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    Clinical Trial Results:
    A double-blind, placebo-controlled, study examining the effect of orally administered QAW039 (450 mg qd) on FEV1 and ACQ in non-atopic, asthmatic patients with a baseline, pre-bronchodilator FEV1 of 40-80% predicted, inadequately controlled with low dose ICS therapy

    Summary
    EudraCT number
    		 2012-003995-38
    Trial protocol
    		 BE   CZ  
    Global end of trial date
    04 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2017
    First version publication date
    15 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQAW039A2214
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01836471
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    CH - 4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharmaceuticals, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharmaceuticals, 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
    04 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the efficacy of QAW039 (450 mg qd) compared to placebo with respect to the change in trough FEV1 from baseline to 12 weeks of postbaseline treatment in non-atopic asthmatic patients who, at randomization, were inadequately controlled on low dose ICS (100 μg fluticasone bid) background therapy.
    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
    		 Patients randomized to QAW039 (non-atopic and atopic) and Placebo (non-atopic and atopic) arms received fluticasone 100 μg as background therapy as powdered inhalation twice daily (AM and PM roughly 12 hours apart) at around the same times for the duration of the treatment period. Patients randomized to Fluticasone 150 μg (atopic) as study treatment received powdered inhalation in one combined dosage from one inhaler (fluticasone 250 μg in total) twice daily (AM and PM roughly 12 hours apart) at around the same times for the duration of the treatment period.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    India: 18
    Country: Number of subjects enrolled
    Korea, Republic of: 21
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Romania: 63
    Country: Number of subjects enrolled
    South Africa: 29
    Country: Number of subjects enrolled
    United States: 95
    Worldwide total number of subjects
    334
    EEA total number of subjects
    158
    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)
    274
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total of 939 subjects were screened, 679 entered the inhaled corticosteroid (ICS) tapering run-in, 345 subjects were randomized; eleven randomized subjects discontinued the study prior to start of study drug. Patient disposition and baseline characteristics were presented for 334 subjects (received study drug)

    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
    		 Investigator, Subject, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QAW039 450 mg qd Non-atopic
    Arm description
    		 QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QAW039 450 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    450 mg once daily (3 capsules of QAW039 150 mg taken with food in the morning)

    Investigational medicinal product name
    Fluticasone propionate 100 µg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Inhaled corticosteroid (ICS) fluticasone 100 µg dose strength inhaler (background therapy) taken morning and evening with approximately 12 hours between doses .

    Arm title
    		 Placebo Non-atopic
    Arm description
    		 Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    QAW039 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The matching placebos for QAW039 were identical in appearance to their active counterparts. Dosage was QAW039 Placebo (3 capsules taken with food in the morning)

    Investigational medicinal product name
    Fluticasone propionate 100 µg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Inhaled corticosteroid (ICS) fluticasone 100 µg dose strength inhaler (background therapy) taken morning and evening with approximately 12 hours between doses .

    Arm title
    		 QAW039 450 mg qd Atopic
    Arm description
    		 QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QAW039 450 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    450 mg once daily (3 capsules of QAW039 150 mg taken with food in the morning)

    Investigational medicinal product name
    Fluticasone propionate 100 µg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Inhaled corticosteroid (ICS) fluticasone 100 µg dose strength inhaler (background therapy) taken morning and evening with approximately 12 hours between doses .

    Arm title
    		 Fluticasone 150 µg bid Atopic
    Arm description
    		 Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone propionate 250 µg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Inhaled corticosteroid (ICS) fluticasone 250 µg dose strength inhaler taken morning and evening with approximately 12 hours between doses. Background therapy of 100 µg included in 250 µg dose.

    Arm title
    		 Placebo Atopic
    Arm description
    		 Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    QAW039 placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The matching placebos for QAW039 were identical in appearance to their active counterparts. Dosage was QAW039 Placebo (3 capsules taken with food in the morning)

    Investigational medicinal product name
    Fluticasone propionate 100 µg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Inhaled corticosteroid (ICS) fluticasone 100 µg dose strength inhaler (background therapy) taken morning and evening with approximately 12 hours between doses .

