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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, two-period crossover study to assess the effect of inhaled QVA149 on global and regional lung function and gas exchange in patients with moderate to severe COPD.

    Summary
    EudraCT number
    		 2013-004461-13
    Trial protocol
    		 GB  
    Global end of trial date
    26 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2018
    First version publication date
    11 Oct 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CQVA149A2325
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02634983
    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 612241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 612241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess global ventilated lung volume after treatment with QVA149 compared to placebo. Secondary objectives included assessment of regional lung ventilated volume, evaluation of physiologic measures of lung function and assessment of small airway function after treatment with QVA149 compared to placebo. Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    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
    03 Jun 2016
    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
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    13
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study took place in 3 clinical sites in United-Kingdom

    Pre-assignment
    Screening details
    		 31 patients were randomized, all of whom were included in the safety set and PD analysis sets (primary population of interest)

    Period 1
    Period 1 title
    Period One (First treatment, 8-10 days)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Patients were assigned to one of the following two treatment arms in a ratio of 1:1 (active: placebo)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QVA149 110/50 mcg then Matching placebo
    Arm description
    		 QVA149, followed by matching placebo. Each treatment 8-10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QVA149
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of 110/50 mcg QVA149 for 8-10 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of matching placebo for 8-10 days

    Arm title
    		 Matching placebo then QVA149 110/50 mcg
    Arm description
    		 Matching placebo, followed by QVA149. Each treatment 8-10 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    QVA149
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of 110/50 mcg QVA149 for 8-10 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of matching placebo for 8-10 days

    Number of subjects in period 1
    		QVA149 110/50 mcg then Matching placebo Matching placebo then QVA149 110/50 mcg
    Started
    16
    15
    Completed
    16
    15
    Period 2
    Period 2 title
    Washout (approximately 7-14 days)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Patients were assigned to one of the following two treatment arms in a ratio of 1:1 (active: placebo)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QVA149 110/50 mcg then Matching placebo
    Arm description
    		 QVA149, followed by matching placebo. Each treatment 8-10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QVA149
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of 110/50 mcg QVA149 for 8-10 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of matching placebo for 8-10 days

    Arm title
    		 Matching placebo then QVA149 110/50 mcg
    Arm description
    		 Matching placebo, followed by QVA149. Each treatment 8-10 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    QVA149
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of 110/50 mcg QVA149 for 8-10 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of matching placebo for 8-10 days

    Number of subjects in period 2
    		QVA149 110/50 mcg then Matching placebo Matching placebo then QVA149 110/50 mcg
    Started
    16
    15
    Completed
    16
    15
    Period 3
    Period 3 title
    Period 2 (Second treatment, 8-10 days)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Patients were assigned to one of the following two treatment arms in a ratio of 1:1 (active: placebo)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QVA149 110/50 mcg then Matching placebo
    Arm description
    		 QVA149, followed by matching placebo. Each treatment 8-10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QVA149
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of 110/50 mcg QVA149 for 8-10 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of matching placebo for 8-10 days

    Arm title
    		 Matching placebo then QVA149 110/50 mcg
    Arm description
    		 Matching placebo, followed by QVA149. Each treatment 8-10 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    QVA149
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of 110/50 mcg QVA149 for 8-10 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Single daily dose of matching placebo for 8-10 days

    Number of subjects in period 3
    		QVA149 110/50 mcg then Matching placebo Matching placebo then QVA149 110/50 mcg
    Started
    16
    15
    Completed
    14
    15
    Not completed
    2
    0
         Adverse event, non-fatal
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period One (First treatment, 8-10 days)
    Reporting group description
    		 -

