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    Clinical Trial Results:
    A MULTINATIONAL, MULTICENTRE, RANDOMISED, DOUBLE BLIND, PLACEBO-CONTROLLED , 2-WAY CROSSOVER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF GLYCOPYRROLATE BROMIDE ADMINISTERED VIA PMDI (CHF 5259), FOR THE TREATMENT OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

    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
    		 2013-005268-25
    Trial protocol
    		 GB   DE   BG  
    Global end of trial date
    06 Feb 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-05993AA1-09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02189577
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici SpA
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, CHIESI FARMACEUTICI SPA, +39 0521 2791, ClinicalTrial_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, CHIESI FARMACEUTICI SPA, +39 0521 2791, 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
    06 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of CHF 5259 pMDI versus placebo in terms of change from baseline in pre-dose morning FEV1 on Day 28.
    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
    		 The background medication (Qvar, extrafine BDP at 100 μg per actuation) was administered to all patients via inhalation by pMDI from V1 until V5. During the two treatment periods, the background medication was administered concomitantly and always after the study medication. The dose was adjusted by the Investigator according to the patient’s previous treatment based on the reference table; this dose remained unchanged throughout the entire study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jun 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
    Poland: 43
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Bulgaria: 17
    Country: Number of subjects enrolled
    Germany: 39
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    64
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 98 patients (49 patients per sequence) were planned to be randomised to obtain 78 completed and evaluable patients. The study involved a run-in period of 2 weeks (±2 days) followed by a treatment phase consisting of two 4-week (±2 days) treatment period (P1 and P2) separated by 1-week (+2 days) wash-out period.

    Pre-assignment
    Screening details
    		 A total of 161 patients were screened, of whom 100 were randomised to one of the two treatment sequences: • CHF 5259 pMDI/placebo: n=50; • Placebo/CHF 5259 pMDI: n=50. Only 8 (8.0%) patients discontinued the study due to AEs (5 patients), death (1 patient), protocol violation (1 patient) and withdrawal of consent (1 patient).

    Pre-assignment period milestones
    Number of subjects started
    		 100
    Number of subjects completed
    		 100

    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
    The randomisation list was prepared by a specialised external provider and the whole study team, the Investigators and the patients were blind to sequence assignment. To maintain the blind, during the treatment periods, patients inhaled study medication from two canisters daily, regardless of treatment period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence CHF 5259 pMDI - placebo
    Arm description
    		 CHF 5259 pMDI or Test Treatment or Treatment T: Glycopyrronium bromide (GB, CHF 5259) administered via pMDI. Dose: 2 puffs, twice daily (bid) of CHF 5259 pMDI at 12.5 μg GB per actuation. Total daily dose: 50 μg GB. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator. Placebo or Reference therapy: Placebo of CHF 5259 administered via pMDI. Dose: 2 puffs, bid. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.
    Arm type
    		 experimental - placebo

    Investigational medicinal product name
    CHF 5259 pMDI
    Investigational medicinal product code
    GB
    Other name
    Glycopyrronium bromide
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: Glycopyrronium bromide (GB, CHF 5259) administered via pMDI. Dose: 2 puffs, twice daily (bid) of CHF 5259 pMDI at 12.5 μg GB per actuation. Total daily dose: 50 μg GB. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Reference product: Placebo of CHF 5259 administered via pMDI. Dose: 2 puffs, bid. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.

    Arm title
    		 Sequence Placebo - CHF 5259 pMDI
    Arm description
    		 Placebo or Reference therapy: Placebo of CHF 5259 administered via pMDI. Dose: 2 puffs, bid. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator. CHF 5259 pMDI or Tests Treatment or Treatment T: Glycopyrronium bromide (GB, CHF 5259) administered via pMDI. Dose: 2 puffs, twice daily (bid) of CHF 5259 pMDI at 12.5 μg GB per actuation. Total daily dose: 50 μg GB. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.
    Arm type
    		 placebo - experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Reference product: Placebo of CHF 5259 administered via pMDI. Dose: 2 puffs, bid. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator

    Investigational medicinal product name
    CHF 5259 pMDI
    Investigational medicinal product code
    GB
    Other name
    Glycopyrronium bromide
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Test product: Glycopyrronium bromide (GB, CHF 5259) administered via pMDI. Dose: 2 puffs, twice daily (bid) of CHF 5259 pMDI at 12.5 μg GB per actuation. Total daily dose: 50 μg GB. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.

    Number of subjects in period 1
    		Sequence CHF 5259 pMDI - placebo Sequence Placebo - CHF 5259 pMDI
    Started
    50
    50
    Completed
    46
    46
    Not completed
    4
    4
         Adverse event, serious fatal
    1
    -
         protocol violation
    1
    -
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence CHF 5259 pMDI - placebo
    Reporting group description
    		 CHF 5259 pMDI or Test Treatment or Treatment T: Glycopyrronium bromide (GB, CHF 5259) administered via pMDI. Dose: 2 puffs, twice daily (bid) of CHF 5259 pMDI at 12.5 μg GB per actuation. Total daily dose: 50 μg GB. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator. Placebo or Reference therapy: Placebo of CHF 5259 administered via pMDI. Dose: 2 puffs, bid. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.

    Reporting group title
    Sequence Placebo - CHF 5259 pMDI
    Reporting group description
    		 Placebo or Reference therapy: Placebo of CHF 5259 administered via pMDI. Dose: 2 puffs, bid. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator. CHF 5259 pMDI or Tests Treatment or Treatment T: Glycopyrronium bromide (GB, CHF 5259) administered via pMDI. Dose: 2 puffs, twice daily (bid) of CHF 5259 pMDI at 12.5 μg GB per actuation. Total daily dose: 50 μg GB. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.

