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    Clinical Trial Results:
    A randomized, multi-center, parallel group, double blind, study to assess the safety of QMF Twisthaler® (500/400μg) and mometasone furoate Twisthaler® (400μg) in adolescent and adult patients with persistent asthma.

    Summary
    EudraCT number
    		 2009-011539-10
    Trial protocol
    		 CZ   HU   SK  
    Global end of trial date
    06 May 2011

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CQMF149A2210
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00941798
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 May 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 May 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to compare the time to first serious asthma exacerbation resulting in hospitalisation, intubation or death in the subjects treated with the study drug either once daily QMF149 500/400 microgram (μg) or mometasone furoate (MF) 400 μg.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed. Rescue medication was allowed as recommended by the treating physician based on asthma management standard of care. Short acting β2- adrenergic agonists (salbutamol/albuterol) were permitted for the treatment of asthma exacerbations during the study. The investigator provided follow-up medical care for all subjects who were prematurely withdrawn from the study, or referred them for appropriate ongoing care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jul 2009
    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
    Slovakia: 133
    Country: Number of subjects enrolled
    Czech Republic: 194
    Country: Number of subjects enrolled
    Colombia: 59
    Country: Number of subjects enrolled
    Brazil: 64
    Country: Number of subjects enrolled
    India: 223
    Country: Number of subjects enrolled
    Korea, Republic of: 52
    Country: Number of subjects enrolled
    Peru: 104
    Country: Number of subjects enrolled
    United States: 578
    Country: Number of subjects enrolled
    Hungary: 101
    Worldwide total number of subjects
    1508
    EEA total number of subjects
    428
    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)
    66
    Adults (18-64 years)
    1357
    From 65 to 84 years
    85
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 174 centres in 9 countries.

    Pre-assignment
    Screening details
    		 2282 subjects screened, 1519 subjects randomized and 1518 received study drug.11 randomized patients were excluded from all analysis population (i.e. FAS, PPS, Safety Set, and PK Set) because one patient was not treated, three patients did not sign the informed consent form, 7 patients from center 39 where Ethics Committee did not approve Amend 1.

    Period 1
    Period 1 title
    Baseline period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    The identity of the treatments was concealed by the use of study drugs that were all identical in appearence of packaging, labeling and schedule. Unblinding was allowed only in case of subjects emergencies and at the conclusion of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: QMF149
    Arm description
    		 Subjects were administered with QMF149 (Indacaterol maleate 500 μg/mometasone furoate 400 μg), once daily (o.d) in evening via Twisthaler® (a multi-dose powder inhaler).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Indacaterol maleate/mometasone furoate
    Investigational medicinal product code
    QMF149
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    QMF149 (Indacaterol maleate 500 μg/mometasone furoate 400 μg) was administered o.d via Twisthaler®.

    Arm title
    		 Cohort 2: Mometasone furoate
    Arm description
    		 Subjects were administered with MF 400 μg, o.d in evening via Twisthaler (a multi-dose powder inhaler).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mometasone furoate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MF 400 μg was administered o.d via Twisthaler.

    Number of subjects in period 1
    		Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Started
    749
    759
    Full analysis set
    749
    759
    Treated subjects
    749
    759
    Completed
    555
    574
    Not completed
    194
    185
         Abnormal laboratory value(s)
    1
    2
         Consent withdrawn by subject
    72
    74
         Subject's inability to use the device
    6
    1
         Adverse event, non-fatal
    43
    23
         Death
    -
    1
         Unsatisfactory therapeutic effect
    10
    17
         Administrative problems
    13
    23
         Lost to follow-up
    29
    23
         Abnormal test procedure result(s)
    3
    1
         Protocol deviation
    17
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: QMF149
    Reporting group description
    		 Subjects were administered with QMF149 (Indacaterol maleate 500 μg/mometasone furoate 400 μg), once daily (o.d) in evening via Twisthaler® (a multi-dose powder inhaler).

    Reporting group title
    Cohort 2: Mometasone furoate
    Reporting group description
    		 Subjects were administered with MF 400 μg, o.d in evening via Twisthaler (a multi-dose powder inhaler).

    Reporting group values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate Total
    Number of subjects
    		 749 759 1508
    Age categorical
    Units: Subjects
        < 18 years
    		 31 35 66
        18 - 64 years
    		 675 682 1357
        >= 65 years
    		 43 42 85
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.4 ± 14.75 42.3 ± 14.58 -
    Gender categorical
    Units: Subjects
        Female
    		 436 449 885
        Male
    		 313 310 623

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: QMF149
    Reporting group description
    		 Subjects were administered with QMF149 (Indacaterol maleate 500 μg/mometasone furoate 400 μg), once daily (o.d) in evening via Twisthaler® (a multi-dose powder inhaler).