    Reporting group values
    		 Period One (First treatment, 8-10 days) Total
    Number of subjects
    		 31 31
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 13 13
        From 65-84 years
    		 18 18
        85 years and over
    		 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.9 ± 6.31 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 15 15
        Male
    		 16 16
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 31 31
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Forced Expiratory Volume in 1 Second|0 Minutes Pre Inhalation|
    The Forced Expiratory Volume in one second (FEV1) was calculated as the volume of air forcibly exhaled in one second as measured by a spirometer.
    Units: Liter
        arithmetic mean (standard deviation)
    		 1.1584 ± 0.35206 -
    Forced Expiratory Volume in 1 Second|60 Minutes Post Inhalation|
    The Forced Expiratory Volume in one second (FEV1) was calculated as the volume of air forcibly exhaled in one second as measured by a spirometer.
    Units: Liter
        arithmetic mean (standard deviation)
    		 1.3987 ± 0.37266 -
    Percent Predicted FEV1|0 Minutes Pre Inhalation|
    Units: Percent
        arithmetic mean (standard deviation)
    		 43.90 ± 10.873 -
    Percent Predicted FEV1|60 Minutes Post Inhalation|
    Units: Percent
        arithmetic mean (standard deviation)
    		 53.10 ± 11.680 -
    Forced Vital Capacity|0 Minutes Pre Inhalation|
    Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry.
    Units: Liter
        arithmetic mean (standard deviation)
    		 2.7426 ± 0.73932 -
    Forced Vital Capacity|60 Minutes Post Inhalation|
    Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry.
    Units: Liter
        arithmetic mean (standard deviation)
    		 3.0781 ± 0.81113 -
    FEV1/FVC ratio|0 Minutes Pre Inhalation|
    The FEV1/FVC ratio is the proportion of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC).
    Units: Percent
        arithmetic mean (standard deviation)
    		 42.968 ± 8.9797 -
    FEV1/FVC ratio|60 Minutes Post Inhalation|
    The FEV1/FVC ratio is the proportion of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC).
    Units: Percent
        arithmetic mean (standard deviation)
    		 46.365 ± 8.8240 -
    Reversibility
    Reversibility = FEV1 post-inhalation - FEV1 pre-inhalation
    Units: Liter
        arithmetic mean (standard deviation)
    		 0.2403 ± 0.12994 -
    Reversibility
    Reversibility = FEV1 post-inhalation - FEV1 pre-inhalation
    Units: Percent
        arithmetic mean (standard deviation)
    		 9.19 ± 4.743 -
    Subject analysis sets

    Subject analysis set title
    All Study Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomized to receive either QVA149 110/50 mcg or Placebo matching QVA149 110/50 mcg

    Subject analysis set title
    QVA149 110/50 mcg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of 110/50 μg QVA149 for 8-10 days.

    Subject analysis set title
    Matching placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of matching placebo for 8-10 days.

    Subject analysis set title
    QVA149 110/50 mcg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of 110/50 μg QVA149 for 8-10 days.

    Subject analysis set title
    Matching placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of matching placebo for 8-10 days.

    Subject analysis set title
    Matching placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of matching placebo for 8-10 days.

    Subject analysis set title
    QVA149 110/50 mcg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of 110/50 μg QVA149 for 8-10 days.

