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    Clinical Trial Results:
    A multicentre, randomised, double-blind, active-controlled, 3-way cross-over study to evaluate the efficacy and safety of a free combination of 3 doses of CHF 5259 (glycopyrrolate) plus Foster® 100/6µg (fixed combination of beclomethasone dipropionate plus formoterol) in a metered dose inhaler for the treatment of patients with uncontrolled asthma under medium doses of inhaled corticosteroids plus long-acting β2-agonists

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2013-003043-36
    Trial protocol
    DE   GB   HU   IT   PL   BG  
    Global end of trial date
    08 Mar 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-1206-PR-0088
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02127866
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, CHIESI FARMACEUTICI S.p.A, clinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, CHIESI FARMACEUTICI S.p.A, ClinicalTrial_info@chiesi.com
    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
    08 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a free combination of CHF 5259 (glycopyrrolate bromide [GB]) at 3 dose levels plus Foster 100/6 µg (fixed combination of beclomethasone dipropionate [BDP] plus formoterol [FF]) in a pressurised metered dose inhaler by comparison with Foster 100/6 µg in terms of FEV1 AUC0-12h normalised by time on Day 42.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    -
    Evidence for comparator
    Foster® 100/6µg (fixed combination of beclometasone dipropionate plus formoterol) administered via pMDI.
    Actual start date of recruitment
    11 Apr 2014
    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: 2
    Country: Number of subjects enrolled
    Bulgaria: 48
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Hungary: 59
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Poland: 62
    Worldwide total number of subjects
    211
    EEA total number of subjects
    211
    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)
    186
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This multinational study was conducted at 44 clinical sites (43 active) in 6 countries. The recruitment took place in: Bulgaria (10 sites) Germany (8 sites) Hungary (7 sites) Italy (5 sites: 4 active and 1 non-active) Poland (12 sites) UK (2 sites)

    Pre-assignment
    Screening details
    A total of 322 patients were screened, of whom 211 were randomised to one of the following treatment sequence groups: •Sequence A-C-B: n = 53; •Sequence B-D-C: n = 53; •Sequence C-A-D: n = 53; •Sequence D-B-A: n = 52. 201 (95.3%) patients completed the study.

    Period 1
    Period 1 title
    Overall trial by sequence (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    To maintain the blind during the treatment period, patients inhaled study medication from four identical white canisters daily, regardless of treatment regimen. The randomisation list was provided to the labelling facility but was not available to patients, investigators, monitors or employees of CROMSOURCE involved in the management of the trial before unblinding of the data, unless in case of emergency. The Sponsor’s clinical team was also blinded during the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence A-C-B
    Arm description
    Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5259 pMDI
    Investigational medicinal product code
    Other name
    glycopyrronium bromide [GB]
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; • Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; • Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.

    Investigational medicinal product name
    Foster® 100/6 μg pMDI
    Investigational medicinal product code
    Other name
    fixed dose combination [FDC] of beclometasone dipropionate [BDP] plus formoterol [FF]
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; • Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; • Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.

    Arm title
    Sequence B-D-C
    Arm description
    Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg. Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5259 pMDI
    Investigational medicinal product code
    Other name
    glycopyrronium bromide [GB]
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; • Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg; or • Treatment D: two puffs of CHF 5259 placebo BID (plus Foster alone).

    Investigational medicinal product name
    Foster® 100/6 μg pMDI
    Investigational medicinal product code
    Other name
    fixed dose combination [FDC] of beclometasone dipropionate [BDP] plus formoterol [FF]
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; • Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. • Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.

    Arm title
    Sequence C-A-D
    Arm description
    Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5259 pMDI
    Investigational medicinal product code
    Other name
    glycopyrronium bromide [GB]
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; • Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg; or • Treatment D: two puffs of CHF 5259 placebo BID (plus Foster alone).

    Investigational medicinal product name
    Foster® 100/6 μg pMDI
    Investigational medicinal product code
    Other name
    fixed dose combination [FDC] of beclometasone dipropionate [BDP] plus formoterol [FF]
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; • Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. • Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.

    Arm title
    Sequence D-B-A
    Arm description
    Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg; Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg.
    Arm type
    Experimental

    Investigational medicinal product name
    CHF 5259 pMDI
    Investigational medicinal product code
    Other name
    glycopyrronium bromide [GB]
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; • Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; • Treatment D: two puffs of CHF 5259 placebo BID (plus Foster alone).

    Investigational medicinal product name
    Foster® 100/6 μg pMDI
    Investigational medicinal product code
    Other name
    fixed dose combination [FDC] of beclometasone dipropionate [BDP] plus formoterol [FF]
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    • Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; • Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; • Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.

    Number of subjects in period 1
    Sequence A-C-B Sequence B-D-C Sequence C-A-D Sequence D-B-A
    Started
    53
    53
    53
    52
    Completed
    51
    52
    49
    49
    Not completed
    2
    1
    4
    3
         Protocol deviation
    1
    1
    1
    -
         Other
    1
    -
    1
    -
         Consent withdrawn by subject
    -
    -
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A-C-B
    Reporting group description
    Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg.

    Reporting group title
    Sequence B-D-C
    Reporting group description
    Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg. Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.

    Reporting group title
    Sequence C-A-D
    Reporting group description
    Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.

    Reporting group title
    Sequence D-B-A
    Reporting group description
    Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg; Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg.

    Reporting group values
    Sequence A-C-B Sequence B-D-C Sequence C-A-D Sequence D-B-A Total
    Number of subjects
    53 53 53 52 211
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    47 49 46 44 186
        From 65-84 years
    6 4 7 8 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.3 ± 12.3 51.2 ± 11.1 51.5 ± 13.8 49.3 ± 13.9 -
    Gender categorical
    Units: Subjects
        Female
    38 40 30 27 135
        Male
    15 13 23 25 76

    End points

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    End points reporting groups
    Reporting group title
    Sequence A-C-B
    Reporting group description
    Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg.

    Reporting group title
    Sequence B-D-C
    Reporting group description
    Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg. Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg.

    Reporting group title
    Sequence C-A-D
    Reporting group description
    Treatment C: two puffs of CHF 5259 25 μg BID + two puffs of Foster® 100 /6 μg BID – total daily dose of CHF 5259 100 μg + Foster® 400 μg/24 μg. Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg; Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg.

    Reporting group title
    Sequence D-B-A
    Reporting group description
    Treatment D: two puffs of CHF 5259 placebo BID and two puffs of Foster® 100 μg/6 μg BID – total daily dose of Foster® 400 μg/24 μg; Treatment B: one puff of CHF 5259 25 μg BID + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 50 μg + Foster® 400 μg/24 μg; Treatment A: one puff of CHF 5259 12.5 μg twice a day (BID) + one puff of CHF 5259 placebo BID + two puffs of Foster® 100 μg/6 μg BID – total daily dose of CHF 5259 25 μg + Foster® 400 μg/24 μg.

    Subject analysis set title
    Treatment A - ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention-to-Treat (ITT) population: all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after the Baseline were included in the ITT population.

    Subject analysis set title
    Treatment A - safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety population: all randomised patients who received at least one dose of study treatment were included in the safety population.

    Subject analysis set title
    Treatment B - ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention-to-Treat (ITT) population: all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after the Baseline were included in the ITT population.

    Subject analysis set title
    Treatment B - safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety population: all randomised patients who received at least one dose of study treatment were included in the safety population.

