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    Clinical Trial Results:
    A phase II, multicentre, double blind, randomised, 5-way cross-over study to test the non-inferiority of the acute bronchodilator effect of CHF 1535 200/6 µg NEXThaler® versus CHF 1535 100/6 µg NEXThaler® in partially controlled and uncontrolled adult asthmatic patients.

    Summary
    EudraCT number
    		 2013-004826-27
    Trial protocol
    		 GB  
    Global end of trial date
    14 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2016
    First version publication date
    09 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-01535BA1-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02000609
    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 Manager, Chiesi Farmaceutici S.p.A., clinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency Manager, Chiesi Farmaceutici S.p.A., clinicalTrials_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
    14 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority in terms of acute bronchodilator effect (FEV1 AUC0-12h) between a single dose of CHF 1535 NEXThaler® 200 + 6 µg and a single dose of CHF 1535 NEXThaler® 100 + 6 µg at two dose levels (1 and 4 inhalations) in partially-controlled and uncontrolled adult asthmatic patients.
    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
    		 BDP HFA 100 µg (QVAR), 2 inhalations bid (total daily dose BDP 400 µg)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 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: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    60
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Sixty subjects were randomised to one of the 5 treatment sequences and received study drugs: A-B-C-D-E (N=11), B-C-D-E-A (N=11), C-D-E-A-B (N=14), D-E-A-B-C (N=13) and E-A-B-C-D (N=11). Fifty eight (96.7%) subjects completed the study. Two (3.3%) subjects discontinued the study prematurely; 1 (1.7%) subject withdrew consent after randomisation.

    Pre-assignment
    Screening details
    		 In total, 208 subjects were screened. One hundred forty-eight subjects were not randomised (i.e., screening failures), of whom 140 subjects were not eligible to enter the study, 3 subjects withdrew consent before randomisation, 1 subject was lost to follow-up and 4 subjects were not randomized for other reasons.

    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, Assessor
    Blinding implementation details
    This was a double-blind study. The randomisation list was provided to the labelling facility but was not be available to the subjects, Investigators, monitors or employees of the centre involved in the management of the study before unblinding of the data, unless in case of emergency. The Sponsor’s clinical team was also blinded during the study as they did not have direct access to the randomisation list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence A-B-C-D-E
    Arm description
    		 Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®.
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF1535 DPI (BDP 100 μ + FF 6 μ) - CHF1535 DPI (BDP 200 μ + FF 6 μ) - CHF1535 DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test treatments: CHF 1535 inhalation powder (fixed combination of BDP 200 μg plus FF 6 μg per actuation) administered via the NEXThaler® dry powder inhaler (DPI) at two dose levels. • Treatment B: 1 inhalation (total dose BDP 200 μg / FF 6 μg); • Treatment D: 4 inhalations (total dose BDP 800 μg / FF 24 μg). Reference treatments: • Treatment A: 1 inhalation (total dose BDP 100 μg / FF 6 μg); • Treatment C: 4 inhalations (total dose BDP 400 μg / FF 24 μg). • Treatment E: placebo.

    Arm title
    		 Sequence B-C-D-E-A
    Arm description
    		 • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®;
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF1535 DPI (BDP 100 μ + FF 6 μ) - CHF1535 DPI (BDP 200 μ + FF 6 μ) - CHF1535 DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test treatments: CHF 1535 inhalation powder (fixed combination of BDP 200 μg plus FF 6 μg per actuation) administered via the NEXThaler® dry powder inhaler (DPI) at two dose levels. • Treatment B: 1 inhalation (total dose BDP 200 μg / FF 6 μg); • Treatment D: 4 inhalations (total dose BDP 800 μg / FF 24 μg). Reference treatments: • Treatment A: 1 inhalation (total dose BDP 100 μg / FF 6 μg); • Treatment C: 4 inhalations (total dose BDP 400 μg / FF 24 μg). • Treatment E: placebo.

    Arm title
    		 Sequence C-D-E-A-B
    Arm description
    		 • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®;
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF1535 DPI (BDP 100 μ + FF 6 μ) - CHF1535 DPI (BDP 200 μ + FF 6 μ) - CHF1535 DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test treatments: CHF 1535 inhalation powder (fixed combination of BDP 200 μg plus FF 6 μg per actuation) administered via the NEXThaler® dry powder inhaler (DPI) at two dose levels. • Treatment B: 1 inhalation (total dose BDP 200 μg / FF 6 μg); • Treatment D: 4 inhalations (total dose BDP 800 μg / FF 24 μg). Reference treatments: • Treatment A: 1 inhalation (total dose BDP 100 μg / FF 6 μg); • Treatment C: 4 inhalations (total dose BDP 400 μg / FF 24 μg). • Treatment E: placebo.

