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    Clinical Trial Results:
    A 12-week treatment, multi-center, randomized, double-blind, parallel-group, placebo and active controlled study to assess the efficacy, safety, and tolerability of indacaterol maleate / glycopyrronium bromide in COPD patients with moderate to severe airflow limitation

    Summary
    EudraCT number
    		 2012-003347-30
    Trial protocol
    		 HU   SI   SK  
    Global end of trial date
    28 Feb 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    25 Jul 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CQVA149A2337
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01712516
    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 Pharmas 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
    28 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of QVA149 27.5/12.5 μg b.i.d. compared to monotherapy components, QAB149 27.5 μg b.i.d. and NVA237 12.5 μg b.i.d., in terms of standardized FEV1AUC0-12h at Week 12.
    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
    		 Salmeterol/albuterol inhaler
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2012
    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
    Colombia: 8
    Country: Number of subjects enrolled
    Egypt: 1
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Guatemala: 40
    Country: Number of subjects enrolled
    Hungary: 142
    Country: Number of subjects enrolled
    Panama: 12
    Country: Number of subjects enrolled
    Slovakia: 167
    Country: Number of subjects enrolled
    Slovenia: 20
    Country: Number of subjects enrolled
    United States: 597
    Worldwide total number of subjects
    1001
    EEA total number of subjects
    343
    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)
    565
    From 65 to 84 years
    429
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were randomized to each treatment arm in a 1:1:1:1 ratio.

    Pre-assignment
    Screening details
    		 One thousand one participants were randomized. (One participant was randomized twice, took study drug twice and was counted twice in the randomized and safety sets). In the safety set, participants were analyzed according to the treatment received.

    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
    		 QVA149
    Arm description
    		 27.5/12.5 ug twice daily (b.i.d.) via Single Dose Dry Powder Inhaler (SDDPI)
    Arm type
    		 Experimental

    Investigational medicinal product name
    QVA149
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    27.5/12.5 ug twice daily (b.i.d.) via Single Dose Dry Powder Inhaler (SDDPI)

    Arm title
    		 QAB149
    Arm description
    		 27.5 ug b.i.d.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    QAB149
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    27.5 ug b.i.d.

    Arm title
    		 NVA237
    Arm description
    		 12.5 ug b.i.d.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NVA237
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    12.5 ug b.i.d.

    Arm title
    		 Placebo
    Arm description
    		 b.i.d.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    b.i.d.

    Number of subjects in period 1
    		QVA149 QAB149 NVA237 Placebo
    Started
    250
    251
    251
    249
    Full analysis set
    250
    251
    250
    247
    Safety set
    250
    251
    251
    248
    Completed
    244
    241
    245
    236
    Not completed
    6
    10
    6
    13
         Adverse event, serious fatal
    -
    1
    -
    -
         Consent withdrawn by subject
    3
    9
    3
    9
         Physician decision
    2
    -
    -
    1
         Technical problems
    -
    -
    -
    2
         Protocol deviation
    1
    -
    1
    -
         Lost to follow-up
    -
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 27.5/12.5 ug twice daily (b.i.d.) via Single Dose Dry Powder Inhaler (SDDPI)

    Reporting group title
    QAB149
    Reporting group description
    		 27.5 ug b.i.d.

    Reporting group title
    NVA237
    Reporting group description
    		 12.5 ug b.i.d.

    Reporting group title
    Placebo
    Reporting group description
    		 b.i.d.

    Reporting group values
    		 QVA149 QAB149 NVA237 Placebo Total
    Number of subjects
    		 250 251 251 249 1001
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 143 130 144 148 565
        From 65-84 years
    		 106 118 104 101 429
        85 years and over
    		 1 3 3 0 7
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 62.8 ± 8.46 63.7 ± 8.58 63.1 ± 8.53 62.5 ± 8.07 -
    Gender, Male/Female
    Units: Participants
        Female
    		 96 101 107 111 415
        Male
    		 154 150 144 138 586

    End points

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    End points reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 27.5/12.5 ug twice daily (b.i.d.) via Single Dose Dry Powder Inhaler (SDDPI)

    Reporting group title
    QAB149
    Reporting group description
    		 27.5 ug b.i.d.