    Subject analysis set title
    Treatment C - ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention-to-Treat (ITT) population: all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after the Baseline were included in the ITT population.

    Subject analysis set title
    Treatment C - safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety population: all randomised patients who received at least one dose of study treatment were included in the safety population.

    Subject analysis set title
    Treatment D - ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intention-to-Treat (ITT) population: all randomised patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after the Baseline were included in the ITT population.

    Subject analysis set title
    Treatment D - safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety population: all randomised patients who received at least one dose of study treatment were included in the safety population.

    Primary: FEV1 AUC0-12h normalised by time on Day 42

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    End point title
    FEV1 AUC0-12h normalised by time on Day 42
    End point description
    AUC0-12= area under the curve between the time 0 and 12 hours. Post-dose FEV1 on Day 42 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.
    End point type
    Primary
    End point timeframe
    On Day 42
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [1]
    150 [2]
    152 [3]
    152 [4]
    Units: liters
        arithmetic mean (standard deviation)
    2.327 ± 0.751
    2.332 ± 0.752
    2.272 ± 0.717
    2.296 ± 0.692
    Notes
    [1] - This is the actual number of patients on which the analysis was performed.
    [2] - This is the actual number of patients on which the analysis was performed.
    [3] - This is the actual number of patients on which the analysis was performed.
    [4] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.059
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.021
         upper limit
    0.096
    Notes
    [5] - FEV1 AUC0-12h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each dose level of the free combination and Foster alone will be calculated with their simultaneous 95% confidence intervals (CIs) and p-values.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.084
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.047
         upper limit
    0.121
    Notes
    [6] - FEV1 AUC0-12h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each dose level of the free combination and Foster alone will be calculated with their simultaneous 95% confidence intervals (CIs) and p-values.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.084
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.047
         upper limit
    0.121
    Notes
    [7] - FEV1 AUC0-12h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each dose level of the free combination and Foster alone will be calculated with their simultaneous 95% confidence intervals (CIs) and p-values.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=299 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.113
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.025
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.006
         upper limit
    0.057
    Notes
    [8] - FEV1 AUC0-12h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each higher dose of the free combination (Treatment B and Treatment C) and the lowest dose of the free combination (Treatment A) will be calculated with their simultaneous 95% CIs and p-values.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.106
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.006
         upper limit
    0.057
    Notes
    [9] - FEV1 AUC0-12h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each higher dose of the free combination (Treatment B and Treatment C) and the lowest dose of the free combination (Treatment A) will be calculated with their simultaneous 95% CIs and p-values.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.983
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.031
         upper limit
    0.031
    Notes
    [10] - FEV1 AUC0-12h normalized by time at Day 42 will be analysed using an ANCOVA model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate. The adjusted mean differences between each higher dose of the free combination (Treatment B and Treatment C) and the lowest dose of the free combination (Treatment A) will be calculated with their simultaneous 95% CIs and p-values.

    Secondary: Change from baseline in peak FEV1 on Day 42

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    End point title
    Change from baseline in peak FEV1 on Day 42
    End point description
    The maximum FEV1 value obtained between 15 minutes and 12 hours post-dose is the peak FEV1. Post-dose FEV1 on Day 42 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FEV1 pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).
    End point type
    Secondary
    End point timeframe
    On Day 42.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [11]
    152 [12]
    153 [13]
    152 [14]
    Units: liters
        arithmetic mean (standard deviation)
    0.438 ± 0.34
    0.463 ± 0.327
    0.418 ± 0.327
    0.396 ± 0.3
    Notes
    [11] - This is the actual number of patients on which the analysis was performed.
    [12] - This is the actual number of patients on which the analysis was performed.
    [13] - This is the actual number of patients on which the analysis was performed.
    [14] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    least square mean difference
    Point estimate
    0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.022
         upper limit
    0.098
    Notes
    [15] - The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.091
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.054
         upper limit
    0.128
    Notes
    [16] - The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.038
         upper limit
    0.113
    Notes
    [17] - The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable.
    Statistical analysis title
    treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    P-value
    = 0.051
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.031
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.062
    Notes
    [18] - The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.32
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.047
    Notes
    [19] - The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    P-value
    = 0.332
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.046
         upper limit
    0.016
    Notes
    [20] - The key secondary efficacy variable (i.e. change from Baseline in peak FEV1 on Day 42) was analysed on both the ITT and the PP populations using the ANCOVA model described for the primary efficacy variable

    Secondary: FEV1 AUC0-3h normalised by time on Day 1

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    End point title
    FEV1 AUC0-3h normalised by time on Day 1
    End point description
    AUC0-3h = area under the curve between time 0 and 3 hours. The pre-dose and post-dose lung function assessments were recorded under supervision at the following timings: •Pre-dose FEV1 on Day 1 at 45 and 10 minutes prior to study drug intake (baseline FEV1); •Post-dose FEV1 on Day 1 of each treatment period: at 15’; 30’; 45’; 1h; 2h; 3h post-study drug intake.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [21]
    153 [22]
    155 [23]
    152 [24]
    Units: liters
        arithmetic mean (standard deviation)
    2.379 ± 0.741
    2.366 ± 0.758
    2.311 ± 0.7
    2.364 ± 0.717
    Notes
    [21] - This is the actual number of patients on which the analysis was performed.
    [22] - This is the actual number of patients on which the analysis was performed.
    [23] - This is the actual number of patients on which the analysis was performed.
    [24] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    = 0.002
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.049
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.019
         upper limit
    0.079
    Notes
    [25] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment D - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    = 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.049
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.019
         upper limit
    0.079
    Notes
    [26] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.053
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.083
    Notes
    [27] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    = 0.995
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.03
    Notes
    [28] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    = 0.778
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.026
         upper limit
    0.034
    Notes
    [29] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    = 0.771
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.025
         upper limit
    0.034
    Notes
    [30] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates

    Secondary: FEV1 AUC0-3h normalised by time on Day 42

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    End point title
    FEV1 AUC0-3h normalised by time on Day 42
    End point description
    AUC0-3h = area under the curve between time 0 and 3 hours. The pre-dose and post-dose lung function assessments were recorded under supervision at the following timings: •Pre-dose FEV1 on Day 1 at 45 and 10 minutes prior to study drug intake (baseline FEV1); •Post-dose FEV1 on Day 42 of each treatment period: at 15’; 30’; 45’; 1h; 2h; 3h post-study drug intake.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [31]
    152 [32]
    152 [33]
    152 [34]
    Units: liters
        arithmetic mean (standard deviation)
    2.389 ± 0.763
    2.415 ± 0.764
    2.342 ± 0.727
    2.367 ± 0.703
    Notes
    [31] - This is the actual number of patients on which the analysis was performed.
    [32] - This is the actual number of patients on which the analysis was performed.
    [33] - This is the actual number of patients on which the analysis was performed.
    [34] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.024
         upper limit
    0.089
    Notes
    [35] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.092
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.124
    Notes
    [36] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.089
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.057
         upper limit
    0.122
    Notes
    [37] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [38]
    P-value
    = 0.029
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.036
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    0.069
    Notes
    [38] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    = 0.044
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.066
    Notes
    [39] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    P-value
    = 0.859
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.003
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.035
         upper limit
    0.029
    Notes
    [40] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: Change from baseline in FEV1 pre-dose on Day 14

