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    Clinical Trial Results:
    A MULTICENTRE, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 2-WAY CROSS-OVER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CHF 5259 (GLYCOPYRROLATE BROMIDE) pMDI ON TOP OF QVAR® pMDI FOR THE TREATMENT OF PATIENTS WITH UNCONTROLLED ASTHMA ON LOW-MEDIUM DOSE OF INHALED CORTICOSTEROIDS

    Summary
    EudraCT number
    		 2014-001442-16
    Trial protocol
    		 DE   IT   PL   BG   NL  
    Global end of trial date
    13 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Aug 2016
    First version publication date
    14 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CCD-05993AB1-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02296411
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A, +39 05212791, ClinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A, +39 05212791 , 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
    13 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the superiority of CHF 5259 pMDI (glycopyrrolate bromide) (50 μg total daily dose) versus placebo in terms of FEV1 AUC0-12h normalised by time on Day 42.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    		 At Screening visit (V1), all eligible patients had to switch to an ICS monotherapy at a clinical dose comparable to their previous treatment. Background medication: Qvar® pMDI 50 μg or100 μg. Dose: Qvar® pMDI 50 μg or 100 μg b.i.d., total daily dose of Qvar® pMDI ranged from 100 μg to 400 μg. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Nov 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
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    Bulgaria: 37
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Italy: 2
    Worldwide total number of subjects
    98
    EEA total number of subjects
    98
    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)
    89
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multinational study was conducted at 28 sites (24 active) in 5 countries: Bulgaria, Germany, Italy, The Netherlands and Poland.

    Pre-assignment
    Screening details
    		 A total of 138 patients were screened, 98 patients were randomised and 97 (99.0%) patients completed the study.

    Period 1
    Period 1 title
    Overall trial by sequence (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The randomisation list was provided to the labelling facility but was not available to patients, Investigators, monitors or employees of the centre involved in the management of the trial before unblinding of the data, unless in case of emergency. The Sponsor’s clinical team was also blinded during the study as they did not have direct access to the randomisation list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CHF5259 pMDI - placebo pMDI
    Arm description
    		 Two puffs of CHF 5259 pMDI 12.5 μg twice a day (b.i.d.), total daily dose of CHF 5259 pMDI was 50 μg. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator. Two puffs of matched placebo of CHF 5259 pMDI b.i.d. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF 5259 pMDI
    Investigational medicinal product code
    Other name
    Glycopirrolate bromide
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Two puffs of CHF 5259 12.5 μg b.i.d.

    Investigational medicinal product name
    Placebo pMDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Dose: two puffs b.i.d.

    Arm title
    		 Placebo pMDI - CHF 5259 pMDI
    Arm description
    		 Two puffs of matched placebo of CHF 5259 pMDI b.i.d. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator. Two puffs of CHF 5259 pMDI 12.5 μg twice a day (b.i.d.), total daily dose of CHF 5259 pMDI was 50 μg. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF 5259 pMDI
    Investigational medicinal product code
    Other name
    Glycopirrolate bromide
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Two puffs of CHF 5259 12.5 μg b.i.d.

    Investigational medicinal product name
    Placebo pMDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Two puffs of matched placebo of CHF 5259 pMDI b.i.d.

    Number of subjects in period 1
    		CHF5259 pMDI - placebo pMDI Placebo pMDI - CHF 5259 pMDI
    Started
    50
    48
    Completed
    50
    47
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CHF5259 pMDI - placebo pMDI
    Reporting group description
    		 Two puffs of CHF 5259 pMDI 12.5 μg twice a day (b.i.d.), total daily dose of CHF 5259 pMDI was 50 μg. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator. Two puffs of matched placebo of CHF 5259 pMDI b.i.d. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator.

    Reporting group title
    Placebo pMDI - CHF 5259 pMDI
    Reporting group description
    		 Two puffs of matched placebo of CHF 5259 pMDI b.i.d. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator. Two puffs of CHF 5259 pMDI 12.5 μg twice a day (b.i.d.), total daily dose of CHF 5259 pMDI was 50 μg. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator.