    Arm title
    		 Sequence D-E-A-B-C
    Arm description
    		 • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®;
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF1535 DPI (BDP 100 μ + FF 6 μ) - CHF1535 DPI (BDP 200 μ + FF 6 μ) - CHF1535 DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test treatments: CHF 1535 inhalation powder (fixed combination of BDP 200 μg plus FF 6 μg per actuation) administered via the NEXThaler® dry powder inhaler (DPI) at two dose levels. • Treatment B: 1 inhalation (total dose BDP 200 μg / FF 6 μg); • Treatment D: 4 inhalations (total dose BDP 800 μg / FF 24 μg). Reference treatments: • Treatment A: 1 inhalation (total dose BDP 100 μg / FF 6 μg); • Treatment C: 4 inhalations (total dose BDP 400 μg / FF 24 μg). • Treatment E: placebo.

    Arm title
    		 Sequence E-A-B-C-D
    Arm description
    		 • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®;
    Arm type
    		 experimental - active comparator - placebo

    Investigational medicinal product name
    CHF1535 DPI (BDP 100 μ + FF 6 μ) - CHF1535 DPI (BDP 200 μ + FF 6 μ) - CHF1535 DPI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test treatments: CHF 1535 inhalation powder (fixed combination of BDP 200 μg plus FF 6 μg per actuation) administered via the NEXThaler® dry powder inhaler (DPI) at two dose levels. • Treatment B: 1 inhalation (total dose BDP 200 μg / FF 6 μg); • Treatment D: 4 inhalations (total dose BDP 800 μg / FF 24 μg). Reference treatments: • Treatment A: 1 inhalation (total dose BDP 100 μg / FF 6 μg); • Treatment C: 4 inhalations (total dose BDP 400 μg / FF 24 μg). • Treatment E: placebo.

    Number of subjects in period 1
    		Sequence A-B-C-D-E Sequence B-C-D-E-A Sequence C-D-E-A-B Sequence D-E-A-B-C Sequence E-A-B-C-D
    Started
    11
    11
    14
    13
    11
    Completed
    10
    11
    14
    12
    11
    Not completed
    1
    0
    0
    1
    0
         personal issues
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A-B-C-D-E
    Reporting group description
    		 Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®.

    Reporting group title
    Sequence B-C-D-E-A
    Reporting group description
    		 • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®;

    Reporting group title
    Sequence C-D-E-A-B
    Reporting group description
    		 • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®;

    Reporting group title
    Sequence D-E-A-B-C
    Reporting group description
    		 • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®;

    Reporting group title
    Sequence E-A-B-C-D
    Reporting group description
    		 • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®;

    Reporting group values
    		 Sequence A-B-C-D-E Sequence B-C-D-E-A Sequence C-D-E-A-B Sequence D-E-A-B-C Sequence E-A-B-C-D Total
    Number of subjects
    		 11 11 14 13 11 60
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.4 ( 14.5 ) 36.2 ( 9.6 ) 35.8 ( 13.9 ) 35 ( 9.2 ) 40.9 ( 11 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 5 7 7 5 28
        Male
    		 7 6 7 6 6 32
    Subject analysis sets

    Subject analysis set title
    Treatment A - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment B - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment C - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment D - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment E - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment A - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment B - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment C - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment D - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment E - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment A - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis set title
    Treatment B - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis set title
    Treatment C - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis set title
    Treatment D - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis set title
    Treatment E - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis sets values
    		 Treatment A - ITT Treatment B - ITT Treatment C - ITT Treatment D - ITT Treatment E - ITT Treatment A - PP Treatment B - PP Treatment C - PP Treatment D - PP Treatment E - PP Treatment A - safety Treatment B - safety Treatment C - safety Treatment D - safety Treatment E - safety
    Number of subjects
    60
    58
    58
    59
    59
    60
    57
    58
    59
    59
    60
    58
    58
    59
    59
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    28
    27
    27
    28
    28
    28
    26
    27
    28
    28
    28
    27
    27
    28
    28
        Male
    32
    31
    31
    31
    31
    32
    31
    31
    31
    31
    32
    31
    31
    31
    31

    End points

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    End points reporting groups
    Reporting group title
    Sequence A-B-C-D-E
    Reporting group description
    		 Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®.

