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    Clinical Trial Results:
    A 26-week, randomized, double blind, parallel-group multicenter study to assess the efficacy and safety of QVA149 (110/50 mcg o.d.) vs. tiotropium (18 mcg o.d.) + salmeterol/fluticasone propionate FDC (50/500 mcg b.i.d.) in patients with moderate to severe COPD Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results

    Summary
    EudraCT number
    		 2015-000114-22
    Trial protocol
    		 BE   EE   NL   LV   LT   DE   CZ   HU   DK   SK   ES   AT   PL   GR   HR   BG  
    Global end of trial date
    18 Jul 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CQVA149A2316
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02603393
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of QVA149 (110/50 μg o.d.) on post-dose trough forced expiratory volume in 1 second (FEV1) versus tiotropium (18 μg o.d.) + salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.) after 26 weeks of treatment in moderate-to-severe 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
    20 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 106
    Country: Number of subjects enrolled
    Austria: 22
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Bulgaria: 26
    Country: Number of subjects enrolled
    Canada: 46
    Country: Number of subjects enrolled
    Croatia: 12
    Country: Number of subjects enrolled
    Czech Republic: 31
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Estonia: 88
    Country: Number of subjects enrolled
    Germany: 204
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    Latvia: 30
    Country: Number of subjects enrolled
    Lithuania: 25
    Country: Number of subjects enrolled
    Netherlands: 28
    Country: Number of subjects enrolled
    Poland: 163
    Country: Number of subjects enrolled
    Romania: 98
    Country: Number of subjects enrolled
    Serbia: 59
    Country: Number of subjects enrolled
    Slovakia: 21
    Country: Number of subjects enrolled
    Spain: 14
    Worldwide total number of subjects
    1053
    EEA total number of subjects
    842
    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)
    470
    From 65 to 84 years
    576
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This was a multicenter, randomized, parallel-group, double-blind, triple-dummy study to assess the efficacy of the 2 active treatment groups in patients with moderate to severe COPD.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QVA149
    Arm description
    		 110/50 μg capsules o.d. for inhalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    indacaterol maleate/glycopyrronium bromide
    Investigational medicinal product code
    QVA149
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    110/50 μg o.d.)

    Arm title
    		 Tiotropium + salmeterol/fluticasone
    Arm description
    		 tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium + salmeterol/fluticasone
    Investigational medicinal product code
    Other name
    FDC 50/500 μg b.i.d
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    50/500 μg b.i.d

    Number of subjects in period 1
    		QVA149 Tiotropium + salmeterol/fluticasone
    Started
    527
    526
    Completed
    456
    472
    Not completed
    71
    54
         Adverse event, serious fatal
    3
    4
         Physician decision
    3
    3
         Adverse event, non-fatal
    17
    15
         Technical problems
    4
    7
         Protocol deviation
    2
    3
         Non-compliance with study treatment
    1
    -
         Patient/guardian decision
    32
    18
         Lost to follow-up
    1
    2
         Sponsor decision
    1
    -
         Lack of efficacy
    7
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 110/50 μg capsules o.d. for inhalation

    Reporting group title
    Tiotropium + salmeterol/fluticasone
    Reporting group description
    		 tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)

    Reporting group values
    		 QVA149 Tiotropium + salmeterol/fluticasone Total
    Number of subjects
    		 527 526 1053
    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)
    		 234 236 470
        From 65-84 years
    		 288 288 576
        85 years and over
    		 5 2 7
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.4 ( 7.99 ) 65.2 ( 7.62 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 149 161 310
        Male
    		 378 365 743
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 3 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 526 523 1049
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 110/50 μg capsules o.d. for inhalation

    Reporting group title
    Tiotropium + salmeterol/fluticasone
    Reporting group description
    		 tiotropium (18 μg o.d.), and salmeterol/fluticasone propionate FDC (50/500 μg b.i.d.)

    Primary: Mean change from baseline in post-dose trough FEV1

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    End point title
    		 Mean change from baseline in post-dose trough FEV1
    End point description
    Mean change from baseline in post-dose trough forced expiratory volume in 1 second (FEV1) following 26 weeks of treatment. Trough FEV1 is defined as the mean of the two FEV1 values measured at 23 hr 15 min and 23 hr 45 min after the morning dose taken at site on Day 181. Baseline FEV1 is defined as the average of the pre-dose FEV1 measured at -45 min and -15 min at Day 1.
    End point type
    Primary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: Liters
        least squares mean (standard error)
    -0.029 ( 0.0119 )
    -0.003 ( 0.0115 )
    Statistical analysis title
    		 Mean change from baseline in post-dose trough FEV1
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.0404 [2]
    Method
    		 Mixed Model for Repeated Measures Analys
    Confidence interval
         level
    		 95%
    Notes
    [1] - Non-inferiority will be demonstrated if the 95% confidence interval of the treatment difference lies entirely to the right of (higher than) –50 mL.
    [2] - 1 sided