    Reporting group values
    		 CHF5259 pMDI - placebo pMDI Placebo pMDI - CHF 5259 pMDI Total
    Number of subjects
    		 50 48 98
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 45 44 89
        From 65-84 years
    		 5 4 9
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.8 ± 14 47.2 ± 12.8 -
    Gender categorical
    Units: Subjects
        Female
    		 30 31 61
        Male
    		 20 17 37

    End points

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    End points reporting groups
    Reporting group title
    CHF5259 pMDI - placebo pMDI
    Reporting group description
    		 Two puffs of CHF 5259 pMDI 12.5 μg twice a day (b.i.d.), total daily dose of CHF 5259 pMDI was 50 μg. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator. Two puffs of matched placebo of CHF 5259 pMDI b.i.d. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator.

    Reporting group title
    Placebo pMDI - CHF 5259 pMDI
    Reporting group description
    		 Two puffs of matched placebo of CHF 5259 pMDI b.i.d. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator. Two puffs of CHF 5259 pMDI 12.5 μg twice a day (b.i.d.), total daily dose of CHF 5259 pMDI was 50 μg. Mode of administration: Metered dose inhalation of pressurised solution using a standard actuator.

    Subject analysis set title
    CHF5259 pMDI - ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    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 pMDI - ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    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
    CHF5259 pMDI - safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all randomised patients who received at least one dose of the study medication.

    Subject analysis set title
    Placebo pMDI - safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients who received at least one dose of the study medication.

    Subject analysis set title
    CHF5259 pMDI - PP population
    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 pMDI - PP population
    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: FEV1 AUC0-12h normalized by time on Day 42

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    End point title
    		 FEV1 AUC0-12h normalized by time on Day 42
    End point description
    AUC0-12h = area under the curve between time 0 and 12 hours; FEV1 was measured at 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11.5h and 12h post-dose.
    End point type
    Primary
    End point timeframe
    On day 42
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population CHF5259 pMDI - PP population Placebo pMDI - PP population
    Number of subjects analysed
    95 [1]
    96 [2]
    86 [3]
    82 [4]
    Units: Liter
        arithmetic mean (standard deviation)
    2.47 ± 0.857
    2.373 ± 0.83
    2.48 ± 0.849
    2.365 ± 0.827
    Notes
    [1] - This is the actual number of patients on which the analysis was performed
    [2] - This is the actual number of patients on which the analysis was performed
    [3] - This is the actual number of patients on which the analysis was performed
    [4] - This is the actual number of patients on which the analysis was performed
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=191 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Placebo pMDI - ITT population v CHF5259 pMDI - ITT population
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.135
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.092
         upper limit
    		 0.177
    Notes
    [5] - The FEV1 AUC0-12h normalised by time on Day 42 was analysed using an analysis of covariance (ANCOVA) model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=168 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - PP population v Placebo pMDI - PP population
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.082
         upper limit
    		 0.174
    Notes
    [6] - The FEV1 AUC0-12h normalised by time on Day 42 was analysed using an analysis of covariance (ANCOVA) model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate.

    Secondary: Change from baseline in peak FEV1 at Day 42

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    End point title
    		 Change from baseline in peak FEV1 at Day 42
    End point description
    The peak FEV1 is determined as the maximum FEV1 value obtained between 15 minutes and 12 hours post-dose. The baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population CHF5259 pMDI - PP population Placebo pMDI - PP population
    Number of subjects analysed
    97 [7]
    97 [8]
    91 [9]
    89 [10]
    Units: Liter
        arithmetic mean (standard deviation)
    0.394 ± 0.281
    0.278 ± 0.293
    0.392 ± 0.263
    0.258 ± 0.299
    Notes
    [7] - This is the actual number of patients on which the analysis was performed
    [8] - This is the actual number of patients on which the analysis was performed
    [9] - This is the actual number of patients on which the analysis was performed
    [10] - This is the actual number of patients on which the analysis was performed
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.137
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.094
         upper limit
    		 0.18
    Notes
    [11] - The change from baseline in peak FEV1 on Day 42 was analysed using an analysis of covariance (ANCOVA) model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=180 (subject analysis set) is an innate error of the EudraCT database system
    Comparison groups
    CHF5259 pMDI - PP population v Placebo pMDI - PP population
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.144
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.098
         upper limit
    		 0.191
    Notes
    [12] - The change from baseline in peak FEV1 on Day 42 was analysed using an analysis of covariance (ANCOVA) model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate.