    Reporting group title
    Sequence B-C-D-E-A
    Reporting group description
    		 • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®;

    Reporting group title
    Sequence C-D-E-A-B
    Reporting group description
    		 • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®;

    Reporting group title
    Sequence D-E-A-B-C
    Reporting group description
    		 • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®; • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®;

    Reporting group title
    Sequence E-A-B-C-D
    Reporting group description
    		 • Treatment E: placebo NEXThaler®, 1 inhalation plus placebo NEXThaler®, 3 inhalations, further referred to as placebo NEXThaler®. • Treatment A: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 100 μg / FF 6 μg) further referred to as BDP/FF 100/6 μg NEXThaler®; • Treatment B: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus placebo CHF 1535 NEXThaler®, 3 inhalations (total dose: BDP 200 μg / FF 6 μg) further referred to as BDP/FF 200/6 μg NEXThaler®; • Treatment C: CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 100 μg / FF 6 μg, 3 inhalations (total dose: BDP 400 μg / FF 24 μg) further referred to as BDP/FF 400/24 μg NEXThaler®; • Treatment D: CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 1 inhalation plus CHF 1535 NEXThaler® BDP 200 μg / FF 6 μg, 3 inhalations (total dose: BDP 800 μg / FF 24 μg) further referred to as BDP/FF 800/24 μg NEXThaler®;

    Subject analysis set title
    Treatment A - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment B - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment C - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment D - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment E - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of the study drug and who had at least one available evaluation of efficacy after randomisation.

    Subject analysis set title
    Treatment A - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment B - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment C - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment D - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment E - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects from the ITT population without any major protocol violations (i.e., wrong inclusions, poor compliance, non-permitted medications). Since a cross-over design was used, the exclusion from the PP-population was defined on a per-period basis.

    Subject analysis set title
    Treatment A - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis set title
    Treatment B - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis set title
    Treatment C - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis set title
    Treatment D - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Subject analysis set title
    Treatment E - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised subjects who received at least one dose of study drug.

    Primary: FEV1 AUC0-12h/12h

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    End point title
    		 FEV1 AUC0-12h/12h
    End point description
    FEV1 AUC0-12h was measured standardised by time (L)
    End point type
    Primary
    End point timeframe
    FEV1 was measured from visit 3 to visit 7, at the following timepoints: at pre-dose within 60 min of the dose and at 10 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h and 12 h post-dose.
    End point values
    		 Treatment A - PP Treatment B - PP Treatment C - PP Treatment D - PP Treatment E - PP
    Number of subjects analysed
    60
    57
    58
    59
    59
    Units: Liters
        arithmetic mean (confidence interval 95%)
    2.754 (2.722 to 2.786)
    2.783 (2.749 to 2.818)
    2.87 (2.837 to 2.903)
    2.897 (2.863 to 2.93)
    2.477 (2.444 to 2.51)
    Statistical analysis title
    		 Treatment B vs Treatment A
    Comparison groups
    Treatment A - PP v Treatment B - PP
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.224
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.018
         upper limit
    		 0.076
    Statistical analysis title
    		 Treatment D vs Treatment C
    Comparison groups
    Treatment D - PP v Treatment C - PP
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.258
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.073
    Statistical analysis title
    		 Treatment D vs Treatment E
    Comparison groups
    Treatment E - PP v Treatment D - PP
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.374
         upper limit
    		 0.466
    Notes
    [1] - Assay sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment E
    Comparison groups
    Treatment C - PP v Treatment E - PP
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.393
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.347
         upper limit
    		 0.439
    Notes
    [2] - Assy sensitivity analysis
    Statistical analysis title
    		 Treatment B vs Treatment E
    Comparison groups
    Treatment B - PP v Treatment E - PP
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.306
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.259
         upper limit
    		 0.354
    Notes
    [3] - Assay sensitivity analysis
    Statistical analysis title
    		 Treatment A vs Treatment E
    Comparison groups
    Treatment A - PP v Treatment E - PP
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.277
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.231
         upper limit
    		 0.324
    Notes
    [4] - Assay sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment A
    Comparison groups
    Treatment A - PP v Treatment C - PP
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.116
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.069
         upper limit
    		 0.162
    Notes
    [5] - dose-effect analysis
    Statistical analysis title
    		 Treatment D vs Treatment B
    Comparison groups
    Treatment D - PP v Treatment B - PP
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.113
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.066
         upper limit
    		 0.161
    Notes
    [6] - dose-effect analysis