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    End point title
    Change from baseline in FEV1 pre-dose on Day 14
    End point description
    The pre-dose morning FEV1 is defined as the mean of the two measurements at 45 and 10 minutes pre-dose.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152 [41]
    155 [42]
    155 [43]
    152 [44]
    Units: liters
        arithmetic mean (standard deviation)
    0.082 ± 0.279
    0.103 ± 0.281
    0.085 ± 0.267
    0.08 ± 0.25
    Notes
    [41] - This is the actual number of patients on which the analysis was performed.
    [42] - This is the actual number of patients on which the analysis was performed.
    [43] - This is the actual number of patients on which the analysis was performed.
    [44] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    P-value
    = 0.168
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.031
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.013
         upper limit
    0.075
    Notes
    [45] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [46]
    P-value
    = 0.016
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.053
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.096
    Notes
    [46] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [47]
    P-value
    = 0.058
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.042
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.001
         upper limit
    0.086
    Notes
    [47] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [48]
    P-value
    = 0.315
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.021
         upper limit
    0.066
    Notes
    [48] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [49]
    P-value
    = 0.607
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.032
         upper limit
    0.055
    Notes
    [49] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=310 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    superiority [50]
    P-value
    = 0.621
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.054
         upper limit
    0.032
    Notes
    [50] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: Change from baseline in FEV1 pre-dose on Day 42

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    End point title
    Change from baseline in FEV1 pre-dose on Day 42
    End point description
    The pre-dose morning FEV1 is defined as the mean of the two measurements at 45 and 10 minutes pre-dose.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    150 [51]
    153 [52]
    155 [53]
    152 [54]
    Units: liters
        arithmetic mean (standard deviation)
    0.048 ± 0.298
    0.087 ± 0.299
    0.072 ± 0.295
    0.067 ± 0.273
    Notes
    [51] - This is the actual number of patients on which the analysis was performed.
    [52] - This is the actual number of patients on which the analysis was performed.
    [53] - This is the actual number of patients on which the analysis was performed.
    [54] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [55]
    P-value
    = 0.484
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.027
         upper limit
    0.058
    Notes
    [55] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [56]
    P-value
    = 0.005
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.018
         upper limit
    0.102
    Notes
    [56] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [57]
    P-value
    = 0.016
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.052
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.094
    Notes
    [57] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [58]
    P-value
    = 0.038
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.002
         upper limit
    0.087
    Notes
    [58] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    P-value
    = 0.087
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.079
    Notes
    [59] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority [60]
    P-value
    = 0.709
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.05
         upper limit
    0.034
    Notes
    [60] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: Change from baseline in through FEV1 at 12 h post-dose on Day 1

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    End point title
    Change from baseline in through FEV1 at 12 h post-dose on Day 1
    End point description
    Trough FEV1 at 12 hours is determined as the average of the 11.5 and 12 hours post-dose FEV1 assessments. Baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period recorded at 45 and 10 minutes prior to study drug intake.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    150 [61]
    153 [62]
    156 [63]
    149 [64]
    Units: liters
        arithmetic mean (standard deviation)
    0.146 ± 0.294
    0.137 ± 0.262
    0.138 ± 0.266
    0.127 ± 0.273
    Notes
    [61] - This is the actual number of patients on which the analysis was performed.
    [62] - This is the actual number of patients on which the analysis was performed.
    [63] - This is the actual number of patients on which the analysis was performed.
    [64] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=299 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    superiority [65]
    P-value
    = 0.159
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.011
         upper limit
    0.067
    Notes
    [65] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [66]
    P-value
    = 0.089
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.072
    Notes
    [66] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [67]
    P-value
    = 0.008
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.053
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.014
         upper limit
    0.091
    Notes
    [67] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [68]
    P-value
    = 0.781
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.033
         upper limit
    0.044
    Notes
    [68] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [69]
    P-value
    = 0.205
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.025
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.014
         upper limit
    0.063
    Notes
    [69] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [70]
    P-value
    = 0.32
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.019
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.019
         upper limit
    0.057
    Notes
    [70] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: Change from baseline in through FEV1 at 12 h post-dose on Day 42

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    End point title
    Change from baseline in through FEV1 at 12 h post-dose on Day 42
    End point description
    Trough FEV1 at 12 hours is determined as the average of the 11.5 and 12 hours post-dose FEV1 assessments. Baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period recorded at 45 and 10 minutes prior to study drug intake.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [71]
    150 [72]
    154 [73]
    152 [74]
    Units: liters
        arithmetic mean (standard deviation)
    0.143 ± 0.345
    0.143 ± 0.297
    0.135 ± 0.308
    0.109 ± 0.28
    Notes
    [71] - This is the actual number of patients on which the analysis was performed.
    [72] - This is the actual number of patients on which the analysis was performed.
    [73] - This is the actual number of patients on which the analysis was performed.
    [74] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment D - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [75]
    P-value
    = 0.015
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.046
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.083
    Notes
    [75] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [76]
    P-value
    = 0.008
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.013
         upper limit
    0.087
    Notes
    [76] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [77]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.068
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.031
         upper limit
    0.105
    Notes
    [77] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=299 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    superiority [78]
    P-value
    = 0.832
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.033
         upper limit
    0.041
    Notes
    [78] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [79]
    P-value
    = 0.234
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.015
         upper limit
    0.059
    Notes
    [79] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [80]
    P-value
    = 0.328
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.018
         upper limit
    0.055
    Notes
    [80] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: Change from baseline in peak FEV1 on Day 1

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    End point title
    Change from baseline in peak FEV1 on Day 1
    End point description
    The peak FEV1 is the maximum FEV1 value obtained between 15 minutes and 12 hours post-dose. Post-dose FEV1 on Day 1 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FEV1 pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    150 [81]
    153 [82]
    156 [83]
    153 [84]
    Units: liters
        arithmetic mean (standard deviation)
    0.455 ± 0.308
    0.441 ± 0.278
    0.424 ± 0.26
    0.408 ± 0.252
    Notes
    [81] - This is the actual number of patients on which the analysis was performed.
    [82] - This is the actual number of patients on which the analysis was performed.
    [83] - This is the actual number of patients on which the analysis was performed.
    [84] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [85]
    P-value
    = 0.002
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.058
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.022
         upper limit
    0.094
    Notes
    [85] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [86]
    P-value
    = 0.012
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.081
    Notes
    [86] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [87]
    P-value
    = 0.004
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.053
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.017
         upper limit
    0.088
    Notes
    [87] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [88]
    P-value
    = 0.492
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.048
         upper limit
    0.023
    Notes
    [88] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a Cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [89]
    P-value
    = 0.772
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.005
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.041
         upper limit
    0.03
    Notes
    [89] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and Baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [90]
    P-value
    = 0.689
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.028
         upper limit
    0.042
    Notes
    [90] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: FEV1 AUC0-12h normalised by time on Day 1