    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 = Area Under the Curve between time 0 and 12 hours. FEV1 was measured at 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11.5h and 12h post-dose.
    End point type
    Secondary
    End point timeframe
    On day 1
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [13]
    96 [14]
    Units: Liter
        arithmetic mean (standard deviation)
    2.482 ± 0.862
    2.356 ± 0.835
    Notes
    [13] - This is the actual number of patients on which the analysis was performed.
    [14] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=193 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.115
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.074
         upper limit
    		 0.155
    Notes
    [15] - The FEV1 AUC0-12h normalised by time on Day 1 was analysed using an analysis of covariance (ANCOVA) model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate.

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

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    End point title
    		 FEV1 AUC0-3h normalised by time on Day 1
    End point description
    AUC0-3h =Area Under the Curve between time 0 and 3 hours. FEV1 was measured at 15 min, 30 min, 45 min, 1h, 2h, 3h.
    End point type
    Secondary
    End point timeframe
    On day 1
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [16]
    97 [17]
    Units: Liters
        arithmetic mean (standard deviation)
    2.496 ± 0.863
    2.344 ± 0.815
    Notes
    [16] - This is the actual number of patients on which the analysis was performed.
    [17] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.099
         upper limit
    		 0.187
    Notes
    [18] - The FEV1 AUC0-3h normalised by time on Day 1 was analysed using an analysis of covariance (ANCOVA) model including treatment,period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate.

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

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    End point title
    		 FEV1 AUC0-3h normalised by time on Day 42
    End point description
    AUC0-3h Area Under the Curve between time 0 and 3 hours. FEV1 was measured at 15 min, 30 min, 45 min, 1h, 2h, 3h.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    96 [19]
    97 [20]
    Units: Liters
        arithmetic mean (standard deviation)
    2.498 ± 0.87
    2.357 ± 0.839
    Notes
    [19] - This is the actual number of patients on which the analysis was performed.
    [20] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=193 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.151
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.101
         upper limit
    		 0.201
    Notes
    [21] - The FEV1 AUC0-3h normalised by time on Day 42 was analysed using an analysis of covariance (ANCOVA) model including treatment, period and patient as fixed effects and baseline (average of the FEV1 pre-dose measurements on Day 1 of each treatment period) as a covariate.

    Secondary: Change from Baseline in peak FEV1 on Day 1

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    End point title
    		 Change from Baseline in peak FEV1 on Day 1
    End point description
    The peak FEV1 is determined as the maximum FEV1 value obtained between 15 minutes and 12 hours post-dose. The baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On day 1
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [22]
    97 [23]
    Units: Liters
        arithmetic mean (standard deviation)
    0.384 ± 0.248
    0.286 ± 0.237
    Notes
    [22] - This is the actual number of patients on which the analysis was performed.
    [23] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.071
         upper limit
    		 0.154
    Notes
    [24] - The peak FEV1 on Day 1 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FEV1 (mean of the pre-dose measurements of FEV1 at Day 1) as a covariate.

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

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    End point title
    		 Change from baseline in pre-dose morning through FEV1 on Day 42
    End point description
    The pre-dose morning FEV1 is defined as the mean of the two measurements at 45 and 15 minutes pre-dose.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [25]
    97 [26]
    Units: liters
        arithmetic mean (standard deviation)
    0.136 ± 0.291
    0.041 ± 0.258
    Notes
    [25] - This is the actual number of patients on which the analysis was performed.
    [26] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.061
         upper limit
    		 0.164
    Notes
    [27] - The changes from baseline in pre-dose morning FEV1 were analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline FEV1 (mean of the pre-dose measurements of FEV1 at Day 1) as a covariate.