    Subject analysis sets values
    		 All Study Participants QVA149 110/50 mcg Matching placebo QVA149 110/50 mcg Matching placebo Matching placebo QVA149 110/50 mcg
    Number of subjects
    31
    31
    28
    27
    26
    31
    29
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    13
    0
    0
    0
    0
    0
    0
        From 65-84 years
    18
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    65.9 ± 6.31
    65.9 ± 6.31
    65.9 ± 6.31
    65.9 ± 6.31
    65.9 ± 6.31
    65.9 ± 6.31
    65.9 ± 6.31
    Sex: Female, Male
    Units: Subjects
        Female
    15
        Male
    16
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0
        Asian
    0
        Native Hawaiian or Other Pacific Islander
    0
        Black or African American
    0
        White
    31
        More than one race
    0
        Unknown or Not Reported
    0
    Forced Expiratory Volume in 1 Second|0 Minutes Pre Inhalation|
    The Forced Expiratory Volume in one second (FEV1) was calculated as the volume of air forcibly exhaled in one second as measured by a spirometer.
    Units: Liter
        arithmetic mean (standard deviation)
    1.1584 ± 0.35206
    1.1584 ± 0.35206
    1.1584 ± 0.35206
    1.1584 ± 0.35206
    1.1584 ± 0.35206
    1.1584 ± 0.35206
    1.1584 ± 0.35206
    Forced Expiratory Volume in 1 Second|60 Minutes Post Inhalation|
    The Forced Expiratory Volume in one second (FEV1) was calculated as the volume of air forcibly exhaled in one second as measured by a spirometer.
    Units: Liter
        arithmetic mean (standard deviation)
    1.3987 ± 0.37266
    1.3987 ± 0.37266
    1.3987 ± 0.37266
    1.3987 ± 0.37266
    1.3987 ± 0.37266
    1.3987 ± 0.37266
    1.3987 ± 0.37266
    Percent Predicted FEV1|0 Minutes Pre Inhalation|
    Units: Percent
        arithmetic mean (standard deviation)
    43.90 ± 10.873
    43.90 ± 10.873
    43.90 ± 10.873
    43.90 ± 10.873
    43.90 ± 10.873
    43.90 ± 10.873
    43.90 ± 10.873
    Percent Predicted FEV1|60 Minutes Post Inhalation|
    Units: Percent
        arithmetic mean (standard deviation)
    53.10 ± 11.680
    53.10 ± 11.680
    53.10 ± 11.680
    53.10 ± 11.680
    53.10 ± 11.680
    53.10 ± 11.680
    53.10 ± 11.680
    Forced Vital Capacity|0 Minutes Pre Inhalation|
    Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry.
    Units: Liter
        arithmetic mean (standard deviation)
    2.7426 ± 0.73932
    2.7426 ± 0.73932
    2.7426 ± 0.73932
    2.7426 ± 0.73932
    2.7426 ± 0.73932
    2.7426 ± 0.73932
    2.7426 ± 0.73932
    Forced Vital Capacity|60 Minutes Post Inhalation|
    Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry.
    Units: Liter
        arithmetic mean (standard deviation)
    3.0781 ± 0.81113
    3.0781 ± 0.81113
    3.0781 ± 0.81113
    3.0781 ± 0.81113
    3.0781 ± 0.81113
    3.0781 ± 0.81113
    3.0781 ± 0.81113
    FEV1/FVC ratio|0 Minutes Pre Inhalation|
    The FEV1/FVC ratio is the proportion of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC).
    Units: Percent
        arithmetic mean (standard deviation)
    42.968 ± 8.9797
    42.968 ± 8.9797
    42.968 ± 8.9797
    42.968 ± 8.9797
    42.968 ± 8.9797
    42.968 ± 8.9797
    42.968 ± 8.9797
    FEV1/FVC ratio|60 Minutes Post Inhalation|
    The FEV1/FVC ratio is the proportion of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC).
    Units: Percent
        arithmetic mean (standard deviation)
    46.365 ± 8.8240
    46.365 ± 8.8240
    46.365 ± 8.8240
    46.365 ± 8.8240
    46.365 ± 8.8240
    46.365 ± 8.8240
    46.365 ± 8.8240
    Reversibility
    Reversibility = FEV1 post-inhalation - FEV1 pre-inhalation
    Units: Liter
        arithmetic mean (standard deviation)
    0.2403 ± 0.12994
    0.2403 ± 0.12994
    0.2403 ± 0.12994
    0.2403 ± 0.12994
    0.2403 ± 0.12994
    0.2403 ± 0.12994
    0.2403 ± 0.12994
    Reversibility
    Reversibility = FEV1 post-inhalation - FEV1 pre-inhalation
    Units: Percent
        arithmetic mean (standard deviation)
    9.19 ± 4.743
    9.19 ± 4.743
    9.19 ± 4.743
    9.19 ± 4.743
    9.19 ± 4.743
    9.19 ± 4.743
    9.19 ± 4.743

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    QVA149 110/50 mcg then Matching placebo
    Reporting group description
    		 QVA149, followed by matching placebo. Each treatment 8-10 days.