    Number of subjects in period 1
    		QAW039 450 mg qd Non-atopic Placebo Non-atopic QAW039 450 mg qd Atopic Fluticasone 150 µg bid Atopic Placebo Atopic
    Started
    93
    94
    51
    42
    54
    Completed
    82
    85
    49
    40
    49
    Not completed
    11
    9
    2
    2
    5
         Consent withdrawn by subject
    3
    4
    1
    -
    2
         Physician decision
    -
    1
    -
    -
    -
         Non compliance with tx
    1
    1
    -
    -
    -
         Adverse event, non-fatal
    6
    3
    1
    1
    2
         Pregnancy
    1
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QAW039 450 mg qd Non-atopic
    Reporting group description
    		 QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.

    Reporting group title
    Placebo Non-atopic
    Reporting group description
    		 Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.

    Reporting group title
    QAW039 450 mg qd Atopic
    Reporting group description
    		 QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.

    Reporting group title
    Fluticasone 150 µg bid Atopic
    Reporting group description
    		 Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.

    Reporting group title
    Placebo Atopic
    Reporting group description
    		 Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.

    Reporting group values
    		 QAW039 450 mg qd Non-atopic Placebo Non-atopic QAW039 450 mg qd Atopic Fluticasone 150 µg bid Atopic Placebo Atopic Total
    Number of subjects
    		 93 94 51 42 54 334
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 70 73 45 41 45 274
        From 65-84 years
    		 23 21 6 1 9 60
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.9 ( 14.33 ) 53.5 ( 14.37 ) 50.3 ( 12.75 ) 48.2 ( 12.16 ) 48.2 ( 13.58 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 60 60 26 23 25 194
        Male
    		 33 34 25 19 29 140
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 2 3 3 3 2 13
        Asian
    		 15 16 4 6 3 44
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 1 1
        Black or African American
    		 6 6 3 3 4 22
        White
    		 68 68 40 29 43 248
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0
        Other
    		 2 1 1 1 1 6
    Subject population
    Non-atopic defined as history of perennial symptoms with no clear inhaled allergic trigger AND a negative skin prick test (< 3mm diameter above background) or a negative specific IgE (<0.35 IU eq./ml). Atopic/allergic defined as skin prick test (≥ 3mm diameter above background) or a positive specific IgE (e.g.,RAST/CAP) test (≥0.35 IU eq/ml)
    Units: Subjects
        Non-atopic
    		 93 94 0 0 0 187
        Atopic
    		 0 0 51 42 54 147
    Study Specific Characteristic | Duration of asthma
    Units: years
        arithmetic mean (standard deviation)
    		 14.88 ( 12.349 ) 12.82 ( 12.196 ) 24.69 ( 17.446 ) 27.78 ( 18.039 ) 24.09 ( 16.055 ) -
    Study Specific Characteristic | Percentage of predicted FEV1 (%) pre-bronchodilator
    Units: Percentage
        arithmetic mean (standard deviation)
    		 67.5446 ( 11.81404 ) 65.7286 ( 13.94056 ) 69.0662 ( 12.16292 ) 68.7483 ( 10.52156 ) 64.8709 ( 12.97729 ) -
    Study Specific Characteristic | ACQ-6 score
    Number of participants (n=92,94,51,42,54)
    Units: points
        arithmetic mean (standard deviation)
    		 1.7 ( 0.762 ) 1.53 ( 0.745 ) 1.55 ( 0.665 ) 1.68 ( 0.749 ) 1.72 ( 0.675 ) -

    End points

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    End points reporting groups
    Reporting group title
    QAW039 450 mg qd Non-atopic
    Reporting group description
    		 QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.

    Reporting group title
    Placebo Non-atopic
    Reporting group description
    		 Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo.

    Reporting group title
    QAW039 450 mg qd Atopic
    Reporting group description
    		 QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.

    Reporting group title
    Fluticasone 150 µg bid Atopic
    Reporting group description
    		 Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.

    Reporting group title
    Placebo Atopic
    Reporting group description
    		 Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo.