    Reporting group title
    Cohort 2: Mometasone furoate
    Reporting group description
    		 Subjects were administered with MF 400 μg, o.d in evening via Twisthaler (a multi-dose powder inhaler).

    Primary: Time to first serious asthma exacerbation

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    End point title
    		 Time to first serious asthma exacerbation
    End point description
    Time to first serious asthma exacerbation was defined as the number of days from start of treatment up to the first date when an asthma exacerbation becomes serious (i.e. the date of hospitalisation, intubation or death, whichever occurred first). Subjects who did not experience a serious asthma exacerbation were censored at their last follow-up date. The analysis was performed in full analysis set (FAS), defined as all randomised subjects who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Months
        median (full range (min-max))
    13.3 (0 to 19.6)
    13.4 (0 to 20.3)
    Statistical analysis title
    		 Time to first serious asthma exacerbation
    Statistical analysis description
    The Cox proportional hazards regression model was used to analyse serious asthma exacerbation stratified by asthma related hospitalization, asthma worsening and African American subjects.
    Comparison groups
    Cohort 1: QMF149 v Cohort 2: Mometasone furoate
    Number of subjects included in analysis
    1508
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.076 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.31
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 0.08
         upper limit
    		 -
    Notes
    [1] - The one-sided p-value was based on the hypothesis 'Hazard ratio QMF149 / MF >=1' vs. the alternative 'Hazard ratio QMF149 / MF <1. A hazard ratio <1 favors QMF149.

    Secondary: Incidence of serious asthma exacerbation resulting in hospitalisation, intubation or death

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    End point title
    		 Incidence of serious asthma exacerbation resulting in hospitalisation, intubation or death
    End point description
    The incidence rate of the first serious asthma exacerbation was defined as the number of subjects with at least one serious asthma exacerbations over the course of the study. A serious asthma exacerbation was one that resulted in hospitalisation, intubation or death. The analysis was performed in FAS population.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Subjects
    2
    6
    No statistical analyses for this end point

    Secondary: Number of subjects with asthma exacerbations that required treatment with systemic corticosteroids

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    End point title
    		 Number of subjects with asthma exacerbations that required treatment with systemic corticosteroids
    End point description
    Number of subjects with asthma exacerbations that required treatment with systemic corticosteroids (oral or parenteral) during the study was estimated. Subjects who did not experience an asthma exacerbation requiring treatment with systemic corticosteroids were censored at their last follow-up date. The analysis was performed in FAS population.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Subjects
    124
    171
    No statistical analyses for this end point

    Secondary: Number of subjects with at least one asthma worsening

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    End point title
    		 Number of subjects with at least one asthma worsening
    End point description
    Asthma worsening was evaluated based on following criteria, 1; decrease in peak expiratory flow (PEF) greater than or equal to (≥) 20 percent (%) from mean baseline on ≥ 3 consecutive days, 2; night-time symptom score ≥ 2 on ≥ 2 consecutive nights, 3; decrease in forced expiration volume in 1 second (FEV1) ≥ 20% from baseline at evening visits, 4; daytime symptom score of 3 or 4 on ≥ 2 consecutive days, 5; requiring an urgent unscheduled visit for medical care, 6; 24 hour rescue medication use ≥ 8 puffs on ≥ 2 consecutive days and 7; any other clinically important symptoms included pre-specified MedDRA preferred terms. The analysis was performed in FAS population.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Subjects
    533
    637
    No statistical analyses for this end point

    Secondary: Change from baseline in trough forced expiration volume in 1 second (trough FEV1) to Month 21

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    End point title
    		 Change from baseline in trough forced expiration volume in 1 second (trough FEV1) to Month 21
    End point description
    Trough FEV1 was defined as the volume of air expired in 1 second. Trough FEV1 was assessed as a pulmonary function by using spirometry tests in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) criteria. Change from baseline in trough FEV1 measured at 15 minutes before dosing was analysed. Trough FEV1 measurements within 6 hours of rescue medication use were excluded from analysis. Positive change from baseline indicated improvement. The analysis was performed in FAS population. Here, "Number of subjects analysed" signifies those subjects evaluable for trough FEV1 at specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    674
    699
    Units: Liter (L)
        least squares mean (standard error)
    0.06 ± 0.025
    -0.07 ± 0.024
    No statistical analyses for this end point

    Secondary: Change from baseline in forced expiration volume in 1 second (FEV1) to Month 21