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

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    End point title
    		 Change from baseline in ACQ total score at Day 42
    End point description
    ACQ = Asthma Control Questionnaire. The ACQ total score is the sum of the 7 ACQ scores.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [28]
    97 [29]
    Units: Number
        arithmetic mean (standard deviation)
    -0.39 ± 0.59
    -0.17 ± 0.56
    Notes
    [28] - This is the actual number of patients on which the analysis was performed
    [29] - This is the actual number of patients on which the analysis was performed
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.026
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 -0.02
    Notes
    [30] - The change from baseline in ACQ total score on Day 42 was analysed by means of an ANCOVA model with treatment, patient and period as fixed effects and baseline ACQ total score as a covariate. Baseline is the calculated Asthma Control Questionnaire (ACQ) score of Day 1 of the respective treatment period.

    Secondary: Average daily morning PEF

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    End point title
    		 Average daily morning PEF
    End point description
    The average daily morning PEF is the mean value of all morning PEF measurements.
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    96 [31]
    97 [32]
    Units: liters/ min
        arithmetic mean (standard deviation)
    363.2 ± 117.7
    346.9 ± 111.5
    Notes
    [31] - This is the actual number of patients on which the analysis was performed.
    [32] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=193 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    Placebo pMDI - ITT population v CHF5259 pMDI - ITT population
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    14.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.8
         upper limit
    		 20.6
    Notes
    [33] - The average morning PEFs were analysed by means of an ANOVA model with treatment, patient and period as fixed effects.

    Secondary: Average daily evening PEF

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    End point title
    		 Average daily evening PEF
    End point description
    The average daily evening PEF is the mean value of all evening PEF measurements. It is set to missing when there are less than 20 non-missing values
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    96 [34]
    97 [35]
    Units: liters/min
        arithmetic mean (standard deviation)
    372.4 ± 117
    355.5 ± 110.5
    Notes
    [34] - This is the actual number of patients on which the analysis was performed.
    [35] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=193 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    14.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.3
         upper limit
    		 21
    Notes
    [36] - The average evening PEFs were analysed by means of an ANOVA model with treatment, patient and period as fixed effects.

    Secondary: Average daily asthma symptoms, day-time

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    End point title
    		 Average daily asthma symptoms, day-time
    End point description
    The average of daily asthma symptoms (daytime) of a symptom (Cough, Wheeze, Chest Tightness, Breathlessness) is the mean value of all daytime measurements of that symptom. If there are less than 20 non-missing values, the average is considered missing.
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    96 [37]
    97 [38]
    Units: number
        arithmetic mean (standard deviation)
    2.62 ± 1.98
    2.66 ± 1.84
    Notes
    [37] - This is the actual number of patients on which the analysis was performed.
    [38] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=193 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.608
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.12
    Notes
    [39] - The average daily morning Asthma Symptom Scores were analysed by means of an ANOVA model with treatment, patient and period as fixed effects.

    Secondary: Average daily asthma symptoms, night-time

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    End point title
    		 Average daily asthma symptoms, night-time
    End point description
    The average of daily asthma symptoms (nighttime) of a symptom (Cough, Wheeze, Chest Tightness, Breathlessness) is the mean value of all nighttime measurements of that symptom. If there are less than 20 non-missing values, the average is considered missing.
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    96 [40]
    97 [41]
    Units: number
        arithmetic mean (standard deviation)
    2.35 ± 2.1
    2.39 ± 2
    Notes
    [40] - This is the actual number of patients on which the analysis was performed.
    [41] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=193 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.435
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.1
    Notes
    [42] - The average daily evening Asthma Symptom Scores were analysed by means of an ANOVA model with treatment, patient and period as fixed effects.