    Primary: Change from baseline in trough FEV1 (L) in non-atopic patients at Week 12 - full analysis set

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    End point title
    		 Change from baseline in trough FEV1 (L) in non-atopic patients at Week 12 - full analysis set [1]
    End point description
    Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the last available FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    baseline,12 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    		 QAW039 450 mg qd Non-atopic Placebo Non-atopic
    Number of subjects analysed
    91
    93
    Units: liter
        least squares mean (standard error)
    0.05 ( 0.029 )
    0.03 ( 0.029 )
    Statistical analysis title
    		 QAW039 450 mg Non-atoopic vs placebo Non-atopic
    Comparison groups
    QAW039 450 mg qd Non-atopic v Placebo Non-atopic
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7269
    Method
    		 Mixed models analysis
    Parameter type
    		 least squares mean
    Point estimate
    0.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.038

    Secondary: Change from baseline in trough FEV1 (L) in atopic patients at Week 12 - full analysis set

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    End point title
    		 Change from baseline in trough FEV1 (L) in atopic patients at Week 12 - full analysis set [2]
    End point description
    Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    baseline,12 weeks
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    		 QAW039 450 mg qd Atopic Fluticasone 150 µg bid Atopic Placebo Atopic
    Number of subjects analysed
    50
    41
    52
    Units: liter
        least squares mean (standard error)
    0.06 ( 0.038 )
    0.01 ( 0.042 )
    0.05 ( 0.037 )
    Statistical analysis title
    		 QAW039 450 mg Atopic vs placebo Atopic
    Comparison groups
    QAW039 450 mg qd Atopic v Placebo Atopic
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 least sqares mean
    Point estimate
    0.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Statistical analysis title
    		 QAW039 450 mg Atopic vs fluticasone 150 µg Atopic
    Comparison groups
    QAW039 450 mg qd Atopic v Fluticasone 150 µg bid Atopic
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 least squares mean
    Point estimate
    0.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.054
    Statistical analysis title
    		 Fluticasone 150 µg Atopic vs placebo Atopic
    Comparison groups
    Fluticasone 150 µg bid Atopic v Placebo Atopic
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 least squares mean
    Point estimate
    -0.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.053

    Secondary: Change from baseline in trough FEV1 (L) in non-atopic compared to atopic patients at Week 12 - full analysis set

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    End point title
    		 Change from baseline in trough FEV1 (L) in non-atopic compared to atopic patients at Week 12 - full analysis set
    End point description
    Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population, treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    baseline,12 weeks
    End point values
    		 QAW039 450 mg qd Non-atopic Placebo Non-atopic QAW039 450 mg qd Atopic Fluticasone 150 µg bid Atopic Placebo Atopic
    Number of subjects analysed
    91
    93
    50
    41
    52
    Units: liter
        least squares mean (standard error)
    0.05 ( 0.029 )
    0.03 ( 0.029 )
    0.06 ( 0.038 )
    0.01 ( 0.042 )
    0.05 ( 0.037 )
    Statistical analysis title
    		 FEV1 Non-atopic vs Atopic
    Comparison groups
    QAW039 450 mg qd Non-atopic v Placebo Non-atopic v QAW039 450 mg qd Atopic v Fluticasone 150 µg bid Atopic v Placebo Atopic
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9179
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change from baseline in ACQ-6 score at Week 12 non-atopic and atopic patients at Week 12 - full analysis set