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    End point title
    		 Change from baseline in forced expiration volume in 1 second (FEV1) to Month 21
    End point description
    FEV1 was defined as the volume of air expired in 1 second. FEV1 was assessed as a pulmonary function by using spirometry tests in accordance with ATS/ERS criteria. FEV1 data taken within 6 hours of rescue medication was excluded from the analysis. Positive change from baseline indicated improvement. The analysis was performed in FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Litres
    least squares mean (standard error)
        5 minutes post-dose (n = 578, 607)
    0.09 ± 0.018
    -0.04 ± 0.018
        30 minutes post-dose (n = 576, 605)
    0.12 ± 0.02
    -0.05 ± 0.02
        1 hour post-dose (n = 575, 602)
    0.13 ± 0.021
    -0.06 ± 0.021
        2 hours post-dose (n = 568, 601)
    0.14 ± 0.022
    -0.05 ± 0.022
    No statistical analyses for this end point

    Secondary: Change from baseline in forced vital capacity (FVC) to Month 21

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    End point title
    		 Change from baseline in forced vital capacity (FVC) to Month 21
    End point description
    FVC was defined as the maximum volume of air exhaled with maximally forced effort from a position of maximal inspiration. FVC was determined from spirometry tests in accordance with ATS/ERS criteria. FVC data taken within 6 hours of rescue medication was excluded from the analysis. Negative change from baseline indicated improvement. The analysis was performed in FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Litres
    least squares mean (standard error)
        5 minutes post-dose (n = 578, 607)
    -0.03 ± 0.023
    -0.11 ± 0.023
        30 minutes post-dose (n = 576, 605)
    -0.03 ± 0.025
    -0.13 ± 0.024
        1 hour post-dose (n = 575, 602)
    -0.01 ± 0.025
    -0.13 ± 0.025
        2 hours post-dose (n = 568, 601)
    -0.02 ± 0.026
    -0.13 ± 0.026
    No statistical analyses for this end point

    Secondary: Change from baseline in morning peak expiratory flow (PEF) and evening trough PEF averaged to Month 21

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    End point title
    		 Change from baseline in morning peak expiratory flow (PEF) and evening trough PEF averaged to Month 21
    End point description
    PEF was measured at every morning and evening prior to study medication use except evenings on the day of clinic visits. The baseline value was defined as the average over the last 14 days prior to start of treatment. Positive change from baseline indicated improvement. The analysis was performed in FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Liters per second
    least squares mean (standard error)
        Morning PEF (n = 730, 746)
    0.43 ± 0.075
    0 ± 0.075
        Evening PEF (n = 731, 748)
    0.27 ± 0.076
    -0.15 ± 0.075
    No statistical analyses for this end point

    Secondary: Change from baseline in percentage of days with no asthma symptoms during the morning, daytime and night-time to Month 21

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    End point title
    		 Change from baseline in percentage of days with no asthma symptoms during the morning, daytime and night-time to Month 21
    End point description
    The percentage of days with no asthma symptoms during morning, daytime and night time was estimated. Baseline was the last 14 days prior to start of treatment. Positive change from baseline indicated improvement. The analysis was performed in FAS. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Percentage of days
    least squares mean (standard error)
        Morning (n = 730, 746)
    22.3 ± 2.17
    18.4 ± 2.17
        Daytime (n = 731, 749)
    27.1 ± 2.96
    19.5 ± 2.95
        Night-time (n = 730, 746)
    23.6 ± 2.69
    17.3 ± 2.68
    No statistical analyses for this end point

    Secondary: Change from baseline in average asthma symptom score to Month 21

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    End point title
    		 Change from baseline in average asthma symptom score to Month 21
    End point description
    The average total asthma symptom score was defined as the daily sum of morning asthma symptom score (score range 0-1), daytime asthma symptom scores (score range 0-4) and night-time asthma symptom scores (score range 0-4) and the score range of total asthma symptom score was from 0 to 9. Baseline was the last 14 days prior to start of treatment. Negative change from baseline indicated improvement. The analysis was performed in FAS. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Units on a scale
    least squares mean (standard error)
        Total (n = 708, 733)
    -1.22 ± 0.088
    -0.94 ± 0.088
        Daytime (n = 731, 749)
    -0.5 ± 0.043
    -0.39 ± 0.043
        Night-time (n = 730, 746)
    -0.46 ± 0.037
    -0.36 ± 0.037
    No statistical analyses for this end point

    Secondary: Change from baseline in percentage of days with no rescue medication use to Month 21