    Reporting group title
    NVA237
    Reporting group description
    		 12.5 ug b.i.d.

    Reporting group title
    Placebo
    Reporting group description
    		 b.i.d.

    Primary: Primary: Change from baseline in standardized forced expiratory volume in 1 second (FEV1) Area Under the Curve (AUC) (0-12 hours (h))

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    End point title
    		 Primary: Change from baseline in standardized forced expiratory volume in 1 second (FEV1) Area Under the Curve (AUC) (0-12 hours (h))
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. Missing values of FEV1 AUC0-12 at Day 1 and Week 12 will not imputed. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time.
    End point type
    Primary
    End point timeframe
    baseline (BL), 12 weeks
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    249
    251
    250
    246
    Units: Liters
        least squares mean (standard error)
    0.234 ± 0.0134
    0.122 ± 0.0134
    0.155 ± 0.0134
    -0.028 ± 0.0137
    Statistical analysis title
    		 FEV1 (L) AUC(0-12h) change from baseline
    Comparison groups
    QAB149 v QVA149
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model for repeated measures (MMRM)
    Confidence interval
    Statistical analysis title
    		 FEV1 (L) AUC(0-12h) change from baseline
    Comparison groups
    QVA149 v NVA237
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model for repeated measures (MMRM)
    Confidence interval

    Secondary: Change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score

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    End point title
    		 Change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score
    End point description
    Participants reported change in health status by using the 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 cause 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 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. Missing week 12 data were imputed with Last Observation Carried Forward (LOCF) method but only if measured at day >= 29. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    BL, 12 Weeks
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    238
    234
    237
    226
    Units: score on a scale
        least squares mean (standard error)
    -7.5 ± 0.85
    -5.9 ± 0.86
    -6 ± 0.86
    -1.1 ± 0.88
    No statistical analyses for this end point

    Secondary: Percentage of participants with a clinically important improvement of at least 4 units in the SGRQ total score

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    End point title
    		 Percentage of participants with a clinically important improvement of at least 4 units in the SGRQ total score
    End point description
    Participants reported change in health status by using the 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 cause 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 3 subscales and a "Total" score was calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    238
    234
    237
    226
    Units: Percentage of participants
        number (not applicable)
    59.2
    56.8
    51.5
    34.5
    No statistical analyses for this end point

    Secondary: Change from baseline in trough FEV1

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    End point title
    		 Change from baseline in trough FEV1
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards. Trough FEV1 was analyzed using the same MMRM as specified for FEV1. Trough FEV1 was defined as the mean of FEV1 at 23 h 15 min and 23 h 45 min after the morning dose of the previous day. Before the mean was calculated, a time window of 10 – 13 hours post-evening dose was applied to these 2 measurements. Recordings outside the time window were set to missing.
    End point type
    Secondary
    End point timeframe
    BL, day 2, day 86
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    246
    251
    249
    245
    Units: Liters
    least squares mean (standard error)
        day 2
    0.208 ± 0.0107
    0.111 ± 0.0106
    0.132 ± 0.0107
    0.01 ± 0.0107
        day 86
    0.216 ± 0.0142
    0.138 ± 0.0141
    0.128 ± 0.0142
    -0.017 ± 0.0145
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose trough FEV1

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    End point title
    		 Change from baseline in pre-dose trough FEV1
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards. Pre-dose trough FEV1 was analyzed using the same MMRM as specified for FEV1. Pre-dose trough FEV1 was defined as the mean of FEV1 at -45 min and -15 min before the morning dose. Since the time of evening dose of the previous day was not recorded at these visits, no time window was applied.
    End point type
    Secondary
    End point timeframe
    BL, day 85
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    243
    249
    246
    241
    Units: Liters
        least squares mean (standard error)
    0.193 ± 0.0132
    0.1 ± 0.0132
    0.108 ± 0.0133
    -0.027 ± 0.0135
    No statistical analyses for this end point