    Reporting group values
    		 Sequence CHF 5259 pMDI - placebo Sequence Placebo - CHF 5259 pMDI Total
    Number of subjects
    		 50 50 100
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 30 34 64
        From 65-84 years
    		 20 16 36
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.3 ( 8.5 ) 62.4 ( 7.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 23 17 40
        Male
    		 27 33 60

    End points

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    End points reporting groups
    Reporting group title
    Sequence CHF 5259 pMDI - placebo
    Reporting group description
    		 CHF 5259 pMDI or Test Treatment or Treatment T: Glycopyrronium bromide (GB, CHF 5259) administered via pMDI. Dose: 2 puffs, twice daily (bid) of CHF 5259 pMDI at 12.5 μg GB per actuation. Total daily dose: 50 μg GB. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator. Placebo or Reference therapy: Placebo of CHF 5259 administered via pMDI. Dose: 2 puffs, bid. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.

    Reporting group title
    Sequence Placebo - CHF 5259 pMDI
    Reporting group description
    		 Placebo or Reference therapy: Placebo of CHF 5259 administered via pMDI. Dose: 2 puffs, bid. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator. CHF 5259 pMDI or Tests Treatment or Treatment T: Glycopyrronium bromide (GB, CHF 5259) administered via pMDI. Dose: 2 puffs, twice daily (bid) of CHF 5259 pMDI at 12.5 μg GB per actuation. Total daily dose: 50 μg GB. Mode of action: Metered dose inhalation of pressurised solution using a standard actuator.

    Subject analysis set title
    CHF 5259 pMDI - ITT
    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 medication and with at least one available evaluation of efficacy after baseline. One patient was allocated to the treatment sequence placebo-CHF 5259 pMDI, received a placebo kit in both treatment periods. He was counted only in the placebo column in the Safety population (i.e. actual treatment) and in both the CHF 5259 pMDI column and the placebo column in the ITT population (i.e. planned treatment).

    Subject analysis set title
    CHF 5259 pMDI - safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population: all randomised patients who received at least one dose of the study medication. Patient 202302 was allocated to the treatment sequence placebo-CHF 5259 pMDI, received a placebo kit in both treatment periods. He was counted only in the placebo column in the Safety population (i.e. actual treatment) and in both the CHF 5259 pMDI column and the placebo column in the ITT population (i.e. planned treatment).

    Subject analysis set title
    CHF 5259 pMDI - Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol (PP) population: all patients from the ITT population without any major protocol deviations;

    Subject analysis set title
    Placebo - 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 medication and with at least one available evaluation of efficacy after baseline;

    Subject analysis set title
    Placebo - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population: all randomised patients who received at least one dose of the study medication. Patient 202302 was allocated to the treatment sequence placebo-CHF 5259 pMDI, received a placebo kit in both treatment periods. He was counted only in the placebo column in the Safety population (i.e. actual treatment) and in both the CHF 5259 pMDI column and the placebo column in the ITT population (i.e. planned treatment).

    Subject analysis set title
    Placebo - Per protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol (PP) population: all patients from the ITT population without any major protocol deviations;

    Primary: Change from baseline in pre-dose morning FEV1 on Day 28

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    End point title
    		 Change from baseline in pre-dose morning FEV1 on Day 28
    End point description
    All pulmonary function tests (FEV1, FVC and IC) were carried out under medical supervision at either a clinic or hospital and were recorded using a computer-operated spirometer. At screening (V1), the post-bronchodilator FEV1 values (30 minutes after administration of 4 x 100 μg salbutamol for reversibility testing) were considered for eligibility. Lung function measurements and daily calibration of the spirometer were done according to the recommendation of the Official Statement of the European Respiratory Society and American Thoracic Society. For FEV1 (L) and FVC (L) measurements, the highest value from three technically satisfactory attempts (irrespective of the curve they were derived from) was recorded. The chosen value should have not exceeded the next one by more than 150 mL. If the difference was larger, up to 8 measurements were performed and the largest value was reported.
    End point type
    Primary
    End point timeframe
    Pre-dose morning spirometry was performed at screening (Visit 1), Visit 2 (Period 1 Day 1), Visit 3 (Period 1 Day 28), Visit 4 (Period 2 Day 1), Visit 5 (Period 2 Day 28). FEV1 value at baseline is the mean of measures at 45- and 10-min predose on Day 1.
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    97 [1]
    95 [2]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.067 (0.023 to 0.11)
    -0.024 (-0.082 to 0.034)
    Notes
    [1] - number of subjects of the ITT population actually analysed
    [2] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=192 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.039
         upper limit
    		 0.137
    Notes
    [3] - The primary variable was analysed using an Analysis of Covariance (ANCOVA) model, including treatment, patient and period as fixed effects and baseline FEV1 (mean of the two measurements at 45- and 10-minute pre-dose on Day 1 in each treatment period) as covariate. The adjusted mean change from baseline for each treatment and the adjusted mean difference between CHF 5259 pMDI and placebo with their 95% CIs and p-values were estimated by the model. Superiority was demonstrated.

    Secondary: FEV1 AUC0-12h normalised by time on day 28

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    End point title
    		 FEV1 AUC0-12h normalised by time on day 28
    End point description
    FEV1 AUC0-12h normalised by time on Day 28 was a key secondary efficacy variable . All pulmonary function tests (FEV1, FVC and IC) were carried out under medical supervision at either a clinic or hospital and were recorded using a computer-operated spirometer. At screening (V1), the post-bronchodilator FEV1 values (30 minutes after administration of 4 x 100 μg salbutamol for reversibility testing) were considered for eligibility. Lung function measurements and daily calibration of the spirometer were done according to the recommendation of the Official Statement of the European Respiratory Society and American Thoracic Society. For FEV1 (L) and FVC (L) measurements, the highest value from three technically satisfactory attempts (irrespective of the curve they were derived from) was recorded. The chosen value should have not exceeded the next one by more than 150 mL. If the difference was larger, up to 8 measurements were performed and the largest value was reported.
    End point type
    Secondary
    End point timeframe
    On day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    93 [4]
    94 [5]
    Units: liters
        arithmetic mean (confidence interval 95%)
    1.473 (1.358 to 1.588)
    1.344 (1.236 to 1.452)
    Notes
    [4] - number of subjects of the ITT population actually analysed
    [5] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=187 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.121
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.079
         upper limit
    		 0.162
    Notes
    [6] - The key secondary efficacy variable was FEV1 AUC0-12h normalised by time on Day 28 and was analysed using an ANCOVA model, including treatment, patient and period as fixed effects and baseline FEV1 as covariate. The adjusted mean for each treatment and the adjusted mean difference between CHF 5259 pMDI and placebo with their 95% CIs and p-values were estimated by the model.

