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    Clinical Trial Results:
    A prospective, multicenter, randomised, double-blind, placebo-controlled, 2-parallel groups, Phase 3 study to compare the efficacy and the safety of masitinib at 6 mg/kg/day versus placebo in the treatment of patients with Severe Persistent Asthma treated with oral corticosteroids

    Summary
    EudraCT number
    		 2010-020803-63
    Trial protocol
    		 FR   CZ   BG   DE   SK   ES   GR  
    Global end of trial date
    29 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AB07015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01449162
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AB Science
    Sponsor organisation address
    3 avenue George V, Paris, France, 75008
    Public contact
    Clinical Study Coordinator, AB Science, clinical@ab-science.com
    Scientific contact
    Clinical Study Coordinator, AB Science, clinical@ab-science.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study was to compare the efficacy and the safety of masitinib at 6.0 mg/kg/day versus placebo in the treatment of patients with severe uncontrolled asthma treated with oral corticosteroids at ≥7.5 mg/day without and with an elevated eosinophil count (≥150 cells/µL). Results showed that orally administered masitinib reduces the risk of asthma exacerbations in severe asthma patients, with an acceptable safety profile. Overall, these positive findings provide further clinical evidence implicating mast cells and/or PDFGR signaling to the pathophysiology of severe asthma, which could influence the future direction of drug development. In conclusion, orally administered masitinib, as used in the present randomized control study, may potentially provide a treatment option for oral corticosteroid-dependent severe asthma, including severe asthmatics that are either ineligible to receive or in failure to registered biologics.
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All participants were required to read and sign an informed consent form prior to participation in the study. Only investigators qualified by training and/or experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 A growing body of research implicates mast cells as being a crucial factor for initiating, promoting and sustaining pathophysiological processes that drive asthma exacerbations and structural changes of the airway in severe asthmatics. This occurs directly via intercellular cross-talk and indirectly through mediator release; moreover, increased mast cell activity is associated with both Type-2-high and Type-2-low asthma, suggesting it represents a steroid insensitive pathway. Hence, there is a strong rationale to target mast cells in severe asthma. Masitinib is an oral tyrosine kinase inhibitor that selectively targets mast cell activity via its action on the c-Kit (stem cell factor receptor), Lyn, and Fyn protein kinases. Masitinib is also a potent inhibitor of platelet-derived growth factor receptor (PDGFR) signaling, which is associated with pathologic airway smooth muscle cell proliferation and airway remodeling. In preclinical models of asthma, masitinib significantly improved airway inflammation and lung mechanics in cats. Proof-of-concept that masitinib may improve the control of severe corticosteroid-dependent asthma with respect to placebo was previously demonstrated in a small (n = 44) placebo-controlled study. Our hypothesis was that masitinib as an add-on to standard maintenance therapy would significantly reduce asthma related symptoms (eg, rate of exacerbations and pulmonary function) as compared with placebo in the treatment of oral corticosteroid-dependent severe asthma.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 20
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Czechia: 20
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Algeria: 2
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    India: 73
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Romania: 41
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Thailand: 2
    Country: Number of subjects enrolled
    Tunisia: 20
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Ukraine: 133
    Country: Number of subjects enrolled
    South Africa: 18
    Worldwide total number of subjects
    419
    EEA total number of subjects
    150
    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)
    341
    From 65 to 84 years
    78
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient randomized (09 February 2011) Last patient, last visit (29 May 2018).

    Pre-assignment
    Screening details
    		 Patients aged from 18 to 75, with severe asthma and already treated with oral corticosteroids at a minimal daily dose of 7.5 mg prednisone or equivalent or history of asthma ≥1 year, patients treated during at least one period of 21 days with oral corticosteroids, non smokers for at least a year and normal organ function

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Investigators were provided with technical options and password information to selectively break the code for an individual patient, if necessary. The premature breaking of the code was to be done only in emergency cases in which knowledge of the administered drug was necessary to provide adequate treatment. Whenever possible, the sponsor was contacted before the blinding was broken.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Masitinib 6.0 mg/kg/day
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Masitinib mesylate
    Investigational medicinal product code
    AB1010
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Masitinib was supplied as 100 mg and 200 mg tablets of AB1010 base (respectively corresponding to 119.3 mg and 238.5 mg of the mesylate salt AB1010) packaged in polyethylene bottles.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomized to the placebo group received matching placebo at 6.0 mg/kg/day