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    End point title
    FEV1 AUC0-12h normalised by time on Day 1
    End point description
    AUC0-12h = area under the curve between time 0 and 12 hours. Post-dose FEV1 on Day 1 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [91]
    152 [92]
    154 [93]
    148 [94]
    Units: liters
        arithmetic mean (standard deviation)
    2.33 ± 0.742
    2.313 ± 0.754
    2.26 ± 0.693
    2.329 ± 0.708
    Notes
    [91] - This is the actual number of patients on which the analysis was performed.
    [92] - This is the actual number of patients on which the analysis was performed.
    [93] - This is the actual number of patients on which the analysis was performed.
    [94] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=297 (subject analysis set) is an innate error of the EudraCT database system
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [95]
    P-value
    = 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    0.082
    Notes
    [95] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=300 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    superiority [96]
    P-value
    = 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.052
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.021
         upper limit
    0.083
    Notes
    [96] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [97]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.034
         upper limit
    0.096
    Notes
    [97] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [98]
    P-value
    = 0.972
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.001
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.031
    Notes
    [98] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [99]
    P-value
    = 0.375
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.017
         upper limit
    0.045
    Notes
    [99] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [100]
    P-value
    = 0.389
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.013
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.017
         upper limit
    0.044
    Notes
    [100] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: FEV1 percentage of predicted normal value at each time point post-dose on Day 1 and mean changes from Baseline

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    End point title
    FEV1 percentage of predicted normal value at each time point post-dose on Day 1 and mean changes from Baseline
    End point description
    Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done: 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11h and 30 min, 12h post-dose on Day 1. Only data about the change from baseline at the last timepoint (12h post-dose) of the Day 1 are reported in the database. For the data about the other timepoints on Day 1 see pdf attached.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    150 [101]
    153 [102]
    156 [103]
    149 [104]
    Units: percentage
        arithmetic mean (standard deviation)
    4.6 ± 8.5
    4.3 ± 8.7
    4.4 ± 8.6
    3.6 ± 8.3
    Attachments
    Untitled (Filename: FEV1 Change D1.pdf)
    Untitled (Filename: FEV1 Value D1.pdf)
    Notes
    [101] - This is the actual number of patients on which the analysis was performed.
    [102] - This is the actual number of patients on which the analysis was performed.
    [103] - This is the actual number of patients on which the analysis was performed.
    [104] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: FEV1 percentage of predicted normal value at 2h post-dose on Day 14 and mean changes from Baseline

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    End point title
    FEV1 percentage of predicted normal value at 2h post-dose on Day 14 and mean changes from Baseline
    End point description
    Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done 2h post-dose on Day 14. Only the change from baseline (not the actual value) is reported in the database. For the actual values on the same endpoint , please see the pdf attached.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152 [105]
    155 [106]
    155 [107]
    152 [108]
    Units: percentage
        arithmetic mean (standard deviation)
    11.5 ± 9.5
    11.7 ± 9.9
    10.8 ± 9.1
    9.2 ± 9.5
    Attachments
    Untitled (Filename: FEV1 Value D14.pdf)
    Notes
    [105] - This is the actual number of patients on which the analysis was performed.
    [106] - This is the actual number of patients on which the analysis was performed.
    [107] - This is the actual number of patients on which the analysis was performed.
    [108] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: FEV1 percentage of predicted normal value at each time point post-dose on Day 42 and mean changes from Baseline

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    End point title
    FEV1 percentage of predicted normal value at each time point post-dose on Day 42 and mean changes from Baseline
    End point description
    Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done: 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11h and 30 min, 12h post-dose on Day 42. Only data about the change from baseline at the last timepoint (12h post-dose) of the Day 42 are reported in the database. For the data about the other timepoints on Day 42, please see the pdf attached.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [109]
    150 [110]
    154 [111]
    152 [112]
    Units: percentage
        arithmetic mean (standard deviation)
    4.5 ± 10.2
    4.5 ± 9.5
    4.3 ± 10.1
    3.4 ± 8.7
    Attachments
    Untitled (Filename: FEV1 changes D42.pdf)
    Untitled (Filename: FEV1 Value D42.pdf)
    Notes
    [109] - This is the actual number of patients on which the analysis was performed.
    [110] - This is the actual number of patients on which the analysis was performed.
    [111] - This is the actual number of patients on which the analysis was performed.
    [112] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: FEV1 at 2 hours post-dose on Day 14

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    End point title
    FEV1 at 2 hours post-dose on Day 14
    End point description
    Post dose FEV1 on Day 14 of each treatment period was recorded at 2h post-study drug intake.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    155 [113]
    155 [114]
    152 [115]
    Units: liters
        arithmetic mean (standard deviation)
    2.429 ± 0.744
    2.426 ± 0.782
    2.365 ± 0.739
    2.388 ± 0.704
    Notes
    [113] - This is the actual number of patients on which the analysis was performed.
    [114] - This is the actual number of patients on which the analysis was performed.
    [115] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Change from baseline in FEV1 2 Hours Post-Dose on Day 14

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    End point title
    Change from baseline in FEV1 2 Hours Post-Dose on Day 14
    End point description
    Baseline is the average of the pre-dose measurements FEV1 measurements that were recorded at 45 and 10 minutes prior to study intake. Post dose FEV1 on Day 14 of each treatment period was recorded at 2h post-study drug intake.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    155 [116]
    155 [117]
    152 [118]
    Units: liters
        arithmetic mean (standard deviation)
    0.362 ± 0.324
    0.364 ± 0.329
    0.335 ± 0.291
    0.298 ± 0.312
    Notes
    [116] - This is the actual number of patients on which the analysis was performed.
    [117] - This is the actual number of patients on which the analysis was performed.
    [118] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Average daily morning PEF

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    End point title
    Average daily morning PEF
    End point description
    E-peakflow meter/e-diary was completed at home on a daily basis morning and evening (daily download of the e-peakflow meter/e-diary). During the two wash-out periods, only the compliance to the wash-out medication was collected. During the run-in period and the three treatment periods, PEF (L/min) was monitored twice daily before the intake of the run-in medication or study medication. Morning measurements were done approximately between 7:00 am and 9:00 am and evening measurements approximately between 7:00 pm and 9:00 pm. An alarm reminded the patients to perform measurements. During each measurement session, the patient performed three blows and data were recorded in the device.
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    153 [119]
    155 [120]
    151 [121]
    Units: L/min
        arithmetic mean (standard deviation)
    342.16 ± 115
    339.41 ± 111.42
    337.26 ± 112.33
    339.89 ± 108.66
    Notes
    [119] - This is the actual number of patients on which the analysis was performed.
    [120] - This is the actual number of patients on which the analysis was performed.
    [121] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [122]
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    10.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.52
         upper limit
    14.63
    Notes
    [122] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [123]
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    11.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.6
         upper limit
    15.64
    Notes
    [123] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [124]
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    9.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.98
         upper limit
    14
    Notes
    [124] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [125]
    P-value
    = 0.649
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.47
         upper limit
    5.57
    Notes
    [125] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [126]
    P-value
    = 0.798
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.09
         upper limit
    3.92
    Notes
    [126] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority [127]
    P-value
    = 0.474
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -1.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.12
         upper limit
    2.85
    Notes
    [127] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.

