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    Clinical Trial Results:
    A multi-center, randomized, 12-week treatment, doubleblind study to assess the efficacy and safety of QMF149 (150/80 μg) compared with mometasone furoate (MF) Twisthaler® (200 μg) in adult and adolescent patients with asthma

    Summary
    EudraCT number
    		 2016-000472-22
    Trial protocol
    		 DE   EE   IT   SE   LT   SK   LV   HU   BG   PL  
    Global end of trial date
    30 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2019
    First version publication date
    14 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQVM149B2303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02892344
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharmaceutical, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharmaceuticals, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of QMF149 150/80 μg o.d. (in the evening) delivered via Concept1 compared with MF 200 μg o.d. (in the evening) delivered via Twisthaler in terms of trough FEV1 after 12 weeks of treatment in adults and adolescents
    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
    17 Mar 2017
    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
    Bulgaria: 40
    Country: Number of subjects enrolled
    Chile: 12
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Estonia: 24
    Country: Number of subjects enrolled
    Germany: 111
    Country: Number of subjects enrolled
    Hungary: 116
    Country: Number of subjects enrolled
    India: 73
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 52
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 25
    Country: Number of subjects enrolled
    Latvia: 44
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Peru: 54
    Country: Number of subjects enrolled
    Philippines: 11
    Country: Number of subjects enrolled
    Poland: 50
    Country: Number of subjects enrolled
    Russian Federation: 34
    Country: Number of subjects enrolled
    Slovakia: 80
    Country: Number of subjects enrolled
    South Africa: 23
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    Vietnam: 22
    Worldwide total number of subjects
    802
    EEA total number of subjects
    475
    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)
    64
    Adults (18-64 years)
    630
    From 65 to 84 years
    108
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study used a 12-week treatment, randomized, double-blind, double-dummy, parallel-group design. The 12 week treatment epoch was followed by a 30 day Follow-up epoch.

    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
    		 QMF149 150/80 μg
    Arm description
    		 QMF149 150/80 microgram o.d. delivered via Concept1
    Arm type
    		 Experimental

    Investigational medicinal product name
    QMF149 150/80 μg
    Investigational medicinal product code
    QMF149 150/80 μg
    Other name
    QMF149 150/80 μg
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QMF149 150/80 μg o.d. delivered via Concept1

    Arm title
    		 MF 200 µg
    Arm description
    		 MF 200 microgram o.d. delivered via Twisthaler®
    Arm type
    		 Active comparator

    Investigational medicinal product name
    MF 200 µg
    Investigational medicinal product code
    MF 200 µg
    Other name
    MF 200 µg
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MF 200 μg o.d. delivered via a Twisthaler

    Number of subjects in period 1
    		QMF149 150/80 μg MF 200 µg
    Started
    398
    404
    Full analysis set
    395
    399
    Completed
    394
    383
    Not completed
    4
    21
         Physician decision
    -
    2
         Adverse event, non-fatal
    1
    8
         Technical problems
    -
    1
         Protocol deviation
    3
    4
         Non-compliance with study treatment
    -
    1
         Lost to follow-up
    -
    1
         Subject/guardian decision
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QMF149 150/80 μg
    Reporting group description
    		 QMF149 150/80 microgram o.d. delivered via Concept1

    Reporting group title
    MF 200 µg
    Reporting group description
    		 MF 200 microgram o.d. delivered via Twisthaler®

    Reporting group values
    		 QMF149 150/80 μg MF 200 µg Total
    Number of subjects
    		 398 404 802
    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)
    		 31 33 64
        Adults (18-64 years)
    		 312 318 630
        From 65-84 years
    		 55 53 108
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 46.1 ( 16.26 ) 45.1 ( 16.27 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 247 241 488
        Male
    		 151 163 314
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 98 101 199
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 5 6
        White
    		 262 265 527
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 37 33 70