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

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    End point title
    		 Average use of rescue medication (number of puffs/day)
    End point description
    The average use of rescue medication (number of puffs per day) is determined as the total number of puffs of rescue mediation taken / number of days with available data.
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [43]
    97 [44]
    Units: number of puffs/ day
        arithmetic mean (standard deviation)
    1 ± 1.6
    1.1 ± 1.5
    Notes
    [43] - This is the actual number of patients on which the analysis was performed
    [44] - This is the actual number of patients on which the analysis was performed
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.462
    Method
    		 ANOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.1
    Notes
    [45] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects.

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

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    End point title
    		 Average use of rescue medication (number of times/day)
    End point description
    The average use of rescue medication (number of times per day) is determined as the total number of times of rescue medication taken/ number of days with available data.
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [46]
    97 [47]
    Units: times/ day
        arithmetic mean (standard deviation)
    0.8 ± 1.4
    0.9 ± 1.3
    Notes
    [46] - This is the actual number of patients on which the analysis was performed.
    [47] - This is the actual number of patients on which the analysis was performed.
    Statistical analysis title
    		 CHF5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 = 0.379
    Method
    		 ANOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0
    Notes
    [48] - The average use of rescue medication was analysed by means of an ANOVA model with treatment, patient and period as fixed effects.

    Secondary: Change from baseline in FEV1 percentage of predicted normal value on Day 1

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    End point title
    		 Change from baseline in FEV1 percentage of predicted normal value on Day 1
    End point description
    FEV1 was measured at 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11.5h and 12h post-dose. The baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period. Only changes from baseline at 12h post-dose data are reported. For the changes from baseline of other time points, please see the attached file.
    End point type
    Secondary
    End point timeframe
    On day 1
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [49]
    97 [50]
    Units: percentage
        arithmetic mean (standard deviation)
    5.1 ± 8.1
    2.9 ± 7.5
    Attachments
    		 Untitled (Filename: FEV1 Day 1 Change from Baseline.pdf)
    Notes
    [49] - This is the actual number of patients on which the analysis was performed.
    [50] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Change from baseline in FEV1 percentage of predicted normal value on Day 42

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    End point title
    		 Change from baseline in FEV1 percentage of predicted normal value on Day 42
    End point description
    FEV1 was measured at 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11.5h and 12h post-dose. The baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period. Only changes from baseline at 12h post-dose data are reported. For the changes from baseline of other time points, please see the attached file.
    End point type
    Secondary
    End point timeframe
    On Day 42
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    95 [51]
    96 [52]
    Units: percentage
        arithmetic mean (standard deviation)
    5.8 ± 8.9
    2.9 ± 8.5
    Attachments
    		 Untitled (Filename: FEV1 Day 42 Change from Baseline.pdf)
    Notes
    [51] - This is the actual number of patients on which the analysis was performed.
    [52] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Change from baseline in FVC on Day 1

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    End point title
    		 Change from baseline in FVC on Day 1
    End point description
    FVC was measured at 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11.5h and 12h post-dose. The baseline value is the mean of the pre-dose measurement of FVC at Day 1 of each treatment period. Only changes from baseline at 12h post-dose data are reported. For the changes from baseline of other time points, please see the attached file.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [53]
    97 [54]
    Units: Liters
        arithmetic mean (standard deviation)
    0.105 ± 0.348
    0.114 ± 0.319
    Attachments
    		 Untitled (Filename: FVC Day 1 Change from Baseline.pdf)
    Notes
    [53] - This is the actual number of patients on which the analysis was performed.
    [54] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Change from baseline in FVC on Day 42

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    End point title
    		 Change from baseline in FVC on Day 42
    End point description
    FVC was measured at 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11.5h and 12h post-dose. The baseline value is the mean of the pre-dose measurement of FVC at Day 1 of each treatment period. Only changes from baseline at 12h post-dose data are reported. For the changes from baseline of other time points, please see the attached file.
    End point type
    Secondary
    End point timeframe
    On day 42
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    95 [55]
    96 [56]
    Units: liters
        arithmetic mean (standard deviation)
    0.096 ± 0.34
    0.068 ± 0.346
    Attachments
    		 Untitled (Filename: FVC Day 42 Change from Baseline.pdf)
    Notes
    [55] - This is the actual number of patients on which the analysis was performed.
    [56] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: SBP Change from baseline Day 42

