia was presented at time of enrolment. Pneumonia was diagnosed by a medically qualified doctor and data obtained from review of case-notes and relevant radiology.
    End point type
    Secondary
    End point timeframe
    Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner)
    End point values
    		 Azithromycin Standard care Secondary analysis
    Number of subjects analysed
    119 [17]
    114 [18]
    233 [19]
    Units: Participants
        Progression to pneumonia
    0
    2
    2
        No pneumonia
    119
    112
    231
    Notes
    [17] - This is the number of participants that did not have pneumonia presented at baseline
    [18] - This is the number of participants that did not have pneumonia presented at baseline
    [19] - This is the number of participants that did not have pneumonia presented at baseline
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Fisher Exact test
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.24
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [20] - Due to the very low number of events Fisher’s exact test was used to compare the Azithromycin and control groups

    Secondary: Proportion Progressing to Pneumonia (SARS-CoV-2 PCR Positive)

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    End point title
    		 Proportion Progressing to Pneumonia (SARS-CoV-2 PCR Positive)
    End point description
    Progression to pneumonia as diagnosed by chest x-ray (or CT thorax), with compatible clinical findings, if no pneumonia was presented at time of enrolment. Pneumonia was diagnosed by a medically qualified doctor and data obtained from review of case-notes and relevant radiology.
    End point type
    Secondary
    End point timeframe
    Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner)
    End point values
    		 Azithromycin Standard care Secondary analysis (ITT+ve)
    Number of subjects analysed
    58 [21]
    52 [22]
    110 [23]
    Units: Participants
        Progression to pneumonia
    0
    2
    2
        No pneumonia
    58
    50
    108
    Notes
    [21] - This is the number of participants that did not have pneumonia presented at baseline
    [22] - This is the number of participants that did not have pneumonia presented at baseline
    [23] - This is the number of participants that did not have pneumonia presented at baseline
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Fisher Exact test
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.22
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [24] - Due to the very low number of events Fisher’s exact test was used to compare the Azithromycin and control groups

    Secondary: Proportion Progressing to Severe Pneumonia

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    End point title
    		 Proportion Progressing to Severe Pneumonia
    End point description
    Evolution of pneumonia, as diagnosed by chest x-ray or CT thorax, if pneumonia was presented at time of enrolment. Pneumonia was 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. Note: No statistical analysis was undertaken as there were no instances of participants progressing to severe pneumonia.
    End point type
    Secondary
    End point timeframe
    Ascertain this information at time of pneumonia diagnosis, or at 28 days after randomisation (whichever is sooner)
    End point values
    		 Azithromycin Standard care Secondary analysis
    Number of subjects analysed
    28 [25]
    34 [26]
    62 [27]
    Units: Participants
        Progression to severe pneumonia
    0
    0
    0
        Not progressed to severe pneumonia
    28
    34
    62
    Notes
    [25] - This is the number of participants who had pneumonia presented at time of enrolment.
    [26] - This is the number of participants who had pneumonia presented at time of enrolment.
    [27] - This is the number of participants who had pneumonia presented at time of enrolment.
    No statistical analyses for this end point

    Secondary: Differences in the Peak Severity of Illness

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    End point title
    		 Differences in the Peak Severity of Illness
    End point description
    The 9-point ordinal scoring system is described in the protocol reflects the severity of respiratory illness. The maximum severity scores during the entire study period were compared. The severity scale scores range from 0 to 8 with higher scores indicating the most severe status, death.
    End point type
    Secondary
    End point timeframe
    Ascertain from day 14 and day 28 telephone call and from retrospective ePR/medical notes data at 28 days after randomisation.
    End point values
    		 Azithromycin Standard care Secondary analysis
    Number of subjects analysed
    124 [28]
    131 [29]
    255 [30]
    Units: Participants
        Ambulatory, no limitation of activities
    62
    60
    122
        Limitation of simple activities
    49
    57
    106
        Hospitalised, mild disease, no oxygen therapy
    3
    2
    5
        Hospitalised, oxygen ≤40% mask
    5
    10
    15
        Hospitalised, oxygen >40% mask
    3
    0
    3
        Hospitalised receiving NIV or high-flow oxygen
    1
    1
    2
        Death
    1
    1
    2
    Notes
    [28] - This is the number of participants completed the severity scale scores.
    [29] - This is the number of participants completed the severity scale scores.
    [30] - This is the number of participants completed the severity scale scores.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Unadjusted ordinal logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.57 [32]
    Method
    		 ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.4
    Notes
    [31] - The difference between the treatment arms in terms of peak severity score was assessed using ordinal logistic regression.
    [32] - Unadjusted
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted ordinal logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.69 [34]
    Method
    		 ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.46
    Notes
    [33] - The difference between the treatment arms in terms of peak severity score was assessed using ordinal logistic regression.
    [34] - Adjust for stratification factors: centre, hypertension, diabetes, and sex. Hypertension, diabetes and sex were adjusted for as fixed effects. Centre was included as a random effect.

