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    Clinical Trial Results:
    A multicentre, randomized double-blind placebo-controlled 3-period complete cross-over study to assess the bronchodilator effects and safety of glycopyrronium bromide (NVA237) (25 μg and 50 μg o.d.) in asthma patients Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2015-005565-23
    Trial protocol
    		 DE   BE   LV   LT  
    Global end of trial date
    29 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2018
    First version publication date
    22 Dec 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CQVM149B2204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03137784
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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
    29 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the bronchodilator effects of NVA237 delivered by the Concept1 single-dose dry-powder inhaler in patients with asthma in terms of trough forced expiratory volume in one second (trough forced expiratory volume in one second (FEV1), mean of 23 h 15 min and 23 h 45 min post-dose) following one week of treatment, by comparing NVA237 at a dose of 25 μg and 50 μg o.d. with Placebo.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Latvia: 12
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    United States: 68
    Worldwide total number of subjects
    148
    EEA total number of subjects
    64
    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)
    145
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study used a randomized, double-blind, placebo controlled, 3-period cross-over clinical trial design.

    Period 1
    Period 1 title
    Overall study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 1(NVA237 50 ug/NVA237 25 ug/placebo)
    Arm description
    		 Treatment sequence: NVA 237 50 ug, 25 ug and placebo
    Arm type
    		 Sequence 1

    Investigational medicinal product name
    glycopyrronium bromide
    Investigational medicinal product code
    NVA237
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Oral use
    Dosage and administration details
    50 ug

    Arm title
    		 2(NVA237 50 ug/placebo/NVA237 25 ug)
    Arm description
    		 Treatment sequence: NVA 237 50 ug, placebo and 25 ug
    Arm type
    		 Sequence 2

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 3 (NVA237 25 ug/NVA237 50 ug/placebo)
    Arm description
    		 Treatment sequence: NVA237 25 ug, 50 ug and placebo
    Arm type
    		 Sequence 3

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 4 (NVA237 25 ug/placebo/NVA237 50 ug)
    Arm description
    		 Treatment sequence: NVA 237 25 ug, placebo and 50 ug
    Arm type
    		 Sequence 4

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 5 (placebo/NVA237 50 ug/ NVA237 25 ug)
    Arm description
    		 Treatment sequence: Placebo, NVA237 50 ug and 25 ug
    Arm type
    		 Sequence 5

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 6 (placebo/ NVA237 25 ug/NVA237 50 ug)
    Arm description
    		 Treatment sequence: placebo, NVA237 25 ug and 50 ug
    Arm type
    		 Sequence 6

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		1(NVA237 50 ug/NVA237 25 ug/placebo) 2(NVA237 50 ug/placebo/NVA237 25 ug) 3 (NVA237 25 ug/NVA237 50 ug/placebo) 4 (NVA237 25 ug/placebo/NVA237 50 ug) 5 (placebo/NVA237 50 ug/ NVA237 25 ug) 6 (placebo/ NVA237 25 ug/NVA237 50 ug)
    Started
    24
    25
    25
    24
    25
    25
    Completed
    22
    24
    25
    24
    24
    25
    Not completed
    2
    1
    0
    0
    1
    0
         Adverse event, non-fatal
    1
    1
    -
    -
    -
    -
         Non-compliance with study treatment
    -
    -
    -
    -
    1
    -
         Subject/guardian decision
    1
    -
    -
    -
    -
    -
    Period 2
    Period 2 title
    Baseline
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 Baseline
    Arm description
    		 -
    Arm type
    		 Baseline

    Investigational medicinal product name
    glycopyrronium bromide
    Investigational medicinal product code
    NVA237
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Oral use
    Dosage and administration details
    50 ug

    Investigational medicinal product name
    NVA237 50 ug/NVA237 25 ug/placebo
    Investigational medicinal product code
    NVA237 50 ug/NVA237 25 ug/placebo
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Oral use
    Dosage and administration details
    NVA237 50 ug/NVA237 25 ug/placebo

    Investigational medicinal product name
    glycopyrronium bromide
    Investigational medicinal product code
    NVA237
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Oral use
    Dosage and administration details
    50 ug

    Investigational medicinal product name
    glycopyrronium bromide
    Investigational medicinal product code
    NVA237
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Oral use
    Dosage and administration details
    50 ug

    Investigational medicinal product name
    NVA237 50 ug/NVA237 25 ug/placebo
    Investigational medicinal product code
    NVA237 50 ug/NVA237 25 ug/placebo
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Oral use
    Dosage and administration details
    NVA237 50 ug/NVA237 25 ug/placebo