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    End point title
    		 SBP Change from baseline Day 42
    End point description
    Baseline is the pre-dose measurement on Day 1 in each treatment period.
    End point type
    Secondary
    End point timeframe
    Day 42
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    97
    98
    Units: mmHg
        arithmetic mean (standard deviation)
    2 ± 10
    2.6 ± 9.3
    No statistical analyses for this end point

    Secondary: DBP Change from baseline Day 42

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    End point title
    		 DBP Change from baseline Day 42
    End point description
    Baseline is the pre-dose measurement on Day 1 in each treatment period.
    End point type
    Secondary
    End point timeframe
    Day 42
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    97
    98
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.7 ± 7.1
    0.7 ± 6.4
    No statistical analyses for this end point

    Secondary: HR Change from baseline Day 1 Post dose

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    End point title
    		 HR Change from baseline Day 1 Post dose
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker were excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm were also excluded.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    95 [57]
    96 [58]
    Units: bmp
        arithmetic mean (standard deviation)
    -1.9 ± 6.8
    -2 ± 7.1
    Notes
    [57] - This is the actual number of patients on which the analysis was performed.
    [58] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QTcF Change from baseline Day 1 post dose

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    End point title
    		 QTcF Change from baseline Day 1 post dose
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker were excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm were also excluded.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    95 [59]
    96 [60]
    Units: ms
        arithmetic mean (standard deviation)
    -0.7 ± 11.2
    0.6 ± 10.2
    Notes
    [59] - This is the actual number of patients on which the analysis was performed.
    [60] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QRS Change from baseline Day 1 post dose

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    End point title
    		 QRS Change from baseline Day 1 post dose
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker were excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm were also excluded.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    95 [61]
    96 [62]
    Units: ms
        arithmetic mean (standard deviation)
    0.8 ± 3.8
    0.5 ± 3.8
    Notes
    [61] - This is the actual number of patients on which the analysis was performed.
    [62] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QTcF Change from baseline Day 42 Post dose

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    End point title
    		 QTcF Change from baseline Day 42 Post dose
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker were excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm were also excluded.
    End point type
    Secondary
    End point timeframe
    Day 42
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    95 [63]
    96 [64]
    Units: ms
        arithmetic mean (standard deviation)
    1.8 ± 14.1
    -1 ± 14.1
    Notes
    [63] - This is the actual number of patients on which the analysis was performed.
    [64] - This is the actual number of patients on which the analysis was performed
    No statistical analyses for this end point

    Secondary: HR Change from baseline Day 42 Post dose

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    End point title
    		 HR Change from baseline Day 42 Post dose
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker were excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm were also excluded.
    End point type
    Secondary
    End point timeframe
    Day 42
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    95 [65]
    96 [66]
    Units: bpm
        arithmetic mean (standard deviation)
    -3.6 ± 8.9
    -2.2 ± 10.8
    Notes
    [65] - This is the actual number of patients on which the analysis was performed.
    [66] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: PR Change from baseline Day 42 post dose

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    End point title
    		 PR Change from baseline Day 42 post dose
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker were excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm were also excluded.
    End point type
    Secondary
    End point timeframe
    Day 42
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    95 [67]
    96 [68]
    Units: ms
        arithmetic mean (standard deviation)
    0.9 ± 12.9
    1.1 ± 11.5
    Notes
    [67] - This is the actual number of patients on which the analysis was performed.
    [68] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: PR Change from baseline Day 1 post dose

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    End point title
    		 PR Change from baseline Day 1 post dose
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker were excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm were also excluded.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    95 [69]
    96 [70]
    Units: ms
        arithmetic mean (standard deviation)
    -1 ± 8.5
    -0.8 ± 9.5
    Notes
    [69] - This is the actual number of patients on which the analysis was performed.
    [70] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: QRS Change from baseline Day 42 post dose

