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    Clinical Trial Results:
    Azithromycin for acute COPD exacerbations with hospitalisation: the BACE trial

    Summary
    EudraCT number
    		 2013-004420-11
    Trial protocol
    		 BE  
    Global end of trial date
    19 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    s55829
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02135354
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    KU Leuven
    Sponsor organisation address
    Herestraat 49 Box 706, Leuven, Belgium, 3000
    Public contact
    Kristina Vermeersch, KU Leuven - UZ Leuven , 0032 016342284, kristina.vermeersch@kuleuven.be
    Scientific contact
    Prof. Dr. Wim Janssens, KU Leuven - UZ Leuven , 0032 016346812, wim.janssens@kuleuven.be
    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
    18 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To prove the effectiveness of azithromycin on top of standard therapy in the acute treatment of COPD exacerbations which require hospitalization
    Protection of trial subjects
    Ethics review and approval Informed consent Repeated safety evaluations through: -ECG monitoring -sputum culture assessment -quality of life and symptom assessment questionnaires
    Background therapy
    		 Patients were randomized (1:1) to receive azithromycin or placebo on top of a standardized acute treatment of: *Systemic corticosteroids: methylprednisolone 40mg IV or 32mg PO once daily for 5 days (switch IV to PO as soon as possible) *Antibiotics: -amoxi-clavulanate 1g IV four times a day or 2g PO twice a day for 7 days (alternative regimen: 1g IV four times a day or 875/125mg PO three times a day for 7 days) -or moxifloxacin 400mg IV or 400mg PO once daily for 5 days *Short-acting bronchodilators: via inhalation *Respiratory support: -oxygen -noninvasive ventilation -Mechanical ventilation
    Evidence for comparator
    		 /
    Actual start date of recruitment
    01 Aug 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety, Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 301
    Worldwide total number of subjects
    301
    EEA total number of subjects
    301
    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)
    131
    From 65 to 84 years
    166
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Consortium: patients were recruited in 6 academic and 14 non‐academic hospitals within Belgium Recruitment period: between August‐2014 and April‐2017

    Pre-assignment
    Screening details
    		 A total of 2063 patients were screened by 15 hospitals within the Consortium Patients were screened as per inclusion and exclusion criteria specified in the trial protocol

    Period 1
    Period 1 title
    Overall trial: day 1 up to day 270 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    -Study drug identity was concealed by a format that was identical in packaging, labelling, schedule of administration and appearance -Patients were randomly assigned in a 1:1 ratio to receive either azithromycin or placebo, with a permuted block size of 10 and sequential assignment, stratified by center -Randomization was based on an online generated randomization schedule (http://www.randomization.com). Unique randomization codes were locally obtained through a secured Web-based program

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Azithromycin
    Arm description
    		 From day 1 up to and including day 3: 500 mg azithromycin PO once a day From day 4 up to and including day 90: 250 mg azithromycin PO once every 2 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azithromycin monohydrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From day 1 up to and including day 3: 500 mg PO once a day From day 4 up to and including day 90: 250 mg PO once every 2 days

    Arm title
    		 Placebo
    Arm description
    		 From day 1 up to and including day 3: 500 mg placebo PO once a day From day 4 up to and including day 90: 250 mg placebo PO once every 2 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    From day 1 up to and including day 3: 500 mg once a day From day 4 up to and including day 90: 250 mg once every 2 days

    Number of subjects in period 1
    		Azithromycin Placebo
    Started
    147
    154
    End of intervention (day 90)
    131
    129
    Completed
    118
    115
    Not completed
    29
    39
         Consent withdrawn by subject
    7
    11
         Adverse event, non-fatal
    6
    12
         Death
    7
    9
         Miscellaneous
    3
    -
         Lost to follow-up
    6
    2
         Non-adherence
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Azithromycin
    Reporting group description
    		 From day 1 up to and including day 3: 500 mg azithromycin PO once a day From day 4 up to and including day 90: 250 mg azithromycin PO once every 2 days

    Reporting group title
    Placebo
    Reporting group description
    		 From day 1 up to and including day 3: 500 mg placebo PO once a day From day 4 up to and including day 90: 250 mg placebo PO once every 2 days