    Secondary: FEV1 response on Day 28

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    End point title
    		 FEV1 response on Day 28
    End point description
    A patient was considered a responder if he/she had a change from baseline in pre-dose morning FEV1 on Day 28 ≥ 100 mL. If a patient had a change from baseline in pre-dose morning FEV1 on Day 28 < 100 mL or missing, he/she was considered as non-responder.
    End point type
    Secondary
    End point timeframe
    on Day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    98
    96
    Units: number of responders
        number (not applicable)
    39
    25
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.036
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.871
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 7.708
    Notes
    [7] - FEV1 response on Day 28 was analysed using a conditional logistic regression with treatment and period as fixed effects, baseline FEV1 as covariate and patient as strata.

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

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    End point title
    		 FEV1 AUC0-12h normalized by time on Day 1
    End point description
    FEV1 AUC0-12h normalised by time on Day 1 is one of the secondary efficacy variables of the study.
    End point type
    Secondary
    End point timeframe
    On day 1
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    96 [8]
    94 [9]
    Units: liters
        arithmetic mean (confidence interval 95%)
    1.423 (1.316 to 1.53)
    1.356 (1.242 to 1.47)
    Notes
    [8] - number of subjects of the ITT population actually analysed
    [9] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=190 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.081
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.044
         upper limit
    		 0.118
    Notes
    [10] - Change from baseline in trough FEV1 at 12 hours on Day 1 and Day 28 (mean of the two measurements at 11.5 and 12-hour post-dose), were all analysed using the same model used for the primary efficacy variable.

    Secondary: FEV1 AUC0-4h normalized by time on Day 1

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    End point title
    		 FEV1 AUC0-4h normalized by time on Day 1
    End point description
    FEV1 AUC0-4h normalised by time on Day 1 is one of the secondary efficacy variables of the study.
    End point type
    Secondary
    End point timeframe
    on Day 1
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    97 [11]
    95 [12]
    Units: liters
        arithmetic mean (confidence interval 95%)
    1.48 (1.369 to 1.592)
    1.375 (1.262 to 1.489)
    Notes
    [11] - number of subjects of the ITT population actually analysed
    [12] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=192 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.081
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.044
         upper limit
    		 0.118
    Notes
    [13] - Change from baseline in FEV1 AUC0-4h normalised by time on Day 1 and Day 28 were all analysed using the same model used for the primary efficacy variable.

    Secondary: FEV1 AUC 0-4h normalized by time on Day 28

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    End point title
    		 FEV1 AUC 0-4h normalized by time on Day 28
    End point description
    FEV1 AUC0-4h normalised by time on Day 28 is one of the secondary efficacy variables of the study.
    End point type
    Secondary
    End point timeframe
    on Day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    94 [14]
    94 [15]
    Units: liters
        arithmetic mean (confidence interval 95%)
    1.523 (1.409 to 1.637)
    1.355 (1.274 to 1.463)
    Notes
    [14] - number of subjects of the ITT population actually analysed
    [15] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=188 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.156
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.112
         upper limit
    		 0.2
    Notes
    [16] - Change from baseline in FEV1 AUC0-4h normalised by time on Day 1 and Day 28 were all analysed using the same model used for the primary efficacy variable.

    Secondary: Change from baseline in trough FEV1 at 12 hours on Day 1

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    End point title
    		 Change from baseline in trough FEV1 at 12 hours on Day 1
    End point description
    Change from baseline in trough FEV1 at 12 hours on Day 1 was the mean of the two measurements at 11.5 and 12-hour post-dose.
    End point type
    Secondary
    End point timeframe
    on Day 1
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    97 [17]
    95 [18]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.052 (0.007 to 0.097)
    -0.01 (-0.05 to 0.03)
    Notes
    [17] - number of subjects of the ITT population actually analysed
    [18] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a Cross-over study, groups examined should not be added. The number N=192 (subject analysis set) is an innate error of the EudraCT database system
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.063
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.018
         upper limit
    		 0.107
    Notes
    [19] - Change from baseline in through FEV1 at 12 hours on Day 1 was analysed using the same model used for the primary efficacy variable.

    Secondary: Change from baseline in trough FEV1 at 12 hours on Day 28

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    End point title
    		 Change from baseline in trough FEV1 at 12 hours on Day 28
    End point description
    Change from baseline in trough FEV1 at 12 hours on Day 28 was the mean of the two measurements at 11.5 and 12-hour post-dose.
    End point type
    Secondary
    End point timeframe
    on Day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    93 [20]
    94 [21]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.047 (-0.011 to 0.105)
    -0.012 (-0.062 to 0.039)
    Notes
    [20] - number of subjects of the ITT population actually analysed
    [21] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a Cross-over study, groups examined should not be added. The number N=187 (subject analysis set) is an innate error of the EudraCT database system
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.017
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.011
         upper limit
    		 0.11
    Notes
    [22] - Change from baseline in trough FEV1 at 12 hours on Day 28 was analysed using the same model used for the primary efficacy variable.

    Secondary: Change from baseline in trough FVC at 12 hours on Day 1

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    End point title
    		 Change from baseline in trough FVC at 12 hours on Day 1
    End point description
    Change from baseline in trough FVC at 12 hours on Day 1 was calculated as the mean of the two measurements at 11.5 and 12-hour post-dose.
    End point type
    Secondary
    End point timeframe
    on Day 1
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    97 [23]
    95 [24]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.041 (-0.041 to 0.122)
    -0.019 (-0.081 to 0.044)
    Notes
    [23] - number of subjects of the ITT population actually analysed
    [24] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=192 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.193
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.049
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.025
         upper limit
    		 0.123
    Notes
    [25] - Change from baseline in trough FVC at 12 hours on Day 1 (mean of the two measurements at 11.5 and 12-hour post-dose) was analysed using the same model used for the primary efficacy variable, including baseline FVC instead of baseline FEV1 as covariate.

