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    Clinical Trial Results:
    A randomized, double-blind, parallel group, 26-week study evaluating the efficacy, safety and tolerability of NVA237 given once or twice daily, in patients with moderate and severe chronic obstructive pulmonary disease

    Summary
    EudraCT number
    		 2014-004818-28
    Trial protocol
    		 DE   FI   HU   BE   SE   GB   BG   PL   RO   IT  
    Global end of trial date
    16 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2017
    First version publication date
    30 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CNVA237A2320,
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02371629
    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,
    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
    16 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the efficacy of NVA237 22 μg twice daily (b.i.d.) versus 44 μg once daily (o.d.) (both delivered via a Concept1) in terms of trough forced expiratory volume in the first second (FEV1) (defined as mean evaluation at 23 hours 15 minutes and 23 hours 45 minutes post-dose) following 12 weeks of treatment in patients with stable, symptomatic chronic obstructive pulmonary disease (COPD) with moderate to severe airflow limitation (Stages 2 and 3) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD 2014).
    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
    24 Jun 2015
    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: 19
    Country: Number of subjects enrolled
    Bulgaria: 152
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    Germany: 192
    Country: Number of subjects enrolled
    Hungary: 85
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Poland: 94
    Country: Number of subjects enrolled
    Romania: 103
    Country: Number of subjects enrolled
    Russian Federation: 107
    Country: Number of subjects enrolled
    Sweden: 16
    Worldwide total number of subjects
    776
    EEA total number of subjects
    663
    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)
    418
    From 65 to 84 years
    358
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 1020 patients were screened for participation in this study; 776 were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NVA237 Twice daily
    Arm description
    		 Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glycopyrronium bromide
    Investigational medicinal product code
    NVA237
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg

    Arm title
    		 NVA237 Once daily
    Arm description
    		 Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    glycopyrronium bromide
    Investigational medicinal product code
    NVA237
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 22 μg

    Number of subjects in period 1
    		NVA237 Twice daily NVA237 Once daily
    Started
    388
    388
    Completed
    362
    363
    Not completed
    26
    25
         Adverse event, serious fatal
    1
    1
         Physician decision
    2
    3
         Patient decision
    14
    10
         Adverse event, non-fatal
    8
    8
         Protocol deviation
    -
    1
         Noncompliance with study treatment
    1
    -
         Lack of efficacy
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NVA237 Twice daily
    Reporting group description
    		 Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.

    Reporting group title
    NVA237 Once daily
    Reporting group description
    		 Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.

    Reporting group values
    		 NVA237 Twice daily NVA237 Once daily Total
    Number of subjects
    		 388 388 776
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 216 202 418
        From 65-84 years
    		 172 186 358
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.2 ± 7.71 63.6 ± 7.66 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 122 111 233
        Male
    		 266 277 543

    End points

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    End points reporting groups
    Reporting group title
    NVA237 Twice daily
    Reporting group description
    		 Patients randomized to this arm received an NVA237 22 μg capsule in the morning and evening for 26 weeks. All participants received salbutamol as rescue medicine.

    Reporting group title
    NVA237 Once daily
    Reporting group description
    		 Patients randomized to this arm received an NVA237 44 μg capsule in the morning and a placebo capsule in the evening for 26 weeks. All participants received salbutamol as rescue medicine.

    Primary: Change from baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12

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    End point title
    		 Change from baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12
    End point description
    Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1 at Week 12. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    358
    360
    Units: Liters
        least squares mean (standard error)
    0.092 ± 0.0126
    0.059 ± 0.0125
    Statistical analysis title
    		 Trough Forced (FEV1) at Week 12
    Comparison groups
    NVA237 Twice daily v NVA237 Once daily
    Number of subjects included in analysis
    718
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.051
    Method
    		 Mixed model for repeated measure (MMRM)
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.066
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0169

    Secondary: Change from baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in one second (FEV1) for different time spans post dosing at Week 12

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    End point title
    		 Change from baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in one second (FEV1) for different time spans post dosing at Week 12
    End point description
    The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 12 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 12
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    373
    373
    Units: Liters
    least squares mean (standard error)
        AUC (0-12 hour) (n=373, 373)
    0.136 ± 0.0119
    0.106 ± 0.0118
        AUC (0-24 hour) (n=373, 373)
    0.085 ± 0.0121
    0.043 ± 0.0120
        AUC (12-24 hour) (n=371, 371)
    0.035 ± 0.0125
    -0.019 ± 0.0124
    No statistical analyses for this end point