    Reporting group title
    Matching placebo then QVA149 110/50 mcg
    Reporting group description
    		 Matching placebo, followed by QVA149. Each treatment 8-10 days.
    Reporting group title
    QVA149 110/50 mcg then Matching placebo
    Reporting group description
    		 QVA149, followed by matching placebo. Each treatment 8-10 days.

    Reporting group title
    Matching placebo then QVA149 110/50 mcg
    Reporting group description
    		 Matching placebo, followed by QVA149. Each treatment 8-10 days.
    Reporting group title
    QVA149 110/50 mcg then Matching placebo
    Reporting group description
    		 QVA149, followed by matching placebo. Each treatment 8-10 days.

    Reporting group title
    Matching placebo then QVA149 110/50 mcg
    Reporting group description
    		 Matching placebo, followed by QVA149. Each treatment 8-10 days.

    Subject analysis set title
    All Study Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomized to receive either QVA149 110/50 mcg or Placebo matching QVA149 110/50 mcg

    Subject analysis set title
    QVA149 110/50 mcg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of 110/50 μg QVA149 for 8-10 days.

    Subject analysis set title
    Matching placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of matching placebo for 8-10 days.

    Subject analysis set title
    QVA149 110/50 mcg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of 110/50 μg QVA149 for 8-10 days.

    Subject analysis set title
    Matching placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of matching placebo for 8-10 days.

    Subject analysis set title
    Matching placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of matching placebo for 8-10 days.

    Subject analysis set title
    QVA149 110/50 mcg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single daily dose of 110/50 μg QVA149 for 8-10 days.

    Primary: Global Ventilated Lung Volume

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    End point title
    		 Global Ventilated Lung Volume
    End point description
    The global distribution of inhaled gas within the lung was assessed using an inhaled gaseous contrast agent, Hyperpolarized Helium (3He) Lung Imaging. The Global Ventilated Lung Volume was expressed in percentage (%VV) of total lung volume.
    End point type
    Primary
    End point timeframe
    Day 8 to Day 10 (each treatment period)
    End point values
    		 QVA149 110/50 mcg Matching placebo
    Number of subjects analysed
    31
    28
    Units: Percentage of total lung volume
        least squares mean (confidence interval 90%)
    61.73 (56.16 to 67.30)
    56.73 (51.07 to 62.39)
    Statistical analysis title
    		 Global Ventilated Lung Volume
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.0254
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 8.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.11
    Notes
    [1] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.

    Secondary: Regional Ventilated Lung Volume

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    End point title
    		 Regional Ventilated Lung Volume
    End point description
    The regional distribution of inhaled gas within the lung was assessed using an inhaled gaseous contrast agent, Hyperpolarized Helium (3He) Lung Imaging. The Regional Ventilated Lung Volume was expressed in percentage (% VDV) of total lung volume for each lobar region.
    End point type
    Secondary
    End point timeframe
    Day 8 to Day 10 (each treatment period)
    End point values
    		 QVA149 110/50 mcg Matching placebo
    Number of subjects analysed
    31
    28
    Units: Percentage of total lung volume
    least squares mean (confidence interval 90%)
        Lung, Left Ventilation|
    61.94 (56.04 to 67.83)
    57.16 (51.17 to 63.15)
        Lung, Left Lower Lobe Ventilation|
    58.97 (52.63 to 65.31)
    54.01 (47.52 to 60.49)
        Lung, Left Upper Lobe Ventilation|
    64.17 (57.95 to 70.39)
    59.20 (52.87 to 65.53)
        Lung, Right Ventilation|
    61.63 (55.90 to 67.36)
    56.24 (50.40 to 62.08)
        Lung, Right Lower Lobe Ventilation|
    60.92 (54.62 to 67.21)
    57.65 (51.26 to 64.04)
        Lung, Right Middle Lobe Ventilation|
    59.59 (52.85 to 66.34)
    53.98 (47.01 to 60.95)
        Lung, Right Upper Lobe Ventilation|
    63.25 (56.71 to 69.79)
    55.53 (48.85 to 62.20)
    Statistical analysis title
    		 Lung, Left Ventilation
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.035
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.77
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 8.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.15
    Notes
    [2] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Left Lower Lobe Ventilation
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.0946
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.08
         upper limit
    		 9.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.86
    Notes
    [3] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Left Upper Lobe Ventilation
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.0486
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 9.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.41
    Notes
    [4] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Right Ventilation
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.0286
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.39
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.42
         upper limit
    		 9.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.33
    Notes
    [5] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Right Lower Lobe Ventilation
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.165
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 7.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.29
    Notes
    [6] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Right Middle Lobe Ventilation
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.1421
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.61
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 11.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.71
    Notes
    [7] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Right Upper Lobe Ventilation
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.0099
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.73
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.98
         upper limit
    		 12.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.78
    Notes
    [8] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.

