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    Clinical Trial Results:
    Investigating the mechanism of inhaled corticosteroids associated pneumonia by longitudinal characterisation of the airway microbiome in patients with severe COPD

    Summary
    EudraCT number
    		 2016-000734-21
    Trial protocol
    		 GB  
    Global end of trial date
    26 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2023
    First version publication date
    28 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2014RC07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02972476
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Dundee
    Sponsor organisation address
    Ninewells Hospital and Medical School, Dundee, United Kingdom, DD1 9SY
    Public contact
    James Chalmers, University of Dundee, +44 1382 383642, j.chalmers@dundee.ac.uk
    Scientific contact
    James Chalmers, University of Dundee, +44 1382 383642, j.chalmers@dundee.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
    31 Jan 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/formoterol 400/12 mcg on upper airway bacterial load from oropharyngeal swabs.
    Protection of trial subjects
    Patients were excluded if they were unable to give informed consent, had a known allergy, intolerance or contraindication to any of the study drugs, or had any unstable co-morbidities (cardiovascular disease, active malignancy) which in the opinion of the investigator would make the patient unsuitable to be enrolled in the study
    Background therapy
    		 During the study it was anticipated that the patient should continue on their usual treatment for COPD, excluding ICS or nasal corticosteroids, LABAs and LAMAs.
    Evidence for comparator
    		 The 4 treatment regime arms are as follows: 1. Budesonide/formoterol 400/12 mcg (Symbicort Turbohaler) 1 inhalation twice daily + Aclidinium Bromide 322 mcg (Eklira Genuair) 1 inhalation twice daily 2. Fluticasone propionate/salmeterol 500/50 mcg (Seretide Accuhaler) 1 inhalation twice daily + Aclidinium Bromide 322 mcg (Eklira Genuair) 1 inhalation twice daily 3. Fluticasone propionate/salmeterol 250/50 mcg (Seretide Accuhaler) 1 inhalation twice daily + Aclidinium Bromide 322 mcg (Eklira Genuair) 1 inhalation twice daily 4. Aclidinium/formoterol combination 340/12 mcg (Duaklir Genuair) 1 inhalation twice daily The rationale for these doses were that regime 1 and regime 2 are the licensed doses of Symbicort and Seretide in the UK which are commonly used in this patient population. Treatment regime 3 was included as this is commonly used in clinical practice as an equivalent dose to Symbicort and therefore may help to answer whether there is a dose response relationship effecting the airway microbiome. This treatment is licensed in asthma but is not licensed for the treatment of COPD at this lower dose. It is a lower dose of the licensed fluticasone propionate/salmeterol 500/50 which is licensed in COPD and is administered through the same device. It is equivalent in dose, as measured by BDP, to all other ICS licensed in the treatment of COPD (beclomethasone dipropionate/formoterol fumarate 100/6 2 puff twice daily= 1000BDP, fluticasone furoate + vilanterol trifenatate 92/22 1 puff once daily=1000BDP, and Budesonide/formoterol as described above= 800BDP). Treatment regime 4 is included as LABA/LAMA therapy is considered an appropriate alternative to ICS/LABA therapy in emerging clinical guidelines. This also acts as a control population without ICS treatment, thus demonstrating that any changes during the study period are the results of the effect of ICS.
    Actual start date of recruitment
    01 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 61
    Worldwide total number of subjects
    61
    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)
    23
    From 65 to 84 years
    37
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited at 6 NHS sites in the UK (NHS Tayside, NHS Lothian, NHS Lanarkshire, NHS Fife, NHS Blackpool, NHS Greater Glasgow and Clyde)

    Pre-assignment
    Screening details
    		 158 patients screened. Screen failures-asthma (1), antibiotics or oral steroids in previous 28 days (2), dental infection (1), <10 pack year history (1), FEV1/FVC >0.7 (8), did not meet GOLD criteria (22), could not perform spirometry (1). 122 patients started 4-week wash-out (withdrawal COPD exacerbations (45), other (16). 61 subjects randomised

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Symbicort 400/12 & Eklira Genuair
    Arm description
    		 Budesonide 400mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Budesonide & formoterol fumarate and Aclidinium bromide
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide & formoterol fumarate and Aclidinium bromide
    Investigational medicinal product code
    Other name
    Symbicort 400/12 & Eklira Genuair
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Budesonide 400mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months

    Arm title
    		 Seretide 500/50 & Eklira Genuair
    Arm description
    		 Fluticasone propionate 500mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 500 & salmeterol and Aclidinium bromide
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone 500 & salmeterol and Aclidinium bromide
    Investigational medicinal product code
    Other name
    Seretide 500/50 & Eklira Genuair
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate 500mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months

    Arm title
    		 Seretide 250/50 & Eklira Genuair
    Arm description
    		 Fluticasone propionate 250mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 250 & salmeterol and Aclidinium bromide
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone 250 & salmeterol and Aclidinium bromide
    Investigational medicinal product code
    Other name
    Seretide 250/50 & Eklira Genuair
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    1 inhalation twice daily, inhalation powder for 3 months

    Arm title
    		 Duaklir Genuair
    Arm description
    		 Aclidinium bromide 340mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder for 3 months Aclidinium bromide & formoterol fumarate
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aclidinium bromide & formoterol fumarate
    Investigational medicinal product code
    Other name
    Duaklir Genuair
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Aclidinium bromide 340mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder for 3 months