    Secondary: Change from baseline in FEV1

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    End point title
    		 Change from baseline in FEV1
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction.
    End point type
    Secondary
    End point timeframe
    BL, Day 1: 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h55 min; Day 2: 23h15min, 23h45min; Day 15: -45min, -15min, 1h; Day 29: -45 min, -15min, 1h; Day 57: -45min, -15min, 1h; day 85: -45min, -15min, 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h; day 86: 23h15min; 23h45min
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    250
    251
    250
    247
    Units: Liters
    least squares mean (standard error)
        day 1, 5 min (n=248,249,249,243)
    0.117 ± 0.0061
    0.076 ± 0.006
    0.072 ± 0.0061
    -0.001 ± 0.0062
        day 1, 15 min (n=248,251,249,244)
    0.16 ± 0.007
    0.09 ± 0.0069
    0.126 ± 0.007
    0.005 ± 0.007
        day 1, 1 h (n=249,251,249,246)
    0.199 ± 0.0082
    0.089 ± 0.0082
    0.176 ± 0.0083
    0.008 ± 0.0083
        day 1, 2 h (n=249,249,248,246)
    0.237 ± 0.0091
    0.109 ± 0.0091
    0.197 ± 0.0092
    0.03 ± 0.0092
        day 1, 4 h (n=247,247,248,237)
    0.22 ± 0.0099
    0.108 ± 0.0099
    0.167 ± 0.0099
    0.019 ± 0.0101
        day 1, 6 h (n=247,246,244,239)
    0.181 ± 0.0103
    0.085 ± 0.0104
    0.135 ± 0.0104
    -0.005 ± 0.0106
        day 1, 8 h (n=248,247,245,242)
    0.165 ± 0.0102
    0.077 ± 0.0101
    0.112 ± 0.0103
    -0.019 ± 0.0104
        day 1, 11 h 55 min(n=242,243,244,239)
    0.116 ± 0.0114
    0.029 ± 0.0114
    0.066 ± 0.0114
    -0.045 ± 0.0115
        day 2, 23 h 15 min (n=241,246,245,241)
    0.201 ± 0.0111
    0.105 ± 0.011
    0.128 ± 0.0111
    0.002 ± 0.0111
        day 2, 23 h 45 min (n= 246,251,248,244)
    0.216 ± 0.0111
    0.118 ± 0.0109
    0.137 ± 0.0111
    0.018 ± 0.0111
        day 15, - 45 min (243,249,246,240)
    0.208 ± 0.0126
    0.114 ± 0.0124
    0.108 ± 0.0126
    -0.045 ± 0.0127
        day 15, -15 min (n=243,248,246,241)
    0.238 ± 0.0124
    0.143 ± 0.0123
    0.132 ± 0.0124
    -0.025 ± 0.0124
        day 15, 1 h (n=249,251,249,246)
    0.321 ± 0.0134
    0.179 ± 0.0133
    0.212 ± 0.0134
    -0.019 ± 0.0135
        day 29, -45 min (n=243,249,246,240)
    0.213 ± 0.0132
    0.127 ± 0.0131
    0.117 ± 0.0132
    -0.03 ± 0.0133
        day 29, -15 min (n=243,248,246,241)
    0.235 ± 0.0132
    0.147 ± 0.0131
    0.138 ± 0.0132
    -0.013 ± 0.0134
        day 29, 1 h (n=249,251,249,246)
    0.32 ± 0.0135
    0.17 ± 0.0135
    0.216 ± 0.0136
    -0.004 ± 0.0137
        day 57, -45 min (n=243,249,246,240)
    0.203 ± 0.0136
    0.104 ± 0.0136
    0.117 ± 0.0137
    -0.037 ± 0.014
        day 57, -15 min (n=243,248,246,241)
    0.224 ± 0.0136
    0.125 ± 0.0135
    0.147 ± 0.0136
    -0.014 ± 0.0139
        day 57, 1 h (n=249,251,249,246)
    0.319 ± 0.0143
    0.163 ± 0.0143
    0.221 ± 0.0144
    -0.016 ± 0.0146
        day 85, -45 min (n=243,249,246,240)
    0.187 ± 0.0134
    0.09 ± 0.0135
    0.096 ± 0.0135
    -0.032 ± 0.0138
        day 85, - 15 min (n=243,248,246,241)
    0.199 ± 0.0138
    0.109 ± 0.0137
    0.123 ± 0.0138
    -0.018 ± 0.0141
        day 85, 5 min (n=248,249,249,243)
    0.246 ± 0.0142
    0.151 ± 0.0143
    0.143 ± 0.0142
    -0.02 ± 0.0144
        day 85, 15 min (n=248,251,249,244)
    0.269 ± 0.0141
    0.153 ± 0.0142
    0.179 ± 0.0141
    -0.001 ± 0.0145
        day 85, 1 h (n=249,251,249,246)
    0.293 ± 0.0144
    0.141 ± 0.0144
    0.208 ± 0.0144
    -0.018 ± 0.0147
        day 85, 2 h (n=249,249,248,246)
    0.315 ± 0.0146
    0.159 ± 0.0147
    0.216 ± 0.0148
    -0.001 ± 0.015
        day 85, 4 h (n=247,247,248,237)
    0.26 ± 0.015
    0.145 ± 0.0151
    0.172 ± 0.0151
    -0.004 ± 0.0157
        day 85, 6 h (n=247,246,244,239)
    0.226 ± 0.0149
    0.122 ± 0.015
    0.139 ± 0.0151
    -0.011 ± 0.0155
        day 85, 8 h (n=248,247,245,242)
    0.198 ± 0.0146
    0.107 ± 0.0147
    0.133 ± 0.0149
    -0.039 ± 0.0153
        day 85, 11 h 55 min(n=242,243,244,239)
    0.163 ± 0.0147
    0.078 ± 0.015
    0.105 ± 0.015
    -0.073 ± 0.0154
        day 86, 23 h 15 min (n=241,246,245,241)
    0.206 ± 0.0148
    0.13 ± 0.0147
    0.117 ± 0.0149
    -0.023 ± 0.015
        day 86, 23 h 45 min (n=246,251,248,244)
    0.221 ± 0.0144
    0.144 ± 0.0144
    0.132 ± 0.0146
    -0.012 ± 0.0149
    No statistical analyses for this end point