    Secondary: Annualized rate of moderate or severe COPD exacerbations

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    End point title
    		 Annualized rate of moderate or severe COPD exacerbations
    End point description
    Moderate or severe COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: COPD exacerbations/year
        number (confidence interval 95%)
    0.52 (0.43 to 0.63)
    0.48 (0.40 to 0.58)
    Statistical analysis title
    		 Annualized rate of COPD exacerbations
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5802 [3]
    Method
    		 Generalized Linear Model Analysis
    Parameter type
    		 Ratio of rates
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.4
    Notes
    [3] - 2 sided

    Secondary: Annualized Rate of COPD exacerbations requiring treatment with systemic glucocorticosteroids and/or antibiotics, moderate exacerbations only

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    End point title
    		 Annualized Rate of COPD exacerbations requiring treatment with systemic glucocorticosteroids and/or antibiotics, moderate exacerbations only
    End point description
    COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: COPD Exacerbations/year
        number (confidence interval 95%)
    0.47 (0.39 to 0.58)
    0.44 (0.36 to 0.53)
    Statistical analysis title
    		 Annualized Rate of COPD exacerbations
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5651 [4]
    Method
    		 Generalized Linear Model Analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.43
    Notes
    [4] - 2-sided

    Secondary: Annualized Rate of COPD exacerbations requiring hospitalisation

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    End point title
    		 Annualized Rate of COPD exacerbations requiring hospitalisation
    End point description
    COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: COPD Exacerbations/year
        number (confidence interval 95%)
    0.001 (0.0 to 9999)
    0.001 (0.00 to 9999)
    Statistical analysis title
    		 Annualized Rate of COPD exacerbations
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9665 [5]
    Method
    		 Generalized Linear Model Analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 2.34
    Notes
    [5] - 2-sided

    Secondary: Mean change from baseline in pre-dose trough FEV1

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    End point title
    		 Mean change from baseline in pre-dose trough FEV1
    End point description
    Trough FEV1 is defined as the average of the pre-dose FEV1 measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FEV1 measurements at 23h15min and 23h45min after dosing at Day 181. Baseline FEV1 is considered the Day 1 average of pre-dose measurements.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: Liters
        least squares mean (standard error)
    -0.029 ( 0.0119 )
    -0.003 ( 0.0115 )
    Statistical analysis title
    		 Mean change from baseline in pre-dose trough FEV1
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0573 [6]
    Method
    		 Mixed Model for Repeated Measures Analys
    Confidence interval
         level
    		 95%
    Notes
    [6] - 2-Sided

    Secondary: Mean change from baseline in St. George’s Respiratory Questionnaire

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    End point title
    		 Mean change from baseline in St. George’s Respiratory Questionnaire
    End point description
    The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: Score on a scale
        least squares mean (standard error)
    -0.7 ( 0.53 )
    -2.5 ( 0.51 )
    Statistical analysis title
    		 St. George’s Respiratory Questionnaire
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0022 [7]
    Method
    		 Mixed Model for Repeated Measures Analys
    Confidence interval
         level
    		 95%
    Notes
    [7] - 2-Sided

    Secondary: Mean change from baseline in St. George’s Respiratory Questionnaire

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    End point title
    		 Mean change from baseline in St. George’s Respiratory Questionnaire
    End point description
    The St. George Respiratory Questionnaire C (SGRQ-C) is used to provide the health status measurements in this study. Baseline SGRQ-C is defined as the assessment taken right before the first dose of the double-blind drug on Day 1. Higher values correspond to greater impairment of health status.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: Score on a scale
        least squares mean (standard error)
    -1.0 ( 0.54 )
    -2.5 ( 0.52 )
    Statistical analysis title
    		 St. George’s Respiratory Questionnaire
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0221 [8]
    Method
    		 Mixed Model for Repeated measures Analys
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 2.6
    Notes
    [8] - 2-Sided

    Secondary: Transition Dyspnea Index (TDI) score

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    End point title
    		 Transition Dyspnea Index (TDI) score
    End point description
    Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: Score on a scale
        least squares mean (standard error)
    1.177 ( 0.1558 )
    1.418 ( 0.1508 )
    Statistical analysis title
    		 TDI
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1724
    Method
    		 Mixed Model for Repeated Measures Analys
    Confidence interval
         level
    		 95%

    Secondary: Transition Dyspnea Index (TDI) score

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    End point title
    		 Transition Dyspnea Index (TDI) score
    End point description
    Transitional Dyspnea Index (TDI) score presents the degree of impairment due to dyspnea. The lower the score the worse the severity of dyspnea.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: Score on a scale
        least squares mean (standard error)
    1.382 ( 0.1567 )
    1.671 ( 0.1519 )
    Statistical analysis title
    		 TDI
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1055 [9]
    Method
    		 Mixed Model for Repated Measures Analysi
    Confidence interval
         level
    		 95%
    Notes
    [9] - 2-Sided