    Number of subjects in period 1
    		Symbicort 400/12 & Eklira Genuair Seretide 500/50 & Eklira Genuair Seretide 250/50 & Eklira Genuair Duaklir Genuair
    Started
    18
    13
    15
    15
    Completed
    16
    13
    14
    14
    Not completed
    2
    0
    1
    1
         Consent withdrawn by subject
    1
    -
    1
    1
         Adverse event, non-fatal
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 61 61
    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
    Age (years)
    Units: years
        arithmetic mean (standard deviation)
    		 66.9 ( 7.8 ) -
    Gender categorical
    Gender
    Units: Subjects
        Female
    		 28 28
        Male
    		 33 33
    Smoking status
    Smoking status at enrolment
    Units: Subjects
        Ex-smoker
    		 37 37
        Current smoker
    		 24 24
    Blood eosinophil count at baseline
    Units: Subjects
        <150
    		 21 21
        150-299
    		 28 28
        >=300
    		 12 12
    GOLD classification
    Units: Subjects
        GOLD B
    		 8 8
        GOLD C
    		 1 1
        GOLD D
    		 52 52
    Pack years
    Smoking pack years
    Units: Years
        arithmetic mean (standard deviation)
    		 44.4 ( 21.5 ) -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 28.9 ( 6.9 ) -
    MRC Dyspnoea Score
    Units: MRC Dyspnoea Score
        arithmetic mean (standard deviation)
    		 3.3 ( 1.0 ) -
    CAT Score
    COPD Assessment Test
    Units: CAT Score
        arithmetic mean (standard deviation)
    		 21.5 ( 7.2 ) -
    FEV1 (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 1.32 ( 0.61 ) -
    FEV1 (%)
    Units: percent
        arithmetic mean (standard deviation)
    		 53.0 ( 25.5 ) -
    FVC (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.74 ( 0.94 ) -
    FVC (%)
    Units: percent
        arithmetic mean (standard deviation)
    		 88.9 ( 28.7 ) -
    FEV1/FEVC ratio
    Units: percent
        arithmetic mean (standard deviation)
    		 46.6 ( 16.1 ) -
    FEF 25-75%
    Units: percent
        arithmetic mean (standard deviation)
    		 20.8 ( 15.3 ) -
    Oxygen saturation at rest
    Units: percent
        arithmetic mean (standard deviation)
    		 95 ( 2.4 ) -
    Number of exacerbations in the last year
    Units: exacerbations
        arithmetic mean (standard deviation)
    		 2.2 ( 1.5 ) -
    Subject analysis sets

    Subject analysis set title
    Arm 1: BF400
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Budesonide & formoterol fumarate and Aclidinium bromide

    Subject analysis set title
    Arm 2: FS500
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Fluticasone 500 & salmeterol and Aclidinium bromide

    Subject analysis set title
    Arm 3: FS250
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Fluticasone 250 & salmeterol and Aclidinium bromide

    Subject analysis set title
    Arm 4: AF
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Aclidinium bromide & formoterol fumarate

    Subject analysis set title
    Pooled Fluticasone propionate ICS
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Pooled Arms 2 and Arm 3 Fluticasone propionate 250mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 250 & salmeterol and Aclidinium bromide Fluticasone propionate 500mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 500 & salmeterol and Aclidinium bromide

    Subject analysis set title
    Pooled ICS
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Pooled ICS treatments: Budesonide 400mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months. Budesonide & formoterol fumarate and Aclidinium bromide Fluticasone propionate 500mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months. Fluticasone 500 & salmeterol and Aclidinium bromide Fluticasone propionate 250mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months. Fluticasone 250 & salmeterol and Aclidinium bromide