    Number of subjects in period 1
    		Masitinib 6.0 mg/kg/day Placebo
    Started
    279
    140
    Completed
    86
    43
    Not completed
    193
    97
         Adverse event, serious fatal
    3
    1
         Consent withdrawn by subject
    78
    40
         Physician decision
    10
    5
         Adverse event, non-fatal
    30
    7
         Other
    6
    3
         Lost to follow-up
    16
    9
         Exited study at week 36
    24
    14
         GCP violation
    8
    7
         Lack of efficacy
    14
    8
         Protocol deviation
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Masitinib 6.0 mg/kg/day
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Masitinib 6.0 mg/kg/day Placebo Total
    Number of subjects
    		 279 140 419
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 219 122 341
        From 65-84 years
    		 60 18 78
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 55.0 (18 to 79) 51.0 (21 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 179 90 269
        Male
    		 100 50 150
    Eosinophil level
    Patients with eosinophil count ≥0.15 K/μL (150 cells/μL), n %
    Units: Subjects
        >= 0.15
    		 213 107 320
        <0.15
    		 66 33 99
    Long acting Beta-agonist
    Long-acting beta-agonists (LABAs) are taken on a daily basis to relax the muscles lining the airways that carry air to the lungs. This allows the tubes to remain open, making breathing easier. LABAs should be taken only in combination with a corticosteroid to treat asthma.
    Units: Subjects
        Yes
    		 222 107 329
        No
    		 57 33 90
    Former smoker
    Units: Subjects
        Yes
    		 45 18 63
        No
    		 234 122 356
    History of asthma exacerbations (previous year)
    Inclusion criterion that patients had experienced a minimum of two exacerbations in the previous year (including one severe asthma exacerbation as per protocol definition).
    Units: events per year
        arithmetic mean (standard deviation)
    		 2.3 ± 0.9 2.1 ± 0.7 -
    Stable dose of oral corticosteroid, mg/day
    Units: mg/day
        arithmetic mean (standard deviation)
    		 12.2 ± 8.8 12.0 ± 7.6 -
    AQLQ
    Asthma Quality of Life Questionnaire. A disease-specific health-related quality of life instrument that taps both physical and emotional impact of disease
    Units: Points
        median (full range (min-max))
    		 3.84 (1.17 to 6.97) 4.03 (1.63 to 6.53) -
    ACQ
    Asthma Control Questionnaire (ACQ) A simple questionnaire to measure the adequacy of asthma control and change in asthma control which occurs either spontaneously or as a result of treatment.
    Units: Points
        median (full range (min-max))
    		 3.00 (0.00 to 5.17) 3.00 (0.00 to 5.86) -
    FEV1
    Forced expiratory volume in 1 second (FEV1) is the maximum amount of air that the subject can forcibly expel during the first second following maximal inhalation.
    Units: litre(s)
        median (full range (min-max))
    		 1.45 (0.43 to 3.30) 1.59 (0.71 to 3.55) -
    FVC
    Forced vital capacity; the total volume of air that can be exhaled during a maximal forced expiration effort.
    Units: litre(s)
        median (full range (min-max))
    		 2.33 (0.86 to 5.83) 2.42 (1.03 to 4.95) -
    FEV1/FVC %
    The FEV1/FVC ratio is the amount of air exhaled in the first second divided by all of the air exhaled during a maximal exhalation.
    Units: percent
        median (full range (min-max))
    		 62.67 (0.38 to 111.0) 66.67 (0.61 to 104.0) -
    Eosinophil level
    Blood test
    Units: cells/μL
        arithmetic mean (standard deviation)
    		 290 ± 300 310 ± 300 -

    End points

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    End points reporting groups
    Reporting group title
    Masitinib 6.0 mg/kg/day
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Masitinib 6.0 mg/kg/d (Primary Analysis Population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Primary analysis was performed on patients with severe asthma in a cohort referred to as the “primary population”. These patients had confirmed severe asthma with an oral corticosteroids (OCS) intake of ≥7.5 mg/d (no minimum baseline blood eosinophil count was specified). A total of 355 patients (240 masitinib and 115 placebo) were included in the primary population.