    Secondary: Average daily evening PEF

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    End point title
    Average daily evening PEF
    End point description
    E-peakflow meter/e-diary was completed at home on a daily basis morning and evening (daily download of the e-peakflow meter/e-diary). During the two wash-out periods, only the compliance to the wash-out medication was collected. During the run-in period and the three treatment periods, PEF (L/min) was monitored twice daily before the intake of the run-in medication or study medication. Morning measurements were done approximately between 7:00 am and 9:00 am and evening measurements approximately between 7:00 pm and 9:00 pm. An alarm reminded the patients to perform measurements. During each measurement session, the patient performed three blows and data were recorded in the device.
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    153 [128]
    155 [129]
    152 [130]
    Units: L/min
        arithmetic mean (standard deviation)
    353.45 ± 113.91
    351.65 ± 111.36
    348.04 ± 112.66
    348.02 ± 105.52
    Notes
    [128] - This is the actual number of patients on which the analysis was performed.
    [129] - This is the actual number of patients on which the analysis was performed.
    [130] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [131]
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    11.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.41
         upper limit
    16.47
    Notes
    [131] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [132]
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    14.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.72
         upper limit
    18.72
    Notes
    [132] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [133]
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    11.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.44
         upper limit
    16.44
    Notes
    [133] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [134]
    P-value
    = 0.32
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    2.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.23
         upper limit
    6.8
    Notes
    [134] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [135]
    P-value
    = 0.999
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.49
         upper limit
    4.5
    Notes
    [135] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority [136]
    P-value
    = 0.317
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -2.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.76
         upper limit
    2.2
    Notes
    [136] - This secondary efficacy variable was analysed on the ITT population using an ANOVA (analysis of variance) model including treatment, period and patient as fixed effects.

    Secondary: Change from baseline in pre-dose FVC on Day 14

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    End point title
    Change from baseline in pre-dose FVC on Day 14
    End point description
    Pre-dose FVC was recorded on Day 14 at 45 minutes and 10 minutes prior to study drug intake.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    155 [137]
    155 [138]
    152 [139]
    Units: liters
        arithmetic mean (standard deviation)
    0.07 ± 0.337
    0.149 ± 0.372
    0.087 ± 0.318
    0.081 ± 0.282
    Notes
    [137] - This is the actual number of patients on which the analysis was performed.
    [138] - This is the actual number of patients on which the analysis was performed.
    [139] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [140]
    P-value
    = 0.645
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.044
         upper limit
    0.072
    Notes
    [140] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [141]
    P-value
    = 0.01
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.076
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.018
         upper limit
    0.133
    Notes
    [141] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [142]
    P-value
    = 0.508
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.019
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.038
         upper limit
    0.077
    Notes
    [142] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [143]
    P-value
    = 0.035
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.062
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    0.12
    Notes
    [143] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [144]
    P-value
    = 0.842
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.052
         upper limit
    0.063
    Notes
    [144] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=310 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    superiority [145]
    P-value
    = 0.054
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.113
         upper limit
    0.001
    Notes
    [145] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: Change from baseline in pre-dose FVC on Day 42

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    End point title
    Change from baseline in pre-dose FVC on Day 42
    End point description
    Pre-dose FVC was recorded on Day 42 at 45 minutes and 10 minutes prior to study drug intake.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    150 [146]
    153 [147]
    155 [148]
    152 [149]
    Units: liters
        arithmetic mean (standard deviation)
    0.05 ± 0.367
    0.109 ± 0.378
    0.083 ± 0.308
    0.051 ± 0.327
    Notes
    [146] - This is the actual number of patients on which the analysis was performed.
    [147] - This is the actual number of patients on which the analysis was performed.
    [148] - This is the actual number of patients on which the analysis was performed.
    [149] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    TReatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [150]
    P-value
    = 0.503
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.034
         upper limit
    0.068
    Notes
    [150] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and Baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [151]
    P-value
    = 0.046
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.052
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.102
    Notes
    [151] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [152]
    P-value
    = 0.118
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.091
    Notes
    [152] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [153]
    P-value
    = 0.188
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.017
         upper limit
    0.085
    Notes
    [153] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305(subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [154]
    P-value
    = 0.374
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.028
         upper limit
    0.074
    Notes
    [154] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority [155]
    P-value
    = 0.663
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.062
         upper limit
    0.039
    Notes
    [155] - This secondary efficacy variable was analysed on the ITT population using ANCOVA model including treatment, period and patient as fixed effects and baseline values as covariates.

    Secondary: Change from baseline in peak FVC on Day 1

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    End point title
    Change from baseline in peak FVC on Day 1
    End point description
    The peak FVC is the maximum FVC value obtained between 15 minutes and 12 hours post-dose. Post-dose FVC on Day 1 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FVC pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).
    End point type
    Secondary
    End point timeframe
    On Day 1.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    150 [156]
    153 [157]
    156 [158]
    153
    Units: liters
        arithmetic mean (standard deviation)
    0.435 ± 0.363
    0.433 ± 0.334
    0.421 ± 0.311
    0.388 ± 0.258
    Notes
    [156] - This is the actual number of patients on which the analysis was performed.
    [157] - This is the actual number of patients on which the analysis was performed.
    [158] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [159]
    P-value
    = 0.085
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.079
    Notes
    [159] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [160]
    P-value
    = 0.502
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.028
         upper limit
    0.056
    Notes
    [160] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [161]
    P-value
    = 0.16
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.012
         upper limit
    0.072
    Notes
    [161] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment B vs treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [162]
    P-value
    = 0.285
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.065
         upper limit
    0.019
    Notes
    [162] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [163]
    P-value
    = 0.735
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.049
         upper limit
    0.035
    Notes
    [163] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [164]
    P-value
    = 0.46
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.026
         upper limit
    0.057
    Notes
    [164] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.

    Secondary: Change from baseline in peak FVC on Day 42

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    End point title
    Change from baseline in peak FVC on Day 42
    End point description
    The peak FVC is the maximum FVC value obtained between 15 minutes and 12 hours post-dose. Post-dose FVC on Day 1 of each treatment period was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FVC pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).
    End point type
    Secondary
    End point timeframe
    On Day 42.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [165]
    152 [166]
    153 [167]
    152 [168]
    Units: liters
        arithmetic mean (standard deviation)
    0.395 ± 0.379
    0.456 ± 0.422
    0.423 ± 0.417
    0.373 ± 0.35
    Notes
    [165] - This is the actual number of patients on which the analysis was performed.
    [166] - This is the actual number of patients on which the analysis was performed.
    [167] - This is the actual number of patients on which the analysis was performed.
    [168] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [169]
    P-value
    = 0.4
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.026
         upper limit
    0.066
    Notes
    [169] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [170]
    P-value
    = 0.043
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.092
    Notes
    [170] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [171]
    P-value
    = 0.029
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.005
         upper limit
    0.097
    Notes
    [171] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=301 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    superiority [172]
    P-value
    = 0.245
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.027
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.019
         upper limit
    0.073
    Notes
    [172] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [173]
    P-value
    = 0.179
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.031
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.014
         upper limit
    0.077
    Notes
    [173] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [174]
    P-value
    = 0.859
    Method
    ANCOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.041
         upper limit
    0.05
    Notes
    [174] - The peak FVC was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FVC (average of 45 and 10 minutes pre-dose FVC at Day 1) as covariate.