    End points

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    End points reporting groups
    Reporting group title
    QMF149 150/80 μg
    Reporting group description
    		 QMF149 150/80 microgram o.d. delivered via Concept1

    Reporting group title
    MF 200 µg
    Reporting group description
    		 MF 200 microgram o.d. delivered via Twisthaler®

    Primary: trough FEV1

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    End point title
    		 trough FEV1
    End point description
    demonstrate the superiority of QMF149 150/80 microgram o.d. (in the evening) delivered via Concept1 compared with MF 200 microgram o.d. (in the evening) delivered via Twisthaler® in terms of trough FEV1 after 12 weeks of treatment in adults and adolescents. Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured by spirometry.
    End point type
    Primary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    377
    375
    Units: Liters
        least squares mean (standard error)
    2.562 ( 0.0134 )
    2.379 ( 0.0134 )
    Statistical analysis title
    		 Trough FEV1
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    752
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.182
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.148
         upper limit
    		 0.217

    Secondary: ACQ-7

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    End point title
    		 ACQ-7
    End point description
    ACQ-7 is an asthma control questionnaire (scoring 5 symptoms, FEV1 entered by the investigator and daily rescue bronchodilator use entered by the patient) validated to evaluate different levels of asthma control. the ACQ-7 was used to assess improvements in asthma symptom control. The ACQ-7, a seven-item disease-specific instrument developed and validated to assess asthma control in patients in clinical trials as well as in individuals in clinical practice, was provided to the site. All seven items were then scored on a 7-point Likert scale, with 0 indicating total control and 6 indicating no control. The questions were equally weighted and the total score was the mean of the seven items. The first 6 questions of the ACQ-7 were completed by the patient while the last question (question 7) was completed by the study investigator using spirometry data generated by the spirometry equipment.
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    375
    369
    Units: Units on a scale
        least squares mean (standard error)
    1.323 ( 0.0411 )
    1.540 ( 0.0411 )
    Statistical analysis title
    		 ACQ-7
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    744
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.218
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.293
         upper limit
    		 -0.143

    Secondary: trough FEV1 at day 2

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    End point title
    		 trough FEV1 at day 2
    End point description
    Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing
    End point type
    Secondary
    End point timeframe
    Day 2
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    389
    393
    Units: Liters
        least squares mean (standard error)
    2.490 ( 0.0108 )
    2.358 ( 0.0108 )
    Statistical analysis title
    		 trough FEV1 at day 2
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    782
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.132
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.105
         upper limit
    		 0.158

    Secondary: Pre-dose FEV1 at week 4

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    End point title
    		 Pre-dose FEV1 at week 4
    End point description
    Pre-dose FEV1 is defined as the mean of -45 min and -15 min FEV1 values pre-evening dose
    End point type
    Secondary
    End point timeframe
    week 4
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    389
    386
    Units: Liters
        least squares mean (standard error)
    2.545 ( 0.0132 )
    2.369 ( 0.0131 )
    Statistical analysis title
    		 Pre-dose FEV1 at week 4
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    775
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.176
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.145
         upper limit
    		 0.207

    Secondary: FVC over 12 weeks

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    End point title
    		 FVC over 12 weeks
    End point description
    FVC is the total amount of air exhaled during the FEV test. Forced Vital Capacity (FVC) and Forced Expiratory Flow between 25% and 75% of FVC (FEF25-75) will be measured
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    383
    379
    Units: Liters
    least squares mean (standard error)
        Pre dose trough FVC
    3.453 ( 0.0169 )
    3.353 ( 0.0169 )
        Pre-dose trough FEF25-75%
    2.030 ( 0.0228 )
    1.742 ( 0.0228 )
    Statistical analysis title
    		 Pre-dose trough FEF25-75%
    Statistical analysis description
    Pre-dose trough FEF25-75%
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    762
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.288
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.231
         upper limit
    		 0.345
    Statistical analysis title
    		 Pre-dose trough FVC
    Statistical analysis description
    Pre-dose trough FVC
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    762
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.061
         upper limit
    		 0.139