    Secondary: Change from baseline in FVC

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    End point title
    		 Change from baseline in FVC
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FVC was defined as the average of the pre-dose FVC measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FVC measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction.
    End point type
    Secondary
    End point timeframe
    BL, Day 1: 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h55 min; Day 2: 23h15min, 23h45min; Day 15: -45min, -15min, 1h; Day 29: -45 min, -15min, 1h; Day 57: -45min, -15min, 1h; day 85: -45min, -15min, 5min, 15min, 1h, 2h, 4h, 6h, 8h, 11h; day 86: 23h15min; 23h45min
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    250
    251
    250
    247
    Units: Liters
    least squares mean (standard error)
        day 1, 5 min (n=248,249,249,243)
    0.245 ± 0.0138
    0.175 ± 0.0136
    0.158 ± 0.0137
    -0.006 ± 0.014
        day 1, 15 min (n=248,251,249,244)
    0.318 ± 0.0154
    0.185 ± 0.0153
    0.238 ± 0.0155
    0.009 ± 0.0155
        day 1, 1 h (n=249,251,249,246)
    0.355 ± 0.0165
    0.153 ± 0.0164
    0.309 ± 0.0166
    0.013 ± 0.0166
        day 1, 2 h (n=249,249,248,246)
    0.395 ± 0.0181
    0.214 ± 0.018
    0.324 ± 0.0182
    0.044 ± 0.0183
        day 1, 4 h (n=247,247,248,237)
    0.364 ± 0.0187
    0.189 ± 0.0187
    0.271 ± 0.0188
    0.026 ± 0.0192
        day 1, 6 h (n=247,246,244,239)
    0.316 ± 0.0186
    0.159 ± 0.0188
    0.244 ± 0.0189
    0.004 ± 0.0192
        day 1, 8 h (n=248,247,245,242)
    0.285 ± 0.0179
    0.154 ± 0.0178
    0.212 ± 0.0182
    -0.021 ± 0.0183
        day 1, 11 h 55 min (n=242,243,244,239)
    0.235 ± 0.0188
    0.093 ± 0.0188
    0.125 ± 0.0188
    -0.06 ± 0.019
        day 2, 23 h 15 min (n=241,246,245,241)
    0.343 ± 0.0193
    0.191 ± 0.0191
    0.217 ± 0.0194
    0.001 ± 0.0194
        day 2, 23 h 45 min (n=246,251,248,244)
    0.355 ± 0.0195
    0.196 ± 0.0192
    0.229 ± 0.0194
    0.027 ± 0.0195
        day 15, -45 min (n=243,249,246,240)
    0.313 ± 0.0205
    0.163 ± 0.0201
    0.168 ± 0.0204
    -0.047 ± 0.0206
        day 15, -15 min (n=243,248,246,241)
    0.358 ± 0.0207
    0.201 ± 0.0204
    0.198 ± 0.0207
    -0.02 ± 0.0207