    Subject analysis set title
    Masitinib 6.0 mg/kg/d (Eosinophil Subgroup)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A predefined subgroup analysis was performed based on patients with a baseline blood eosinophil count of ≥150 cell/μL. The primary endpoint analysis was performed sequentially, first on the primary population and then on the eosinophil (≥150 cell/μL) subgroup, using a hierarchical alpha-spending procedure with alpha set to 5% at each step. A total of 268 patients (181 masitinib and 87 placebo) were included in the eosinophil (≥150 cell/μL) subgroup.

    Subject analysis set title
    Placebo (Primary Analysis Population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Primary analysis was performed on patients with severe asthma in a cohort referred to as the “primary population”. These patients had confirmed severe asthma with an oral corticosteroids (OCS) intake of ≥7.5 mg/d (no minimum baseline blood eosinophil count was specified). A total of 355 patients (240 masitinib and 115 placebo) were included in the primary population.

    Subject analysis set title
    Placebo (Eosinophil Subgroup)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A predefined subgroup analysis was performed based on patients with a baseline blood eosinophil count of ≥150 cell/μL. The primary endpoint analysis was performed sequentially, first on the primary population and then on the eosinophil (≥150 cell/μL) subgroup, using a hierarchical alpha-spending procedure with alpha set to 5% at each step. A total of 268 patients (181 masitinib and 87 placebo) were included in the eosinophil (≥150 cell/μL) subgroup.

    Primary: Severe asthma exacerbation rate

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    End point title
    		 Severe asthma exacerbation rate
    End point description
    The primary endpoint was the annualized severe asthma exacerbation rate (SAER) in each treatment group adjusted for the overall time on treatment. A severe asthma exacerbation was defined as a worsening in asthma symptoms that required an increase in the stable maintenance dose of systemic corticosteroids for at least 3 days, with or without hospital admission. The primary endpoint analysis was performed sequentially, first on the primary population and then on the eosinophil (≥150 cell/μL) subgroup, using a hierarchical alpha-spending procedure with alpha set to 5% at each step.
    End point type
    Primary
    End point timeframe
    Overall duration of patient exposure
    End point values
    		 Masitinib 6.0 mg/kg/d (Primary Analysis Population) Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) Placebo (Primary Analysis Population) Placebo (Eosinophil Subgroup)
    Number of subjects analysed
    240
    181
    115
    87
    Units: events per year
        number (not applicable)
    0.34
    0.34
    0.48
    0.51
    Statistical analysis title
    		 Ratio Rate (Primary Analysis Population)
    Comparison groups
    Masitinib 6.0 mg/kg/d (Primary Analysis Population) v Placebo (Primary Analysis Population)
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [1]
    Method
    		 Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [1] - Poisson regression is a generalized linear model used for counting data
    Statistical analysis title
    		 Ratio Rate (Eosinophil Subgroup)
    Comparison groups
    Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) v Placebo (Eosinophil Subgroup)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016 [2]
    Method
    		 Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [2] - Poisson regression is a generalized linear model used for counting data

    Secondary: Moderate/Severe exacerbation rate

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    End point title
    		 Moderate/Severe exacerbation rate
    End point description
    A key secondary endpoint was the overall (moderate/severe) annualized rate of asthma exacerbations (adjusted for the overall time on treatment). This endpoint included both moderate and severe asthma exacerbations; a moderate asthma exacerbation being defined as a worsening in asthma symptoms and/or an increase in rescue medication use that lasted for 2 or more days and required a change in asthma treatment without hospitalization. Secondary endpoints were tested at the 0.05 significance level.
    End point type
    Secondary
    End point timeframe
    Overall duration of patient exposure
    End point values
    		 Masitinib 6.0 mg/kg/d (Primary Analysis Population) Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) Placebo (Primary Analysis Population) Placebo (Eosinophil Subgroup)
    Number of subjects analysed
    240
    181
    115
    87
    Units: events per year
        number (not applicable)
    0.48
    0.48
    0.69
    0.71
    Statistical analysis title
    		 Rate Ratio (Primary Analysis Population)
    Statistical analysis description
    Measure of reduction in the moderate/severe asthma exacerbation rate for the masitinib treatment-arm relative to placebo
    Comparison groups
    Masitinib 6.0 mg/kg/d (Primary Analysis Population) v Placebo (Primary Analysis Population)
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [3]
    Method
    		 Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Notes
    [3] - Poisson regression is a generalized linear model used for counting data
    Statistical analysis title
    		 Rate Ratio (Eosinophil Subgroup)
    Statistical analysis description
    Measure of reduction in the moderate/severe asthma exacerbation rate for the masitinib treatment-arm relative to placebo
    Comparison groups
    Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) v Placebo (Eosinophil Subgroup)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025 [4]
    Method
    		 Poisson regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Notes
    [4] - Poisson regression is a generalized linear model used for counting data