    Secondary: Change from baseline in FVC at each time point post-dose on Day 1

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    End point title
    Change from baseline in FVC at each time point post-dose on Day 1
    End point description
    The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake on Day 1. Only change from baseline at the last timepoint (12h post-dose) on Day 1 is reported in the system. For the data on the other timepoints on the same day see pdf attached.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    150 [175]
    153 [176]
    156 [177]
    149 [178]
    Units: liters
        arithmetic mean (standard deviation)
    0.098 ± 0.312
    0.086 ± 0.348
    0.098 ± 0.3
    0.075 ± 0.321
    Attachments
    Untitled (Filename: FVC Change D1.pdf)
    Notes
    [175] - This is the actual number of patients on which the analysis was performed.
    [176] - This is the actual number of patients on which the analysis was performed.
    [177] - This is the actual number of patients on which the analysis was performed.
    [178] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Change from baseline in FVC at 2h post-dose on Day 14

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    End point title
    Change from baseline in FVC at 2h post-dose on Day 14
    End point description
    The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 2h on Day 14.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    155 [179]
    155 [180]
    152 [181]
    Units: liters
        arithmetic mean (standard deviation)
    0.278 ± 0.367
    0.318 ± 0.407
    0.254 ± 0.309
    0.225 ± 0.308
    Attachments
    Untitled (Filename: FVC Change D14.pdf)
    Notes
    [179] - This is the actual number of patients on which the analysis was performed.
    [180] - This is the actual number of patients on which the analysis was performed.
    [181] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Change from baseline in FVC at each time point post-dose on Day 42

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    End point title
    Change from baseline in FVC at each time point post-dose on Day 42
    End point description
    The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 15’; 30’; 45’; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake on Day 42. Only change from baseline at the last timepoint (12h post-dose) on Day 42 is reported in the system. For the data on the other timepoints on the same day, please see the pdf attached.
    End point type
    Secondary
    End point timeframe
    On Day 42.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    149 [182]
    150 [183]
    154 [184]
    152 [185]
    Units: liters
        arithmetic mean (standard deviation)
    0.069 ± 0.399
    0.088 ± 0.395
    0.118 ± 0.421
    0.034 ± 0.347
    Attachments
    Untitled (Filename: FVC Change D42.pdf)
    Notes
    [182] - This is the actual number of patients on which the analysis was performed.
    [183] - This is the actual number of patients on which the analysis was performed.
    [184] - This is the actual number of patients on which the analysis was performed.
    [185] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Average total daily asthma symptoms, night-time

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    End point title
    Average total daily asthma symptoms, night-time
    End point description
    The average of daily asthma symptoms (morning/ evening) of a subgroup (Cough, Wheeze, Chest Tightness, Breathlessness) is the mean value of all morning/ evening measurements of that subgroup. Results on the average total daily asthma symptoms score (night-time) during the treatment period are presented for the ITT population.
    End point type
    Secondary
    End point timeframe
    At visit 1 (Screening Visit) and at the first and third visit of each tratment period.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    154 [186]
    155 [187]
    151 [188]
    Units: score
        arithmetic mean (standard deviation)
    2.111 ± 2.145
    1.998 ± 1.896
    2.181 ± 2.082
    1.974 ± 1.943
    Notes
    [186] - This is the actual number of patients on which the analysis was performed.
    [187] - This is the actual number of patients on which the analysis was performed.
    [188] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [189]
    P-value
    = 0.77
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.173
         upper limit
    0.128
    Notes
    [189] - This secondary efficacy variables were analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [190]
    P-value
    = 0.682
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.031
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.181
         upper limit
    0.118
    Notes
    [190] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [191]
    P-value
    = 0.85
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.164
         upper limit
    0.135
    Notes
    [191] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [192]
    P-value
    = 0.909
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.158
         upper limit
    0.141
    Notes
    [192] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [193]
    P-value
    = 0.915
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.141
         upper limit
    0.157
    Notes
    [193] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [194]
    P-value
    = 0.825
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.132
         upper limit
    0.165
    Notes
    [194] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.

    Secondary: Average total daily asthma symptoms, day-time

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    End point title
    Average total daily asthma symptoms, day-time
    End point description
    The average of daily asthma symptoms (morning/ evening) of a subgroup (Cough, Wheeze, Chest Tightness, Breathlessness) is the mean value of all morning/ evening measurements of that subgroup. Results on the average total daily asthma symptoms score (day-time) during the treatment period are presented for the ITT population.
    End point type
    Secondary
    End point timeframe
    At visit 1 (Screening Visit) and at the first and third visit of each tratment period.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    153 [195]
    155 [196]
    152 [197]
    Units: score
        arithmetic mean (standard deviation)
    2.384 ± 2.056
    2.3 ± 1.905
    2.472 ± 2.098
    2.215 ± 1.908
    Notes
    [195] - This is the actual number of patients on which the analysis was performed.
    [196] - This is the actual number of patients on which the analysis was performed.
    [197] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [198]
    P-value
    = 0.917
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.165
         upper limit
    0.148
    Notes
    [198] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [199]
    P-value
    = 0.792
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.134
         upper limit
    0.176
    Notes
    [199] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [200]
    P-value
    = 0.656
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    0.19
    Notes
    [200] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [201]
    P-value
    = 0.713
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.127
         upper limit
    0.185
    Notes
    [201] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [202]
    P-value
    = 0.582
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.043
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.112
         upper limit
    0.199
    Notes
    [202] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority [203]
    P-value
    = 0.855
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    0.169
    Notes
    [203] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.

    Secondary: Percentage of asthma control days

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    End point title
    Percentage of asthma control days
    End point description
    The percentage is calculated as the number of asthma control days / number of days with available data.
    End point type
    Secondary
    End point timeframe
    Measured between the first and the third visit of each treatment period.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    154 [204]
    155 [205]
    152 [206]
    Units: percent
        arithmetic mean (standard deviation)
    25.7 ± 33.1
    27.3 ± 34.5
    25.1 ± 34.1
    26.6 ± 34.2
    Notes
    [204] - This is the actual number of patients on which the analysis was performed.
    [205] - This is the actual number of patients on which the analysis was performed.
    [206] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [207]
    P-value
    = 0.481
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    4.8
    Notes
    [207] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [208]
    P-value
    = 0.484
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    4.8
    Notes
    [208] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [209]
    P-value
    = 0.562
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    4.6
    Notes
    [209] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [210]
    P-value
    = 0.99
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    3.5
    Notes
    [210] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [211]
    P-value
    = 0.896
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    3.3
    Notes
    [211] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [212]
    P-value
    = 0.906
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    3.3
    Notes
    [212] - This secondary efficacy variable was analysed on the ITT population using an analysis of variance (ANOVA) model including treatment, period and patient as fixed effects.

    Secondary: Average use of rescue medication (number of puffs/day)

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    End point title
    Average use of rescue medication (number of puffs/day)
    End point description
    The average use of rescue medication (number of puffs per day) is determined as the total number of puffs of rescue mediation taken / number of days with available data.
    End point type
    Secondary
    End point timeframe
    Daily during run-in/wash-out & treatment periods.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    154 [213]
    155 [214]
    152 [215]
    Units: number of puffs/ day
        arithmetic mean (standard deviation)
    0.9 ± 1.3
    0.8 ± 1.3
    0.9 ± 1.5
    0.8 ± 1.5
    Notes
    [213] - This is the actual number of patients on which the analysis was performed.
    [214] - This is the actual number of patients on which the analysis was performed.
    [215] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [216]
    P-value
    = 0.55
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [216] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment D - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [217]
    P-value
    = 0.883
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [217] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment D - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [218]
    P-value
    = 0.325
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [218] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [219]
    P-value
    = 0.649
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [219] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [220]
    P-value
    = 0.701
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [220] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [221]
    P-value
    = 0.4
    Method
    ANOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [221] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.