    Reporting group values
    		 Azithromycin Placebo Total
    Number of subjects
    		 147 154 301
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66 ( 9 ) 67 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 66 66 132
        Male
    		 81 88 169
    GOLD stage
    GOLD= Global Initiative for Chronic Obstructive Lung Disease (guideline 2017)
    Units: Subjects
        GOLD A
    		 0 1 1
        GOLD B
    		 26 30 56
        GOLD C
    		 1 2 3
        GOLD D
    		 120 121 241
    Smoking status
    Units: Subjects
        Current smoker
    		 63 65 128
        Non smoker
    		 84 89 173
    Number of AECOPD in the previous year
    AECOPD= acute exacerbation of COPD
    Units: Subjects
        One
    		 38 51 89
        Two
    		 41 37 78
        Three
    		 31 19 50
        More than three
    		 37 47 84
    Number of AECOPD in previous year requiring hospitalization
    Units: Subjects
        None
    		 64 64 128
        One
    		 55 58 113
        Two
    		 15 16 31
        Three
    		 6 6 12
        More than three
    		 7 10 17
    Intervention by general practitioner before admission
    Units: Subjects
        Systemic corticosteroids
    		 48 37 85
        Antibiotics
    		 50 54 104
        None
    		 49 63 112
    Lower respiratory symptoms at admission - Sputum production
    Units: Subjects
        Sputum
    		 97 86 183
        No sputum
    		 50 68 118
    Lower respiratory symptoms at admission - Sputum purulence
    Units: Subjects
        Purulence
    		 67 57 124
        None
    		 80 97 177
    Lower respiratory symptoms at admission - Cough
    Units: Subjects
        Cough
    		 115 108 223
        None
    		 32 46 78
    Inhaled respiratory medicine - LABA
    LABA: long acting B2 agonist
    Units: Subjects
        Yes
    		 136 145 281
        No
    		 11 9 20
    Inhaled respiratory therapy - LAMA
    LAMA: long acting muscarinic antagonist
    Units: Subjects
        Yes
    		 118 123 241
        No
    		 29 31 60
    Inhaled respiratory therapy - ICS
    ICS: inhaled corticosteroids
    Units: Subjects
        Yes
    		 118 123 241
        No
    		 29 31 60
    Inhaled respiratory therapy - SAMA
    SAMA: short-acting muscarinic antagonist
    Units: Subjects
        Yes
    		 108 109 217
        No
    		 39 45 84
    Standardized acute treatment - Respected
    Units: Subjects
        Yes
    		 134 141 275
        No
    		 13 13 26
    Standardized acute treatment - Received antibiotics
    Units: Subjects
        Yes
    		 145 152 297
        No
    		 2 2 4
    Standardized acute treatment - Pathogen susceptible to antibiotic
    Units: Subjects
        Yes
    		 136 144 280
        No
    		 11 10 21
    Height Continuous
    Units: Meter
        arithmetic mean (standard deviation)
    		 1.66 ( 9 ) 1.66 ( 9 ) -
    Weight Continuous
    Units: Kg
        arithmetic mean (standard deviation)
    		 67 ( 20 ) 70 ( 18 ) -
    Body Mass Index Continuous
    Units: Kg/m²
        arithmetic mean (standard deviation)
    		 24.5 ( 5.9 ) 25.1 ( 6.5 ) -
    Smoking history
    Units: Pack-years
        median (inter-quartile range (Q1-Q3))
    		 44 (37 to 50) 43 (35 to 50) -
    Laboratory value: C-reactive protein
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    		 14.2 (3.5 to 61.4) 21.6 (4.5 to 59.6) -
    Laboratory value: leucocytes
    Units: x10^9/L
        median (inter-quartile range (Q1-Q3))
    		 10.95 (9.00 to 13.89) 9.90 (8.20 to 13.70) -
    Laboratory value: neutrophils
    Units: x10^9/L
        median (inter-quartile range (Q1-Q3))
    		 8.20 (6.00 to 11.20) 7.70 (5.60 to 11.20) -
    Laboratory value: eosinophils
    Units: x10^9/L
        median (inter-quartile range (Q1-Q3))
    		 0.06 (0.00 to 0.20) 0.07 (0.00 to 0.20) -
    mMRC dyspnea score
    mMRC= modified Medical Research Council questionnaire Scale between 0 and 4 The higher the score, the worse the outcome
    Units: Scale between 0 and 4
        median (inter-quartile range (Q1-Q3))
    		 4 (2 to 4) 4 (2 to 4) -
    Pre-bronchodilator FEV1
    FEV1= forced expiratory volume in 1 second
    Units: Liter
        median (inter-quartile range (Q1-Q3))
    		 0.90 (0.69 to 1.23) 0.95 (0.71 to 1.36) -
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who consented to participate in the study and fulfilled all inclusion/exclusion criteria.