    Secondary: ΔFEV1

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    End point title
    		 ΔFEV1
    End point description
    Assessment of pulmonary function was performed according to change from baseline in prebronchodilator forced expiratory volume in 1 s (FEV1) . For the analysis of secondary endpoints, changes from baseline over 96 weeks were estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI). Secondary endpoints were tested at the 0.05 significance level. For FEV1, a positive between-group difference favors masitinib. Precision/Dispersion type = Standard Error.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib 6.0 mg/kg/d (Primary Analysis Population) Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) Placebo (Primary Analysis Population) Placebo (Eosinophil Subgroup)
    Number of subjects analysed
    240
    181
    115
    87
    Units: litre(s)
        least squares mean (standard deviation)
    0.0989 ± 0.02298
    0.1599 ± 0.0265
    0.0314 ± 0.02751
    0.0470 ± 0.0305
    Statistical analysis title
    		 ΔFEV1 (Primary Analysis Population)
    Statistical analysis description
    Change from baseline over 96 weeks in FEV1, estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI).
    Comparison groups
    Placebo (Primary Analysis Population) v Masitinib 6.0 mg/kg/d (Primary Analysis Population)
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 difference in least-squares mean change
    Point estimate
    0.0675
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0125
         upper limit
    		 0.1225
    Notes
    [5] - multivariate mixed model of repeated measures (MMRM)
    Statistical analysis title
    		 ΔFEV1 (Eosinophil Subgroup)
    Statistical analysis description
    Change from baseline over 96 weeks in FEV1, estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI).
    Comparison groups
    Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) v Placebo (Eosinophil Subgroup)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.1129
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0523
         upper limit
    		 0.1734

    Secondary: ΔFVC

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    End point title
    		 ΔFVC
    End point description
    Assessment of pulmonary function was performed according to change from baseline in forced vital capacity (FVC). For the analysis of secondary endpoints, changes from baseline over 96 weeks were estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI). Secondary endpoints were tested at the 0.05 significance level. For FVC, a positive between-group difference favors masitinib.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib 6.0 mg/kg/d (Primary Analysis Population) Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) Placebo (Primary Analysis Population) Placebo (Eosinophil Subgroup)
    Number of subjects analysed
    240
    181
    115
    87
    Units: litre(s)
        least squares mean (standard error)
    0.009926 ± 0.03337
    0.0801 ± 0.03984
    -0.02625 ± 0.04020
    -0.0223 ± 0.04594
    Statistical analysis title
    		 FVC (Primary Analysis Population)
    Statistical analysis description
    Change from baseline over 96 weeks in FVC, estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI).
    Comparison groups
    Masitinib 6.0 mg/kg/d (Primary Analysis Population) v Placebo (Primary Analysis Population)
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.386
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.03617
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04576
         upper limit
    		 0.1181
    Statistical analysis title
    		 FVC (Eosinophil Subgroup)
    Statistical analysis description
    Change from baseline over 96 weeks in FVC, estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI).
    Comparison groups
    Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) v Placebo (Eosinophil Subgroup)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.1024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0086
         upper limit
    		 0.1961