        day 15, 1 h (n=249,251,249,246)
    0.473 ± 0.0025
    0.269 ± 0.0223
    0.311 ± 0.0225
    -0.009 ± 0.0227
        day 29, -45 min (n=243,249,246,240)
    0.32 ± 0.0217
    0.194 ± 0.0216
    0.188 ± 0.0217
    -0.025 ± 0.022
        day 29, -15 min (n=243,248,246,241)
    0.332 ± 0.0216
    0.218 ± 0.0215
    0.197 ± 0.0216
    -0.004 ± 0.0219
        day 29, 1 h (n=249,251,249,246)
    0.449 ± 0.0224
    0.259 ± 0.0223
    0.322 ± 0.0225
    0.008 ± 0.0227
        day 57, -45 min (n=243,249,246,240)
    0.293 ± 0.0215
    0.142 ± 0.0215
    0.173 ± 0.0217
    -0.034 ± 0.0221
        day 57, -15 min (n=243,248,246,241)
    0.298 ± 0.0223
    0.167 ± 0.0222
    0.222 ± 0.0224
    -0.009 ± 0.0229
        day 57, 1 h (n=249,251,249,246)
    0.445 ± 0.0233
    0.227 ± 0.0233
    0.326 ± 0.0234
    -0.011 ± 0.0238
        day 85, -45 min (n=243,249,246,240)
    0.252 ± 0.0223
    0.121 ± 0.0224
    0.143 ± 0.0225
    -0.029 ± 0.0229
        day 85, -15 min (n=243,248,246,241)
    0.263 ± 0.0224
    0.142 ± 0.0223
    0.18 ± 0.0225
    -0.031 ± 0.0229
        day 85, 5 min (n=248,249,249,243)
    0.331 ± 0.0243
    0.215 ± 0.0244
    0.225 ± 0.0243
    -0.048 ± 0.0247
        day 85, 15 min (n=248,251,249,244)
    0.377 ± 0.0242
    0.223 ± 0.0243
    0.276 ± 0.0243
    -0.004 ± 0.0248
        day 85, 1 h (n=249,251,249,246)
    0.4 ± 0.0243
    0.209 ± 0.0243
    0.295 ± 0.0244
    -0.023 ± 0.0248
        day 85, 2h (n=249,249,248,246)
    0.414 ± 0.0244
    0.218 ± 0.0245
    0.301 ± 0.0247
    -0.001 ± 0.0251
        day 85, 4 h (n=247,247,248,237)
    0.338 ± 0.0247
    0.203 ± 0.0249
    0.261 ± 0.025
    0.002 ± 0.0259
        day 85, 6 h (n=247,246,244,239)
    0.305 ± 0.0239
    0.164 ± 0.024
    0.211 ± 0.0241
    -0.011 ± 0.0248
        day 85, 8 h (n=248,247,245,242)
    0.273 ± 0.0233
    0.152 ± 0.0235
    0.213 ± 0.0237
    -0.038 ± 0.0244
        day 85, 11 55 min (n=242,243,244,239)
    0.233 ± 0.0239
    0.131 ± 0.0243
    0.197 ± 0.0243
    -0.093 ± 0.025
        day 86, 23 h 15 min (n=241,246,245,241)
    0.278 ± 0.0248
    0.172 ± 0.0247
    0.176 ± 0.025
    -0.021 ± 0.0251
        day 86, 23 h 45 min (n=246,251,248,244)
    0.298 ± 0.024
    0.199 ± 0.0239
    0.21 ± 0.0244
    -0.017 ± 0.0248
    No statistical analyses for this end point