    Subject analysis sets values
    		 Intention-to-treat set
    Number of subjects
    301
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66 ( 10 )
    Gender categorical
    Units: Subjects
        Female
        Male
    GOLD stage
    GOLD= Global Initiative for Chronic Obstructive Lung Disease (guideline 2017)
    Units: Subjects
        GOLD A
        GOLD B
        GOLD C
        GOLD D
    Smoking status
    Units: Subjects
        Current smoker
        Non smoker
    Number of AECOPD in the previous year
    AECOPD= acute exacerbation of COPD
    Units: Subjects
        One
        Two
        Three
        More than three
    Number of AECOPD in previous year requiring hospitalization
    Units: Subjects
        None
        One
        Two
        Three
        More than three
    Intervention by general practitioner before admission
    Units: Subjects
        Systemic corticosteroids
        Antibiotics
        None
    Lower respiratory symptoms at admission - Sputum production
    Units: Subjects
        Sputum
        No sputum
    Lower respiratory symptoms at admission - Sputum purulence
    Units: Subjects
        Purulence
        None
    Lower respiratory symptoms at admission - Cough
    Units: Subjects
        Cough
        None
    Inhaled respiratory medicine - LABA
    LABA: long acting B2 agonist
    Units: Subjects
        Yes
        No
    Inhaled respiratory therapy - LAMA
    LAMA: long acting muscarinic antagonist
    Units: Subjects
        Yes
        No
    Inhaled respiratory therapy - ICS
    ICS: inhaled corticosteroids
    Units: Subjects
        Yes
        No
    Inhaled respiratory therapy - SAMA
    SAMA: short-acting muscarinic antagonist
    Units: Subjects
        Yes
        No
    Standardized acute treatment - Respected
    Units: Subjects
        Yes
        No
    Standardized acute treatment - Received antibiotics
    Units: Subjects
        Yes
        No
    Standardized acute treatment - Pathogen susceptible to antibiotic
    Units: Subjects
        Yes
        No
    Height Continuous
    Units: Meter
        arithmetic mean (standard deviation)
    ( )
    Weight Continuous
    Units: Kg
        arithmetic mean (standard deviation)
    ( )
    Body Mass Index Continuous
    Units: Kg/m²
        arithmetic mean (standard deviation)
    ( )
    Smoking history
    Units: Pack-years
        median (inter-quartile range (Q1-Q3))
    Laboratory value: C-reactive protein
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    Laboratory value: leucocytes
    Units: x10^9/L
        median (inter-quartile range (Q1-Q3))
    Laboratory value: neutrophils
    Units: x10^9/L
        median (inter-quartile range (Q1-Q3))
    Laboratory value: eosinophils
    Units: x10^9/L
        median (inter-quartile range (Q1-Q3))
    mMRC dyspnea score
    mMRC= modified Medical Research Council questionnaire Scale between 0 and 4 The higher the score, the worse the outcome
    Units: Scale between 0 and 4
        median (inter-quartile range (Q1-Q3))
    Pre-bronchodilator FEV1
    FEV1= forced expiratory volume in 1 second
    Units: Liter
        median (inter-quartile range (Q1-Q3))

    End points

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    End points reporting groups
    Reporting group title
    Azithromycin
    Reporting group description
    		 From day 1 up to and including day 3: 500 mg azithromycin PO once a day From day 4 up to and including day 90: 250 mg azithromycin PO once every 2 days

    Reporting group title
    Placebo
    Reporting group description
    		 From day 1 up to and including day 3: 500 mg placebo PO once a day From day 4 up to and including day 90: 250 mg placebo PO once every 2 days

    Subject analysis set title
    Intention-to-treat set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who consented to participate in the study and fulfilled all inclusion/exclusion criteria.