    Secondary: ΔACQ-7

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    End point title
    		 ΔACQ-7
    End point description
    Evaluation of asthma disease control was according to change from baseline in the 7-question version of the Asthma Control Questionnaire (ACQ-7) score (with a change of 0.5 points considered the minimum clinically significant difference). For the analysis of secondary endpoints, changes from baseline over 96 weeks were estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI). Secondary endpoints were tested at the 0.05 significance level. For ACQ-7, a negative between-group difference favors masitinib.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib 6.0 mg/kg/d (Primary Analysis Population) Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) Placebo (Primary Analysis Population) Placebo (Eosinophil Subgroup)
    Number of subjects analysed
    240
    181
    115
    87
    Units: Points
        least squares mean (standard error)
    -0.5369 ± 0.08198
    -0.5036 ± 0.09785
    -0.3241 ± 0.09851
    -0.3337 ± 0.1073
    Statistical analysis title
    		 ACQ-7 (Primary Analysis Population)
    Statistical analysis description
    Change from baseline over 96 weeks in ACQ-7, estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI).
    Comparison groups
    Masitinib 6.0 mg/kg/d (Primary Analysis Population) v Placebo (Primary Analysis Population)
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    -0.2128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4259
         upper limit
    		 0.0004
    Statistical analysis title
    		 ACQ-7 (Eosinophil Subgroup)
    Statistical analysis description
    Change from baseline over 96 weeks in ACQ-7, estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI).
    Comparison groups
    Placebo (Eosinophil Subgroup) v Masitinib 6.0 mg/kg/d (Eosinophil Subgroup)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    -0.1699
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4076
         upper limit
    		 0.0678

    Secondary: ΔAQLQ

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    End point title
    		 ΔAQLQ
    End point description
    Evaluation of quality-of-life assessment was according to change from baseline in the Asthma Quality of Life Questionnaire score (AQLQ). For the analysis of secondary endpoints, changes from baseline over 96 weeks were estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI). Secondary endpoints were tested at the 0.05 significance level. For AQLQ, a positive between-group difference favors masitinib.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib 6.0 mg/kg/d (Primary Analysis Population) Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) Placebo (Primary Analysis Population) Placebo (Eosinophil Subgroup)
    Number of subjects analysed
    240
    181
    115
    87
    Units: Points
        least squares mean (standard error)
    0.5582 ± 0.1250
    0.4549 ± 0.1346
    0.5900 ± 0.1369
    0.5724 ± 0.1415
    Statistical analysis title
    		 AQLQ (Primary Analysis Population)
    Statistical analysis description
    Change from baseline over 96 weeks in AQLQ, estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI).
    Comparison groups
    Masitinib 6.0 mg/kg/d (Primary Analysis Population) v Placebo (Primary Analysis Population)
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    -0.0318
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3625
         upper limit
    		 0.299
    Statistical analysis title
    		 AQLQ (Eosinophil Subgroup)
    Statistical analysis description
    Change from baseline over 96 weeks in AQLQ, estimated using a multivariate mixed model of repeated measures (MMRM) with treatment effect (masitinib versus placebo) reported as the between-group difference with corresponding 95% confidence intervals (CI).
    Comparison groups
    Masitinib 6.0 mg/kg/d (Eosinophil Subgroup) v Placebo (Eosinophil Subgroup)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.492
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    -0.1175
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4541
         upper limit
    		 0.2191

