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    Clinical Trial Results:
    A randomized, double-blinded, single-center, placebo controlled, cross-over study to assess the effect of QVA149 (indacaterol maleate/glycopyrronium bromide) on cardiac function in patients with chronic obstructive pulmonary disease (COPD). Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2014-004680-21
    Trial protocol
    		 DE  
    Global end of trial date
    15 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2018
    First version publication date
    12 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CQVA149ADE05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02442206
    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, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 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 determine the effect of once-daily QVA149 (110/50) compared with placebo on left ventricular end-diastolic volume (LV EDV), as measured by magnetic resonance imaging (MRI) after 2 weeks of treatment in hyperinflated COPD patients.
    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
    18 May 2015
    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
    Germany: 62
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    29
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This was a randomized, double-blind, placebo controlled, single-center, 2-period cross-over study to compare the effects of a 2 week therapy each with QVA149 versus placebo. The study duration was about 13 weeks

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind [1]
    Roles blinded
    		 Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment sequence 1
    Arm description
    		 QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43
    Arm type
    		 Experimental

    Investigational medicinal product name
    QVA149 (110/50 μg) followed by placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    QVA149 (110/50 μg) o.d. from Day 1 to Day 15, followed by placebo o.d. from Day 29 to Day 43.

    Arm title
    		 Treatment sequence 2
    Arm description
    		 Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo followed by QVA149 (110/50 μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo o.d. from Day 1 to Day 15, followed by QVA149 (110/50 μg) o.d. from Day 29 to Day 43.

    Notes
    [1] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: All data verified
    Number of subjects in period 1
    		Treatment sequence 1 Treatment sequence 2
    Started
    30
    32
    Completed
    29
    29
    Not completed
    1
    3
         withdrew consent
    -
    1
         Adverse event, non-fatal
    1
    1
         COPD exacerbation
    -
    1
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind [2]
    Roles blinded
    		 Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment sequence 1
    Arm description
    		 QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43
    Arm type
    		 Experimental

    Investigational medicinal product name
    QVA149 (110/50 μg) followed by placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    QVA149 (110/50 μg) o.d. from Day 1 to Day 15, followed by placebo o.d. from Day 29 to Day 43.

    Arm title
    		 Treatment sequence 2
    Arm description
    		 Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo followed by QVA149 (110/50 μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo o.d. from Day 1 to Day 15, followed by QVA149 (110/50 μg) o.d. from Day 29 to Day 43.

    Notes
    [2] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: All data verified
    Number of subjects in period 2
    		Treatment sequence 1 Treatment sequence 2
    Started
    29
    29
    Completed
    28
    29
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment sequence 1
    Reporting group description
    		 QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43

    Reporting group title
    Treatment sequence 2
    Reporting group description
    		 Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43

    Reporting group values
    		 Treatment sequence 1 Treatment sequence 2 Total
    Number of subjects
    		 30 32 62
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 15 14 29
        From 65-84 years
    		 15 18 33
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.1 ( 8.00 ) 63.8 ( 7.80 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 8 9 17
        Male
    		 22 23 45
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 30 32 62
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Treatment sequence 1
    Reporting group description
    		 QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43

    Reporting group title
    Treatment sequence 2
    Reporting group description
    		 Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43
    Reporting group title
    Treatment sequence 1
    Reporting group description
    		 QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43

    Reporting group title
    Treatment sequence 2
    Reporting group description
    		 Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43

    Subject analysis set title
    QVA149
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43

    Subject analysis set title
    QVA149
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43

    Primary: Left ventricular end-diastolic volume (LVEDV)

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    End point title
    		 Left ventricular end-diastolic volume (LVEDV)
    End point description
    Left ventricular enddiastolic volume (LVEDV) is a measurement of the volume of blood in the heart’s left ventricular chamber at the end of the chamber’s filling with blood and will be determined as measured by MRI.
    End point type
    Primary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: ML
        arithmetic mean (standard deviation)
    11.873 ( 14.3215 )
    -0.954 ( 12.2463 )
    Statistical analysis title
    		 Left ventricular enddiastolic volume (LVEDV)
    Comparison groups
    Placebo v QVA149
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    10.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.209
         upper limit
    		 14.331