    Primary: Treatment failure rate at day 90

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    End point title
    		 Treatment failure rate at day 90
    End point description
    Event rate (95% CI) obtained using Kaplan-Meier methodology.
    End point type
    Primary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    49.5 (41.5 to 58.1)
    60.4 (52.4 to 68.5)
    Statistical analysis title
    		 Difference in treatment failure rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0526
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.01

    Secondary: Treatment failure rate at day 270

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    End point title
    		 Treatment failure rate at day 270
    End point description
    Event rate (95% CI) obtained using Kaplan-Meier methodology.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    82.2 (75.2 to 88.2)
    84.8 (78.3 to 90.3)
    Statistical analysis title
    		 Difference in treatment failure rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.157
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.08

    Secondary: Number of treatment failures at day 90

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    End point title
    		 Number of treatment failures at day 90
    End point description
    Mean Cumulative Function (MCF) (95% CI).
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Events
        number (confidence interval 95%)
    0.79 (0.62 to 0.95)
    1.03 (0.85 to 1.20)
    Statistical analysis title
    		 Difference in number of treatment failures
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0395
    Method
    		 Logrank
    Parameter type
    		 Difference in MCF
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0

    Secondary: Number of treatment failures at day 270

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    End point title
    		 Number of treatment failures at day 270
    End point description
    Mean Cumulative Function (MCF) (95% CI).
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Events
        number (confidence interval 95%)
    2.41 (2.08 to 2.73)
    2.54 (2.21 to 2.87)
    Statistical analysis title
    		 Difference in number of treatment failures
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1103 [1]
    Method
    		 Logrank
    Parameter type
    		 Difference in MCF
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.34
    Notes
    [1] - Unadjusted

    Secondary: COPD Assessment Test (CAT) score at day 90

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    End point title
    		 COPD Assessment Test (CAT) score at day 90
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Score
        arithmetic mean (confidence interval 95%)
    17.7 (16.4 to 19.0)
    16.9 (15.5 to 18.3)
    Statistical analysis title
    		 Difference in COPD Assessment Test score
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.697
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.43
         upper limit
    		 2.13

    Secondary: COPD Assessment Test (CAT) score at day 270

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    End point title
    		 COPD Assessment Test (CAT) score at day 270
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Score
        arithmetic mean (confidence interval 95%)
    18.3 (16.8 to 19.8)
    18.5 (17.0 to 20.0)
    Statistical analysis title
    		 Difference in COPD Assessment Test score
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3921
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    -0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.85
         upper limit
    		 1.12

    Secondary: Total days of systemic corticosteroid use at day 90

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    End point title
    		 Total days of systemic corticosteroid use at day 90
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Days
        number (confidence interval 95%)
    15.9 (14.9 to 16.9)
    14.8 (13.9 to 15.7)
    Statistical analysis title
    		 Difference in total days of corticosteroid use
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1217
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.17

    Secondary: Total days of systemic corticosteroid use at day 270

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    End point title
    		 Total days of systemic corticosteroid use at day 270
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Days
        number (confidence interval 95%)
    27.1 (26.1 to 28.2)
    27.2 (26.2 to 28.3)
    Statistical analysis title
    		 Difference in total days of corticosteroid use
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8817
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.05

    Secondary: Treatment intensification rate at day 90

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    End point title
    		 Treatment intensification rate at day 90
    End point description
    Cumulative Incidence Function (CIF) (95% CI), using overall mortality as competing risk.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    47.4 (38.8 to 55.4)
    59.7 (51.1 to 67.4)
    Statistical analysis title
    		 Difference in treatment intensification rate
    Comparison groups
    Placebo v Azithromycin
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0272
    Method
    		 Gray's test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.96

    Secondary: Treatment intensification rate at day 270

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    End point title
    		 Treatment intensification rate at day 270
    End point description
    Cumulative Incidence Function (CIF) (95% CI), using overall mortality as competing risk.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    79.2 (71.2 to 85.3)
    84.1 (76.7 to 89.4)
    Statistical analysis title
    		 Difference in treatment intensification rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0709
    Method
    		 Gray's test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.02

    Secondary: Step-up in hospital care rate at day 90

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    End point title
    		 Step-up in hospital care rate at day 90
    End point description
    Cumulative Incidence Function (CIF) (95% CI), using overall mortality as competing risk.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    13.2 (8.2 to 19.5)
    27.7 (20.6 to 35.3)
    Statistical analysis title
    		 Difference in step-up in hospital care rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Gray's test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.75