    Secondary: Change from baseline in Area Under The Curve (AUC 0-12 hour) for Forced Expiratory Volume in one second (FEV1) post dosing at Day 1

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    End point title
    		 Change from baseline in Area Under The Curve (AUC 0-12 hour) for Forced Expiratory Volume in one second (FEV1) post dosing at Day 1
    End point description
    The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for 0-12 hour, post dosing at Day 1 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, 0-12 hour post dose at Day 1
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    387
    387
    Units: Liters
        least squares mean (standard error)
    0.143 ± 0.0089
    0.139 ± 0.0087
    No statistical analyses for this end point

    Secondary: Change from baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in one second (FEV1) for different time spans post dosing at Week 26

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    End point title
    		 Change from baseline in Area Under The Curve (AUC) for Forced Expiratory Volume in one second (FEV1) for different time spans post dosing at Week 26
    End point description
    The standardized Area Under the Curve (AUC) for Forced Expiratory Volume in one second (FEV1) is assessed for different time spans (0-12h, 0-24h, 12-24h) within the overall serial measurement post dosing at week 26 of treatment. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, 0-12 hour, 0-24 hour , 12-24 hour post dose at Week 26
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    360
    364
    Units: Liters
    least squares mean (standard error)
        AUC (0-12 hour) (n=360, 363)
    0.123 ± 0.0121
    0.091 ± 0.0120
        AUC (0-24 hour) (n=360, 364)
    0.076 ± 0.0122
    0.030 ± 0.0121
        AUC (12-24 hour) (n=357, 361)
    0.032 ± 0.0127
    -0.028 ± 0.0126
    No statistical analyses for this end point

    Secondary: Change from baseline in total St. George's Respiratory Questionnaire (SGRQ) score at week 12 and week 26

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    End point title
    		 Change from baseline in total St. George's Respiratory Questionnaire (SGRQ) score at week 12 and week 26
    End point description
    The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: • Part I covers “Symptoms” and is concerned with respiratory symptoms, their frequency and severity • Part II covers “Activity” and is concerned with activities that caused or are limited by breathlessness • Part II is also concerned with “Impacts”, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. Higher values corresponded to greater impairment of health status.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 Weeks, 26 Weeks
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: score on a scale
    least squares mean (standard error)
        Change from Baseline to WK 12 (n=369, 369)
    -5.320 ± 0.6000
    -3.563 ± 0.5987
        Change from Baseline to WK 26 (n=357, 359)
    -6.587 ± 0.6543
    -4.644 ± 0.6527
    No statistical analyses for this end point

    Secondary: Percentage of patients with a clinically significant improvement in St George Respiratory Questionnaire at week 12 and week 26

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    End point title
    		 Percentage of patients with a clinically significant improvement in St George Respiratory Questionnaire at week 12 and week 26
    End point description
    The health status, as reported by the patients, is assessed using the St. George's Respiratory Questionnaire (SGRQ). The SGRQ contains 50 items divided into 2 parts covering 3 aspects of health related to COPD: • Part I covers “Symptoms” and is concerned with respiratory symptoms, their frequency and severity • Part II covers “Activity” and is concerned with activities that caused or are limited by breathlessness • Part II is also concerned with “Impacts”, which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score was calculated for each of these three subscales and the total score was calculated. In each case, the lowest possible value was 0 and the highest 100. A clinically significant improvement is defined as ≥ 4 unit improvement from baseline score (a decrease of ≥ 4).
    End point type
    Secondary
    End point timeframe
    Baseline, 12 Weeks, 26 Weeks
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: percentage of patients
    number (not applicable)
        Change from Baseline to WK 12 (n=369, 369)
    54.5
    46.9
        Change from Baseline to WK 26 (n=357, 359)
    59.4
    49.6
    No statistical analyses for this end point

    Secondary: Change from baseline in Transitional Dyspnea Index (TDI) focal score at Week 12 and Week 26

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    End point title
    		 Change from baseline in Transitional Dyspnea Index (TDI) focal score at Week 12 and Week 26
    End point description
    Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 Weeks, 26 Weeks
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: score on a scale
    least squares mean (standard error)
        Change from Baseline to WK 12 (n=360, 356)
    1.346 ± 0.1430
    0.849 ± 0.1433
        Change from Baseline to WK 26 (n=347, 348)
    1.523 ± 0.1539
    1.170 ± 0.1534
    No statistical analyses for this end point