    Secondary: Differences in Peak Severity of Illness (SARS-CoV-2 PCR Positive)

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    End point title
    		 Differences in Peak Severity of Illness (SARS-CoV-2 PCR Positive)
    End point description
    The 9-point ordinal scoring system is described in the protocol reflects the severity of respiratory illness. The maximum severity scores during the entire study period were compared. The severity scale scores range from 0 to 8 with higher scores indicating the most severe status, death.
    End point type
    Secondary
    End point timeframe
    Ascertain from day 14 and day 28 telephone call and from retrospective ePR/medical notes data at 28 days after randomisation.
    End point values
    		 Azithromycin Standard care Secondary analysis (ITT+ve)
    Number of subjects analysed
    65 [35]
    70 [36]
    135 [37]
    Units: Participants
        Ambulatory, no limitation of activities
    26
    32
    58
        Limitation of simple activities
    29
    28
    57
        Hospitalised, mild disease, no oxygen therapy
    2
    1
    3
        Hospitalised, oxygen ≤40% mask
    3
    7
    10
        Hospitalised, oxygen >40% mask
    3
    0
    3
        Hospitalised receiving NIV or high-flow oxygen
    1
    1
    2
        Death
    1
    1
    2
    Notes
    [35] - This is the number of participants who completed the severity scale scores.
    [36] - This is the number of participants who completed the severity scale scores.
    [37] - This is the number of participants who completed the severity scale scores.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Unadjusted ordinal logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.53 [39]
    Method
    		 ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 2.32
    Notes
    [38] - The difference between the treatment arms was assessed using ordinal logistic regression.
    [39] - Unadjusted
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted ordinal logistic regression
    Comparison groups
    Azithromycin v Standard care
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.29 [41]
    Method
    		 ordinal logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 2.78
    Notes
    [40] - The difference between the treatment arms was assessed using ordinal logistic regression.
    [41] - Adjust for stratification factors: centre, hypertension, diabetes, and sex. Hypertension, diabetes, and sex were adjusted for as fixed effects. Centre was included as a random effect.

    Secondary: Safety and Tolerability

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    End point title
    		 Safety and Tolerability
    End point description
    Serious adverse events and concomitant medications. Recorded at enrolment, emergently during study period and proactively elicit at day 14 and at day 28. Note: No statistical analysis was undertaken as there were no instances of SAE
    End point type
    Secondary
    End point timeframe
    Emergent data collection days 0-28 and elicit proactively at day 14 and day 28 post randomisation.
    End point values
    		 Azithromycin Standard care Secondary analysis
    Number of subjects analysed
    145
    147
    292
    Units: Participants
        SAE
    0
    0
    0
        No SAE
    145
    147
    292
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation until 14 days of IMP administration
    Adverse event reporting additional description
    All SAEs (other than those defined as foreseeable below) occurring within the first 14 days of the IMP administration were recorded. Deaths due to COVID-19 disease during the study were exempt from reporting as SAEs since they were captured as part of the primary outcome.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Azithromycin
    Reporting group description
    		 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.

    Reporting group title
    Usual Standard Care
    Reporting group description
    		 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.

    Serious adverse events
    		 Azithromycin Usual Standard Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 147 (0.00%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Azithromycin Usual Standard Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 147 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Only non-serious adverse events were collected.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 May 2020
    Increased information in Clinical Trial Label due to some pharmacies wanting to re-pack in one box.
    16 Jun 2020
    Addition of sites: ELHT, Royal Derby, Royal London, Royal Berkshire and change of PI at OUH.
    22 Jul 2020
    Protocol – change to inclusion criteria (symptoms <14 days, confirmed COVID & include participants on SSRIs) and clarification of safety reporting. Addition of compulsory ECG.
    29 Jul 2020
    Addition of new sites: South Tees and King’s College
    21 Aug 2020
    Addition of new sites: North Tees, Darlington, St Georges and UCLH
    03 Mar 2021
    Change to primary endpoint and sample size recalculation. Halt to recruitment.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This trial was open-label, and is at risk of bias particularly on patient reported outcomes. We used a clinical diagnosis for inclusion, rather than requiring PCR confirmation. No data on microbiology and no long term outcomes beyond 28 days.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34252378
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