    Secondary: FEV1 AUC0-4h/4h

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    End point title
    		 FEV1 AUC0-4h/4h
    End point description
    FEV1 AUC0-4h standardised by time (L)
    End point type
    Secondary
    End point timeframe
    FEV1 was measured from visit 3 to visit 7 (treatment visits) at the following timepoints: at pre-dose within 60 min of the dose and at 10 min, 30 min, 1 h, 2 h, 3 h, 4 h post-dose.
    End point values
    		 Treatment A - ITT Treatment B - ITT Treatment C - ITT Treatment D - ITT Treatment E - ITT
    Number of subjects analysed
    60
    58
    58
    59
    59
    Units: Liters
        arithmetic mean (confidence interval 95%)
    2.773 (2.742 to 2.804)
    2.802 (2.77 to 2.834)
    2.887 (2.855 to 2.919)
    2.9 (2.869 to 2.931)
    2.52 (2.488 to 2.551)
    Statistical analysis title
    		 Treatment B vs Treatment A
    Comparison groups
    Treatment A - ITT v Treatment B - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.015
         upper limit
    		 0.074
    Statistical analysis title
    		 Treatment D vs Treatment C
    Comparison groups
    Treatment C - ITT v Treatment D - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.013
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.031
         upper limit
    		 0.057
    Statistical analysis title
    		 Treatment D vs Treatment E
    Comparison groups
    Treatment D - ITT v Treatment E - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.336
         upper limit
    		 0.424
    Notes
    [7] - Sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment E
    Comparison groups
    Treatment C - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.367
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.323
         upper limit
    		 0.412
    Notes
    [8] - sensitivity analysis
    Statistical analysis title
    		 Treatment B vs Treatment E
    Comparison groups
    Treatment B - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.283
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.238
         upper limit
    		 0.327
    Notes
    [9] - sensitivity analisys
    Statistical analysis title
    		 Treatment A vs Treatment E
    Comparison groups
    Treatment E - ITT v Treatment A - ITT
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.253
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.208
         upper limit
    		 0.298
    Notes
    [10] - sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment A
    Comparison groups
    Treatment A - ITT v Treatment C - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.159
    Notes
    [11] - Dose-effect analysis
    Statistical analysis title
    		 Treatment D vs Treatment B
    Comparison groups
    Treatment B - ITT v Treatment D - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.098
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.053
         upper limit
    		 0.142
    Notes
    [12] - Dose-effect analysis

    Secondary: FEV1 AUC4-12h/8h

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    End point title
    		 FEV1 AUC4-12h/8h
    End point description
    FEV1 AUC4-12h was measured in a standardised by time (L) way.
    End point type
    Secondary
    End point timeframe
    FEV1 was measured from visit 3 to visit 7 (treatment visits) at the following time points: pre-dose within 60 min of the dose and at 10 min, 30 min, 1 h, 2 h, 3 h, 4 h post-dose.
    End point values
    		 Treatment A - ITT Treatment B - ITT Treatment C - ITT Treatment D - ITT Treatment E - ITT
    Number of subjects analysed
    60
    58
    58
    59
    59
    Units: Liters
        arithmetic mean (confidence interval 95%)
    2.74 (2.706 to 2.775)
    2.768 (2.732 to 2.803)
    2.857 (2.821 to 2.892)
    2.89 (2.855 to 2.926)
    2.449 (2.413 to 2.484)
    Statistical analysis title
    		 Treatment B vs Treatment A
    Comparison groups
    Treatment A - ITT v Treatment B - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.022
         upper limit
    		 0.077
    Statistical analysis title
    		 Treatment D vs Treatment C
    Comparison groups
    Treatment D - ITT v Treatment C - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.016
         upper limit
    		 0.083
    Statistical analysis title
    		 Treatment D vs Treatment E
    Comparison groups
    Treatment D - ITT v Treatment E - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.442
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.392
         upper limit
    		 0.491
    Notes
    [13] - sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment E
    Comparison groups
    Treatment C - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.408
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.359
         upper limit
    		 0.458
    Notes
    [14] - sensitivity analysis
    Statistical analysis title
    		 Treatment B vs Treatment E
    Comparison groups
    Treatment E - ITT v Treatment B - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.319
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.269
         upper limit
    		 0.369
    Notes
    [15] - Sensitivity analisys
    Statistical analysis title
    		 Treatment A vs Treatment E
    Comparison groups
    Treatment A - ITT v Treatment E - ITT
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.292
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.242
         upper limit
    		 0.342
    Notes
    [16] - Sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment A
    Comparison groups
    Treatment C - ITT v Treatment A - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.117
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.067
         upper limit
    		 0.167
    Notes
    [17] - Dose-effect analysis
    Statistical analysis title
    		 Treatment D vs Treatment B
    Comparison groups
    Treatment D - ITT v Treatment B - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.123
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.073
         upper limit
    		 0.172
    Notes
    [18] - Dose-effect analysis