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    End point title
    		 Change from baseline in ACQ-6 score at Week 12 non-atopic and atopic patients at Week 12 - full analysis set
    End point description
    ACQ-6 consists of:5 items on symptoms, 1 item on rescue bronchodilator use, and 1 item on airway caliber (FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or smallest change that could be considered clinically important (0.5). The ACQ was self-administered at the clinic and patients scored each item on a 7-point response scale: 0 = ‘totally controlled’ and 6 = ‘severely uncontrolled.’ Study staff scored question 7 based on % predicted FEV1 (ideally pre-bronchodilator). The total score=average of first 6 questions. Baseline=the ACQ-6 measurement taken prior to first dose of randomized study drug. The single missing score was interpolated by utilizing prior or subsequent completions of the questionnaire. Estimates were from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline ACQ-6 and region as fixed effects and center nested within region as random effects.
    End point type
    Secondary
    End point timeframe
    baseline,12 weeks
    End point values
    		 QAW039 450 mg qd Non-atopic Placebo Non-atopic QAW039 450 mg qd Atopic Fluticasone 150 µg bid Atopic Placebo Atopic
    Number of subjects analysed
    80
    85
    48
    40
    48
    Units: score
        least squares mean (standard error)
    -0.05 ( 0.077 )
    -0.03 ( 0.073 )
    -0.25 ( 0.096 )
    -0.35 ( 0.104 )
    -0.18 ( 0.096 )
    Statistical analysis title
    		 QAW039 450 mg Non-atopic vs placebo Non-atopic
    Comparison groups
    QAW039 450 mg qd Non-atopic v Placebo Non-atopic
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 least squares mean
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.098
    Statistical analysis title
    		 QAW039 450 mg Atopic vs placebo Atopic
    Comparison groups
    QAW039 450 mg qd Atopic v Placebo Atopic
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 least sqares mean
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.128
    Statistical analysis title
    		 QAW039 450 mg Atopic vs fluticasone 150 µg Atopic
    Comparison groups
    QAW039 450 mg qd Atopic v Fluticasone 150 µg bid Atopic
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 least squares mean
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.134
    Statistical analysis title
    		 Fluticasone 150 µg Atopic vs placebo Atopic
    Comparison groups
    Fluticasone 150 µg bid Atopic v Placebo Atopic
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 least squares mean
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.134

    Secondary: Change from baseline in ACQ-6 score at Week 12 non-atopic compared to atopic patients at Week 12 - full analysis set

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    End point title
    		 Change from baseline in ACQ-6 score at Week 12 non-atopic compared to atopic patients at Week 12 - full analysis set
    End point description
    ACQ-6 consists of:5 items on symptoms, 1 item on rescue bronchodilator use, and 1 item on airway caliber (FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or smallest change that could be considered clinically important (0.5). The ACQ was self-administered at the clinic and patients scored each item on a 7-point response scale: 0 = ‘totally controlled’ and 6 = ‘severely uncontrolled.’ Study staff scored question 7 based on % predicted FEV1 (ideally pre-bronchodilator). The total score=average of first 6 questions. Baseline=the ACQ-6 measurement taken prior to first dose of randomized study drug. The single missing score was interpolated by utilizing prior or subsequent completions of the questionnaire. Estimates were from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline ACQ-6 and region as fixed effects and center nested within region as random effects.
    End point type
    Secondary
    End point timeframe
    baseline,12 weeks
    End point values
    		 QAW039 450 mg qd Non-atopic Placebo Non-atopic QAW039 450 mg qd Atopic Fluticasone 150 µg bid Atopic Placebo Atopic
    Number of subjects analysed
    80
    85
    48
    40
    48
    Units: score
        least squares mean (standard error)
    -0.05 ( 0.077 )
    -0.03 ( 0.073 )
    -0.25 ( 0.096 )
    -0.35 ( 0.104 )
    -0.18 ( 0.096 )
    Statistical analysis title
    		 ACQ-6 Non-atopic vs Atopic
    Comparison groups
    QAW039 450 mg qd Non-atopic v Placebo Non-atopic v QAW039 450 mg qd Atopic v Fluticasone 150 µg bid Atopic v Placebo Atopic
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.793
    Method
    		 Mixed models analysis
    Confidence interval

    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    QAW039 450 mg qd
    Reporting group description
    		 QAW039 450 mg qd

    Reporting group title
    Fluticasone 150 mcg bid
    Reporting group description
    		 Fluticasone 150 mcg bid