    Secondary: Percentage of patients with a clinically important improvement on Transitional Dyspnea Index (TDI) focal score at Week 12 and Week 26

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    End point title
    		 Percentage of patients with a clinically important improvement on Transitional Dyspnea Index (TDI) focal score at Week 12 and Week 26
    End point description
    Breathlessness at Week 12 and Week 26 is measured using the Transition Dyspnea Index (TDI). On day 1, breathlessness is assessed by the Baseline Dyspnea Index (BDI). Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort and captures changes from baseline. BDI was measured at day 1 prior to the first dose with domain scores ranging from 0=very severe to 4=no impairment and a total score ranging from 0 to 12(best). TDI captures changes from baseline. Each domain is scored from -3=major deterioration to 3=major improvement to give an overall TDI focal score of -9 to 9. Higher numbers indicate a better score. Clinically important improvement indicates ≥ 1 unit in the TDI focal score at Weeks 12 and 26 in comparison to BDI focal score (an increase of ≥ 1).
    End point type
    Secondary
    End point timeframe
    Baseline, 12 Weeks, 26 Weeks
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: Percentage of patients
    number (not applicable)
        Change from Baseline to WK 12 (n=360, 356)
    56.9
    52.0
        Change from Baseline to WK 26 (n=347, 348)
    61.1
    54.6
    No statistical analyses for this end point

    Secondary: Change from baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26

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    End point title
    		 Change from baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 1 and Week 26
    End point description
    Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 defined as the mean of two measurements at 23 hours 15 minutes and 23 hour 45 minutes post dosing. Baseline FEV1 was defined as the average of the -45 minutes and -15 minutes FEV1 values taken on Day 1. An analysis-of-covariance (ANCOVA) for repeated measurements, also known as mixed model for repeated measures (MMRM), was performed for the change from baseline of trough FEV1. The model included treatment, COPD severity, baseline smoking status, baseline ICS use, region, and visit (Day 1, and Weeks 12 and 26) as factors and baseline FEV1 as a covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1, Week 26
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: Liters
    least squares mean (standard error)
        Change from baseline to Day 1 (n= 381, 381)
    0.119 ± 0.0099
    0.070 ± 0.0097
        Change from baseline to Week 26 (n= 341, 349)
    0.104 ± 0.0129
    0.056 ± 0.0128
    No statistical analyses for this end point

    Secondary: Change from baseline in Forced Vital Capacity (FVC) at individual timepoints at week 26

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    End point title
    		 Change from baseline in Forced Vital Capacity (FVC) at individual timepoints at week 26
    End point description
    Mixed model for repeated measures was used to analyze change from baseline in FVC. Baseline FVC is defined as the average of the -45 min and -15 min FVC values taken on Day 1 prior to first dose.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 (Day 183)
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: Liters
    least squares mean (standard error)
        Day 183/-45 min: (n= 334, 342)
    0.079 ± 0.0195
    0.025 ± 0.0192
        Day 183/-15 min: (n= 340, 345)
    0.102 ± 0.0193
    0.029 ± 0.0191
        Day 183/5 min: (n= 335, 337)
    0.159 ± 0.0194
    0.085 ± 0.0194
        Day 183/15 min: (n= 333, 334)
    0.177 ± 0.0195
    0.132 ± 0.0195
        Day 183/30 min: (n= 344, 346)
    0.194 ± 0.0192
    0.144 ± 0.0191
        Day 183/1 h: (n= 335, 343)
    0.190 ± 0.0194
    0.154 ± 0.0192
        Day 183/2 h:(n= 340, 345)
    0.229 ± 0.0193
    0.200 ± 0.0191
        Day 183/3 h: (n=327, 344)
    0.229 ± 0.0197
    0.186 ± 0.0192
        Day 183/4 h: (n=335, 347)
    0.216 ± 0.0194
    0.169 ± 0.0191
        Day 183/6 h:(n= 330, 347)
    0.146 ± 0.0196
    0.116 ± 0.0191
        Day 183/8 h: (n= 331, 341)
    0.137 ± 0.0195
    0.085 ± 0.0193
        Day 183/10 h: (n= 323, 345)
    0.071 ± 0.0198
    0.039 ± 0.0191
        Day 183/12 h:(n= 318, 331)
    0.041 ± 0.0200
    0.026 ± 0.0196
        Day 183/13 h: (n= 320, 326)
    0.096 ± 0.0199
    0.004 ± 0.0197
        Day 184/16 h: (n= 295, 298)
    -0.014 ± 0.0207
    -0.081 ± 0.0206
        Day 184/22 h: (n=323, 333)
    -0.036 ± 0.0198
    -0.076 ± 0.0195
        Day 184/23 h 15 min: (n=314, 336)
    0.075 ± 0.0201
    0.031 ± 0.0194
        Day 184/23 h 45 min: (n=325, 329)
    0.129 ± 0.0197
    0.077 ± 0.0196
    No statistical analyses for this end point