    Secondary: PEF over 4 and 12 weeks

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    End point title
    		 PEF over 4 and 12 weeks
    End point description
    Morning and Evening Peak Expiratory Flow Rate (PEF) will be measured. PEF is the peak expiratory flow, the maximum speed of expiration
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    398
    404
    Units: L/min
    least squares mean (standard error)
        Mean Morning PEF(n=382, 382)
    31.0 ( 1.98 )
    3.8 ( 1.97 )
        Mean Evening PEF(n=386,386)
    26.8 ( 1.84 )
    0.7 ( 1.84 )
    Statistical analysis title
    		 Mean Morning PEF
    Statistical analysis description
    Mean Morning PEF
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    27.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.1
         upper limit
    		 32.4
    Statistical analysis title
    		 Mean Evening PEF
    Statistical analysis description
    Mean Evening PEF
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    26.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21
         upper limit
    		 31.2

    Secondary: Percentage of patients with ACQ-7 MID at week 12

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    End point title
    		 Percentage of patients with ACQ-7 MID at week 12
    End point description
    MID is Minimum Important Difference. ACQ-7 is an asthma control questionnaire (scoring 5 symptoms, FEV1 entered by the investigator and daily rescue bronchodilator use entered by the patient) validated to evaluate different levels of asthma control. Percent of patients achieving the minimal important difference (MID) in ACQ-7 (i.e. at least 0.5 decrease from baseline) will be measured.
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    375
    370
    Units: Percentage
        number (not applicable)
    74.7
    64.9
    No statistical analyses for this end point

    Secondary: Daily e-diary over 12 weeks

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    End point title
    		 Daily e-diary over 12 weeks
    End point description
    Percentage of asthma symptoms free days, the percentage of nights without nighttime awakenings, and the percentage of mornings without symptoms on awakening as recorded by daily electronic Diary (e-Diary) over 12 weeks of treatment
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    398
    404
    Units: Percentage
    least squares mean (standard error)
        % of nights with no night-time awakenings
    13.4 ( 1.37 )
    8.7 ( 1.36 )
        % of mornings with no symptoms on awakening
    14.7 ( 1.53 )
    11.2 ( 1.53 )
        % of asthma symptom-free days
    17.1 ( 1.68 )
    14.4 ( 1.65 )
    No statistical analyses for this end point

    Secondary: ACQ-7 at week 4

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    End point title
    		 ACQ-7 at week 4
    End point description
    ACQ-7 is an asthma control questionnaire (scoring 5 symptoms, FEV1 entered by the investigator and daily rescue bronchodilator use entered by the patient) validated to evaluate different levels of asthma control
    End point type
    Secondary
    End point timeframe
    week 4
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    372
    378
    Units: Units on a scale
        least squares mean (standard error)
    1.454 ( 0.0408 )
    1.658 ( 0.0406 )
    Statistical analysis title
    		 ACQ-7 at week 4
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    750
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.204
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.277
         upper limit
    		 -0.131

    Secondary: Rescue medication use over 12 weeks

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    End point title
    		 Rescue medication use over 12 weeks
    End point description
    Rescue salbutamol/albuterol usage (mean daily, nighttime and daytime use) from e-Diary recordings over 12 weeks of treatment
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    398
    404
    Units: Number of puffs of rescue medication
    least squares mean (standard error)
        Night-time number of puffs of rescue medication
    -0.26 ( 0.025 )
    -0.16 ( 0.025 )
        Daytime number of puffs of rescue medication
    -0.39 ( 0.033 )
    -0.24 ( 0.032 )
    Statistical analysis title
    		 Night-time number of puffs of rescue medication
    Statistical analysis description
    Night-time number of puffs of rescue medication
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 -0.05
    Statistical analysis title
    		 Daytime number of puffs of rescue medication
    Statistical analysis description
    Daytime number of puffs of rescue medication
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 -0.08