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline added to complete record
    Number of subjects in period 2
    		Baseline
    Started
    148
    Completed
    145
    Not completed
    3
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    2

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 148 148
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 145 145
        From 65-84 years
    		 3 3
        85 years and over
    		 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 47.3 ( 11.8 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 75 75
        Male
    		 73 73
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0
        Asian
    		 16 16
        Native Hawaiian or Other Pacific Islander
    		 0
        Black or African American
    		 12 12
        White
    		 120 120
        More than one race
    		 0
        Unknown or Not Reported
    		 0
    Subject analysis sets

    Subject analysis set title
    All participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants randomized to one of six treatment sequences

    Subject analysis set title
    NVA237 50 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 50 g capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo

    Subject analysis set title
    NVA237 50 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 50 g capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    NVA237 50 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 50 g capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo

    Subject analysis set title
    NVA237 50 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 50 g capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis sets values
    		 All participants NVA237 50 ug NVA237 25 ug Placebo NVA237 50 ug NVA237 25 ug NVA237 50 ug NVA237 25 ug Placebo NVA237 25 ug NVA237 25 ug Placebo NVA237 50 ug NVA237 25 ug
    Number of subjects
    148
    144
    142
    146
    146
    143
    141
    138
    143
    144
    145
    144
    147
    146
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    47.3 ( 11.8 )
    Sex: Female, Male
    Units: Subjects
        Female
    75
        Male
    73
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0
        Asian
    16
        Native Hawaiian or Other Pacific Islander
    0
        Black or African American
    12
        White
    120
        More than one race
    0
        Unknown or Not Reported
    0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    1(NVA237 50 ug/NVA237 25 ug/placebo)
    Reporting group description
    		 Treatment sequence: NVA 237 50 ug, 25 ug and placebo

    Reporting group title
    2(NVA237 50 ug/placebo/NVA237 25 ug)
    Reporting group description
    		 Treatment sequence: NVA 237 50 ug, placebo and 25 ug

    Reporting group title
    3 (NVA237 25 ug/NVA237 50 ug/placebo)
    Reporting group description
    		 Treatment sequence: NVA237 25 ug, 50 ug and placebo

    Reporting group title
    4 (NVA237 25 ug/placebo/NVA237 50 ug)
    Reporting group description
    		 Treatment sequence: NVA 237 25 ug, placebo and 50 ug

    Reporting group title
    5 (placebo/NVA237 50 ug/ NVA237 25 ug)
    Reporting group description
    		 Treatment sequence: Placebo, NVA237 50 ug and 25 ug

    Reporting group title
    6 (placebo/ NVA237 25 ug/NVA237 50 ug)
    Reporting group description
    		 Treatment sequence: placebo, NVA237 25 ug and 50 ug
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Subject analysis set title
    All participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants randomized to one of six treatment sequences

    Subject analysis set title
    NVA237 50 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 50 g capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo

    Subject analysis set title
    NVA237 50 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 50 g capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    NVA237 50 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 50 g capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo

    Subject analysis set title
    NVA237 50 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 50 g capsule

    Subject analysis set title
    NVA237 25 ug
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NVA237 25 μg capsule

    Primary: Trough FEV1 after one week of treatment

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    End point title
    		 Trough FEV1 after one week of treatment
    End point description
    To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared to placebo in terms of trough FEV1 (mean of 23h 15 min and 23 h 45 min post -dose) following 1 week of treatment in the respective treatment period. Trough FEV1 was assessed by performing spirometry measurements in the clinic for each treatment period. For the primary efficacy variable, trough FEV1 is the mean of two measurements taken at 23h 15 min and 23h 45 min post dose.
    End point type
    Primary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 NVA237 50 ug NVA237 25 ug Placebo
    Number of subjects analysed
    144
    142
    146
    Units: Liters
        least squares mean (standard error)
    2.392 ( 0.0249 )
    2.392 ( 0.0250 )
    2.303 ( 0.0247 )
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.089
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.047
         upper limit
    		 0.132
    Notes
    [1] - Treatment difference
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.047
         upper limit
    		 0.132

    Secondary: FEV1 AUC (5 min-1 h) after one week of treatment

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    End point title
    		 FEV1 AUC (5 min-1 h) after one week of treatment
    End point description
    To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 5min-1h)
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 Placebo NVA237 50 ug NVA237 25 ug
    Number of subjects analysed
    146
    146
    143
    Units: Liters
        least squares mean (standard error)
    2.324 ( 0.0227 )
    2.489 ( 0.0226 )
    2.492 ( 0.0228 )
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.165
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.127
         upper limit
    		 0.203
    Notes
    [2] - Treatment difference
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.168
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.129
         upper limit
    		 0.206
    Notes
    [3] - Treatment difference