    Secondary: Change from baseline in Inspiratory Capacity (IC) at individual timepoints at week 26

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    End point title
    		 Change from baseline in Inspiratory Capacity (IC) at individual timepoints at week 26
    End point description
    Mixed model for repeated measures was used to analyze change from baseline in IC.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 (Day 183)
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: Liters
    least squares mean (standard error)
        Day 183/-20 min: (n= 225, 224)
    0.094 ± 0.0221
    0.054 ± 0.0221
        Day 183/25 min: (n= 220, 237)
    0.181 ± 0.0224
    0.173 ± 0.0215
        Day 183/1 h 55 min:: (n= 222, 232)
    0.193 ± 0.0223
    0.171 ± 0.0218
        Day 183/3 h 55 min: (n= 215, 225)
    0.163 ± 0.0226
    0.159 ± 0.0221
        Day 183/7 h 55 min: (n= 213, 223)
    0.108 ± 0.0228
    0.110 ± 0.0222
        Day 183/11 h 55 min: (n= 210, 231)
    0.042 ± 0.0229
    0.030 ± 0.0218
        Day 184/23 h 40 min:(n= 203, 221)
    0.045 ± 0.0233
    0.062 ± 0.0224
    No statistical analyses for this end point

    Secondary: Change from baseline in Forced Expiratory Volume in one second (FEV1) at individual timepoints at week 26

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    End point title
    		 Change from baseline in Forced Expiratory Volume in one second (FEV1) at individual timepoints at week 26
    End point description
    Mixed model for repeated measures was used to analyze change from baseline in FEV1. Baseline FEV1 is defined as the average of the -45 min and -15 min FEV1 values taken on Day 1 prior to first dose.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 (Day 183)
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: Liters
    least squares mean (standard error)
        Day 183/-45 min: (n= 334, 342)
    0.058 ± 0.0120
    0.012 ± 0.0119
        Day 183/-15 min: (n= 340, 345)
    0.086 ± 0.0119
    0.034 ± 0.0118
        Day 183/5 min: (n= 335, 337)
    0.111 ± 0.0120
    0.070 ± 0.0119
        Day 183/15 min: (n= 333, 334)
    0.145 ± 0.0120
    0.106 ± 0.0120
        Day 183/30 min: (n= 344, 346)
    0.155 ± 0.0118
    0.122 ± 0.0118
        Day 183/1 h: (n= 335, 343)
    0.158 ± 0.0120
    0.132 ± 0.0118
        Day 183/2 h:(n= 340, 345)
    0.194 ± 0.0119
    0.163 ± 0.0118
        Day 183/3 h: (n=327, 344)
    0.179 ± 0.0121
    0.154 ± 0.0118
        Day 183/4 h: (n=335, 347)
    0.166 ± 0.0120
    0.132 ± 0.0118
        Day 183/6 h:(n= 330, 347)
    0.110 ± 0.0121
    0.080 ± 0.0118
        Day 183/8 h: (n= 331, 341)
    0.118 ± 0.0121
    0.064 ± 0.0119
        Day 183/10 h: (n= 323, 345)
    0.067 ± 0.0122
    0.038 ± 0.0118
        Day 183/12 h:(n= 318, 331)
    0.056 ± 0.0123
    0.024 ± 0.0121
        Day 183/13 h: (n= 320, 326)
    0.093 ± 0.0123
    0.000 ± 0.0121
        Day 184/16 h: (n= 295, 298)
    -0.001 ± 0.0128
    -0.063 ± 0.0127
        Day 184/22 h: (n=323, 333)
    -0.012 ± 0.0122
    -0.043 ± 0.0120
        Day 184/23 h 15 min: (n=314, 336)
    0.076 ± 0.0124
    0.032 ± 0.0120
        Day 184/23 h 45 min: (n=325, 329)
    0.122 ± 0.0122
    0.067 ± 0.0121
    No statistical analyses for this end point