    Secondary: Peak FEV1

    		 Close Top of page
    End point title
    		 Peak FEV1
    End point description
    Maximum FEV1 value over 12h post-dose
    End point type
    Secondary
    End point timeframe
    FEV1 was measured over 12 hours after single administration
    End point values
    		 Treatment A - ITT Treatment B - ITT Treatment C - ITT Treatment D - ITT Treatment E - ITT
    Number of subjects analysed
    60
    58
    58
    59
    59
    Units: Liters
        arithmetic mean (confidence interval 95%)
    2.898 (2.865 to 2.93)
    2.919 (2.886 to 2.953)
    3.008 (2.975 to 3.041)
    3.023 (2.991 to 3.056)
    2.641 (2.608 to 2.673)
    Statistical analysis title
    		 Treatment B vs Treatment A
    Comparison groups
    Treatment A - ITT v Treatment B - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.022
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.024
         upper limit
    		 0.068
    Statistical analysis title
    		 Treatment D vs Treatment C
    Comparison groups
    Treatment C - ITT v Treatment D - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.061
    Statistical analysis title
    		 Treatment D vs Treatment E
    Comparison groups
    Treatment D - ITT v Treatment E - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.383
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.337
         upper limit
    		 0.429
    Notes
    [19] - Sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment E
    Comparison groups
    Treatment C - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.367
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.321
         upper limit
    		 0.413
    Notes
    [20] - Sensitivity analysis
    Statistical analysis title
    		 Treatment B vs Treatment E
    Comparison groups
    Treatment B - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.279
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.232
         upper limit
    		 0.325
    Notes
    [21] - Sensitivity analysis
    Statistical analysis title
    		 Treatment A vs Treatment E
    Comparison groups
    Treatment A - ITT v Treatment E - ITT
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.257
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.211
         upper limit
    		 0.303
    Notes
    [22] - Sensitivity anlysis
    Statistical analysis title
    		 Treatment C vs Treatment A
    Comparison groups
    Treatment C - ITT v Treatment A - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.064
         upper limit
    		 0.157
    Notes
    [23] - Dose-effect analysis
    Statistical analysis title
    		 Treatment D vs Treatment B
    Comparison groups
    Treatment B - ITT v Treatment D - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.104
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.058
         upper limit
    		 0.15
    Notes
    [24] - Dose-effect analysis

    Secondary: Peak FVC

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    End point title
    		 Peak FVC
    End point description
    maximum FEV1 value over 12h post-dose
    End point type
    Secondary
    End point timeframe
    FVC was measured over 12 hours after single administration
    End point values
    		 Treatment A - ITT Treatment B - ITT Treatment C - ITT Treatment D - ITT Treatment E - ITT
    Number of subjects analysed
    60
    58
    58
    59
    59
    Units: Liters
        arithmetic mean (confidence interval 95%)
    4.121 (4.09 to 4.153)
    4.149 (4.116 to 4.182)
    4.172 (4.14 to 4.205)
    4.187 (4.155 to 4.22)
    4.014 (3.982 to 4.046)
    Statistical analysis title
    		 Treatment B vs Treatment A
    Comparison groups
    Treatment A - ITT v Treatment B - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.028
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.018
         upper limit
    		 0.073
    Statistical analysis title
    		 Treatment D vs Treatment C
    Comparison groups
    Treatment C - ITT v Treatment D - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.06
    Statistical analysis title
    		 Treatment D vs Treatment E
    Comparison groups
    Treatment D - ITT v Treatment E - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.173
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.128
         upper limit
    		 0.218
    Notes
    [25] - Sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment E
    Comparison groups
    Treatment C - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.158
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.113
         upper limit
    		 0.204
    Notes
    [26] - Sensitivity analysis
    Statistical analysis title
    		 Treatment B vs Treatment E
    Comparison groups
    Treatment B - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.135
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.089
         upper limit
    		 0.181
    Notes
    [27] - SEnsitivity analysis
    Statistical analysis title
    		 Treatment A vs Treatment E
    Comparison groups
    Treatment A - ITT v Treatment E - ITT
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.107
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.062
         upper limit
    		 0.152
    Notes
    [28] - Sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment A
    Comparison groups
    Treatment A - ITT v Treatment C - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.027
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.051
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.006
         upper limit
    		 0.096
    Notes
    [29] - Dose-effect analysis
    Statistical analysis title
    		 Treatment D vs Treatment B
    Comparison groups
    Treatment D - ITT v Treatment B - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.102
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.038
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.008
         upper limit
    		 0.084
    Notes
    [30] - Dose-effect analysis