    Secondary: Percentage of rescue medication free days over 12 weeks

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    End point title
    		 Percentage of rescue medication free days over 12 weeks
    End point description
    Percentage of rescue medication free days over 12 weeks of treatment period
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    384
    385
    Units: Percentage
        least squares mean (standard error)
    22.2 ( 1.81 )
    14.1 ( 1.80 )
    Statistical analysis title
    		 Percentage of rescue medication free days
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    769
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.3
         upper limit
    		 11.8

    Secondary: Quality of life assessed by AQLQ-S 12

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    End point title
    		 Quality of life assessed by AQLQ-S 12
    End point description
    The AQLQ-S +12 is a 32-item disease specific questionnaire designed to measure functional impairments that were most important to patients with asthma. It consists of 4 domains: symptoms, emotions, exposure to environmental stimuli and activity limitation
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    381
    379
    Units: Score
        least squares mean (standard error)
    5.779 ( 0.0475 )
    5.630 ( 0.0473 )
    Statistical analysis title
    		 Quality of life assessed by AQLQ-S 12
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    760
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.149
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.064
         upper limit
    		 0.234

    Secondary: Asthma exacerbation over 12 weeks

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    End point title
    		 Asthma exacerbation over 12 weeks
    End point description
    The exacerbation categories are: mild, moderate, severe and the combination of moderate or severe. Time to first asthma exacerbation by exacerbation category. Annual rate of asthma exacerbations by exacerbation category.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    395
    399
    Units: Number of patients
        Mild asthma exacerbation
    11
    29
        Moderate asthma exacerbation
    7
    23
        Severe asthma exacerbation
    3
    11
        Moderate or severe asthma exacerbation
    10
    32
    No statistical analyses for this end point

    Secondary: The Annual Rate of Asthma Exacerbations (Moderate or Severe) Over the 12 Week Treatment Period

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    End point title
    		 The Annual Rate of Asthma Exacerbations (Moderate or Severe) Over the 12 Week Treatment Period
    End point description
    Annual incidence rate of asthma exacerbation by severity of exacerbation. The number of asthma exacerbation is used to calculate annual incidence rate. A severe asthma exacerbation is SCS (Systemic Corticosteroids) use ≥3 days and hospitalization or emergency department visit (greater than 24 h) or death due to asthma. A moderate asthma exacerbation is SCS use ≥3 days either as an outpatient or in emergency department visits (less than or equal to 24 h). Worsening of asthma not requiring more than 3 days of SCS or hospitalization/emergency room will be considered mild asthma exacerbations
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    394
    397
    Units: Number of exacerbation
    number (not applicable)
        Moderate or severe asthma exacerbation
    0.08
    0.31
        All (mild, moderate, severe) asthma exacerbation
    0.20
    0.67
    No statistical analyses for this end point

    Secondary: Time to first Asthma Exacerbations (Moderate or Severe) Over the 12 Week Treatment Period

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    End point title
    		 Time to first Asthma Exacerbations (Moderate or Severe) Over the 12 Week Treatment Period
    End point description
    Defined as the number of days from start of treatment up to the first date when an asthma exacerbation occurs.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 QMF149 150/80 μg MF 200 µg
    Number of subjects analysed
    394
    397
    Units: Count of participants
        number (not applicable)
    10
    32
    Statistical analysis title
    		 The annual rate of asthma exacerbations
    Comparison groups
    QMF149 150/80 μg v MF 200 µg
    Number of subjects included in analysis
    791
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.59

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    MF 200
    Reporting group description
    		 MF 200

    Reporting group title
    QMF149 150/80
    Reporting group description
    		 QMF149 150/80