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    96 weeks
    Adverse event reporting additional description
    Adverse events (AEs) were collected for all patients from the time of informed consent signature until 28 days after the last dose of study treatment. Treatment-emergent AEs (TEAEs) were defined as those with an onset date on or after the first dose of study treatment and before 28 days after the last dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Masitinib
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Masitinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 271 (33.21%)
    31 / 133 (23.31%)
         number of deaths (all causes)
    3
    1
         number of deaths resulting from adverse events
    3
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
      Lipoma
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Lung Neoplasm Malignant
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Pelvic Neoplasm
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Myeloproliferative Neoplasm
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
      Deep Vein Thrombosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
      Face Oedema
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Mucosal Ulceration
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
      Hypersensitivity
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
      Cervical Dysplasia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Postmenopausal Haemorrhage
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (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
    20 / 271 (7.38%)
    13 / 133 (9.77%)
         occurrences causally related to treatment / all
    1 / 28
    2 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Respiratory Failure
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Bronchospasm
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Pneumonitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Pulmonary Embolism
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
      Pulmonary Oedema
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Nasal Polyps
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
      Adjustment Disorder
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Drug Use Disorder
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         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
      Foreign Body
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Neutrophil Count Decreased
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
      Acute Coronary Syndrome
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Myocardial Ischaemia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Cardiopulmonary Failure
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
      Sciatica
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Ischaemic Stroke
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
      Diabetic Neuropathy
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (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
      Neutropenia
         subjects affected / exposed
    2 / 271 (0.74%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Febrile Neutropenia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
      Mouth Ulceration
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Nausea
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Oral Mucosa Erosion
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Rectal Polyp
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Vomiting
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
      Cholecystitis Acute
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Cholelithiasis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
      Rash Maculo-Papular
         subjects affected / exposed
    3 / 271 (1.11%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Urticaria
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Drug Eruption
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Purpura
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Rash Macular
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Rash Morbilliform
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Swelling Face
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
      Nephrolithiasis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Renal Failure
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Urethral Polyp
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
      Goitre
         subjects affected / exposed
    1 / 271 (0.37%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
      Lumbar Spinal Stenosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Spinal Pain
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Synovial Cyst
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (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
      Pneumonia
         subjects affected / exposed
    4 / 271 (1.48%)
    3 / 133 (2.26%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Pneumonia Bacterial
         subjects affected / exposed
    3 / 271 (1.11%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Bronchitis
         subjects affected / exposed
    2 / 271 (0.74%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Dermatitis Infected
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Erysipelas
         subjects affected / exposed
    1 / 271 (0.37%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Herpes Virus Infection
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Pharyngitis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Pneumonia Pseudomonal
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
      Pneumonia Viral
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Respiratory Tract Infection
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Urinary Tract Infection
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Genital Herpes Simplex
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Sinusitis
         subjects affected / exposed
    0 / 271 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
      Hyperglycaemia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Hyperkalaemia
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
      Lipomatosis
         subjects affected / exposed
    1 / 271 (0.37%)
    0 / 133 (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
    		 Masitinib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    184 / 271 (67.90%)
    92 / 133 (69.17%)
    Investigations
      Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    32 / 271 (11.81%)