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

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    End point title
    		 Change from baseline in the mean daily number of puffs of rescue medication
    End point description
    Change from baseline in mean daily number of puffs of rescue medication (number of puffs taken in the previous 12 hours) over 26 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: Number of puffs per day
        least squares mean (standard error)
    -0.307 ( 0.1006 )
    -0.484 ( 0.0983 )
    Statistical analysis title
    		 Rescue medication
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0641 [10]
    Method
    		 Linear Mixed Model Analysis
    Confidence interval
         level
    		 95%
    Notes
    [10] - 2-Sided

    Secondary: Mean change From baseline in Forced Vital Capacity (FVC)

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    End point title
    		 Mean change From baseline in Forced Vital Capacity (FVC)
    End point description
    Change from baseline in forced vital capacity following 26 weeks of treatment. Trough FVC is defined as the average of the pre-dose FVC measurements at -45 min and -15 min prior to dosing at each visit except Day 182 which is the average of the post-dose FVC measurements at 23h15min and 23h45min after dosing at Day 181. Baseline is considered the Day 1 average of pre-dose measurements.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 QVA149 Tiotropium + salmeterol/fluticasone
    Number of subjects analysed
    527
    526
    Units: Liters
        least squares mean (standard error)
    -0.030 ( 0.0192 )
    -0.048 ( 0.0186 )
    Statistical analysis title
    		 FVC
    Comparison groups
    QVA149 v Tiotropium + salmeterol/fluticasone
    Number of subjects included in analysis
    1053
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4107 [11]
    Method
    		 Mixed Model for Repeated Measures Analys
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.025
         upper limit
    		 0.061
    Notes
    [11] - 2-Sided

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The study consists of four epochs: screening (1 week), run-in (4 weeks), blinded treatment (26 weeks) and follow-up (4 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 QVA149

    Reporting group title
    Tio+Salm/flut
    Reporting group description
    		 Tio+Salm/flut

    Serious adverse events
    		 QVA149 Tio+Salm/flut
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 527 (6.07%)
    34 / 526 (6.46%)
         number of deaths (all causes)
    4
    5
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 527 (0.00%)
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pituitary tumour benign
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic dissection
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    12 / 527 (2.28%)
    13 / 526 (2.47%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 527 (0.38%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 527 (0.19%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac tamponade
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 527 (0.38%)
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Anal fissure
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 527 (0.00%)
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 527 (0.76%)
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 527 (0.19%)
    0 / 526 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 QVA149 Tio+Salm/flut
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    398 / 527 (75.52%)
    392 / 526 (74.52%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    26 / 527 (4.93%)
    24 / 526 (4.56%)
         occurrences all number
    29
    24
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 527 (1.33%)
    10 / 526 (1.90%)
         occurrences all number
    8
    10
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 527 (0.19%)
    6 / 526 (1.14%)
         occurrences all number
    1
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 527 (1.33%)
    13 / 526 (2.47%)
         occurrences all number
    12
    14
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 527 (0.57%)
    6 / 526 (1.14%)
         occurrences all number
    4
    6
    Oedema peripheral
         subjects affected / exposed
    7 / 527 (1.33%)
    3 / 526 (0.57%)
         occurrences all number
    8
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 527 (0.57%)
    6 / 526 (1.14%)
         occurrences all number
    3
    6
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    370 / 527 (70.21%)
    353 / 526 (67.11%)
         occurrences all number
    1024
    1014
    Cough
         subjects affected / exposed
    24 / 527 (4.55%)
    15 / 526 (2.85%)
         occurrences all number
    27
    17
    Oropharyngeal pain
         subjects affected / exposed
    7 / 527 (1.33%)
    7 / 526 (1.33%)
         occurrences all number
    7
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 527 (1.52%)
    9 / 526 (1.71%)
         occurrences all number
    9
    9
    Pain in extremity
         subjects affected / exposed
    2 / 527 (0.38%)
    6 / 526 (1.14%)
         occurrences all number
    2
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    13 / 527 (2.47%)
    5 / 526 (0.95%)
         occurrences all number
    13
    6
    Influenza
         subjects affected / exposed
    6 / 527 (1.14%)
    6 / 526 (1.14%)
         occurrences all number
    8
    6
    Oral candidiasis
         subjects affected / exposed
    12 / 527 (2.28%)
    18 / 526 (3.42%)
         occurrences all number
    16
    25
    Oropharyngeal candidiasis
         subjects affected / exposed
    6 / 527 (1.14%)
    7 / 526 (1.33%)
         occurrences all number
    7
    7
    Pneumonia
         subjects affected / exposed
    2 / 527 (0.38%)
    6 / 526 (1.14%)
         occurrences all number
    2
    6
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 527 (0.19%)
    6 / 526 (1.14%)
         occurrences all number
    1
    6
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    2 / 527 (0.38%)
    6 / 526 (1.14%)
         occurrences all number
    2
    6
    Urinary tract infection
         subjects affected / exposed
    7 / 527 (1.33%)
    1 / 526 (0.19%)
         occurrences all number
    7
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    57 / 527 (10.82%)
    59 / 526 (11.22%)
         occurrences all number
    65
    73

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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