    Secondary: Pulmonary Perfusion

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    End point title
    		 Pulmonary Perfusion
    End point description
    Lung Perfusion Imaging, or MR perfusion imaging of the lung with gadolinium contrast agent, was performed to determine whether vascular abnormalities producing perfusion deficits corresponded to abnormalities in ventilation (hypoxic vasoconstriction). Pulmonary Perfusion was expressed in ml/100 g lung tissue/min of each lobar region.
    End point type
    Secondary
    End point timeframe
    Day 8 to Day 10 (each treatment period)
    End point values
    		 QVA149 110/50 mcg Matching placebo
    Number of subjects analysed
    27
    26
    Units: ml/100 g lung tissue/min
    least squares mean (confidence interval 90%)
        Lung Perfusion|
    13.96 (12.50 to 15.41)
    13.03 (11.56 to 14.50)
        Lung, Left Perfusion|
    14.42 (12.94 to 15.90)
    13.08 (11.58 to 14.57)
        Lung, Left Lower Lobe Perfusion|
    13.48 (11.91 to 15.06)
    12.79 (11.20 to 14.38)
        Lung, Left Upper Lobe Perfusion|
    15.35 (13.69 to 17.01)
    13.45 (11.77 to 15.12)
        Lung, Right Perfusion|
    13.54 (12.07 to 15.01)
    12.97 (11.49 to 14.46)
        Lung, Right Lower Lobe Perfusion|
    13.26 (11.74 to 14.79)
    13.25 (11.71 to 14.79)
        Lung, Right Middle Lobe Perfusion|
    14.86 (12.72 to 17.00)
    13.36 (11.19 to 15.53)
        Lung, Right Upper Lobe Perfusion|
    13.57 (11.91 to 15.23)
    12.70 (11.03 to 14.37)
    Statistical analysis title
    		 Lung Perfusion
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.323
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.93
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 2.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.92
    Notes
    [9] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Left Perfusion
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.1717
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.34
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 2.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95
    Notes
    [10] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Left Lower Lobe Perfusion
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.5031
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.69
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 2.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.02
    Notes
    [11] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Left Upper Lobe Perfusion
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.076
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 3.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.03
    Notes
    [12] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Right Perfusion
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.5465
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.57
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.02
         upper limit
    		 2.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.93
    Notes
    [13] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Right Lower Lobe Perfusion
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.9913
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.85
         upper limit
    		 1.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.08
    Notes
    [14] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Right Middle Lobe Perfusion
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.3837
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.51
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.39
         upper limit
    		 4.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7
    Notes
    [15] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.
    Statistical analysis title
    		 Lung, Right Upper Lobe Perfusion
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 [16]
    P-value
    		 = 0.3624
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.87
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 2.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.94
    Notes
    [16] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.