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    End point title
    		 QRS Change from baseline Day 42 post dose
    End point description
    Baseline is the average of the 3 individual pre-dose values on Day 1 in each treatment period. Patients with a pacemaker were excluded from this summary. ECGs at a timepoint with Atrial Fibrillation, Atrial Flutter or Ectopic Supraventricular Rhythm were also excluded.
    End point type
    Secondary
    End point timeframe
    Day 42
    End point values
    		 CHF5259 pMDI - safety population Placebo pMDI - safety population
    Number of subjects analysed
    95 [71]
    96 [72]
    Units: ms
        arithmetic mean (standard deviation)
    0.4 ± 4.7
    -0.1 ± 5.3
    Notes
    [71] - This is the actual number of patients on which the analysis was performed.
    [72] - This is the actual number of patients on which the analysis was performed.
    No statistical analyses for this end point

    Secondary: Percentage asthma control days

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    End point title
    		 Percentage asthma control days
    End point description
    An asthma control day is derived from patient diary data, and is defined as any day during the treatment period that has a total asthma score of 0 (nighttime plus daytime) and where no rescue medication was used. The percentage is calculated as the number of asthma control days / number of days with available data.
    End point type
    Secondary
    End point timeframe
    Daily during run-in and treatment periods.
    End point values
    		 CHF5259 pMDI - ITT population Placebo pMDI - ITT population
    Number of subjects analysed
    97 [73]
    97 [74]
    Units: percent
        arithmetic mean (standard deviation)
    21.7 ± 32.3
    19.4 ± 28.5
    Notes
    [73] - This is the actual number of patients on which the analysis was performed.
    [74] - This is the actual number of patientson which the analysis was performed.
    Statistical analysis title
    		 CHF 5259 pMDI vs Placebo pMDI
    Statistical analysis description
    In a Cross-over study, groups examined should not be added up. The number N=194 (subject analysis set) is an innate error of the EudraCT database system.
    Comparison groups
    CHF5259 pMDI - ITT population v Placebo pMDI - ITT population
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [75]
    P-value
    		 = 0.188
    Method
    		 ANOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 6.2
    Notes
    [75] - Percentage of Daily Asthma Control Days was analysed by means of an ANOVA model with treatment, patient and period as fixed effects

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At each visit, from screening (Visit 1) to follow-up (Visit 6) or, in case, at early termination
    Adverse event reporting additional description
    Overall, 31 TEAEs were reported in 20 (20.4%) patients during the treatment periods. The number of TEAEs was higher during treatment with CHF 5259 pMDI than placebo, but the number of patients was similar between the treatments (20 events in13 [13.4%] patients with CHF 5259 and 11 events in 11 [11.2%] patients with placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    CHF5259 pMDI
    Reporting group description
    		 No serious TEAEs, ADRs, serious ADRs, TEAEs leading to study discontinuation or TEAEs leading to death were reported during the study.

    Reporting group title
    Placebo pMDI
    Reporting group description
    		 No serious TEAEs, ADRs, serious ADRs, TEAEs leading to study discontinuation or TEAEs leading to death were reported during the study.

    Serious adverse events
    		 CHF5259 pMDI Placebo pMDI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 97 (0.00%)
    0 / 98 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 CHF5259 pMDI Placebo pMDI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 97 (13.40%)
    11 / 98 (11.22%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
    Additional description: 1 mild TEAE of worsening asthma symptoms was reported for one patient during treatment with placebo. This TEAE was not considered by the investigator as an episode of asthma exacerbation.
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Weight increased
         subjects affected / exposed
    2 / 97 (2.06%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Forearm fracture
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Neuritis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    1 / 97 (1.03%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 97 (4.12%)
    3 / 98 (3.06%)
         occurrences all number
    4
    3
    Fungal skin infection
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 97 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    Periodontitis
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Skin bacterial infection
         subjects affected / exposed
    1 / 97 (1.03%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    There are no limitations or caveats to this summary of results.
    For support, Contact us.
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