    Secondary: Secondary: Change from baseline in standardized FEV1 AUC (0-4 h), FEV1 AUC (4-8h), FEV1 AUC (8-12h) and FEV1 AUC (0-12 h)

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    End point title
    		 Secondary: Change from baseline in standardized FEV1 AUC (0-4 h), FEV1 AUC (4-8h), FEV1 AUC (8-12h) and FEV1 AUC (0-12 h)
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 * visit interaction, and visit, treatment * visit interaction. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time.
    End point type
    Secondary
    End point timeframe
    BL, day 1, 12 weeks
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    250
    251
    250
    247
    Units: Liters
    least squares mean (standard error)
        Day 1, AUC 0-4h (n=249,251,250,246)
    0.213 ± 0.0077
    0.101 ± 0.0077
    0.174 ± 0.0077
    0.019 ± 0.0078
        Day 1, AUC 4-8h (n=248,248,250,243)
    0.187 ± 0.0093
    0.09 ± 0.0093
    0.134 ± 0.0093
    -0.003 ± 0.0095
        Day 1, AUC 8-12h (n=248,249,249,245)
    0.143 ± 0.0099
    0.054 ± 0.0099
    0.092 ± 0.01
    -0.031 ± 0.0101
        Day 1, AUC 0-12h (n=249,251,250,246)
    0.184 ± 0.0084
    0.08 ± 0.0084
    0.135 ± 0.0084
    -0.003 ± 0.0085
        Week 12, AUC 0-4h (n=249,251,250,246)
    0.289 ± 0.0138
    0.147 ± 0.0138
    0.196 ± 0.0138
    -0.008 ± 0.0141
        Week 12, AUC 4-8h (n=248,248,250,243)
    0.229 ± 0.014
    0.12 ± 0.0141
    0.148 ± 0.0141
    -0.021 ± 0.0145
        Week 12, AUC 8-12h (n=248,249,249,245)
    0.182 ± 0.0141
    0.095 ± 0.0142
    0.123 ± 0.0143
    -0.055 ± 0.0146
        Week 12, AUC 0-12h (n=249,251,250,246)
    0.234 ± 0.0134
    0.122 ± 0.0134
    0.155 ± 0.0134
    -0.028 ± 0.0137
    No statistical analyses for this end point

    Secondary: Transitional Dyspnea Index (TDI) focal score

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    End point title
    		 Transitional Dyspnea Index (TDI) focal score
    End point description
    The Baseline Dyspnea Index (BDI) / TDI is an instrument used to assess a participant's level of dyspnea. The BDI and TDI each have three domains: functional impairment, magnitude of task and magnitude of effort. BDI domains were rated from 0 (severe) to 4 (unimpaired) and rates summed for baseline focal score ranged from 0 to 12; lower scores mean worse severity. TDI domains were rated from -3 (major deterioration) to 3 (major improvement) and rates summed for transition focal score ranged from -9 to 9; negative scores indicate deterioration. A TDI focal score of ≥1 was defined as a clinically important improvement from baseline.
    End point type
    Secondary
    End point timeframe
    BL, 12 weeks
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    233
    238
    232
    222
    Units: score on a scale
        least squares mean (standard error)
    2.88 ± 0.251
    1.98 ± 0.252
    1.88 ± 0.252
    0.85 ± 0.256
    No statistical analyses for this end point

    Secondary: Secondary: Change from baseline in mean daily number of puffs of rescue medication

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    End point title
    		 Secondary: Change from baseline in mean daily number of puffs of rescue medication
    End point description
    Participants completed an electronic diary (eDiary) twice daily at the same time in the morning and evening to record the number of puffs of rescue medication taken in the previous 12 hours. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    BL, 12 weeks
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    243
    242
    242
    235
    Units: number of puffs
        least squares mean (standard error)
    -2.19 ± 0.15
    -2.05 ± 0.15
    -1.78 ± 0.151
    -1.04 ± 0.153
    No statistical analyses for this end point