    Secondary: Forced Expiratory Volume in 1 second (FEV1)

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    End point title
    		 Forced Expiratory Volume in 1 second (FEV1)
    End point description
    The Forced Expiratory Volume in one second (FEV1) was calculated as the volume of air forcibly exhaled in one second as measured by a spirometer.
    End point type
    Secondary
    End point timeframe
    Day 1 (0.25, 1 and 2 hours post-dose), Day 8 (-0.75, -0.25, 0.25, 1 and 2 hours post-dose) (each treatment period)
    End point values
    		 QVA149 110/50 mcg Matching placebo
    Number of subjects analysed
    31
    31
    Units: Liter
    least squares mean (confidence interval 90%)
        FEV1 Day 1 (0.25 hrs post-dose) (n=31, 29)|
    1.27 (1.25 to 1.30)
    1.13 (1.10 to 1.15)
        FEV1 Day 1 (1 hrs post-dose) (n=31,28)|
    1.32 (1.29 to 1.36)
    1.12 (1.09 to 1.16)
        FEV1 Day 1 (2 hrs post-dose) (n=31,30)|
    1.34 (1.30 to 1.38)
    1.15 (1.11 to 1.19)
        FEV1 Day 8 (-0.75 hrs post-dose) (n=31,28)|
    1.30 (1.26 to 1.34)
    1.09 (1.05 to 1.13)
        FEV1 Day 8 (-0.25 hrs post-dose) (n=30,27)|
    1.33 (1.29 to 1.37)
    1.11 (1.07 to 1.15)
        FEV1 Day 8 (0.25 hrs post-dose) (n=31,28)|
    1.38 (1.35 to 1.42)
    1.10 (1.06 to 1.14)
        FEV1 Day 8 (1 hrs post-dose) (n=30, 26)|
    1.45 (1.41 to 1.49)
    1.13 (1.09 to 1.17)
        FEV1 Day 8 (2 hrs post-dose) (n=31,28)|
    1.43 (1.39 to 1.47)
    1.11 (1.07 to 1.15)
    Statistical analysis title
    		 FEV1 Day 1 (0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.15
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Notes
    [17] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1 Day 1 (1 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [18]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [18] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1 Day 1 (2 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [19]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [19] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1 Day 8 (-0.75 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [20]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.22
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [20] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1 Day 8 (-0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [21]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.22
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [21] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1 Day 8 (0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [22]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.28
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [22] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1 Day 8 (1 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [23]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.32
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [23] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1 Day 8 (2 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [24]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.32
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Notes
    [24] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.

    Secondary: Forced Vital Capacity (FVC)

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    End point title
    		 Forced Vital Capacity (FVC)
    End point description
    Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was assessed via spirometry. An increase in FVC indicates improvement in lung function.
    End point type
    Secondary
    End point timeframe
    Day 1 (0.25, 1 and 2 hours post-dose), Day 8 (-0.75, -0.25, 0.25, 1 and 2 hours post-dose) (each treatment period)
    End point values
    		 QVA149 110/50 mcg Matching placebo
    Number of subjects analysed
    31
    31
    Units: Liter
    least squares mean (confidence interval 90%)
        FVC Day 1 (0.25 hrs post-dose) (n=31,29)|
    2.92 (2.85 to 2.98)
    2.68 (2.61 to 2.74)
        FVC Day 1 (1 hrs post-dose) (n=31,28)|
    2.99 (2.91 to 3.06)
    2.63 (2.56 to 2.71)
        FVC Day 1 (2 hrs post-dose) (n=31,30)|
    2.99 (2.91 to 3.07)
    2.68 (2.59 to 2.76)
        FVC Day 8 (-0.75 hrs post-dose) (n=31,29)|
    2.91 (2.84 to 2.98)
    2.56 (2.49 to 2.64)
        FVC Day 8 (-0.25 hrs post-dose) (n=30,27)|
    2.91 (2.84 to 2.98)
    2.63 (2.56 to 2.70)
        FVC Day 8 (0.25 hrs post-dose) (n=31,28)|
    3.02 (2.95 to 3.09)
    2.59 (2.51 to 2.66)
        FVC Day 8 (1 hrs post-dose) (n=30,26)|
    3.10 (3.04 to 3.17)
    2.65 (2.58 to 2.72)
        FVC Day 8 (2 hrs post-dose) (n=31,28)|
    3.06 (2.98 to 3.13)
    2.62 (2.54 to 2.70)
    Statistical analysis title
    		 FVC Day 1 (0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [25]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.24
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Notes
    [25] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FVC Day 1 (1 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [26]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.35
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [26] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FVC Day 1 (2 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [27]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.31
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Notes
    [27] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FVC Day 8 (-0.75 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [28]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.35
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [28] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FVC Day 8 (-0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [29]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.28
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [29] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FVC Day 8 (0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [30]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.43
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [30] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FVC Day 8 (1 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [31]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.45
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [31] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FVC Day 8 (2 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [32]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.44
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [32] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.