    Secondary: Step-up in hospital care rate at day 270

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    End point title
    		 Step-up in hospital care rate at day 270
    End point description
    Cumulative Incidence Function (CIF) (95% CI), using overall mortality as competing risk.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    36.5 (28.3 to 44.7)
    45.2 (36.6 to 53.3)
    Statistical analysis title
    		 Difference in step-up in hospital care rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0536
    Method
    		 Gray's test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.01

    Secondary: Mortality rate at day 90

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    End point title
    		 Mortality rate at day 90
    End point description
    Event rate (95% CI) obtained using Kaplan-Meier methodology.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    2.2 (0.7 to 6.5)
    3.6 (1.5 to 8.3)
    Statistical analysis title
    		 Difference in momrtality rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5075
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 2.59

    Secondary: Mortality rate at day 270

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    End point title
    		 Mortality rate at day 270
    End point description
    Event rate (95% CI) obtained using Kaplan-Meier methodology.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    5.3 (2.6 to 10.8)
    6.7 (3.5 to 12.5)
    Statistical analysis title
    		 Difference in mortality rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.617
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 2.09

    Secondary: New exacerbation rate at day 90

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    End point title
    		 New exacerbation rate at day 90
    End point description
    Cumulative Incidence Function (CIF) (95% CI), using overall mortality as competing risk.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    39.6 (31.3 to 47.7)
    51.0 (42.3 to 59.0)
    Statistical analysis title
    		 Difference in new exacerbation rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0497
    Method
    		 Gray's test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1

    Secondary: New exacerbation rate at day 270

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    End point title
    		 New exacerbation rate at day 270
    End point description
    Cumulative Incidence Function (CIF) (95% CI), using overall mortality as competing risk.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Percentage
        number (confidence interval 95%)
    75.1 (66.6 to 81.7)
    79.5 (71.5 to 85.5)
    Statistical analysis title
    		 Difference in new exacerbation rate
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1324
    Method
    		 Gray's test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.06

    Secondary: Number of new exacerbations at day 90

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    End point title
    		 Number of new exacerbations at day 90
    End point description
    Mean Cumulative Function (MCF) (95% CI).
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Events
        number (confidence interval 95%)
    0.57 (0.44 to 0.70)
    0.75 (0.60 to 0.90)
    Statistical analysis title
    		 Difference in number of new exacerbations
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Logrank
    Parameter type
    		 Difference in MCF
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.02

    Secondary: Number of new exacerbations at day 270

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    End point title
    		 Number of new exacerbations at day 270
    End point description
    Mean Cumulative Function (MCF) (95% CI).
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Events
        number (confidence interval 95%)
    2.08 (1.80 to 2.36)
    2.18 (1.92 to 2.45)
    Statistical analysis title
    		 Difference in number of new exacerbations
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5997
    Method
    		 Logrank
    Parameter type
    		 Difference in MCF
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.28

    Secondary: Total dose of systemic corticosteroid use at day 90

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    End point title
    		 Total dose of systemic corticosteroid use at day 90
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Mg
        number (confidence interval 95%)
    340.2 (335.4 to 345.1)
    321.8 (317.6 to 326.0)
    Statistical analysis title
    		 Difference in total dose of corticosteroid use
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 1.08

    Secondary: Total dose of systemic corticosteroid use at day 270

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    End point title
    		 Total dose of systemic corticosteroid use at day 270
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Mg
        number (confidence interval 95%)
    603.4 (598.4 to 608.5)
    603.5 (598.4 to 608.6)
    Statistical analysis title
    		 Difference in total dose of corticosteroid use
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9903
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.01

    Secondary: Total days of non-study antibiotics at day 90

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    End point title
    		 Total days of non-study antibiotics at day 90
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Days
        number (confidence interval 95%)
    10.5 (9.6 to 11.5)
    13.7 (12.8 to 14.7)
    Statistical analysis title
    		 Difference in total days of non-study antibiotics
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.86

    Secondary: Total days of non-study antibiotics at day 270

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    End point title
    		 Total days of non-study antibiotics at day 270
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Days
        number (confidence interval 95%)
    21.1 (20.2 to 22.1)
    21.6 (20.7 to 22.6)
    Statistical analysis title
    		 Difference in total day of non-study antibiotics
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4592
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.04