    Secondary: FEV1 AUC (5 min-4 h) after one week of treatment

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    End point title
    		 FEV1 AUC (5 min-4 h) after one week of treatment
    End point description
    To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day (AUC 5min-4h)
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 Placebo NVA237 50 ug NVA237 25 ug
    Number of subjects analysed
    146
    146
    143
    Units: Liters
        least squares mean (standard error)
    2.346 ( 0.0223 )
    2.522 ( 0.0223 )
    2.525 ( 0.0224 )
    Statistical analysis title
    		 AUC FEV1
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.176
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.141
         upper limit
    		 0.212
    Notes
    [4] - Treatment difference
    Statistical analysis title
    		 AUC FEV1
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.179
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.144
         upper limit
    		 0.215
    Notes
    [5] - Treatment difference

    Secondary: FEV1 AUC (5 min – 23 h 45 min) after one week of treatment

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    End point title
    		 FEV1 AUC (5 min – 23 h 45 min) after one week of treatment
    End point description
    To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Standardized FEV1 AUC following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The standardized AUC FEV1 was calculated as the sum of trapezoids divided by the length of time over an entire day AUC (5 min – 23 h 45 min)
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 Placebo NVA237 50 ug NVA237 25 ug
    Number of subjects analysed
    146
    146
    143
    Units: Liters
        least squares mean (standard error)
    2.304 ( 0.0226 )
    2.443 ( 0.0226 )
    2.450 ( 0.0227 )
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.139
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.106
         upper limit
    		 0.173
    Notes
    [6] - Treatment difference
    Statistical analysis title
    		 Treatment difference
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.146
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.112
         upper limit
    		 0.179
    Notes
    [7] - Treatment difference

    Secondary: Peak FEV1 during 4 Hours post-dose after 1 week of treatment

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    End point title
    		 Peak FEV1 during 4 Hours post-dose after 1 week of treatment
    End point description
    To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of Peak FEV1 following 1 week of treatment in the respective treatment period. FEV1 was measured with spirometry conducted according to internationally accepted standards. The peak effect following 1 week of treatment was defined as the maximum FEV1 during the first 4 hour on that day.
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 Placebo NVA237 50 ug NVA237 25 ug
    Number of subjects analysed
    146
    146
    143
    Units: Liters
        least squares mean (standard error)
    2.457 ( 0.0228 )
    2.621 ( 0.0228 )
    2.630 ( 0.0229 )
    Statistical analysis title
    		 Peak FEV1
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.164
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.127
         upper limit
    		 0.201
    Notes
    [8] - Treatment difference
    Statistical analysis title
    		 Peak FEV1
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.174
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.137
         upper limit
    		 0.211
    Notes
    [9] - Treatment difference

    Secondary: Trough Forced Vital Capacity (FVC) after 1 week of treatment

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    End point title
    		 Trough Forced Vital Capacity (FVC) after 1 week of treatment
    End point description
    To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of FVC following 1 week of treatment in respective treatment period. Trough Forced Vital Capacity (FVC) following 7 Days. FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 NVA237 50 ug NVA237 25 ug Placebo
    Number of subjects analysed
    144
    142
    146
    Units: Liters
        least squares mean (standard error)
    3.509 ( 0.0268 )
    3.530 ( 0.0269 )
    3.472 ( 0.0267 )
    Statistical analysis title
    		 Trough Forced Vital Capacity (FVC)
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.079
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.036
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.004
         upper limit
    		 0.077
    Notes
    [10] - Treatment difference
    Statistical analysis title
    		 Trough Forced Vital Capacity (FVC)
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.006
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    0.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.017
         upper limit
    		 0.099
    Notes
    [11] - Treatment difference

    Secondary: FEV1/FVC ratio

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    End point title
    		 FEV1/FVC ratio
    End point description
    To evaluate the bronchodilator effects of NVA237 (25 ug and 50 ug) compared with placebo in terms of FEV1/FVC ratio following 1 week of treatment in respective treatment period
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 NVA237 50 ug NVA237 25 ug Placebo
    Number of subjects analysed
    141
    138
    143
    Units: Ratio
        arithmetic mean (standard deviation)
    0.018 ( 0.0421 )
    0.016 ( 0.0438 )
    0.003 ( 0.0398 )
    No statistical analyses for this end point

    Secondary: Mean Morning Peak Expiratory Flow (PEF) Following the 1-week Treatment Period