    Subject analysis sets values
    		 Arm 1: BF400 Arm 2: FS500 Arm 3: FS250 Arm 4: AF Pooled Fluticasone propionate ICS Pooled ICS
    Number of subjects
    18
    13
    15
    15
    25
    40
    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
    Age (years)
    Units: years
        arithmetic mean (standard deviation)
    68.8 ( 8.4 )
    67.4 ( 10.2 )
    65.1 ( 5.3 )
    66.0 ( 6.8 )
    ( )
    ( )
    Gender categorical
    Gender
    Units: Subjects
        Female
    6
    9
    5
    8
        Male
    12
    4
    10
    7
    Smoking status
    Smoking status at enrolment
    Units: Subjects
        Ex-smoker
    10
    8
    8
    11
        Current smoker
    8
    5
    7
    4
    Blood eosinophil count at baseline
    Units: Subjects
        <150
    4
    4
    5
    8
        150-299
    9
    7
    7
    5
        >=300
    5
    2
    3
    2
    GOLD classification
    Units: Subjects
        GOLD B
    1
    1
    2
    4
        GOLD C
    0
    1
    0
    0
        GOLD D
    17
    11
    13
    11
    Pack years
    Smoking pack years
    Units: Years
        arithmetic mean (standard deviation)
    46.1 ( 20.3 )
    49.4 ( 26.9 )
    39.7 ( 12.9 )
    42.9 ( 25.3 )
    ( )
    ( )
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    26.4 ( 6.0 )
    28.5 ( 7.8 )
    29.8 ( 8.7 )
    28.7 ( 4.5 )
    ( )
    ( )
    MRC Dyspnoea Score
    Units: MRC Dyspnoea Score
        arithmetic mean (standard deviation)
    .71 ( 1.0 )
    3.4 ( 0.8 )
    2.9 ( 1.0 )
    3.1 ( 1.1 )
    ( )
    ( )
    CAT Score
    COPD Assessment Test
    Units: CAT Score
        arithmetic mean (standard deviation)
    21.1 ( 7.2 )
    21.6 ( 10.1 )
    23.0 ( 6.5 )
    20.3 ( 4.9 )
    ( )
    ( )
    FEV1 (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    1.49 ( 0.67 )
    1.21 ( 0.55 )
    1.45 ( 0.58 )
    1.08 ( 0.57 )
    ( )
    ( )
    FEV1 (%)
    Units: percent
        arithmetic mean (standard deviation)
    58.9 ( 24.7 )
    57.6 ( 33.6 )
    54.3 ( 20.0 )
    40.4 ( 21.0 )
    ( )
    ( )
    FVC (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    2.72 ( 0.95 )
    2.68 ( 1.1 )
    3.10 ( 0.87 )
    2.45 ( 0.83 )
    ( )
    ( )
    FVC (%)
    Units: percent
        arithmetic mean (standard deviation)
    86.5 ( 32.2 )
    98.6 ( 39.3 )
    91.9 ( 19.2 )
    80.5 ( 20.2 )
    ( )
    ( )
    FEV1/FEVC ratio
    Units: percent
        arithmetic mean (standard deviation)
    51.5 ( 18.1 )
    43.3 ( 20.4 )
    46.6 ( 10.6 )
    43.5 ( 14.1 )
    ( )
    ( )
    FEF 25-75%
    Units: percent
        arithmetic mean (standard deviation)
    23.2 ( 14.3 )
    17.5 ( 13.7 )
    22.6 ( 2.08 )
    18.9 ( 2.40 )
    ( )
    ( )
    Oxygen saturation at rest
    Units: percent
        arithmetic mean (standard deviation)
    94.2 ( 3.4 )
    95.8 ( 2.4 )
    95.1 ( 1.5 )
    94.3 ( 2.9 )
    ( )
    ( )
    Number of exacerbations in the last year
    Units: exacerbations
        arithmetic mean (standard deviation)
    2.89 ( 1.8 )
    2.28 ( 1.3 )
    20.8 ( 1.3 )
    2.40 ( 2.0 )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Symbicort 400/12 & Eklira Genuair
    Reporting group description
    		 Budesonide 400mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Budesonide & formoterol fumarate and Aclidinium bromide

    Reporting group title
    Seretide 500/50 & Eklira Genuair
    Reporting group description
    		 Fluticasone propionate 500mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 500 & salmeterol and Aclidinium bromide

    Reporting group title
    Seretide 250/50 & Eklira Genuair
    Reporting group description
    		 Fluticasone propionate 250mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 250 & salmeterol and Aclidinium bromide

    Reporting group title
    Duaklir Genuair
    Reporting group description
    		 Aclidinium bromide 340mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder for 3 months Aclidinium bromide & formoterol fumarate

    Subject analysis set title
    Arm 1: BF400
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Budesonide & formoterol fumarate and Aclidinium bromide

    Subject analysis set title
    Arm 2: FS500
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Fluticasone 500 & salmeterol and Aclidinium bromide

    Subject analysis set title
    Arm 3: FS250
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Fluticasone 250 & salmeterol and Aclidinium bromide

    Subject analysis set title
    Arm 4: AF
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Aclidinium bromide & formoterol fumarate

    Subject analysis set title
    Pooled Fluticasone propionate ICS
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Pooled Arms 2 and Arm 3 Fluticasone propionate 250mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 250 & salmeterol and Aclidinium bromide Fluticasone propionate 500mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 500 & salmeterol and Aclidinium bromide

    Subject analysis set title
    Pooled ICS
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Pooled ICS treatments: Budesonide 400mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months. Budesonide & formoterol fumarate and Aclidinium bromide Fluticasone propionate 500mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months. Fluticasone 500 & salmeterol and Aclidinium bromide Fluticasone propionate 250mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months. Fluticasone 250 & salmeterol and Aclidinium bromide

    Primary: Change in Bacterial Load of Total Respiratory Pathogens in Oropharyngeal Samples FS500 vs BF400

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    End point title
    		 Change in Bacterial Load of Total Respiratory Pathogens in Oropharyngeal Samples FS500 vs BF400
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/ formoterol 400/12 mcg on upper airway bacterial load from oropharyngeal swabs.
    End point type
    Primary
    End point timeframe
    Month 1 to month 3
    End point values
    		 Arm 1: BF400 Arm 2: FS500
    Number of subjects analysed
    16
    12
    Units: cfu/g equivalents
        arithmetic mean (confidence interval 95%)
    8.88 (8.46 to 9.30)
    8.89 (8.34 to 9.44)
    Statistical analysis title
    		 Change in Bacterial Load FS500 vs BF400
    Statistical analysis description
    Change in Bacterial Load of Total Respiratory Pathogens in Oropharyngeal Samples FS500 vs BF400
    Comparison groups
    Arm 1: BF400 v Arm 2: FS500
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5666
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.648
         upper limit
    		 1.176

    Secondary: Change in Bacterial Load of Total Respiratory Pathogens in Sputum Samples FS500 vs BF400