    Secondary: Total hospital days at day 90

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    End point title
    		 Total hospital days at day 90
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Days
        number (confidence interval 95%)
    10.7 (9.3 to 12.3)
    14.0 (12.3 to 16.1)
    Statistical analysis title
    		 Difference in total hospital days
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0061
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 0.92

    Secondary: Total hospital days at day 270

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    End point title
    		 Total hospital days at day 270
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Days
        number (confidence interval 95%)
    22.2 (18.3 to 27.0)
    28.5 (23.8 to 34.2)
    Statistical analysis title
    		 Difference in total hospital days
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0631
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.01

    Secondary: Total ICU days at day 90

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    End point title
    		 Total ICU days at day 90
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Days
        number (confidence interval 95%)
    3.0 (1.8 to 5.1)
    11.4 (9.1 to 14.3)
    Statistical analysis title
    		 Difference in total ICU days
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.47

    Secondary: Total ICU days at day 270

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    End point title
    		 Total ICU days at day 270
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Days
        number (confidence interval 95%)
    5.1 (4.0 to 6.5)
    11.1 (9.2 to 13.3)
    Statistical analysis title
    		 Difference in total ICU days
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.63

    Secondary: Number of general practitionner contacts at day 90

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    End point title
    		 Number of general practitionner contacts at day 90
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Events
        number (confidence interval 95%)
    2.4 (2.0 to 2.7)
    2.6 (2.3 to 3.0)
    Statistical analysis title
    		 Difference in number of GP contacts
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3119
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.1

    Secondary: Number of general practitionner contacts at day 270

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    End point title
    		 Number of general practitionner contacts at day 270
    End point description
    Analyzed using a Poisson regression model. The natural logarithm of the total number of days up to the visit day was used as offset.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Events
        number (confidence interval 95%)
    6.1 (5.7 to 6.6)
    6.6 (6.1 to 7.1)
    Statistical analysis title
    		 Difference in number of GP contacts
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1511
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.03

    Secondary: Pre-bronchodilator FEV1 at day 90

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    End point title
    		 Pre-bronchodilator FEV1 at day 90
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Liter
        arithmetic mean (confidence interval 95%)
    1.3 (0.9 to 1.7)
    1.2 (1.1 to 1.3)
    Statistical analysis title
    		 Difference in pre-bronchodilator FEV1
    Comparison groups
    Placebo v Azithromycin
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5008
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.53

    Secondary: Pre-bronchodilator FEV1 at day 270

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    End point title
    		 Pre-bronchodilator FEV1 at day 270
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Liter
        arithmetic mean (confidence interval 95%)
    1.1 (1.0 to 1.2)
    1.2 (1.1 to 1.3)
    Statistical analysis title
    		 Difference in pre-bronchodilator FEV1
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1933
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.05

    Secondary: mMRC questionnaire score at day 90

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    End point title
    		 mMRC questionnaire score at day 90
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Score
        arithmetic mean (confidence interval 95%)
    3.1 (3.0 to 3.3)
    3.2 (3.0 to 3.4)
    Statistical analysis title
    		 Difference in mMRC questionnaire score
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.17

    Secondary: mMRC questionnaire score at day 270

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    End point title
    		 mMRC questionnaire score at day 270
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Score
        arithmetic mean (confidence interval 95%)
    3.3 (3.2 to 3.5)
    3.2 (3.0 to 3.4)
    Statistical analysis title
    		 Difference in mMRC questionnaire qcore
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5886
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.35

    Secondary: EQ5D questionnaire score at day 90

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    End point title
    		 EQ5D questionnaire score at day 90
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Score
        arithmetic mean (confidence interval 95%)
    61.6 (58.3 to 65.0)
    61.2 (57.7 to 64.6)
    Statistical analysis title
    		 Difference in EQ5D questionnaire score
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8842
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.28
         upper limit
    		 4.97

    Secondary: EQ5D questionnaire score at day 270

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    End point title
    		 EQ5D questionnaire score at day 270
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Score
        arithmetic mean (confidence interval 95%)
    57.3 (53.7 to 60.9)
    60.2 (56.3 to 64.1)
    Statistical analysis title
    		 Difference in EQ5D questionnaire score
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2967
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    -2.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.86
         upper limit
    		 2.4