    Secondary: Change from baseline in trough FVC at 12 hours on Day 28

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    End point title
    		 Change from baseline in trough FVC at 12 hours on Day 28
    End point description
    Change from baseline in trough FVC at 12 hours on Day 28 was calculated as the mean of the two measurements at 11.5 and 12-hour post-dose.
    End point type
    Secondary
    End point timeframe
    on Day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    93 [26]
    94 [27]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.084 (-0.022 to 0.19)
    -0.012 (-0.082 to 0.057)
    Notes
    [26] - number of subjects of the ITT population actually analysed
    [27] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=187 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.052
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.079
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.001
         upper limit
    		 0.159
    Notes
    [28] - Change from baseline in trough FVC at 12 hours on Day 28 (mean of the two measurements at 11.5 and 12-hour post-dose) was analysed using the same model used for the primary efficacy variable, including baseline FVC instead of baseline FEV1 as covariate.

    Secondary: Change from baseline in peak FEV1 over 12 hours on Day 1

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    End point title
    		 Change from baseline in peak FEV1 over 12 hours on Day 1
    End point description
    The maximum value obtained between 15 min and 12h post-dose assessments.
    End point type
    Secondary
    End point timeframe
    on Day 1
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    98 [29]
    96 [30]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.28 (0.236 to 0.324)
    0.187 (0.15 to 0.225)
    Notes
    [29] - number of subjects of the ITT population actually analysed
    [30] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.092
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.052
         upper limit
    		 0.133
    Notes
    [31] - Peak FEV1 over 12 hours on Day 1 was analysed using the same model used for the primary efficacy variable.

    Secondary: Change from baseline in peak FEV1 over 12 hours on Day 28

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    End point title
    		 Change from baseline in peak FEV1 over 12 hours on Day 28
    End point description
    End point type
    Secondary
    End point timeframe
    on Day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    94 [32]
    94 [33]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.294 (0.239 to 0.349)
    0.179 (0.127 to 0.231)
    Notes
    [32] - number of subjects of the ITT population actually analysed
    [33] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=188 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.068
         upper limit
    		 0.156
    Notes
    [34] - Peak FEV1 over 12 hours on Day 1 and Day 28, were analysed using the same model used for the primary efficacy variable.

    Secondary: Change from baseline in peak FVC over 12 hours on Day 1

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    End point title
    		 Change from baseline in peak FVC over 12 hours on Day 1
    End point description
    The maximum value obtained between 15 min and 12h post-dose assessments.
    End point type
    Secondary
    End point timeframe
    on Day 1
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    98
    96
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.435 (0.362 to 0.508)
    0.311 (0.259 to 0.364)
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean difference
    Point estimate
    0.107
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.041
         upper limit
    		 0.172
    Notes
    [35] - Peak FVC over 12 hours on Day 1 was analysed using the same model used for the primary efficacy variable, including baseline FVC as covariate.

    Secondary: Change from baseline in peak FVC over 12 hours on Day 28

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    End point title
    		 Change from baseline in peak FVC over 12 hours on Day 28
    End point description
    The maximum value obtained between 15 min and 12h post-dose assessments.
    End point type
    Secondary
    End point timeframe
    on Day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    94 [36]
    94 [37]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.469 (0.371 to 0.567)
    0.282 (0.21 to 0.354)
    Notes
    [36] - number of subjects of the ITT population actually analysed
    [37] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=188 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    0.168
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.094
         upper limit
    		 0.242
    Notes
    [38] - Peak FVC over 12 hours on Day 28 was analysed using the same model used for the primary efficacy variable, including baseline FVC as covariate.

    Secondary: Change from baseline in pre-dose morning IC on Day 28

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    End point title
    		 Change from baseline in pre-dose morning IC on Day 28
    End point description
    For IC, at Day 1 (both Visits 2 and 4), the measurement performed 45 min pre-dose was considered as the baseline value for the period.
    End point type
    Secondary
    End point timeframe
    on Day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    94 [39]
    94 [40]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.106 (0.04 to 0.171)
    -0.031 (-0.107 to 0.044)
    Notes
    [39] - number of subjects of the ITT population actually analysed
    [40] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=188 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.076
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    0.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.007
         upper limit
    		 0.144
    Notes
    [41] - Change from baseline in pre-dose morning IC on Day 28 was analysed using the same model used for the primary efficacy variable, including baseline IC instead of baseline FEV1 as covariate.

    Secondary: Change from baseline in 2-hour post-dose IC on Day 1

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    End point title
    		 Change from baseline in 2-hour post-dose IC on Day 1
    End point description
    For IC, at Day 1 (both Visits 2 and 4), the measurement performed 45 min pre-dose was considered as the baseline value for the period.
    End point type
    Secondary
    End point timeframe
    on Day 1
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    98
    96
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.19 (0.127 to 0.254)
    0.066 (0.008 to 0.124)
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a Cross-over study, groups examined should not be added. The number N=194 (subject analysis set) is an innate error of the EudraCT database system
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    0.089
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.021
         upper limit
    		 0.157
    Notes
    [42] - Change from baseline in 2h post-dose IC on Day 1 was analysed using the same model used for the primary efficacy variable, including baseline IC instead of baseline FEV1 as covariate.

    Secondary: Change from baseline in 2-hour post-dose IC on Day 28

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    End point title
    		 Change from baseline in 2-hour post-dose IC on Day 28
    End point description
    For IC, at Day 1 (both Visits 2 and 4), the measurement performed 45 min pre-dose was considered as the baseline value for the period.
    End point type
    Secondary
    End point timeframe
    on Day 28
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    94 [43]
    94 [44]
    Units: liters
        arithmetic mean (confidence interval 95%)
    0.225 (0.15 to 0.3)
    0.058 (-0.02 to 0.136)
    Notes
    [43] - number of subjects of the ITT population actually analysed
    [44] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=188 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.003
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    0.106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.036
         upper limit
    		 0.176
    Notes
    [45] - Change from baseline in 2h post-dose IC on Day 28 was analysed using the same model used for the primary efficacy variable, including baseline IC instead of baseline FEV1 as covariate.