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    End point title
    		 Change from baseline in percentage of days with no rescue medication use to Month 21
    End point description
    Percentage of days with no rescue medication use during 24 hours, daytime and night-time was estimated. Baseline was the last 14 days prior to start of treatment. The analysis was performed in FAS population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Percentage of days
    least squares mean (standard error)
        24 hours (n = 669, 696)
    29.1 ± 2.88
    17.9 ± 2.88
        Daytime (n = 692, 711)
    23.6 ± 2.74
    13.8 ± 2.74
        Night-time (n = 691, 708)
    24.6 ± 2.69
    14.5 ± 2.68
    No statistical analyses for this end point

    Secondary: Change from baseline in asthma control questionnaire (ACQ) at Month 21

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    End point title
    		 Change from baseline in asthma control questionnaire (ACQ) at Month 21
    End point description
    The ACQ was a seven-item disease-specific instrument used to assess asthma control in subjects. The ACQ score ranges from 0 = good control of asthma to 6 = poor control of asthma. A negative change in score indicated improvement in asthma control. The analysis was performed in FAS population. Here, "Number of subjects analysed" signifies those subjects evaluable for ACQ at specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    675
    687
    Units: Units on a scale
        least squares mean (standard error)
    -0.55 ± 0.052
    -0.32 ± 0.052
    No statistical analyses for this end point

    Secondary: Number of subjects with adverse events (AEs), AEs related to study drug, serious adverse events (SAEs), AE/SAEs leading to discontinuation and deaths during the study

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    End point title
    		 Number of subjects with adverse events (AEs), AEs related to study drug, serious adverse events (SAEs), AE/SAEs leading to discontinuation and deaths during the study
    End point description
    An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalisation, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the subject or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs were defined as AEs that were suspected to be related to study treatment as per investigator. Based on the severity, AEs were categorised into 3 types as mild, moderate and severe. Death was a fatal event leading to permanent cessations of all vital functions of the body. The analysis was performed in safety set, defined as all the subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From randomisation up to Month 21
    End point values
    		 Cohort 1: QMF149 Cohort 2: Mometasone furoate
    Number of subjects analysed
    749
    759
    Units: Subjects
        AEs
    554
    557
        Mild AEs
    230
    201
        Moderate AEs
    275
    294
        Severe AEs
    49
    62
        AEs related to study drug
    269
    81
        SAEs
    30
    44
        Death
    0
    1
        Discontinued due to AE(s)
    44
    25
        Discontinued due to SAE(s)
    7
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    MF
    Reporting group description
    		 MF

    Reporting group title
    QMF149
    Reporting group description
    		 QMF149

    Serious adverse events
    		 MF QMF149
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 759 (5.80%)
    30 / 749 (4.01%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondroma
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (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 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 759 (0.13%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Inguinal hernia repair
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    1 / 759 (0.13%)
    3 / 749 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 759 (0.26%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 759 (0.26%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Colpocele
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian mass
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         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
    Asthma
         subjects affected / exposed
    9 / 759 (1.19%)
    2 / 749 (0.27%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 759 (0.26%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus polyp
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 759 (0.13%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery occlusion
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radicular pain
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia obstructive
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 759 (0.26%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 759 (0.00%)
    2 / 749 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 759 (0.00%)
    2 / 749 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 759 (0.00%)
    2 / 749 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess intestinal
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 759 (0.26%)
    2 / 749 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 759 (0.26%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    External ear cellulitis
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaria
         subjects affected / exposed
    0 / 759 (0.00%)
    1 / 749 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 759 (0.53%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 759 (0.13%)
    0 / 749 (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: 5%
    Non-serious adverse events
    		 MF QMF149
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    407 / 759 (53.62%)
    456 / 749 (60.88%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    269 / 759 (35.44%)
    195 / 749 (26.03%)
         occurrences all number
    478
    327
    Cough
         subjects affected / exposed
    63 / 759 (8.30%)
    266 / 749 (35.51%)
         occurrences all number
    71
    441
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    58 / 759 (7.64%)
    39 / 749 (5.21%)
         occurrences all number
    76
    45
    Nasopharyngitis
         subjects affected / exposed
    106 / 759 (13.97%)
    112 / 749 (14.95%)
         occurrences all number
    150
    159
    Sinusitis
         subjects affected / exposed
    52 / 759 (6.85%)
    55 / 749 (7.34%)
         occurrences all number
    64
    74
    Upper respiratory tract infection
         subjects affected / exposed
    96 / 759 (12.65%)
    83 / 749 (11.08%)
         occurrences all number
    123
    107

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2011
    1. Clarification for the premature study drug discontinuation due to prohibited concomitant medication was provided . 2. The primary safety endpoint was ammended from “time to the first serious asthma exacerbation” to “rate of serious asthma exacerbations”. The new key secondary analysis was added for secondary objective to compare the rate of the first serious asthma exacerbations resulting in hospitalization, intubation, or death of subjects.

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

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

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