    Secondary: SSQ5 questionnaire score at day 90

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    End point title
    		 SSQ5 questionnaire score at day 90
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of intervention (day 90)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Score
        arithmetic mean (confidence interval 95%)
    8.1 (7.8 to 8.4)
    7.9 (7.6 to 8.2)
    Statistical analysis title
    		 Difference in SSQ5 questionnaire score
    Comparison groups
    Placebo v Azithromycin
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2559
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.49

    Secondary: SSQ5 questionnaire score at day 270

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    End point title
    		 SSQ5 questionnaire score at day 270
    End point description
    Estimated mean value (95% CI) obtained using a weighted General Estimating Equations (GEE) model with factors for group, treatment and their interaction. Baseline was included as a covariate.
    End point type
    Secondary
    End point timeframe
    From date of randomization (day 1) to end of follow-up (day 270)
    End point values
    		 Azithromycin Placebo
    Number of subjects analysed
    147
    154
    Units: Score
        arithmetic mean (confidence interval 95%)
    8.2 (7.8 to 8.5)
    8.0 (7.7 to 8.3)
    Statistical analysis title
    		 Difference in SSQ5 questionnaire score
    Comparison groups
    Azithromycin v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 Chi-squared
    Parameter type
    		 Difference in expected means
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.52

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe: from the signature of informed consent (day 0) to the end of follow-up (day 270).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Azithromycin
    Reporting group description
    		 From day 1 up to and including day 3: 500 mg azithromycin PO once a day From day 4 up to and including day 90: 250 mg azithromycin PO once every 2 days

    Reporting group title
    Placebo
    Reporting group description
    		 From day 1 up to and including day 3: 500 mg placebo PO once a day From day 4 up to and including day 90: 250 mg placebo PO once every 2 days

    Serious adverse events
    		 Azithromycin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 147 (39.46%)
    69 / 154 (44.81%)
         number of deaths (all causes)
    7
    9
         number of deaths resulting from adverse events
    Investigations
    Laboratory investigations
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm malignant
         subjects affected / exposed
    2 / 147 (1.36%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac disorders
    Cardiovascular disorders
         subjects affected / exposed
    5 / 147 (3.40%)
    7 / 154 (4.55%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Nervous system disorders
    Cerebrovascular disorder
         subjects affected / exposed
    2 / 147 (1.36%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    4 / 147 (2.72%)
    5 / 154 (3.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    50 / 147 (34.01%)
    62 / 154 (40.26%)
         occurrences causally related to treatment / all
    0 / 86
    0 / 116
         deaths causally related to treatment / all
    0 / 2
    0 / 6
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    0 / 147 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychological disorder
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    2 / 147 (1.36%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Azithromycin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 147 (4.08%)
    7 / 154 (4.55%)
    Cardiac disorders
    QT prolongation
    Additional description: Leading to study drug discontinuation Timeframe: from the signature of informed consent (day 0) to the end of intervention (day 90)
         subjects affected / exposed
    2 / 147 (1.36%)
    1 / 154 (0.65%)
         occurrences all number
    2
    1
    NSTEMI
    Additional description: Leading to study drug discontinuation Timeframe: from the signature of informed consent (day 0) to the end of intervention (day 90)
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 154 (0.65%)
         occurrences all number
    0
    1
    Takotsubo cardiomyopathy
    Additional description: Leading to study drug discontinuation Timeframe: from the signature of informed consent (day 0) to the end of intervention (day 90)
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 154 (0.65%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Leading to study drug discontinuation Timeframe: from the signature of informed consent (day 0) to the end of intervention (day 90)
         subjects affected / exposed
    2 / 147 (1.36%)
    0 / 154 (0.00%)
         occurrences all number
    2
    0
    Nausea
    Additional description: Leading to study drug discontinuation Timeframe: from the signature of informed consent (day 0) to the end of intervention (day 90)
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 154 (0.00%)
         occurrences all number
    1
    0
    Abdominal discomfort
    Additional description: Leading to study drug discontinuation Timeframe: from the signature of informed consent (day 0) to the end of intervention (day 90)
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 154 (0.65%)
         occurrences all number
    1
    1
    Pancolitis
    Additional description: Leading to study drug discontinuation Timeframe: from the signature of informed consent (day 0) to the end of intervention (day 90)
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 154 (0.65%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Target enrolment was not met due to early termination, which leaves the trial underpowered

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27099485
    http://www.ncbi.nlm.nih.gov/pubmed/31046405
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