    Secondary: Change from baseline in the percentage of days with no rescue medication use over the 26 weeks

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    End point title
    		 Change from baseline in the percentage of days with no rescue medication use over the 26 weeks
    End point description
    Patients report the number of puffs of rescue medication (salbutamol / albuterol) using an electronic diary. change from baseline in percentage of days without rescue medication usage over 26 weeks was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, 26 Weeks
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    383
    377
    Units: percentage of days
        least squares mean (standard error)
    16.574 ± 2.3519
    15.363 ± 2.3927
    No statistical analyses for this end point

    Secondary: Change from baseline in mean daily symptom score at Week 26

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    End point title
    		 Change from baseline in mean daily symptom score at Week 26
    End point description
    Patients reported symptoms by using an electronic diary. The mean daily total symptom score, the mean morning symptom score and the mean evening symptom score were calculated for each patient over 26 weeks. Only the scores for the 6 COPD symptoms (respiratory symptoms, cough, wheeze, production of sputum, sputum color, and breathlessness) were used to derive the total symptom score. Each symptom measured in a numeric rating scale of 0-10; 0 indicates no symptom and 10 indicates severe symptom. The daily score for an individual symptom score was the worst of the morning and evening scores on a particular day. If either the morning or evening score was missing for a symptom then the non-missing value was taken as the worst. A negative change indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 26 Weeks
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    383
    377
    Units: score on a scale
    least squares mean (standard error)
        Change in mean daily(n= 383, 377)
    -1.336 ± 0.1141
    -1.107 ± 0.1160
        Change in mean morning (n=374, 374)
    -1.032 ± 0.1304
    -0.828 ± 0.1318
        Change in mean evening (n= 372, 375)
    -1.205 ± 0.1141
    -1.056 ± 0.1152
    No statistical analyses for this end point

    Secondary: Number of patients with adverse events, serious adverse events and death

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    End point title
    		 Number of patients with adverse events, serious adverse events and death
    End point description
    This endpoint reports patients affected by any adverse events (AE), serious adverse events (SAE) and death. Only treatment emergent AE, SAE, deaths are reported for this endpoint.
    End point type
    Secondary
    End point timeframe
    26 Weeks
    End point values
    		 NVA237 Twice daily NVA237 Once daily
    Number of subjects analysed
    388
    388
    Units: Participants
        Patients with at least one AE
    203
    224
        Patients with at least one SAE
    33
    30
        Death
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    NVA237 44 mcg o.d.
    Reporting group description
    		 NVA237 44 mcg o.d.

    Reporting group title
    NVA237 22 mcg b.i.d.
    Reporting group description
    		 NVA237 22 mcg b.i.d.

    Serious adverse events
    		 NVA237 44 mcg o.d. NVA237 22 mcg b.i.d.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 388 (7.73%)
    33 / 388 (8.51%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer recurrent
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 388 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brachial plexus injury
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachiocephalic artery stenosis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 388 (0.52%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudoradicular syndrome
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Gastritis erosive
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    15 / 388 (3.87%)
    11 / 388 (2.84%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 388 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 388 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 388 (1.03%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 388 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 NVA237 44 mcg o.d. NVA237 22 mcg b.i.d.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    152 / 388 (39.18%)
    126 / 388 (32.47%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 388 (3.61%)
    10 / 388 (2.58%)
         occurrences all number
    14
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 388 (2.06%)
    4 / 388 (1.03%)
         occurrences all number
    8
    5
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    99 / 388 (25.52%)
    74 / 388 (19.07%)
         occurrences all number
    166
    141
    Dyspnoea
         subjects affected / exposed
    2 / 388 (0.52%)
    9 / 388 (2.32%)
         occurrences all number
    2
    10
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 388 (0.77%)
    10 / 388 (2.58%)
         occurrences all number
    4
    10
    Nasopharyngitis
         subjects affected / exposed
    54 / 388 (13.92%)
    37 / 388 (9.54%)
         occurrences all number
    67
    44

    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.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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