    Serious adverse events
    		 MF 200 QMF149 150/80
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 399 (1.75%)
    5 / 396 (1.26%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    0 / 399 (0.00%)
    1 / 396 (0.25%)
         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
    Ankle fracture
         subjects affected / exposed
    1 / 399 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 399 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 399 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 399 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Appendix disorder
         subjects affected / exposed
    1 / 399 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental cyst
         subjects affected / exposed
    0 / 399 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 399 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 399 (0.25%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 399 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 399 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess oral
         subjects affected / exposed
    0 / 399 (0.00%)
    1 / 396 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 399 (0.25%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 399 (0.50%)
    0 / 396 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 399 (0.25%)
    0 / 396 (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
    		 MF 200 QMF149 150/80
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 399 (26.57%)
    69 / 396 (17.42%)
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    10 / 399 (2.51%)
    5 / 396 (1.26%)
         occurrences all number
    12
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 399 (2.26%)
    4 / 396 (1.01%)
         occurrences all number
    9
    4
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    60 / 399 (15.04%)
    20 / 396 (5.05%)
         occurrences all number
    79
    24
    Cough
         subjects affected / exposed
    4 / 399 (1.00%)
    5 / 396 (1.26%)
         occurrences all number
    4
    6
    Dysphonia
         subjects affected / exposed
    2 / 399 (0.50%)
    5 / 396 (1.26%)
         occurrences all number
    2
    5
    Dyspnoea
         subjects affected / exposed
    4 / 399 (1.00%)
    0 / 396 (0.00%)
         occurrences all number
    4
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 399 (0.00%)
    4 / 396 (1.01%)
         occurrences all number
    0
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 399 (1.25%)
    1 / 396 (0.25%)
         occurrences all number
    5
    1
    Influenza
         subjects affected / exposed
    4 / 399 (1.00%)
    4 / 396 (1.01%)
         occurrences all number
    4
    4
    Nasopharyngitis
         subjects affected / exposed
    19 / 399 (4.76%)
    17 / 396 (4.29%)
         occurrences all number
    21
    19
    Pharyngitis
         subjects affected / exposed
    2 / 399 (0.50%)
    5 / 396 (1.26%)
         occurrences all number
    2
    5
    Sinusitis
         subjects affected / exposed
    5 / 399 (1.25%)
    5 / 396 (1.26%)
         occurrences all number
    5
    5
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 399 (2.51%)
    4 / 396 (1.01%)
         occurrences all number
    10
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    5 / 399 (1.25%)
    1 / 396 (0.25%)
         occurrences all number
    5
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 May 2017
    Adjust the approach to asthma worsening eDiary alerts during the Run-in epoch. It was earlier stated in the protocol, that if an asthma worsening alert is observed during the Run-in epoch, the patients must be discontinued regardless of clinical context and investigator judgment. This protocol amendment allowed investigators to use their discretion in determining the clinical significance of asthma worsening eDiary alerts during the Run-in epoch. This allowed the investigator to make the most appropriate decision as to whether patients may continue in the study or be discontinued. If asthma worsening alert was confirmed as clinically significant by the investigator, patients should be discontinued. A combination of eDiary alerts and investigator judgment was expected to help ensure that the most appropriate patients were enrolled in the study, while maintaining rigorous monitoring and assessment of patient safety
    20 Mar 2018
    The assumptions for Study B2303 key secondary endpoint, ACQ-7 treatment difference, were originally based on data from QMF149 Study A2210. In study A2210, the observed mean difference after 12 weeks of treatment (QMF149 vs MF) was −0.21 with 95% CI (−0.28, −0.15). Based on the upper limit of the CI, a treatment difference of −0.15 was chosen as a conservative estimate, which was used to determine the sample size of Study B2303. However, upon recent evaluation of the treatment difference of Study A2210, it was decided to adopt an ACQ-7 treatment difference of −0.18. This treatment difference is the upper limit of the one-sided 80% CI and more appropriately reflects the expected improvement in ACQ-7 for the patient population of Study B2303. Reflecting the revised assumptions, the sample size re-estimation has allowed for a reduction from 1000 to approximately 750 patients.

    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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