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    End point title
    		 Change in Bacterial Load of Total Respiratory Pathogens in Sputum Samples FS500 vs BF400
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/ formoterol 400/12 mcg on lower airway bacterial load from sputum
    End point type
    Secondary
    End point timeframe
    Month 1 to month 3
    End point values
    		 Arm 1: BF400 Arm 2: FS500
    Number of subjects analysed
    15
    11
    Units: cfu/g equivalent units
        arithmetic mean (confidence interval 95%)
    9.87 (9.447 to 10.300)
    10.44 (10.049 to 10.822)
    Statistical analysis title
    		 Change in Sput BL BF400 vs FS500
    Statistical analysis description
    Change in Bacterial Load of Total Respiratory Pathogens in Sputum Samples FS500 vs BF400
    Comparison groups
    Arm 1: BF400 v Arm 2: FS500
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00037
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.867
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.292
         upper limit
    		 1.442

    Secondary: Change in Bacterial Load of Total Respiratory Pathogens in Nasopharyngeal Samples FS500 vs BF400

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    End point title
    		 Change in Bacterial Load of Total Respiratory Pathogens in Nasopharyngeal Samples FS500 vs BF400
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/ formoterol 400/12 mcg on bacterial load from nasopharyngeal swabs
    End point type
    Secondary
    End point timeframe
    Month 1 to month 3
    End point values
    		 Arm 1: BF400 Arm 2: FS500
    Number of subjects analysed
    16
    13
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    6.96 (6.556 to 7.361)
    6.9 (6.461 to 7.339)
    Statistical analysis title
    		 Change in NP BL BF400 vs FS500
    Statistical analysis description
    Change in Bacterial Load of Total Respiratory Pathogens in Nasopharyngeal Samples FS500 vs BF400
    Comparison groups
    Arm 1: BF400 v Arm 2: FS500
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5793
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.222
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.016
         upper limit
    		 0.572

    Secondary: Change in the Microbiome by Alpha-diversity in Sputum Samples FS500 vs BF400

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Sputum Samples FS500 vs BF400
    End point description
    Treatment period, month 1 to month 3
    End point type
    Secondary
    End point timeframe
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/ formoterol 400/12 mcg on the microbiome by alpha-diversity from sputum
    End point values
    		 Arm 1: BF400 Arm 2: FS500
    Number of subjects analysed
    15
    11
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.62 (1.288 to 1.954)
    1.58 (1.389 to 1.772)
    Statistical analysis title
    		 Change in SWDI FS500 vs BF400
    Statistical analysis description
    Change in the Microbiome by Alpha-diversity in Sputum Samples FS500 vs BF400
    Comparison groups
    Arm 2: FS500 v Arm 1: BF400
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7904
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.055
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.463
         upper limit
    		 0.353

    Secondary: Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS500 vs BF400

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS500 vs BF400
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs budesonide/ formoterol 400/12 mcg on the microbiome by alpha-diversity from nasopharyngeal swabs
    End point type
    Secondary
    End point timeframe
    Treatment period, month 1 to 3
    End point values
    		 Arm 1: BF400 Arm 2: FS500
    Number of subjects analysed
    16
    13
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.46 (1.166 to 1.751)
    1.18 (0.789 to 1.563)
    Statistical analysis title
    		 Change in SWDI NP FS500 vs BF400
    Statistical analysis description
    Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS500 vs BF400
    Comparison groups
    Arm 1: BF400 v Arm 2: FS500
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.324
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.231
         upper limit
    		 0.692

    Secondary: Change in Total Bacterial Load FS250 vs BF400 in Sputum

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    End point title
    		 Change in Total Bacterial Load FS250 vs BF400 in Sputum
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 250/50 mcg vs budesonide/ formoterol 400/12 mcg on lower airway bacterial load from sputum
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 3: FS250
    Number of subjects analysed
    15
    14
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    9.87 (9.447 to 10.300)
    10.35 (9.897 to 10.798)
    Statistical analysis title
    		 Change in BL Sput FS250 vs BF400
    Statistical analysis description
    Change in Total Bacterial Load FS250 vs BF400 in Sputum
    Comparison groups
    Arm 1: BF400 v Arm 3: FS250
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3635
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.286
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.337
         upper limit
    		 0.909

    Secondary: Change in Total Bacterial Load FS250 vs BF400 in Oropharyngeal Samples

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    End point title
    		 Change in Total Bacterial Load FS250 vs BF400 in Oropharyngeal Samples
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 250/50 mcg vs budesonide/formoterol 400/12 mcg on lower airway bacterial load from oropharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 3: FS250
    Number of subjects analysed
    16
    14
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    8.88 (8.462 to 9.298)
    8.08 (7.529 to 8.636)
    Statistical analysis title
    		 Change in BL OP FS250 vs BF400
    Statistical analysis description
    Change in Total Bacterial Load FS250 vs BF400 in Oropharyngeal Samples
    Comparison groups
    Arm 1: BF400 v Arm 3: FS250
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1007
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.863
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.897
         upper limit
    		 0.171

    Secondary: Change in Total Bacterial Load FS250 vs BF400 in Nasopharyngeal Samples

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    End point title
    		 Change in Total Bacterial Load FS250 vs BF400 in Nasopharyngeal Samples
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 250/50 mcg vs budesonide/formoterol 400/12 mcg on lower airway bacterial load from nasopharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 3: FS250
    Number of subjects analysed
    16
    14
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    6.96 (6.556 to 7.361)
    6.89 (6.306 to 7.479)
    Statistical analysis title
    		 Change in BL NP FS250 vs BF400
    Statistical analysis description
    Change in Total Bacterial Load FS250 vs BF400 in Nasopharyngeal Samples
    Comparison groups
    Arm 1: BF400 v Arm 3: FS250
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8345
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.122
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.032
         upper limit
    		 1.276