    Secondary: Change from baseline in SGRQ total score on day 28

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    End point title
    		 Change from baseline in SGRQ total score on day 28
    End point description
    The St George’s Respiratory Questionnaire (SGRQ) was filled by the patient at all visits during the treatment phase. This questionnaire comprised 50 items, with 76 weighted responses, developed to measure health in chronic airflow limitation. Three component scores were calculated: symptoms, activity and impacts on daily life and a total score was then calculated, with lower scores corresponding to a better health.
    End point type
    Secondary
    End point timeframe
    At all visits from Visit 1 (screening) until the last day of the second treatment period (Visit 5).
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    94 [46]
    92 [47]
    Units: integer
        arithmetic mean (confidence interval 95%)
    -0.53 (-2.68 to 1.62)
    1.37 (-0.04 to 2.79)
    Notes
    [46] - number of subjects of the ITT population actually analysed
    [47] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a Cross-over study, groups examined should not be added. The number N=186 (subject analysis set) is an innate error of the EudraCT database system
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 = 0.029
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    -2.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.08
         upper limit
    		 -0.23
    Notes
    [48] - Change from baseline in SGRQ total score Day 28 was analysed using the same model used for the primary efficacy variable, including baseline SGRQ total score (score on Day 1) instead of baseline FEV1 as covariate.

    Secondary: Change from baseline in SGRQ symptoms score on Day 28

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    End point title
    		 Change from baseline in SGRQ symptoms score on Day 28
    End point description
    The St George’s Respiratory Questionnaire (SGRQ) was filled by the patient at all visits during the treatment phase. This questionnaire comprised 50 items, with 76 weighted responses, developed to measure health in chronic airflow limitation. Three component scores were calculated: symptoms, activity and impacts on daily life and a total score was then calculated, with lower scores corresponding to a better health.
    End point type
    Secondary
    End point timeframe
    At all visits from Visit 1 (screening) until the last day of the second treatment period (Visit 5).
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    95 [49]
    94 [50]
    Units: integer
        arithmetic mean (confidence interval 95%)
    -3.14 (-6.62 to 0.35)
    1.6 (-1 to 4.2)
    Notes
    [49] - number of subjects of the ITT population actually analysed
    [50] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=189 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.02
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    -3.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.75
         upper limit
    		 -0.59
    Notes
    [51] - Change from baseline in the SGRQ total score and domain scores on Day 28 was analysed using the same model used for the primary efficacy variable, including baseline SGRQ total/domain score (score on Day 1) instead of baseline FEV1 as covariate.

    Secondary: Change from baseline in SGRQ activity score on Day 28

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    End point title
    		 Change from baseline in SGRQ activity score on Day 28
    End point description
    The St George’s Respiratory Questionnaire (SGRQ) was filled by the patient at all visits during the treatment phase. This questionnaire comprised 50 items, with 76 weighted responses, developed to measure health in chronic airflow limitation. Three component scores were calculated: symptoms, activity and impacts on daily life and a total score was then calculated, with lower scores corresponding to a better health.
    End point type
    Secondary
    End point timeframe
    At all visits from Visit 1 (screening) until the last day of the second treatment period (Visit 5).
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    96 [52]
    93 [53]
    Units: integer
        arithmetic mean (confidence interval 95%)
    0.21 (-2.09 to 2.5)
    2.35 (-0.02 to 4.72)
    Notes
    [52] - number of subjects of the ITT population actually analysed
    [53] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=189 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [54]
    P-value
    		 = 0.064
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    -2.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.89
         upper limit
    		 0.14
    Notes
    [54] - Change from baseline in the SGRQ activity score was analysed using the same model used for the primary efficacy variable, including baseline SGRQ total/domain score (score on Day 1) instead of baseline FEV1 as covariate.

    Secondary: Change from baseline in SGRQ impact score on Day 28

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    End point title
    		 Change from baseline in SGRQ impact score on Day 28
    End point description
    The St George’s Respiratory Questionnaire (SGRQ) was filled by the patient at all visits during the treatment phase. This questionnaire comprised 50 items, with 76 weighted responses, developed to measure health in chronic airflow limitation. Three component scores were calculated: symptoms, activity and impacts on daily life and a total score was then calculated, with lower scores corresponding to a better health.
    End point type
    Secondary
    End point timeframe
    At all visits from Visit 1 (screening) until the last day of the second treatment period (Visit 5).
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    97 [55]
    94 [56]
    Units: integer
        arithmetic mean (confidence interval 95%)
    0.1 (-2.41 to 2.62)
    0.38 (-1.34 to 2.11)
    Notes
    [55] - number of subjects of the ITT population actually analysed
    [56] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=191 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 = 0.427
    Method
    		 ANCOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.55
         upper limit
    		 1.52
    Notes
    [57] - Change from baseline in the SGRQ impact score on Day 28 was analysed using the same model used for the primary efficacy variable, including baseline SGRQ total/domain score (score on Day 1) instead of baseline FEV1 as covariate.

    Secondary: Percentage of days without intake of rescue medication

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    End point title
    		 Percentage of days without intake of rescue medication
    End point description
    Use of rescue medication was evaluated by treatment in terms of percentage of days without intake of rescue medication (secondary efficacy variable), average use of rescue medication (number of puffs/day) (secondary efficacy variable) and average number of times rescue medication used per day (secondary efficacy variable).
    End point type
    Secondary
    End point timeframe
    Dispensation of rescue medication has been at each visit from Visit 1 (screening) to Visit 4; collection of rescue medication has been at Visit 5. Information on rescue medication was collected through all the study using a diary.
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    89 [58]
    89 [59]
    Units: percent
        arithmetic mean (confidence interval 95%)
    48.17 (39.48 to 56.87)
    45.94 (37.42 to 54.46)
    Notes
    [58] - number of subjects of the ITT population actually analysed
    [59] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=178 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [60]
    P-value
    		 = 0.056
    Method
    		 ANOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    4.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 9.89
    Notes
    [60] - Percentage of days without intake of rescue medication will be analysed using an ANOVA model with 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
    Use of rescue medication was evaluated by treatment in terms of percentage of days without intake of rescue medication (secondary efficacy variable), average use of rescue medication (number of puffs/day) (secondary efficacy variable) and average number of times rescue medication used per day (secondary efficacy variable).
    End point type
    Secondary
    End point timeframe
    Dispensation of rescue medication has been at each visit from Visit 1 (screening) to Visit 4; collection of rescue medication has been at Visit 5.
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    90 [61]
    89 [62]
    Units: number
        arithmetic mean (confidence interval 95%)
    1.88 (1.44 to 2.33)
    2.12 (1.6 to 2.64)
    Notes
    [61] - number of subjects of the ITT population actually analysed
    [62] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=179 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [63]
    P-value
    		 = 0.021
    Method
    		 ANOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.05
    Notes
    [63] - Average use of rescue medication will be analysed using an ANOVA model with treatment, period and patient as fixed effects.