    Secondary: Forced Expiratory Volume in one second (FEV1) at each time-point

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    End point title
    		 Forced Expiratory Volume in one second (FEV1) at each time-point
    End point description
    Forced Expiratory Volume in one second (FEV1) will be calculated as the volume of air forcibly exhaled in one second as measured by spirometry.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: Liter
        arithmetic mean (standard deviation)
    0.42 ( 0.211 )
    -0.01 ( 0.168 )
    Statistical analysis title
    		 Forced Expiratory Volume in one second (FEV1)
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.49

    Secondary: Forced Vital Capacity (FVC) at each time-point

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    End point title
    		 Forced Vital Capacity (FVC) at each time-point
    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 will be assessed via spirometry.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: Liter
        arithmetic mean (standard deviation)
    0.67 ( 0.434 )
    0.00 ( 0.293 )
    Statistical analysis title
    		 Forced Vital Capacity (FVC)
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.8

    Secondary: Inspiratory Capacity (IC) at each time-point

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    End point title
    		 Inspiratory Capacity (IC) at each time-point
    End point description
    Inspiratory capacity (IC) was defined as the mean of the maximum IC over 3 values measured by bodyplethysmography according to internationally accepted standards.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: Liters
        arithmetic mean (standard deviation)
    0.475 ( 0.3284 )
    0.014 ( 0.2388 )
    Statistical analysis title
    		 Inspiratory capacity (IC)
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.446
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.352
         upper limit
    		 0.541

    Secondary: Total Lung Capacity (TLC) at each time-point

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    End point title
    		 Total Lung Capacity (TLC) at each time-point
    End point description
    Total Lung Capacity (TLC) will be calculated from the mean Functional Residual Capacity (FRC) plus the highest value of the Inspiratory Capacity, both measured by bodyplethymography according to internationally accepted standards.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: Liters
        arithmetic mean (standard deviation)
    -0.181 ( 0.3408 )
    -0.001 ( 0.3618 )
    Statistical analysis title
    		 Total Lung Capacity (TLC)
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0017
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.285
         upper limit
    		 -0.07

    Secondary: Residual Volume (RVol) at each time-point

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    End point title
    		 Residual Volume (RVol) at each time-point
    End point description
    Residual Volume (RVol) will be calculated from the value of Total Lung Capacity (TLC) minus the highest value of the Slow Vital Capacity, both measured by bodyplethymography according to internationally accepted standards.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: Liters
        arithmetic mean (standard deviation)
    -0.757 ( 0.5833 )
    0.012 ( 0.5141 )
    Statistical analysis title
    		 Residual Volume (RVol)
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.751
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.925
         upper limit
    		 -0.577

    Secondary: Specific Airway Resistance (sRaw) at each time-point

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    End point title
    		 Specific Airway Resistance (sRaw) at each time-point
    End point description
    Specific Airway Resistance (sRaw) will be documented as effective resistance (sReff) calculated as the median of five acceptable measurements. Values will be measured by bodyplethymography according to internationally accepted standards.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    56
    55
    Units: kilopascal (kPa)
        arithmetic mean (standard deviation)
    1.887 ( 1.0979 )
    0.037 ( 1.0383 )
    Statistical analysis title
    		 Specific Airway Resistance (sRaw)
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.639
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.945
         upper limit
    		 -1.332

    Secondary: Functional Residual Capacity (FRC) at each time-point

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    End point title
    		 Functional Residual Capacity (FRC) at each time-point
    End point description
    Functional Residual Capacity (FRC) will be calculated as the mean of three reproducible values as measured by bodyplethymography according to internationally accepted standards.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: Liters
        arithmetic mean (standard deviation)
    -0.656 ( 0.4602 )
    -0.015 ( 0.4257 )
    Statistical analysis title
    		 Functional Residual Capacity (FRC)
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.625
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.761
         upper limit
    		 -0.489

    Secondary: Right ventricular (RV) and left ventricular (LV) ejection fraction (EF) at each time-point

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    End point title
    		 Right ventricular (RV) and left ventricular (LV) ejection fraction (EF) at each time-point
    End point description
    Right and left ventricular ejection fraction is the fraction of blood (in percent) pumped out of the heart’s left and right ventricular chamber, respectively, with each heart beat and will be determined as measured by MRI.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: Percentage
    arithmetic mean (standard deviation)
        LV-EF|
    1.893 ( 5.8486 )
    1.313 ( 5.4261 )
        RV-EF|
    2.046 ( 5.8746 )
    0.361 ( 6.1936 )
    Statistical analysis title
    		 Right and left ventricular ejection fraction
    Statistical analysis description
    LV EF
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.142
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.209
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.419
         upper limit
    		 2.836
    Statistical analysis title
    		 Right and left ventricular ejection fraction
    Statistical analysis description
    RV EF
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1732
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.131
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.512
         upper limit
    		 2.774