    Secondary: Secondary: Change from baseline in mean total daily symptom score, mean daytime total symptom score and mean nighttime total symptom score

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    End point title
    		 Secondary: Change from baseline in mean total daily symptom score, mean daytime total symptom score and mean nighttime total symptom score
    End point description
    The participant recorded symptom scores twice daily in the eDiary. The daily clinical symptoms included: cough, wheezing, shortness of breath, sputum volume, sputum color, and night time awakening. The range of scores for each assessment is 0 to 3 where 0 indications No symptom and 3 indicates a Severe symptom. The total daily symptom score is obtained by adding the scores for the morning and evening symptoms for each day. The maximum possible total daily score is 54. A negative change from baseline indicated improvement.
    End point type
    Secondary
    End point timeframe
    BL, 12 weeks
    End point values
    		 QVA149 QAB149 NVA237 Placebo
    Number of subjects analysed
    250
    251
    250
    247
    Units: score on a scale
    least squares mean (standard error)
        total daily (n=243,242,242,235)
    -1.34 ± 0.108
    -1.22 ± 0.108
    -1.09 ± 0.108
    -0.61 ± 0.11
        total daytime (n=242,239,240,234)
    -1.16 ± 0.105
    -1.05 ± 0.105
    -0.96 ± 0.105
    -0.53 ± 0.106
        total nighttime (n=243,239,238,234)
    -1.09 ± 0.107
    -1.01 ± 0.107
    -0.9 ± 0.108
    -0.41 ± 0.109
    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
    16.1
    Reporting groups
    Reporting group title
    QVA149 27.5/12.5 mcg
    Reporting group description
    		 QVA149 27.5/12.5 mcg

    Reporting group title
    QAB149 27.5 mcg
    Reporting group description
    		 QAB149 27.5 mcg

    Reporting group title
    NVA237 12.5 mcg
    Reporting group description
    		 NVA237 12.5 mcg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 QVA149 27.5/12.5 mcg QAB149 27.5 mcg NVA237 12.5 mcg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 250 (2.40%)
    5 / 251 (1.99%)
    12 / 251 (4.78%)
    13 / 248 (5.24%)
         number of deaths (all causes)
    0
    1
    2
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC CANCER
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    METASTATIC MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NON-SMALL CELL LUNG CANCER
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1 / 250 (0.40%)
    1 / 251 (0.40%)
    5 / 251 (1.99%)
    7 / 248 (2.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 5
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG INFILTRATION
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GUN SHOT WOUND
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    CARDIOPULMONARY FAILURE
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOPERITONEUM
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    EPIGLOTTITIS
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 251 (0.40%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIRECTAL ABSCESS
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SINUSITIS
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    1 / 251 (0.40%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 250 (0.00%)
    0 / 251 (0.00%)
    0 / 251 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 QVA149 27.5/12.5 mcg QAB149 27.5 mcg NVA237 12.5 mcg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 250 (11.20%)
    23 / 251 (9.16%)
    23 / 251 (9.16%)
    36 / 248 (14.52%)
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    28 / 250 (11.20%)
    23 / 251 (9.16%)
    23 / 251 (9.16%)
    36 / 248 (14.52%)
         occurrences all number
    38
    30
    33
    50

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2013
    Amendment 1: The purpose of this amendment was to ensure that there was no overlap of patients between this trial and the replicate trial QVA149A2336, which would protect the integrity of both trials. An exclusion criterion was added to the current trial, which excluded patients that had previously been enrolled in QVA149A2336. Changes were made to the model used to evaluate the primary endpoint and to the sensitivity analysis, in order to ensure that it was analyzed appropriately. Changes were made to the analyses used to evaluate the primary endpoint as follows: 1) a 2-way interaction between baseline and visit in the model was added in order to account for the difference in correlation between the outcome and baseline at each visit; and 2) the sensitivity analysis based only on the completers at Week 12 was removed as the underlying assumption of data being missing completely at random was too restrictive. In addition, patients with moderate renal impairment were allowed to participate in the trial, ensuring that the protocol population was not overly restrictive.

    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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