    Secondary: Average number of times rescue medication used per day

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    End point title
    		 Average number of times rescue medication used per day
    End point description
    Use of rescue medication was evaluated by treatment in terms of percentage of days without intake of rescue medication (secondary efficacy variable), average use of rescue medication (number of puffs/day) (secondary efficacy variable) and average number of times rescue medication used per day (secondary efficacy variable). The average number of times rescue medication as used per day was statistically significantly lower with CHF 5259 pMDI than with placebo.
    End point type
    Secondary
    End point timeframe
    Dispensation of rescue medication has been at each visit from Visit 1 (screening) to Visit 4; collection of rescue medication has been at Visit 5.
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    90 [64]
    90 [65]
    Units: integer
        arithmetic mean (confidence interval 95%)
    1.18 (0.89 to 1.47)
    1.29 (0.98 to 1.59)
    Notes
    [64] - number of subjects of the ITT population actually analysed
    [65] - number of subjects of the ITT population actually analysed
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo
    Statistical analysis description
    In a cross-over study, groups examined should not be added. The number N=180 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF 5259 pMDI - ITT v Placebo - ITT population
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [66]
    P-value
    		 = 0.035
    Method
    		 ANOVA
    Parameter type
    		 adjusted mean differencej
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 -0.01
    Notes
    [66] - Average number of times rescue medication is used per day will be analysed using an ANOVA model with treatment, period and patient as fixed effects.

    Secondary: Change from baseline in SBP post-dose Day 1

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    End point title
    		 Change from baseline in SBP post-dose Day 1
    End point description
    SBP and DBP measurement are made after a 10-minute rest in sitting position. Measurements were performed at pre-dose at V1 and at pre- and 2-hour post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    97
    96
    Units: mmHg
        arithmetic mean (standard deviation)
    0 ( 8.4 )
    0.1 ( 10 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SBP pre-dose Day 28

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    End point title
    		 Change from baseline in SBP pre-dose Day 28
    End point description
    SBP and DBP measurement are made after a 10-minute rest in sitting position. Measurements were performed at pre-dose at V1 and at pre- and 2-hour post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    96 [67]
    95 [68]
    Units: mmHg
        arithmetic mean (standard deviation)
    -1.5 ( 12.1 )
    -0.4 ( 9.4 )
    Notes
    [67] - number of subjects of the safety population actually analysed
    [68] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Change from baseline in SBP post-dose Day 28

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    End point title
    		 Change from baseline in SBP post-dose Day 28
    End point description
    SBP and DBP measurement are made after a 10-minute rest in sitting position. Measurements were performed at pre-dose at V1 and at pre- and 2-hour post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    93 [69]
    94 [70]
    Units: mmHg
        arithmetic mean (standard deviation)
    -2.3 ( 13.2 )
    -0.1 ( 12.6 )
    Notes
    [69] - number of subjects of the safety population actually analysed
    [70] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Change in SBP Day 28 post-dose from Day 28 pre-dose

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    End point title
    		 Change in SBP Day 28 post-dose from Day 28 pre-dose
    End point description
    SBP and DBP measurement are made after a 10-minute rest in sitting position. Measurements were performed at pre-dose at V1 and at pre- and 2-hour post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    93 [71]
    94 [72]
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.9 ( 10.4 )
    0.2 ( 10.9 )
    Notes
    [71] - number of subjects of the safety population actually analysed
    [72] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Change from baseline in DBP post-dose Day 1

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    End point title
    		 Change from baseline in DBP post-dose Day 1
    End point description
    SBP and DBP measurement are made after a 10-minute rest in sitting position. Measurements were performed at pre-dose at V1 and at pre- and 2-hour post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    97
    96
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.2 ( 7.1 )
    -0.2 ( 6.8 )
    No statistical analyses for this end point

    Secondary: Change from baseline in DBP pre-dose Day 28

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    End point title
    		 Change from baseline in DBP pre-dose Day 28
    End point description
    SBP and DBP measurement are made after a 10-minute rest in sitting position. Measurements were performed at pre-dose at V1 and at pre- and 2-hour post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    96 [73]
    95
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.8 ( 8.3 )
    1 ( 8.6 )
    Notes
    [73] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Change from baseline in DBP post-dose Day 28

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    End point title
    		 Change from baseline in DBP post-dose Day 28
    End point description
    SBP and DBP measurement are made after a 10-minute rest in sitting position. Measurements were performed at pre-dose at V1 and at pre- and 2-hour post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    93 [74]
    94 [75]
    Units: mmHg
        arithmetic mean (standard deviation)
    -2.2 ( 8.4 )
    0.2 ( 8.5 )
    Notes
    [74] - number of subjects of the safety population actually analysed
    [75] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Change in DBP Day 28 post-dose from Day 28 pre-dose

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    End point title
    		 Change in DBP Day 28 post-dose from Day 28 pre-dose
    End point description
    SBP and DBP measurement are made after a 10-minute rest in sitting position. Measurements were performed at pre-dose at V1 and at pre- and 2-hour post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    93 [76]
    94
    Units: mmHg
        arithmetic mean (standard deviation)
    -1.3 ( 6 )
    -1 ( 7.3 )
    Notes
    [76] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Change in HR Day 28 post-dose from Day 28 pre-dose

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    End point title
    		 Change in HR Day 28 post-dose from Day 28 pre-dose
    End point description
    The 12-lead ECG was performed in triplicate at pre-dose at V1 and at pre- and 1 hour-45 minute post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    91
    92
    Units: bpm
        arithmetic mean (standard deviation)
    -2.2 ( 7.1 )
    -2.4 ( 7.2 )
    No statistical analyses for this end point