    13 / 133 (9.77%)
         occurrences all number
    42
    15
      Blood Phosphorus Decreased
         subjects affected / exposed
    35 / 271 (12.92%)
    9 / 133 (6.77%)
         occurrences all number
    52
    11
      Aspartate Aminotransferase Increased
         subjects affected / exposed
    33 / 271 (12.18%)
    7 / 133 (5.26%)
         occurrences all number
    43
    8
      Weight Decreased
         subjects affected / exposed
    29 / 271 (10.70%)
    8 / 133 (6.02%)
         occurrences all number
    32
    8
      Blood Triglycerides Increased
         subjects affected / exposed
    23 / 271 (8.49%)
    11 / 133 (8.27%)
         occurrences all number
    31
    14
      Alanine Aminotransferase Increased
         subjects affected / exposed
    22 / 271 (8.12%)
    7 / 133 (5.26%)
         occurrences all number
    26
    9
      Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    21 / 271 (7.75%)
    7 / 133 (5.26%)
         occurrences all number
    28
    11
      Lymphocyte Count Decreased
         subjects affected / exposed
    20 / 271 (7.38%)
    8 / 133 (6.02%)
         occurrences all number
    25
    9
      Alanine Aminotransferase Decreased
         subjects affected / exposed
    16 / 271 (5.90%)
    11 / 133 (8.27%)
         occurrences all number
    20
    15
      Blood Cholesterol Increased
         subjects affected / exposed
    19 / 271 (7.01%)
    8 / 133 (6.02%)
         occurrences all number
    30
    9
      Weight Increased
         subjects affected / exposed
    14 / 271 (5.17%)
    13 / 133 (9.77%)
         occurrences all number
    16
    17
      Haemoglobin Decreased
         subjects affected / exposed
    20 / 271 (7.38%)
    4 / 133 (3.01%)
         occurrences all number
    30
    4
      Haematocrit Increased
         subjects affected / exposed
    11 / 271 (4.06%)
    12 / 133 (9.02%)
         occurrences all number
    12
    19
      Blood Creatinine Decreased
         subjects affected / exposed
    14 / 271 (5.17%)
    8 / 133 (6.02%)
         occurrences all number
    22
    8
      White Blood Cell Count Increased
         subjects affected / exposed
    12 / 271 (4.43%)
    10 / 133 (7.52%)
         occurrences all number
    14
    12
      Protein Total Decreased
         subjects affected / exposed
    14 / 271 (5.17%)
    7 / 133 (5.26%)
         occurrences all number
    17
    10
      Neutrophil Count Increased
         subjects affected / exposed
    12 / 271 (4.43%)
    8 / 133 (6.02%)
         occurrences all number
    16
    12
      Monocyte Count Increased
         subjects affected / exposed
    11 / 271 (4.06%)
    8 / 133 (6.02%)
         occurrences all number
    17
    10
      Blood Calcium Decreased
         subjects affected / exposed
    15 / 271 (5.54%)
    1 / 133 (0.75%)
         occurrences all number
    19
    1
      Red Blood Cell Count Decreased
         subjects affected / exposed
    14 / 271 (5.17%)
    0 / 133 (0.00%)
         occurrences all number
    17
    0
    Vascular disorders
      Hypertension
         subjects affected / exposed
    12 / 271 (4.43%)
    10 / 133 (7.52%)
         occurrences all number
    16
    15
    Nervous system disorders
      Headache
         subjects affected / exposed
    9 / 271 (3.32%)
    10 / 133 (7.52%)
         occurrences all number
    11
    12
    Gastrointestinal disorders
      Nausea
         subjects affected / exposed
    24 / 271 (8.86%)
    6 / 133 (4.51%)
         occurrences all number
    34
    6
      Diarrhoea
         subjects affected / exposed
    25 / 271 (9.23%)
    3 / 133 (2.26%)
         occurrences all number
    31
    3
      Vomiting
         subjects affected / exposed
    16 / 271 (5.90%)
    1 / 133 (0.75%)
         occurrences all number
    26
    1
    Respiratory, thoracic and mediastinal disorders
      Asthma
         subjects affected / exposed
    70 / 271 (25.83%)
    38 / 133 (28.57%)
         occurrences all number
    147
    97
    Infections and infestations
      Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    18 / 271 (6.64%)
    9 / 133 (6.77%)
         occurrences all number
    25
    13
      Bronchitis
         subjects affected / exposed
    13 / 271 (4.80%)
    8 / 133 (6.02%)
         occurrences all number
    16
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2013
    Major protocol amendments were implemented during the study with an aim of improving the study’s benefit/risk balance and to enhance the clinical relevance of response. To ensure enrolment was restricted to severe corticosteroid-dependent asthmatics, and consistent with revised GINA guidance,17 the inclusion criterion for stable baseline OCS dose (prednisone-equivalent) was raised from a minimum of 5 mg/day to a prolonged exposure of ≥7.5 mg/day (protocol version 9.0, after about 27% of patients had been randomized). At this time, exposure for the primary endpoint was also changed from assessment of person-time exposure at week 36 to an overall person-time exposure, i.e., the full exposure period incorporating both initial 36-week period plus blinded extension period (protocol version 9).
    22 May 2014
    Major amendment concerning the primary endpoint which was changed to assess the rate of severe asthma exacerbations instead of moderate and severe exacerbations. Severe exacerbations are more clinically relevant in patients with severe uncontrolled asthma. In addition, moderate exacerbations are more difficult to assess and may not be clinically informative.
    02 Sep 2015
    Major amendment concerning definition of a targeted subgroup with ≥150/µL eosinophils at screening or baseline, and stratification of these patients. Once activated, mast cells release multiple mediators that produce a localized allergic response, and subsequently, secrete various cytokines, which then participate in the local recruitment and activation of other inflammatory cells including eosinophils. Thus, high levels of eosinophils may be an indication of elevated mast cell activity in asthma.

    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.
    One limitation of the current study is that it did not evaluate masitinib’s potential OCS-sparing properties, which is also considered an important therapeutic objective.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35698580
    http://www.ncbi.nlm.nih.gov/pubmed/19614621
    http://www.ncbi.nlm.nih.gov/pubmed/22487554
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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