    Secondary: Average use of rescue medication (number of times/day)

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    End point title
    Average use of rescue medication (number of times/day)
    End point description
    The average use of rescue medication (number of times per day) is determined as the total number of times of rescue medication taken/ number of days with available data.
    End point type
    Secondary
    End point timeframe
    Daily during run-in/wash-out & treatment periods.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    152
    154 [222]
    155 [223]
    152 [224]
    Units: number of times/ day
        arithmetic mean (standard deviation)
    0.7 ± 1
    0.6 ± 0.9
    0.6 ± 1
    0.6 ± 0.9
    Notes
    [222] - This is the actual number of patients on which the analysis was performed.
    [223] - This is the actual number of patients on which the analysis was performed.
    [224] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=304 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    superiority [225]
    P-value
    = 0.95
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [225] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment D - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [226]
    P-value
    = 0.744
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [226] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment D - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [227]
    P-value
    = 0.629
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [227] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=306 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority [228]
    P-value
    = 0.793
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [228] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [229]
    P-value
    = 0.674
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [229] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=309 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    superiority [230]
    P-value
    = 0.875
    Method
    ANOVA
    Parameter type
    adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [230] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects, without multiplicity adjustments.

    Secondary: Change from baseline in ACQ total score on Day 42

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    End point title
    Change from baseline in ACQ total score on Day 42
    End point description
    Baseline is the calculated Asthma Control Questionnaire (ACQ) score of Day 1 of the respective treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 42.
    End point values
    Treatment A - ITT population Treatment B - ITT population Treatment C - ITT population Treatment D - ITT population
    Number of subjects analysed
    150 [231]
    153 [232]
    155 [233]
    152 [234]
    Units: score
        arithmetic mean (standard deviation)
    -0.126 ± 0.599
    -0.246 ± 0.689
    -0.207 ± 0.676
    -0.193 ± 0.552
    Notes
    [231] - This is the actual number of patients on which the analysis was performed.
    [232] - This is the actual number of patients on which the analysis was performed.
    [233] - This is the actual number of patients on which the analysis was performed.
    [234] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    Treatment A vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=302 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment D - ITT population
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    superiority [235]
    P-value
    = 0.835
    Method
    ANCOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.116
         upper limit
    0.093
    Notes
    [235] - The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done.
    Statistical analysis title
    Treatment B vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment D - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [236]
    P-value
    = 0.583
    Method
    ANCOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.132
         upper limit
    0.074
    Notes
    [236] - The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done.
    Statistical analysis title
    Treatment C vs Treatment D
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=307 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment D - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    superiority [237]
    P-value
    = 0.727
    Method
    ANCOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.122
         upper limit
    0.085
    Notes
    [237] - The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done.
    Statistical analysis title
    Treatment B vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=303 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment B - ITT population v Treatment A - ITT population
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [238]
    P-value
    = 0.737
    Method
    ANCOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.122
         upper limit
    0.086
    Notes
    [238] - The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done.
    Statistical analysis title
    Treatment C vs Treatment A
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=305 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment A - ITT population v Treatment C - ITT population
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    superiority [239]
    P-value
    = 0.89
    Method
    ANCOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.111
         upper limit
    0.086
    Notes
    [239] - The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done.
    Statistical analysis title
    Treatment C vs Treatment B
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=308 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Treatment C - ITT population v Treatment B - ITT population
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority [240]
    P-value
    = 0.841
    Method
    ANCOVA
    Parameter type
    Adjusted mean difference
    Point estimate
    0.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.093
         upper limit
    0.114
    Notes
    [240] - The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as covariate. No multiplicity adjustments are done.

    Secondary: SBP change from baseline on Day 14

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    End point title
    SBP change from baseline on Day 14
    End point description
    Baseline is the pre-dose measurement on Day 1 in each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    152
    155 [241]
    155 [242]
    152 [243]
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.7 ± 11.4
    1.9 ± 9.9
    -0.7 ± 9.5
    -0.7 ± 10.2
    Notes
    [241] - This is the actual number of patients on which the analysis was performed.
    [242] - This is the actual number of patients on which the analysis was performed.
    [243] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: HR change from baseline post-dose on Day 1

    Close Top of page
    End point title
    HR change from baseline post-dose on Day 1
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    146 [244]
    153 [245]
    156 [246]
    151 [247]
    Units: bpm
        arithmetic mean (standard deviation)
    -1 ± 6
    -2.1 ± 5.3
    -1.9 ± 6.6
    -1.6 ± 5.3
    Notes
    [244] - This is the actual number of patients on which the analysis was performed.
    [245] - This is the actual number of patients on which the analysis was performed.
    [246] - This is the actual number of patients on which the analysis was performed.
    [247] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: PR change from baseline post-dose on Day 1

    Close Top of page
    End point title
    PR change from baseline post-dose on Day 1
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    146 [248]
    153 [249]
    156 [250]
    151 [251]
    Units: ms
        arithmetic mean (standard deviation)
    -1.2 ± 7.3
    -0.5 ± 8.2
    -0.1 ± 9.4
    0.3 ± 7.4
    Notes
    [248] - This is the actual number of patients on which the analysis was performed.
    [249] - This is the actual number of patients on which the analysis was performed.
    [250] - This is the actual number of patients on which the analysis was performed.
    [251] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QRS change from baseline post-dose on Day 1

    Close Top of page
    End point title
    QRS change from baseline post-dose on Day 1
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    146 [252]
    153 [253]
    156 [254]
    151 [255]
    Units: ms
        arithmetic mean (standard deviation)
    0.7 ± 4.1
    0.7 ± 5.2
    -0.5 ± 4.3
    0.5 ± 4.5
    Notes
    [252] - This is the actual number of patients on which the analysis was performed.
    [253] - This is the actual number of patients on which the analysis was performed.
    [254] - This is the actual number of patients on which the analysis was performed.
    [255] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QTcF change from baseline post-dose on Day 1

    Close Top of page
    End point title
    QTcF change from baseline post-dose on Day 1
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    146 [256]
    153 [257]
    156 [258]
    151 [259]
    Units: ms
        arithmetic mean (standard deviation)
    3.1 ± 9.4
    1.3 ± 8.9
    1.3 ± 9.8
    2.1 ± 8.3
    Notes
    [256] - This is the actual number of patients on which the analysis was performed.
    [257] - This is the actual number of patients on which the analysis was performed.
    [258] - This is the actual number of patients on which the analysis was performed.
    [259] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: SBP change from baseline on Day 42

    Close Top of page
    End point title
    SBP change from baseline on Day 42
    End point description
    Baseline is the pre-dose measurement on Day 1 in each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    150 [260]
    153 [261]
    155 [262]
    152 [263]
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.5 ± 11.2
    2.4 ± 10.3
    1.3 ± 10.2
    -1.5 ± 9.6
    Notes
    [260] - This is the actual number of patients on which the analysis was performed.
    [261] - This is the actual number of patients on which the analysis was performed.
    [262] - This is the actual number of patients on which the analysis was performed.
    [263] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: DBP change from baseline on Day 14