    Secondary: FEV1/FVC ratio

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    End point title
    		 FEV1/FVC ratio
    End point description
    The FEV1/FVC ratio is the proportion of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC). The result of this ratio is expressed as FEV1%.
    End point type
    Secondary
    End point timeframe
    Day 1 (0.25, 1 and 2 hours post-dose), Day 8 (-0.75, -0.25, 0.25, 1 and 2 hours post-dose) (each treatment period)
    End point values
    		 QVA149 110/50 mcg Matching placebo
    Number of subjects analysed
    31
    31
    Units: FEV1 Percentage
    least squares mean (confidence interval 90%)
        FEV1/FVC Day 1 (0.25 hrs post-dose) (n=31,29)|
    44.31 (43.59 to 45.02)
    42.14 (41.39 to 42.89)
        FEV1/FVC Day 1 (1 hrs post-dose) (n=31,28)|
    44.97 (44.05 to 45.88)
    42.91 (41.95 to 43.87)
        FEV1/FVC Day 1 (2 hrs post-dose) (n=31,30)|
    45.25 (44.42 to 46.08)
    42.93 (42.08 to 43.79)
        FEV1/FVC Day 8 (-0.75 hrs post-dose) (n=31,28)|
    45.05 (44.05 to 46.05)
    42.23 (41.16 to 43.30)
        FEV1/FVC Day 8 (-0.25 hrs post-dose) (n=30,27)|
    45.97 (45.05 to 46.89)
    42.17 (41.19 to 43.15)
        FEV1/FVC Day 8 (0.25 hrs post-dose) (n=31,28)|
    46.34 (45.43 to 47.26)
    42.60 (41.63 to 43.58)
        FEV1/FVC Day 8 (1 hrs post-dose) (n=30,26)|
    47.32 (46.31 to 48.33)
    42.72 (41.64 to 43.80)
        FEV1/FVC Day 8 (2 hrs post-dose) (n=31,28)|
    47.39 (46.39 to 48.40)
    42.42 (41.35 to 43.48)
    Statistical analysis title
    		 FEV1/FVC Day 1 (0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [33]
    P-value
    		 = 0.0006
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.17
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 3.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56
    Notes
    [33] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1/FVC Day 1 (1 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [34]
    P-value
    		 = 0.0106
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 3.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75
    Notes
    [34] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1/FVC Day 1 (2 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [35]
    P-value
    		 = 0.0013
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.32
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 3.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.66
    Notes
    [35] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1/FVC Day 8 (-0.75 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [36]
    P-value
    		 = 0.0017
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.82
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.41
         upper limit
    		 4.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.83
    Notes
    [36] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1/FVC Day 8 (-0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [37]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.51
         upper limit
    		 5.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.76
    Notes
    [37] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1/FVC Day 8 (0.25 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [38]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.74
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 2.45
         upper limit
    		 5.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75
    Notes
    [38] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1/FVC Day 8 (1 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [39]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 3.16
         upper limit
    		 6.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85
    Notes
    [39] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.
    Statistical analysis title
    		 FEV1/FVC Day 8 (2 hrs post-dose)
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 [40]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.98
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 3.56
         upper limit
    		 6.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.83
    Notes
    [40] - Parameters were analyzed using mixed effects model including sequence, period, treatment, time and treatment*Day*time interaction term as fixed factors and patient factor as random factor. Day*time was repeated within each patient*period interaction and subject average baseline and period adjusted baseline were included as covariates.