    Secondary: FVC AUC0-12/12h

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    End point title
    		 FVC AUC0-12/12h
    End point description
    AUC0-12h was measured in a standardised by time (L) way.
    End point type
    Secondary
    End point timeframe
    FVC was measured at the following time points during treatment visits (visit 3 to visit 7): at pre-dose within 60 min of the dose and at 10 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h and 12 h post-dose.
    End point values
    		 Treatment A - ITT Treatment B - ITT Treatment C - ITT Treatment D - ITT Treatment E - ITT
    Number of subjects analysed
    60
    58
    58
    59
    59
    Units: LIters
        arithmetic mean (confidence interval 95%)
    3.97 (3.941 to 3.998)
    3.986 (3.956 to 4.016)
    4.023 (3.993 to 4.053)
    4.042 (4.013 to 4.072)
    3.835 (3.805 to 3.864)
    Statistical analysis title
    		 Treatment B vs Treatment A
    Comparison groups
    Treatment B - ITT v Treatment A - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.025
         upper limit
    		 0.058
    Statistical analysis title
    		 Treatment D vs Treatment C
    Comparison groups
    Treatment C - ITT v Treatment D - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.019
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.022
         upper limit
    		 0.06
    Statistical analysis title
    		 Treatment D vs Treatment E
    Comparison groups
    Treatment D - ITT v Treatment E - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.208
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.166
         upper limit
    		 0.249
    Notes
    [31] - Sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment E
    Comparison groups
    Treatment C - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.188
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.147
         upper limit
    		 0.23
    Notes
    [32] - Sensitivity analysis
    Statistical analysis title
    		 Treatment B vs Treatment E
    Comparison groups
    Treatment B - ITT v Treatment E - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.151
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.109
         upper limit
    		 0.193
    Notes
    [33] - Sensitivity analysis
    Statistical analysis title
    		 Treatment A vs Treatment E
    Comparison groups
    Treatment A - ITT v Treatment E - ITT
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.135
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.094
         upper limit
    		 0.176
    Notes
    [34] - Sensitivity analysis
    Statistical analysis title
    		 Treatment C vs Treatment A
    Comparison groups
    Treatment C - ITT v Treatment A - ITT
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.014
         upper limit
    		 0.098
    Notes
    [35] - Dose-effect analysis
    Statistical analysis title
    		 Treatment D vs Treatment B
    Comparison groups
    Treatment D - ITT v Treatment B - ITT
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    P-value
    		 = 0.009
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.014
         upper limit
    		 0.098
    Notes
    [36] - Dose-effect analysis

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signature of informed consent until follow-up phone call.
    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
    		 -

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

    Serious adverse events
    		 Treatment A - safety population Treatment B - safety population Treatment C - safety population Treatment D - safety population Treatment E - safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    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 Treatment E - safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 60 (13.33%)
    9 / 58 (15.52%)
    5 / 58 (8.62%)
    9 / 59 (15.25%)
    13 / 59 (22.03%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Laceration
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Headache
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 58 (6.90%)
    1 / 58 (1.72%)
    2 / 59 (3.39%)
    7 / 59 (11.86%)
         occurrences all number
    2
    4
    2
    2
    7
    Hypersomnia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    4 / 58 (6.90%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    1
    0
    0
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Infections and infestations
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 58 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No limitations or caveats are applicable to this summary of results
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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