    Close Top of page
    End point title
    DBP change from baseline on Day 14
    End point description
    Baseline is the pre-dose measurement on Day 1 in each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    152 [264]
    155 [265]
    155 [266]
    152 [267]
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.3 ± 7.4
    1.4 ± 6.6
    0.3 ± 7.7
    -0.1 ± 8.5
    Notes
    [264] - This is the actual number of patients on which the analysis was performed.
    [265] - This is the actual number of patients on which the analysis was performed.
    [266] - This is the actual number of patients on which the analysis was performed.
    [267] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: DBP change from baseline on Day 42

    Close Top of page
    End point title
    DBP change from baseline on Day 42
    End point description
    Baseline is the pre-dose measurement on Day 1 in each treatment period.
    End point type
    Secondary
    End point timeframe
    On day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    150 [268]
    153 [269]
    155 [270]
    152 [271]
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.4 ± 6.6
    1.2 ± 7.3
    0.1 ± 7.8
    -0.6 ± 7.5
    Notes
    [268] - This is the actual number of patients on which the analysis was performed.
    [269] - This is the actual number of patients on which the analysis was performed.
    [270] - This is the actual number of patients on which the analysis was performed.
    [271] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QTcF change from baseline pre-dose on Day 42

    Close Top of page
    End point title
    QTcF change from baseline pre-dose on Day 42
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    145 [272]
    151 [273]
    153 [274]
    150 [275]
    Units: ms
        arithmetic mean (standard deviation)
    -0.3 ± 11.9
    -2.3 ± 13.9
    -2.1 ± 12.3
    0.9 ± 11.9
    Notes
    [272] - This is the actual number of patients on which the analysis was performed.
    [273] - This is the actual number of patients on which the analysis was performed.
    [274] - This is the actual number of patients on which the analysis was performed.
    [275] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QTcF change from baseline post-dose on Day 42

    Close Top of page
    End point title
    QTcF change from baseline post-dose on Day 42
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    145 [276]
    151 [277]
    151 [278]
    150 [279]
    Units: ms
        arithmetic mean (standard deviation)
    1.6 ± 12.2
    1.2 ± 13.4
    1.1 ± 11.6
    2.9 ± 12.8
    Notes
    [276] - This is the actual number of patients on which the analysis was performed.
    [277] - This is the actual number of patients on which the analysis was performed.
    [278] - This is the actual number of patients on which the analysis was performed.
    [279] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: HR change from baseline pre-dose on Day 42

    Close Top of page
    End point title
    HR change from baseline pre-dose on Day 42
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    145 [280]
    151 [281]
    153 [282]
    150 [283]
    Units: bpm
        arithmetic mean (standard deviation)
    -0.8 ± 7.5
    -0.4 ± 9
    0.3 ± 8.7
    -0.1 ± 8
    Notes
    [280] - This is the actual number of patients on which the analysis was performed.
    [281] - This is the actual number of patients on which the analysis was performed.
    [282] - This is the actual number of patients on which the analysis was performed.
    [283] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: HR change from baseline post-dose on Day 42

    Close Top of page
    End point title
    HR change from baseline post-dose on Day 42
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    145 [284]
    151 [285]
    151 [286]
    150 [287]
    Units: bpm
        arithmetic mean (standard deviation)
    -1.9 ± 7.6
    -1.8 ± 8.7
    -1.5 ± 9.2
    -2.2 ± 8.4
    Notes
    [284] - This is the actual number of patients on which the analysis was performed.
    [285] - This is the actual number of patients on which the analysis was performed.
    [286] - This is the actual number of patients on which the analysis was performed.
    [287] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: PR change from baseline pre-dose on Day 42

    Close Top of page
    End point title
    PR change from baseline pre-dose on Day 42
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    145 [288]
    151 [289]
    153 [290]
    150 [291]
    Units: ms
        arithmetic mean (standard deviation)
    -0.9 ± 10.1
    -1.4 ± 11.8
    -1.5 ± 12.6
    0.5 ± 10.1
    Notes
    [288] - This is the actual number of patients on which the analysis was performed.
    [289] - This is the actual number of patients on which the analysis was performed.
    [290] - This is the actual number of patients on which the analysis was performed.
    [291] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: PR change from baseline post-dose on Day 42

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    End point title
    PR change from baseline post-dose on Day 42
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    145 [292]
    151 [293]
    151 [294]
    150 [295]
    Units: ms
        arithmetic mean (standard deviation)
    -1.3 ± 9.8
    -1.4 ± 11.4
    -0.8 ± 14
    -0.1 ± 10.4
    Notes
    [292] - This is the actual number of patients on which the analysis was performed.
    [293] - This is the actual number of patients on which the analysis was performed.
    [294] - This is the actual number of patients on which the analysis was performed.
    [295] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QRS change from baseline pre-dose on Day 42

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    End point title
    QRS change from baseline pre-dose on Day 42
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    145 [296]
    151 [297]
    153 [298]
    150 [299]
    Units: ms
        arithmetic mean (standard deviation)
    0.7 ± 6.3
    -0.7 ± 5.4
    -0.9 ± 6.1
    0.8 ± 6.2
    Notes
    [296] - This is the actual number of patients on which the analysis was performed.
    [297] - This is the actual number of patients on which the analysis was performed.
    [298] - This is the actual number of patients on which the analysis was performed.
    [299] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QRS change from baseline post-dose on Day 42

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    End point title
    QRS change from baseline post-dose on Day 42
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker are excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm are also excluded.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Number of subjects analysed
    145 [300]
    151 [301]
    151 [302]
    150 [303]
    Units: ms
        arithmetic mean (standard deviation)
    0.7 ± 6.1
    0.8 ± 5.4
    -0.5 ± 5.6
    0.7 ± 6.6
    Notes
    [300] - This is the actual number of patients on which the analysis was performed.
    [301] - This is the actual number of patients on which the analysis was performed.
    [302] - This is the actual number of patients on which the analysis was performed.
    [303] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At each visit from Visit 1 (Screening) to Visit 10 and, afterwards, to follow-up.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Treatment A - safety population
    Reporting group description
    -

    Reporting group title
    Treatment B - safety population
    Reporting group description
    -

    Reporting group title
    Treatment C - safety population
    Reporting group description
    -

    Reporting group title
    Treatment D - safety population
    Reporting group description
    -

    Serious adverse events
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 156 (0.64%)
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 156 (0.00%)
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery stenosis
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 156 (0.64%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 156 (0.00%)
    0 / 157 (0.00%)
    0 / 153 (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
    Frequency threshold for reporting non-serious adverse events: 1%
    <
    Non-serious adverse events
    Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 152 (13.16%)
    19 / 156 (12.18%)
    13 / 157 (8.28%)
    14 / 153 (9.15%)
    Vascular disorders
    Essential hypertension
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 156 (0.64%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 156 (0.00%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 152 (1.32%)
    0 / 156 (0.00%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 156 (0.64%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Breast tenderness
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 156 (0.00%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 156 (0.00%)
    0 / 157 (0.00%)
    1 / 153 (0.65%)
         occurrences all number
    0
    0
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 156 (0.00%)
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Soft tissue injury
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 156 (0.00%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sunburn
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 156 (0.00%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 152 (0.66%)
    1 / 156 (0.64%)
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 152 (0.00%)
    0 / 156 (0.00%)
    1 / 157 (0.64%)
    0 / 153 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 156 (0.00%)
    0 / 157 (0.00%)
    0 / 153 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myocardial ischaemia
         subjects affected / exposed