    Secondary: Change in the Microbiome by Alpha-diversity in Sputum Samples FS250 vs BF400

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Sputum Samples FS250 vs BF400
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 250/50 mcg vs budesonide/ formoterol 400/12 mcg on the microbiome by alpha-diversity from sputum
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 3: FS250
    Number of subjects analysed
    15
    14
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.62 (1.288 to 1.954)
    1.56 (1.298 to 1.831)
    Statistical analysis title
    		 Change in SWD Sputum FS250 vs BF400
    Statistical analysis description
    Change in the Microbiome by Alpha-diversity in Sputum Samples FS250 vs BF400
    Comparison groups
    Arm 1: BF400 v Arm 3: FS250
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8015
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.466
         upper limit
    		 0.361

    Secondary: Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS250 vs BF400

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS250 vs BF400
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 250/50 mcg vs budesonide/ formoterol 400/12 mcg on the microbiome by alpha-diversity from oropharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 3: FS250
    Number of subjects analysed
    16
    14
    Units: Shannon Weiner Diversity Index
        arithmetic mean (confidence interval 95%)
    1.69 (1.413 to 1.975)
    1.28 (0.9 to 1.662)
    Statistical analysis title
    		 Change in SWDI OP FS250 vs BF400
    Statistical analysis description
    Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS250 vs BF400
    Comparison groups
    Arm 1: BF400 v Arm 3: FS250
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.825
         upper limit
    		 -0.194

    Secondary: Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS250 vs BF400

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS250 vs BF400
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 250/50 mcg vs budesonide/ formoterol 400/12 mcg on the microbiome by alpha-diversity from nasopharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 3: FS250
    Number of subjects analysed
    16
    14
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.46 (1.166 to 1.751)
    1.33 (0.962 to 1.701)
    Statistical analysis title
    		 Change in SWDI NP FS250 vs BF400
    Statistical analysis description
    Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS250 vs BF400
    Comparison groups
    Arm 1: BF400 v Arm 3: FS250
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.913
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.026
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.506
         upper limit
    		 0.453

    Secondary: Change in the Microbiome by Alpha-diversity in Sputum Samples FS ICS vs LABA/LAMA

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Sputum Samples FS ICS vs LABA/LAMA
    End point description
    To compare the effects on the lower airway microbiome in sputum of inhaled corticosteroids fluticasone propionate compared to a dual bronchodilator-based regime without ICS
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled Fluticasone propionate ICS
    Number of subjects analysed
    14
    25
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.27 (0.897 to 1.650)
    1.57 (1.412 to 1.731)
    Statistical analysis title
    		 Change in alpha-diversity in sput FS ICS vs LB/LM
    Statistical analysis description
    Change in the Microbiome by Alpha-diversity in Sputum Samples FS ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled Fluticasone propionate ICS
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7553
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.047
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.342
         upper limit
    		 0.249

    Secondary: Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS ICS vs LABA/LAMA

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS ICS vs LABA/LAMA
    End point description
    To compare the effects on the upper airway microbiome in oropharyngeal samples of inhaled corticosteroids fluticasone propionate compared to a dual bronchodilator-based regime without ICS
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1-3
    End point values
    		 Arm 4: AF Pooled Fluticasone propionate ICS
    Number of subjects analysed
    13
    26
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.32 (1.032 to 1.604)
    1.43 (1.207 to 1.646)
    Statistical analysis title
    		 Change in microbiome OP FS ICS vs LABA/LAMA
    Statistical analysis description
    Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS ICS vs LABA/LAMA
    Comparison groups
    Pooled Fluticasone propionate ICS v Arm 4: AF
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5283
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.109
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 0.232

    Secondary: Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS ICS vs LABA/LAMA

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS ICS vs LABA/LAMA
    End point description
    To compare the effects on the upper airway microbiome in nasopharyngeal samples of inhaled corticosteroids fluticasone propionate compared to a dual bronchodilator-based regime without ICS
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1-3
    End point values
    		 Arm 4: AF Pooled Fluticasone propionate ICS
    Number of subjects analysed
    14
    27
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.47 (1.174 to 1.766)
    1.26 (1.006 to 1.507)
    Statistical analysis title
    		 Change in microbiome NP FS ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled Fluticasone propionate ICS
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8247
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.108
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.859
         upper limit
    		 1.075

    Secondary: Change in the Microbiome by Alpha-diversity in Sputum Samples BF ICS vs LABA/LAMA

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Sputum Samples BF ICS vs LABA/LAMA
    End point description
    To compare the effects on the lower airway microbiome in sputum of inhaled corticosteroids budesonide compared to a dual bronchodilator-based regime without ICS
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 4: AF
    Number of subjects analysed
    15
    14
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.62 (1.288 to 1.954)
    1.27 (0.897 to 1.650)
    Statistical analysis title
    		 Change in microbiome Sput BF vs LABA/LAMA
    Comparison groups
    Arm 1: BF400 v Arm 4: AF
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9556
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.141
         upper limit
    		 1.079

    Secondary: Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples BF ICS vs LABA/LAMA

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples BF ICS vs LABA/LAMA
    End point description
    To compare the effects on the upper airway microbiome in oropharyngeal swabs of inhaled corticosteroids budesonide compared to a dual bronchodilator-based regime without ICS
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 4: AF
    Number of subjects analysed
    16
    13
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.69 (1.413 to 1.975)
    1.32 (1.032 to 1.604)
    Statistical analysis title
    		 Change in microbiome OP BF vs LABA/LAMA
    Comparison groups
    Arm 1: BF400 v Arm 4: AF
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1264
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.257
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.587
         upper limit
    		 0.074