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    End point title
    		 Mean Morning Peak Expiratory Flow (PEF) Following the 1-week Treatment Period
    End point description
    A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. Patients were encouraged to perform morning and evening PEF measurements before the use of any LABA or rescue medication. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits LS Mean of change from baseline in mean morning PEF is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 Placebo NVA237 50 ug NVA237 25 ug
    Number of subjects analysed
    146
    146
    144
    Units: L/min
        least squares mean (standard error)
    369.58 ( 2.958 )
    395.09 ( 2.948 )
    393.87 ( 2.962 )
    Statistical analysis title
    		 Peak Expiratory Flow (PEF)
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    25.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.22
         upper limit
    		 31.79
    Notes
    [12] - Treatment difference
    Statistical analysis title
    		 Peak Expiratory Flow (PEF)
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    24.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 17.99
         upper limit
    		 30.59
    Notes
    [13] - Treatment difference

    Secondary: Mean Evening peak expiratory flow rate (PEF) Following 1-week Treatment

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    End point title
    		 Mean Evening peak expiratory flow rate (PEF) Following 1-week Treatment
    End point description
    A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. Patients were encouraged to perform morning and evening PEF measurements before the use of any LABA or rescue medication. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits. LS Mean of change from baseline in mean morning PEF is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 NVA237 50 ug NVA237 25 ug Placebo
    Number of subjects analysed
    146
    145
    144
    Units: L/min
        least squares mean (standard error)
    409.66 ( 2.928 )
    408.08 ( 2.934 )
    378.72 ( 2.949 )
    Statistical analysis title
    		 Peak Expiratory Flow (PEF)
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    30.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.07
         upper limit
    		 36.82
    Notes
    [14] - Treatment difference
    Statistical analysis title
    		 Peak Expiratory Flow (PEF)
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 < 0.001
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    29.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 23.47
         upper limit
    		 35.26
    Notes
    [15] - Treatment difference

    Secondary: Mean daily number of puffs of rescue medication during 1 week of

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    End point title
    		 Mean daily number of puffs of rescue medication during 1 week of
    End point description
    A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. daytime and nighttime (combined) number of puffs is defined as the average of the respective number of puffs.
    End point type
    Secondary
    End point timeframe
    Following 1 week of treatment
    End point values
    		 Placebo NVA237 50 ug NVA237 25 ug
    Number of subjects analysed
    146
    147
    146
    Units: Number of puffs
        least squares mean (standard error)
    1.13 ( 0.094 )
    0.98 ( 0.094 )
    1.02 ( 0.094 )
    Statistical analysis title
    		 Mean daily number of puffs
    Comparison groups
    NVA237 50 ug v Placebo
    Number of subjects included in analysis
    293
    Analysis specification
    Pre-specified
    Analysis type
    		 [16]
    P-value
    		 = 0.053
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0
    Notes
    [16] - Treatment difference
    Statistical analysis title
    		 Mean daily number of puffs
    Comparison groups
    NVA237 25 ug v Placebo
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    P-value
    		 = 0.163
    Method
    		 Linear Mixed Model
    Parameter type
    		 Linear Mixed Model (LMM)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.05
    Notes
    [17] - Treatment difference

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    NVA237 50 ug
    Reporting group description
    		 NVA237 50 ug

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    NVA237 25 ug
    Reporting group description
    		 NVA237 25 ug

    Serious adverse events
    		 NVA237 50 ug Placebo NVA237 25 ug
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 146 (0.00%)
    1 / 146 (0.68%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 146 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Patellofemoral pain syndrome
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 146 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 NVA237 50 ug Placebo NVA237 25 ug
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 147 (6.80%)
    11 / 146 (7.53%)
    11 / 146 (7.53%)
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    1 / 147 (0.68%)
    2 / 146 (1.37%)
    0 / 146 (0.00%)
         occurrences all number
    1
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 147 (0.68%)
    2 / 146 (1.37%)
    0 / 146 (0.00%)
         occurrences all number
    1
    2
    0
    Headache
         subjects affected / exposed
    5 / 147 (3.40%)
    2 / 146 (1.37%)
    2 / 146 (1.37%)
         occurrences all number
    5
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 146 (0.00%)
    2 / 146 (1.37%)
         occurrences all number
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 146 (0.00%)
    2 / 146 (1.37%)
         occurrences all number
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 146 (0.68%)
    2 / 146 (1.37%)
         occurrences all number
    0
    1
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 147 (1.36%)
    3 / 146 (2.05%)
    1 / 146 (0.68%)
         occurrences all number
    2
    3
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 146 (0.68%)
    3 / 146 (2.05%)
         occurrences all number
    1
    1
    3

    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.
    Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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