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 QAW039 450 mg qd Fluticasone 150 mcg bid Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 42 (0.00%)
    3 / 147 (2.04%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 42 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    PRESYNCOPE
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 42 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 42 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    OVARIAN CYST
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 42 (0.00%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATIC STEATOSIS
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 42 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 QAW039 450 mg qd Fluticasone 150 mcg bid Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 145 (24.83%)
    19 / 42 (45.24%)
    35 / 147 (23.81%)
    Investigations
    BLOOD TRIGLYCERIDES INCREASED
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    1
    1
    0
    ELECTROCARDIOGRAM QT PROLONGED
         subjects affected / exposed
    1 / 145 (0.69%)
    2 / 42 (4.76%)
    0 / 147 (0.00%)
         occurrences all number
    1
    2
    0
    Injury, poisoning and procedural complications
    LIGAMENT SPRAIN
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    WOUND
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 42 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    1
    0
    4
    SYNCOPE
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    DENTAL CARIES
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    NAUSEA
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 42 (2.38%)
    1 / 147 (0.68%)
         occurrences all number
    1
    1
    1
    Reproductive system and breast disorders
    DYSMENORRHOEA
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    10 / 145 (6.90%)
    2 / 42 (4.76%)
    13 / 147 (8.84%)
         occurrences all number
    11
    2
    13
    COUGH
         subjects affected / exposed
    3 / 145 (2.07%)
    0 / 42 (0.00%)
    1 / 147 (0.68%)
         occurrences all number
    3
    0
    1
    PRODUCTIVE COUGH
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 42 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    1
    0
    3
    Skin and subcutaneous tissue disorders
    DERMATITIS CONTACT
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 42 (4.76%)
    0 / 147 (0.00%)
         occurrences all number
    0
    2
    0
    ECZEMA
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    ERYTHEMA
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 42 (2.38%)
    1 / 147 (0.68%)
         occurrences all number
    1
    1
    1
    ARTHRITIS
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    SYNOVIAL CYST
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    ACUTE SINUSITIS
         subjects affected / exposed
    0 / 145 (0.00%)
    0 / 42 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    0
    0
    3
    BRONCHITIS
         subjects affected / exposed
    3 / 145 (2.07%)
    0 / 42 (0.00%)
    4 / 147 (2.72%)
         occurrences all number
    3
    0
    4
    CONJUNCTIVITIS VIRAL
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    INFLUENZA
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 42 (0.00%)
    3 / 147 (2.04%)
         occurrences all number
    3
    0
    3
    NASOPHARYNGITIS
         subjects affected / exposed
    5 / 145 (3.45%)
    1 / 42 (2.38%)
    3 / 147 (2.04%)
         occurrences all number
    5
    1
    3
    ORAL CANDIDIASIS
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    1 / 147 (0.68%)
         occurrences all number
    0
    1
    1
    PHARYNGITIS
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    1
    1
    0
    RHINITIS
         subjects affected / exposed
    2 / 145 (1.38%)
    2 / 42 (4.76%)
    0 / 147 (0.00%)
         occurrences all number
    2
    2
    0
    SINUSITIS BACTERIAL
         subjects affected / exposed
    3 / 145 (2.07%)
    0 / 42 (0.00%)
    0 / 147 (0.00%)
         occurrences all number
    3
    0
    0
    SKIN INFECTION
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    TONSILLITIS
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 42 (2.38%)
    0 / 147 (0.00%)
         occurrences all number
    0
    1
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    7 / 145 (4.83%)
    1 / 42 (2.38%)
    5 / 147 (3.40%)
         occurrences all number
    7
    1
    5
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 145 (1.38%)
    1 / 42 (2.38%)
    3 / 147 (2.04%)
         occurrences all number
    2
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2013
    The following were added to prohibited medications: CYP3A4 inhibitors including boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin and voriconazole, CYP3A4 inducers including avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort and indomethacin
    18 Dec 2014
    The planned interim analysis (IA) for the study was removed. The closure of recruitment, once target patient numbers was met for the non-atopic and atopic groups of patients, was clarified. The definition of a positive pregnancy test in the exclusion criteria was updated. ACQ-6 was selected to be the key secondary variable because this form to align with other QAW039 studies. The interval of the data collection for rescue medication use via e-Diary was corrected from 12 hours to 24 hours. The definition of the pharmacokinetic (PK) analysis set was added. The definition of baseline values was clarified to be the values at the end of the initial 14-day, post-randomization placebo treatment period. These amendments were not considered to have affected the interpretation of study results as they were minor and occurred prior to study unblinding.

    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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