    Secondary: Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples BF ICS vs LABA/LAMA

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples BF ICS vs LABA/LAMA
    End point description
    To compare the effects on the upper airway microbiome in nasopharyngeal swabs of inhaled corticosteroids budesonide compared to a dual bronchodilator-based regime without ICS
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 1: BF400 Arm 4: AF
    Number of subjects analysed
    16
    14
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.46 (1.166 to 1.751)
    1.47 (1.174 to 1.766)
    Statistical analysis title
    		 Change in microbiome NP BF vs LABA/LAMA
    Comparison groups
    Arm 1: BF400 v Arm 4: AF
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9367
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.028
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.724
         upper limit
    		 0.668

    Secondary: Change in Total Bacterial Load FS500 vs FS250 in Sputum Samples

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    End point title
    		 Change in Total Bacterial Load FS500 vs FS250 in Sputum Samples
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs fluticasone propionate/salmeterol 250/50 mcg on lower airway bacterial load in sputum samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 2: FS500 Arm 3: FS250
    Number of subjects analysed
    11
    14
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    10.44 (10.049 to 10.822)
    10.35 (9.897 to 10.798)
    Statistical analysis title
    		 Change in BL Sput FS500 vs FS250
    Comparison groups
    Arm 3: FS250 v Arm 2: FS500
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0712
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.626
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.307
         upper limit
    		 0.055

    Secondary: Change in Total Bacterial Load FS500 vs FS250 in Oropharyngeal Swab Samples

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    End point title
    		 Change in Total Bacterial Load FS500 vs FS250 in Oropharyngeal Swab Samples
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs fluticasone propionate/salmeterol 250/50 mcg on upper airway in oropharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 2: FS500 Arm 3: FS250
    Number of subjects analysed
    12
    14
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    8.89 (8.337 to 9.438)
    8.08 (7.529 to 8.636)
    Statistical analysis title
    		 Change in BL OP FS500 vs FS250
    Comparison groups
    Arm 2: FS500 v Arm 3: FS250
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1279
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.556
         upper limit
    		 0.328

    Secondary: Change in Total Bacterial Load FS500 vs FS250 in Nasopharyngeal Swab Samples

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    End point title
    		 Change in Total Bacterial Load FS500 vs FS250 in Nasopharyngeal Swab Samples
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs fluticasone propionate/salmeterol 250/50 mcg on upper airway in nasopharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 2: FS500 Arm 3: FS250
    Number of subjects analysed
    13
    14
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    6.9 (6.461 to 7.339)
    6.89 (6.306 to 7.479)
    Statistical analysis title
    		 Change in BL NP FS250 vs BF400
    Comparison groups
    Arm 2: FS500 v Arm 3: FS250
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7561
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.335
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.807
         upper limit
    		 2.477

    Secondary: Change in the Microbiome by Alpha-diversity in Sputum Samples FS500 vs FS250

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Sputum Samples FS500 vs FS250
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs fluticasone propionate/salmeterol 250/50 mcg on the microbiome by alpha-diversity from sputum
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 2: FS500 Arm 3: FS250
    Number of subjects analysed
    11
    14
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.58 (1.389 to 1.772)
    1.56 (1.298 to 1.831)
    Statistical analysis title
    		 Change in microbiome Sput FS500 vs FS250
    Comparison groups
    Arm 2: FS500 v Arm 3: FS250
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8517
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.341
         upper limit
    		 0.282

    Secondary: Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS500 vs FS250

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS500 vs FS250
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs fluticasone propionate/salmeterol 250/50 mcg on the microbiome by alpha-diversity from oropharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 2: FS500 Arm 3: FS250
    Number of subjects analysed
    12
    14
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.6 (1.398 to 1.794)
    1.28 (0.900 to 1.662)
    Statistical analysis title
    		 Change in alpha-diversity in OP FS500 vs FS250
    Statistical analysis description
    Change in the Microbiome by Alpha-diversity in Oropharyngeal Samples FS500 vs FS250
    Comparison groups
    Arm 2: FS500 v Arm 3: FS250
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0688
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.333
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.693
         upper limit
    		 0.026

    Secondary: Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS500 vs FS250

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    End point title
    		 Change in the Microbiome by Alpha-diversity in Nasopharyngeal Samples FS500 vs FS250
    End point description
    To determine the effects of the inhaled corticosteroids fluticasone propionate/salmeterol 500/50 mcg vs fluticasone propionate/salmeterol 250/50 mcg on the microbiome by alpha-diversity from nasopharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 2: FS500 Arm 3: FS250
    Number of subjects analysed
    13
    14
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.18 (0.789 to 1.563)
    1.33 (0.962 to 1.701)
    Statistical analysis title
    		 Change in alpha-diversity in NP FS500 vs FS250
    Comparison groups
    Arm 2: FS500 v Arm 3: FS250
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3262
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.755
         upper limit
    		 0.254

    Secondary: Change in Total Bacterial Load in Pooled ICS vs LABA/LAMA in Sputum Samples