    Secondary: Change in QTcF Day 28 post-dose from Day 28 pre-dose

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    End point title
    		 Change in QTcF Day 28 post-dose from Day 28 pre-dose
    End point description
    The 12-lead ECG was performed in triplicate at pre-dose at V1 and at pre- and 1 hour-45 minute post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    91
    92
    Units: ms
        arithmetic mean (standard deviation)
    0.2 ( 10.5 )
    2.8 ( 8.2 )
    No statistical analyses for this end point

    Secondary: Change in PR Day 28 post-dose from Day 28 pre-dose

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    End point title
    		 Change in PR Day 28 post-dose from Day 28 pre-dose
    End point description
    The 12-lead ECG was performed in triplicate at pre-dose at V1 and at pre- and 1 hour-45 minute post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    91
    92
    Units: ms
        arithmetic mean (standard deviation)
    1.3 ( 7.6 )
    0.6 ( 11.3 )
    No statistical analyses for this end point

    Secondary: Change in QRS Day 28 post-dose from Day 28 pre-dose

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    End point title
    		 Change in QRS Day 28 post-dose from Day 28 pre-dose
    End point description
    The 12-lead ECG was performed in triplicate at pre-dose at V1 and at pre- and 1 hour-45 minute post-dose from V2 to V5.
    End point type
    Secondary
    End point timeframe
    At each visit, from visit 1 (screening) to visit 5.
    End point values
    		 Sequence CHF 5259 pMDI - placebo Sequence Placebo - CHF 5259 pMDI
    Number of subjects analysed
    49
    48
    Units: ms
        arithmetic mean (standard deviation)
    94 ( 9.9 )
    93.6 ( 9.8 )
    No statistical analyses for this end point

    Secondary: Males with abnormalities in QTcF values (>450 ms)

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    End point title
    		 Males with abnormalities in QTcF values (>450 ms)
    End point description
    The following QTcF abnormalities were reported: • 1 (1.8%) male patient during treatment with placebo had a QTcF value > 450 ms at post-dose on Day 1. No other abnormalities were reported in male patients; • 1 (2.6%) female patient during treatment with CHF 5259 pMDI had a QTcF value > 470 ms at post-dose on Day 1 and at post- dose on Day 28 and the same patient had a QTcF value > 470 ms at post-dose on Day 1 and at post-dose on Day 28 during treatment with placebo; • 4 (4.1%) patients had change from baseline > 30 ms during treatment with CHF 5259 pMDI and 1 (1.0%) patient had a change from baseline > 30 ms during treatment with placebo. In all cases, QTcF value was below the normal threshold (i.e. 450 ms for males and 470 ms for females).
    End point type
    Secondary
    End point timeframe
    post- dose on Day 1 and on Day 28
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    59 [77]
    57 [78]
    Units: unit
    0
    1
    Notes
    [77] - number of subjects of the safety population actually analysed
    [78] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Males with abnormalities in QTcF values (>480 ms)

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    End point title
    		 Males with abnormalities in QTcF values (>480 ms)
    End point description
    The following QTcF abnormalities were reported: • 1 (1.8%) male patient during treatment with placebo had a QTcF value > 450 ms at post-dose on Day 1. No other abnormalities were reported in male patients; • 1 (2.6%) female patient during treatment with CHF 5259 pMDI had a QTcF value > 470 ms at post-dose on Day 1 and at post- dose on Day 28 and the same patient had a QTcF value > 470 ms at post-dose on Day 1 and at post-dose on Day 28 during treatment with placebo; • 4 (4.1%) patients had change from baseline > 30 ms during treatment with CHF 5259 pMDI and 1 (1.0%) patient had a change from baseline > 30 ms during treatment with placebo. In all cases, QTcF value was below the normal threshold (i.e. 450 ms for males and 470 ms for females).
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 1 and Day 28
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    59 [79]
    57 [80]
    Units: unit
    0
    0
    Notes
    [79] - number of subjects of the safety population actually analysed
    [80] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Males with abnormalities in QTcF values (>500 ms)

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    End point title
    		 Males with abnormalities in QTcF values (>500 ms)
    End point description
    The following QTcF abnormalities were reported: • 1 (1.8%) male patient during treatment with placebo had a QTcF value > 450 ms at post-dose on Day 1. No other abnormalities were reported in male patients; • 1 (2.6%) female patient during treatment with CHF 5259 pMDI had a QTcF value > 470 ms at post-dose on Day 1 and at post- dose on Day 28 and the same patient had a QTcF value > 470 ms at post-dose on Day 1 and at post-dose on Day 28 during treatment with placebo; • 4 (4.1%) patients had change from baseline > 30 ms during treatment with CHF 5259 pMDI and 1 (1.0%) patient had a change from baseline > 30 ms during treatment with placebo. In all cases, QTcF value was below the normal threshold (i.e. 450 ms for males and 470 ms for females).
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 1 and Day 28
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    59 [81]
    57 [82]
    Units: unit
    0
    0
    Notes
    [81] - number of subjects of the safety population actually analysed
    [82] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Females with abnormalities in QTcF values (>470 ms)

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    End point title
    		 Females with abnormalities in QTcF values (>470 ms)
    End point description
    The following QTcF abnormalities were reported: • 1 (1.8%) male patient during treatment with placebo had a QTcF value > 450 ms at post-dose on Day 1. No other abnormalities were reported in male patients; • 1 (2.6%) female patient during treatment with CHF 5259 pMDI had a QTcF value > 470 ms at post-dose on Day 1 and at post- dose on Day 28 and the same patient had a QTcF value > 470 ms at post-dose on Day 1 and at post-dose on Day 28 during treatment with placebo; • 4 (4.1%) patients had change from baseline > 30 ms during treatment with CHF 5259 pMDI and 1 (1.0%) patient had a change from baseline > 30 ms during treatment with placebo. In all cases, QTcF value was below the normal threshold (i.e. 450 ms for males and 470 ms for females).
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 1 and Day 28
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    38 [83]
    39 [84]
    Units: unit
    1
    1
    Notes
    [83] - number of subjects of the safety population actually analysed
    [84] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Females with abnormalities in QTcF values (>500 ms)