    Secondary: Lung Clearance Index by Multiple Breath Nitrogen Washout (MBNW)

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    End point title
    		 Lung Clearance Index by Multiple Breath Nitrogen Washout (MBNW)
    End point description
    Multiple Breath Nitrogen Washout (MBNW) was performed after 2 hours post-dose spirometry assessments using a multiple breath inert gas washout technique. The device provides the global index of ventilation inhomogeneity assessment (LCI = Cumulative Expired Volume/Functional Residual Capacity).
    End point type
    Secondary
    End point timeframe
    Day 8 (each treatment period)
    End point values
    		 Matching placebo QVA149 110/50 mcg
    Number of subjects analysed
    26
    29
    Units: Ratio
        least squares mean (confidence interval 90%)
    10.81 (10.20 to 11.41)
    10.80 (10.22 to 11.37)
    Statistical analysis title
    		 Lung Clearance Index
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 [41]
    P-value
    		 = 0.982
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Notes
    [41] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.

    Secondary: Diffusing capacity of the lung for carbon monoxide (DLCO)

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    End point title
    		 Diffusing capacity of the lung for carbon monoxide (DLCO)
    End point description
    The diffusing capacity of the lung for carbon monoxide (DLCO) is a measure of how easily carbon monoxide (CO) molecules transfer from the alveolar gas to the hemoglobin of the red cells in the pulmonary circulation. To measure the DLCO, the patient inhales a single breath containing a minute amount of CO and holds it for 10 seconds. The breath is then exhaled and the exhaled breath is analyzed for CO. The change in the concentration of the CO is then multiplied by the single breath TLC to calculate the DLCO.
    End point type
    Secondary
    End point timeframe
    Day 8 (each treatment period)
    End point values
    		 Matching placebo QVA149 110/50 mcg
    Number of subjects analysed
    26
    29
    Units: mL/min/mmHg
        least squares mean (confidence interval 90%)
    15.73 (14.10 to 17.35)
    16.38 (14.77 to 18.00)
    Statistical analysis title
    		 Diffusion Capacity of Lung for CO
    Comparison groups
    QVA149 110/50 mcg v Matching placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 [42]
    P-value
    		 = 0.0821
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.66
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 1.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Notes
    [42] - Parameters were analyzed using mixed effects model including sequence, period, treatment as fixed factors and patient as random factor.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 1 year.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "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
    20.1
    Reporting groups
    Reporting group title
    QVA149 110/50 mcg
    Reporting group description
    		 QVA149 110/50 mcg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 QVA149 110/50 mcg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 31 (6.45%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 QVA149 110/50 mcg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 31 (16.13%)
    3 / 31 (9.68%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Facial pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Cough
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 31 (3.23%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2016
    The primary purpose of this protocol amendment was to modify the required rescue medication to be used by patients for the entire duration of the trial. At the time of the protocol amendment, no patients were randomized. In addition, this amendment served to correct Exclusion Criteria #6 as this criterion was inadvertently combined with a separate exclusion criteria relating to patients taking prohibited medications prior to dosing. Exclusion Criteria #3 was further defined to allow for clinical judgement on COPD exacerbations and ensure consistency with the protocol. Exclusion Criteria #16, 17, and 18 were revised and aligned with Section 5 of the protocol regarding prohibited treatments. For the MRI assessments, the analysis related to collateral ventilation with regional mapping was moved from a secondary objective to an exploratory objective. Finally, this amendment served to clarify and expand upon Section 5.2 and the minimum cessation for prohibited medications.
    17 Feb 2017
    The primary purpose of this protocol amendment was to update the assessment schedule to clarify that all patients would receive HbA1c testing at screening to confirm if patients met the HbA1c exclusion criterion. In addition, this amendment clarified the definition of randomization and corrected typographical errors throughout the document.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
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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
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