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    End point title
    		 Change in Total Bacterial Load in Pooled ICS vs LABA/LAMA in Sputum Samples
    End point description
    To determine the combined impact of inhaled corticosteroids on bacterial load in upper and lower airway using sputum samples compared to dual bronchodilator regime
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    40
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    9.73 (9.352 to 10.116)
    10.19 (9.953 to 10.434)
    Statistical analysis title
    		 Change in BL Sput All ICS vs LABA/LAMA
    Comparison groups
    Pooled ICS v Arm 4: AF
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1455
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.424
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.148
         upper limit
    		 0.996

    Secondary: Change in Total Bacterial Load in Pooled ICS vs LABA/LAMA in Oropharyngeal Swab Samples

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    End point title
    		 Change in Total Bacterial Load in Pooled ICS vs LABA/LAMA in Oropharyngeal Swab Samples
    End point description
    To determine the combined impact of inhaled corticosteroids on bacterial load in upper and lower airway using oropharyngeal swab samples compared to dual bronchodilator regime
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    13
    42
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    8.53 (7.762 to 9.294)
    8.62 (8.327 to 8.906)
    Statistical analysis title
    		 Change in BL OP All ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.607
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.205
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.581
         upper limit
    		 0.991

    Secondary: Change in Total Bacterial Load in Pooled ICS vs LABA/LAMA in Nasopharyngeal Swab Samples

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    End point title
    		 Change in Total Bacterial Load in Pooled ICS vs LABA/LAMA in Nasopharyngeal Swab Samples
    End point description
    To determine the combined impact of inhaled corticosteroids on bacterial load in upper and lower airway using nasopharyngeal swab samples compared to dual bronchodilator regime
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    43
    Units: CFU/g equivalent units
        arithmetic mean (confidence interval 95%)
    7.27 (6.695 to 7.836)
    6.92 (6.667 to 7.172)
    Statistical analysis title
    		 Change in BL NP All ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.463
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.359
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.322
         upper limit
    		 0.605

    Secondary: Change in Microbiome by Alpha-diversity in Pooled ICS vs LABA/LAMA in Sputum Samples

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    End point title
    		 Change in Microbiome by Alpha-diversity in Pooled ICS vs LABA/LAMA in Sputum Samples
    End point description
    To determine the effects of inhaled corticosteroids vs LABA/LAMA on the microbiome by alpha-diversity in sputum samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1-3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    40
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.27 (0.897 to 1.650)
    1.59 (1.439 to 1.741)
    Statistical analysis title
    		 Change in alpha-diversity Sput All ICS vs LB/LM
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8915
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.022
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.338
         upper limit
    		 0.294

    Secondary: Change in Microbiome by Alpha-diversity in Pooled ICS vs LABA/LAMA in Oropharyngeal Swab Samples

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    End point title
    		 Change in Microbiome by Alpha-diversity in Pooled ICS vs LABA/LAMA in Oropharyngeal Swab Samples
    End point description
    To determine the effects of inhaled corticosteroids vs LABA/LAMA on the microbiome by alpha-diversity in oropharyngeal swab samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    13
    42
    Units: Shannon Weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.32 (1.032 to 1.604)
    1.53 (1.358 to 1.699)
    Statistical analysis title
    		 Change in alpha-diversity in OP ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.846
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.273
         upper limit
    		 0.332

    Secondary: Change in Microbiome by Alpha-diversity in Pooled ICS vs LABA/LAMA in Nasopharyngeal Swab Samples

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    End point title
    		 Change in Microbiome by Alpha-diversity in Pooled ICS vs LABA/LAMA in Nasopharyngeal Swab Samples
    End point description
    To determine the effects of inhaled corticosteroids vs LABA/LAMA on the microbiome by alpha-diversity in nasopharyngeal swab samples
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    43
    Units: Shannon weiner diversity index
        arithmetic mean (confidence interval 95%)
    1.47 (1.174 to 1.766)
    1.33 (1.146 to 1.518)
    Statistical analysis title
    		 Change in alpha-diversity NP All ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.798
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.487
         upper limit
    		 0.632

    Secondary: Change in Airway MPO for ICS vs LABA/LAMA in Sputum Samples

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    End point title
    		 Change in Airway MPO for ICS vs LABA/LAMA in Sputum Samples
    End point description
    To evaluate the impact of inhaled corticosteroids on airway myeloperoxidase compared to LABA/LAMA
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    38
    Units: Units/mL
        arithmetic mean (confidence interval 95%)
    0.53 (0.078 to 0.988)
    0.49 (0.291 to 0.695)
    Statistical analysis title
    		 Change in Sput MPO for ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0376
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.034
         upper limit
    		 1.105

    Secondary: Change in Airway Neutrophil Elastase for ICS vs LABA/LAMA in Sputum Samples

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    End point title
    		 Change in Airway Neutrophil Elastase for ICS vs LABA/LAMA in Sputum Samples
    End point description
    To evaluate the impact of inhaled corticosteroids on airway neutrophil elastase compared to LABA/LAMA
    End point type
    Secondary
    End point timeframe
    Treatment period. months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    38
    Units: Units/mL
        arithmetic mean (confidence interval 95%)
    0.03 (-0.017 to 0.081)
    0.70 (-0.565 to 1.973)
    Statistical analysis title
    		 Change in Sput NE for ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.897
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.307
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.84
         upper limit
    		 3.454

    Secondary: Change in Resistin for ICS vs LABA/LAMA in Whole Blood

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    End point title
    		 Change in Resistin for ICS vs LABA/LAMA in Whole Blood
    End point description
    To evaluate the impact of inhaled corticosteroids on blood resistin compared to LABA/LAMA
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    43
    Units: ng/mL
        arithmetic mean (confidence interval 95%)
    15.08 (11.914 to 18.228)
    151.07 (-113.935 to 416.074)
    Statistical analysis title
    		 Change in blood resistin ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3686
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.261
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.316
         upper limit
    		 0.837