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    End point title
    		 Females with abnormalities in QTcF values (>500 ms)
    End point description
    The following QTcF abnormalities were reported: • 1 (1.8%) male patient during treatment with placebo had a QTcF value > 450 ms at post-dose on Day 1. No other abnormalities were reported in male patients; • 1 (2.6%) female patient during treatment with CHF 5259 pMDI had a QTcF value > 470 ms at post-dose on Day 1 and at post- dose on Day 28 and the same patient had a QTcF value > 470 ms at post-dose on Day 1 and at post-dose on Day 28 during treatment with placebo; • 4 (4.1%) patients had change from baseline > 30 ms during treatment with CHF 5259 pMDI and 1 (1.0%) patient had a change from baseline > 30 ms during treatment with placebo. In all cases, QTcF value was below the normal threshold (i.e. 450 ms for males and 470 ms for females).
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 1 and Day 28
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    38 [85]
    39 [86]
    Units: unit
    0
    0
    Notes
    [85] - number of subjects of the safety population actually analysed
    [86] - number of subjects of the safety population actually analysed
    No statistical analyses for this end point

    Secondary: Patients with abnormalities in change from baseline QTcF values (>30 ms)

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    End point title
    		 Patients with abnormalities in change from baseline QTcF values (>30 ms)
    End point description
    The following QTcF abnormalities were reported: • 1 (1.8%) male patient during treatment with placebo had a QTcF value > 450 ms at post-dose on Day 1. No other abnormalities were reported in male patients; • 1 (2.6%) female patient during treatment with CHF 5259 pMDI had a QTcF value > 470 ms at post-dose on Day 1 and at post- dose on Day 28 and the same patient had a QTcF value > 470 ms at post-dose on Day 1 and at post-dose on Day 28 during treatment with placebo; • 4 (4.1%) patients had change from baseline > 30 ms during treatment with CHF 5259 pMDI and 1 (1.0%) patient had a change from baseline > 30 ms during treatment with placebo. In all cases, QTcF value was below the normal threshold (i.e. 450 ms for males and 470 ms for females).
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 1 and Day 28
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    97
    96
    Units: unit
    4
    1
    No statistical analyses for this end point

    Secondary: Patients with abnormalities in change from baseline QTcF values (>60 ms)

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    End point title
    		 Patients with abnormalities in change from baseline QTcF values (>60 ms)
    End point description
    The following QTcF abnormalities were reported: • 1 (1.8%) male patient during treatment with placebo had a QTcF value > 450 ms at post-dose on Day 1. No other abnormalities were reported in male patients; • 1 (2.6%) female patient during treatment with CHF 5259 pMDI had a QTcF value > 470 ms at post-dose on Day 1 and at post- dose on Day 28 and the same patient had a QTcF value > 470 ms at post-dose on Day 1 and at post-dose on Day 28 during treatment with placebo; • 4 (4.1%) patients had change from baseline > 30 ms during treatment with CHF 5259 pMDI and 1 (1.0%) patient had a change from baseline > 30 ms during treatment with placebo. In all cases, QTcF value was below the normal threshold (i.e. 450 ms for males and 470 ms for females).
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 1 and Day 28
    End point values
    		 CHF 5259 pMDI - safety Placebo - Safety
    Number of subjects analysed
    97
    96
    Units: unit
    0
    0
    No statistical analyses for this end point

    Secondary: BDI focal score on Day 1

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    End point title
    		 BDI focal score on Day 1
    End point description
    BDI was collected at Visits 1, 2 and 4. BDI focal score on Day 1 and TDI focal score on Day 28 are presented by treatment
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    		 CHF 5259 pMDI - ITT Placebo - ITT population
    Number of subjects analysed
    95
    91
    Units: score
        arithmetic mean (confidence interval 95%)
    6.16 (5.73 to 6.59)
    5.99 (5.51 to 6.46)
    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 6 (follow-up call)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    CHF 5259 pMDI - safety population
    Reporting group description
    		 -

    Reporting group title
    Placebo - safety population
    Reporting group description
    		 The Safety population was defined as all randomised patients who received at least one dose of the study medication. Patient 202302 was allocated to the treatment sequence placebo-CHF 5259 pMDI, received a placebo kit in both treatment periods. He was counted only in the placebo column in the Safety population (i.e. actual treatment) and in both the CHF 5259 pMDI column and the placebo column in the ITT population (i.e. planned treatment).

    Serious adverse events
    		 CHF 5259 pMDI - safety population Placebo - safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 97 (3.09%)
    1 / 96 (1.04%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bronchial carcinoma
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    COPD
    Additional description: One Patient experienced 1 serious TEAE of COPD exacerbation during treatment with CHF 5259 pMDI and another patient experienced 1 serious TEAE of COPD exacerbation (and 1 serious TEAE of malignant lung neoplasm) during treatment with placebo.
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 CHF 5259 pMDI - safety population Placebo - safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 97 (20.62%)
    17 / 96 (17.71%)
    Investigations
    Electrocardiogram ST segment depression
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 96 (1.04%)
         occurrences all number
    1
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 97 (3.09%)
    1 / 96 (1.04%)
         occurrences all number
    3
    1
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences all number
    1
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 96 (2.08%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Local swelling
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    COPD
    Additional description: These are non serious cases of COPD
         subjects affected / exposed
    2 / 97 (2.06%)
    3 / 96 (3.13%)
         occurrences all number
    2
    3
    Cough
         subjects affected / exposed
    1 / 97 (1.03%)
    3 / 96 (3.13%)
         occurrences all number
    1
    3
    Dyspnoea
         subjects affected / exposed
    0 / 97 (0.00%)
    2 / 96 (2.08%)
         occurrences all number
    0
    2
    Dysphonia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences all number
    1
    0
    Sputum increased
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
    Additional description: For one patient, one AE (ecchymosis) was allocated to both treatments/periods due to partially missing onset date
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 96 (1.04%)
         occurrences all number
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 97 (5.15%)
    1 / 96 (1.04%)
         occurrences all number
    6
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 96 (1.04%)
         occurrences all number
    1
    1
    Fungal skin infection
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 96 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences all number
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences all number
    0
    1

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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.
    There are no limitation or caveats to this summary of results
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