    Secondary: Left and right ventricular end-systolic volumeat each time-point

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    End point title
    		 Left and right ventricular end-systolic volumeat each time-point
    End point description
    Right ventricular end-systolic volume (RV-ESV) and left ventricular end-systolic volume (LV-ESV) is a measurement of the volume of blood in the heart’s right and left ventricular chamber, respectively, at the end of the heart's contraction and will be determined as measured by MRI.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: ML
    arithmetic mean (standard deviation)
        LV-ESV|
    1.898 ( 8.4565 )
    -2.283 ( 8.1489 )
        RV-ESV|
    2.183 ( 8.7063 )
    0.133 ( 9.3370 )
    Statistical analysis title
    		 (RV-ESV) and (LV-ESV)
    Statistical analysis description
    LV ESV
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0437
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.241
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.066
         upper limit
    		 4.417
    Statistical analysis title
    		 (RV-ESV) and (LV-ESV)
    Statistical analysis description
    RV ESV
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1236
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.095
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.591
         upper limit
    		 4.782

    Secondary: Right ventricular enddiastolic volume at each time-point

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    End point title
    		 Right ventricular enddiastolic volume at each time-point
    End point description
    Right ventricular end-diastolic volume is a measurement of the volume of blood in the heart’s right ventricular chamber at the end of the chamber’s filling with blood and will be determined as measured by MRI.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: ML
        arithmetic mean (standard deviation)
    12.323 ( 13.9683 )
    1.758 ( 14.7904 )
    Statistical analysis title
    		 Right ventricular end-diastolic volume
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    9.357
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.649
         upper limit
    		 14.065

    Secondary: Cardiac output at each time-point, left and right ventricular cardiac output (LVCO and RVCO)

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    End point title
    		 Cardiac output at each time-point, left and right ventricular cardiac output (LVCO and RVCO)
    End point description
    Cardiac output is calculated as the heart rate multiplied by the stroke volume (= difference between ventricular enddiastolic volume and endsystolic volume) that will be determined as measured by MRI.
    End point type
    Secondary
    End point timeframe
    week 2
    End point values
    		 QVA149 Placebo
    Number of subjects analysed
    57
    59
    Units: Liter/min
    arithmetic mean (standard deviation)
        LVCO|
    0.504 ( 0.7919 )
    0.119 ( 0.8970 )
        RVCO|
    0.517 ( 0.8063 )
    0.144 ( 0.9523 )
    Statistical analysis title
    		 Cardiac output
    Statistical analysis description
    RVCO
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0182
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.281
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.512
    Statistical analysis title
    		 Cardiac output
    Statistical analysis description
    LVCO
    Comparison groups
    QVA149 v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0032
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.337
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.118
         upper limit
    		 0.555

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    For the study duration of about 13 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: All data verified

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2015
    Echocardiographic measures were included as additional exploratory objectives.  To account for blood pressure changes as potential confounder of ventricular function, blood pressure measurements were to be performed 4 times during MRI and the mean was considered during data analysis.  Changes to the exclusion criteria were made as follows: a. To allow patients with stents to be enrolled in the study as stent material does not interfere with MRI and the indication for stent implantation does not per se influence the outcome of the study unless significant ischemic cardiac changes were present. b. To exclude patients with uncontrolled hypertension from the study. c. To allow patients with a history of hypersensitivity to i.v. contrast medium to participate in the study. In case patients suffered from such a hypersensitivity, the last MRI protocol sequence that required i.v. contrast medium was not performed.
    14 Jul 2015
    19F MRI technique was included as an optional measurement to assess regional pulmonary ventilation during steady state breathing. Hence, an additional explorative objective of regional lung 19F gas wash-out time was included in the protocol as optional measurement in a subgroup of patients
    20 Apr 2016
    The possibility of re-screening patients who failed the screening (before Visit 4) due to increased blood pressure (mean sitting SBP >160 mmHg and/or mean sitting DBP > 90 mmHg) was implemented in the exclusion criteria. Therefore, these patients were permitted to be re-screened in case they achieved controlled disease status following initiation or intensification of antihypertensive therapy

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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