    Secondary: Change in Airway Resistin for ICS vs LABA/LAMA in Sputum Samples

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    End point title
    		 Change in Airway Resistin for ICS vs LABA/LAMA in Sputum Samples
    End point description
    To evaluate the impact of inhaled corticosteroids on airway resistin compared to LABA/LAMA
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    38
    Units: ng/mL
        arithmetic mean (confidence interval 95%)
    132.83 (17.362 to 248.295)
    96.53 (30.625 to 162.426)
    Statistical analysis title
    		 Change in sput Resistin ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8979
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.064
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.941
         upper limit
    		 1.07

    Secondary: Change in Airway IL-8 for ICS vs LABA/LAMA in Sputum Samples

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    End point title
    		 Change in Airway IL-8 for ICS vs LABA/LAMA in Sputum Samples
    End point description
    To evaluate the impact of inhaled corticosteroids on airway IL-8 compared to LABA/LAMA
    End point type
    Secondary
    End point timeframe
    Treatment window, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    38
    Units: ng/mL
        arithmetic mean (confidence interval 95%)
    1.20 (0.227 to 2.170)
    1.27 (0.572 to 1.977)
    Statistical analysis title
    		 Change in sput IL8 ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1098
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.287
         upper limit
    		 0.24

    Secondary: Change in Airway IL1-beta for ICS vs LABA/LAMA in Sputum Samples

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    End point title
    		 Change in Airway IL1-beta for ICS vs LABA/LAMA in Sputum Samples
    End point description
    To evaluate the impact of inhaled corticosteroids on airway IL1-beta compared to LABA/LAMA
    End point type
    Secondary
    End point timeframe
    Treatment period, months 1 to 3
    End point values
    		 Arm 4: AF Pooled ICS
    Number of subjects analysed
    14
    38
    Units: ug/mL
        arithmetic mean (confidence interval 95%)
    9.57 (-8.659 to 27.803)
    5.86 (2.641 to 9.072)
    Statistical analysis title
    		 Change in sput IL1b ICS vs LABA/LAMA
    Comparison groups
    Arm 4: AF v Pooled ICS
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3261
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.752
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.776
         upper limit
    		 2.28

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from screening to end of study
    Adverse event reporting additional description
    Adverse events were assessed systematically, and defined using MedDRA dictionary
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Symbicort 400/12 & Eklira Genuair
    Reporting group description
    		 Budesonide 400mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Budesonide & formoterol fumarate and Aclidinium bromide

    Reporting group title
    Seretide 500/50 & Eklira Genuair
    Reporting group description
    		 Fluticasone propionate 500mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 500 & salmeterol and Aclidinium bromide

    Reporting group title
    Seretide 250/50 & Eklira Genuair
    Reporting group description
    		 Fluticasone propionate 250mcg & salmeterol 50mcg: 1 inhalation twice daily, inhalation powder and Aclidinium bromide 322mcg: 1 inhalation twice daily, inhalation powder for 3 months Fluticasone 250 & salmeterol and Aclidinium bromide

    Reporting group title
    Duaklir Genuair
    Reporting group description
    		 Aclidinium bromide 340mcg & formoterol fumarate 12mcg: 1 inhalation twice daily, inhalation powder for 3 months Aclidinium bromide & formoterol fumarate

    Serious adverse events
    		 Symbicort 400/12 & Eklira Genuair Seretide 500/50 & Eklira Genuair Seretide 250/50 & Eklira Genuair Duaklir Genuair
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Facial injury
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Symbicort 400/12 & Eklira Genuair Seretide 500/50 & Eklira Genuair Seretide 250/50 & Eklira Genuair Duaklir Genuair
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 18 (72.22%)
    13 / 13 (100.00%)
    12 / 15 (80.00%)
    14 / 15 (93.33%)
    Investigations
    Investigations
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    2
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 13 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Neurological symptom
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 13 (15.38%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    0
    1
    General disorders and administration site conditions
    Oral and laryngeal symptoms
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 13 (15.38%)
    4 / 15 (26.67%)
    0 / 15 (0.00%)
         occurrences all number
    2
    2
    7
    0
    Other
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 13 (15.38%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Immune system disorders
    Allergy
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 13 (7.69%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 13 (7.69%)
    0 / 15 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    1
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 18 (44.44%)
    4 / 13 (30.77%)
    4 / 15 (26.67%)
    7 / 15 (46.67%)
         occurrences all number
    9
    4
    4
    7
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 13 (7.69%)
    4 / 15 (26.67%)
    5 / 15 (33.33%)
         occurrences all number
    4
    1
    5
    8
    Cough
         subjects affected / exposed
    5 / 18 (27.78%)
    0 / 13 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    6
    0
    2
    1
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 13 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    2
    0
    1
    2
    Sputum increased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 13 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 18 (22.22%)
    1 / 13 (7.69%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    4
    1
    1
    3
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 13 (7.69%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    4 / 18 (22.22%)
    4 / 13 (30.77%)
    3 / 15 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    4
    5
    3
    3
    Infections and infestations
    General infections
         subjects affected / exposed
    1 / 18 (5.56%)
    4 / 13 (30.77%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    5
    0
    2

    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.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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