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    Clinical Trial Results:
    A 24-WEEK WITH POSSIBLE EXTENSION, PROSPECTIVE, MULTICENTRE, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED, 2-PARALLEL GROUP WITH A RANDOMIZATION 1:1, PHASE 3 STUDY TO COMPARE EFFICACY AND SAFETY OF MASITINIB AT 6 MG/KG/DAY TO PLACEBO IN TREATMENT OF PATIENTS WITH SMOULDERING SYSTEMIC, INDOLENT SYSTEMIC OR CUTANEOUS MASTOCYTOSIS WITH HANDICAP

    Summary
    EudraCT number
    		 2008-000972-25
    Trial protocol
    		 FR   CZ   SK   LV   AT   DE   GB   IT   BG   HU   GR   ES  
    Global end of trial date
    02 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jun 2020
    First version publication date
    27 Jun 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AB06006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00814073
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AB Science
    Sponsor organisation address
    3 Avenue George V, Paris, France, 75008
    Public contact
    Regulatory affairs manager, AB Science, 33 147 20 97 83, DL_MEDICALWRITERS@ab-science.com
    Scientific contact
    Regulatory affairs manager, AB Science, 33 147209783, DL_MEDICALWRITERS@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
    12 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to compare the safety and efficacy of masitinib to placebo in adult patients with documented severe smouldering or indolent systemic mastocytosis unresponsive to optimal symptomatic treatments.
    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. In the event of severe toxicity related to masitinib, treatment interruption or dose reduction was permitted according to the predefined criteria in the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Feb 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    India: 4
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Slovakia: 10
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    France: 121
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Latvia: 1
    Worldwide total number of subjects
    223
    EEA total number of subjects
    192
    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)
    204
    From 65 to 84 years
    18
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The subjects were recruited in this study between 19 February 2009 and 15 July 2015, at 50 sites in France, USA, Poland, India, Czech-Republic, Slovakia, Russia, Germany, Italy, United Kingdom, Switzerland, Spain and Greece.

    Pre-assignment
    Screening details
    		 A total of 253 subjects were screened of which 30 subjects were screen failures. Out of the 223 subjects selected for randomization, 3 subjects were not randomized due to the withdrawal of consent before treatment allocation. The overall population consisted of 220 subjects randomized in the study, 110 subjects in each treatment group.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Masitinib
    Arm description
    		 Subjects received daily doses of masitinib at the dose of 6 mg/kg/day, taken twice daily (morning, evening) with a meal (breakfast, dinner).
    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
    Subjects received daily doses of masitinib at the dose of 6 mg/kg/day, taken twice daily (morning, evening) with a meal (breakfast, dinner). Tablets of masitinib contained either 100 mg or 200 mg of masitinib base (respectively corresponding to 119.3 mg and 238.5 mg of the mesylate salt AB1010) and were to be given as per the weight of the patient. The tablet had to be taken in a sitting position with a large glass of water (250 ml, or 8 oz.).

    Arm title
    		 Placebo
    Arm description
    		 Subjects received daily doses of matching placebo, taken twice daily (morning, evening) with a meal (breakfast, dinner).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo, taken twice daily (morning, evening) with a meal (breakfast, dinner). The administration of the matching placebo was similar as the experimental drug (masitinib).

    Number of subjects in period 1 [1]
    		Masitinib Placebo
    Started
    110
    110
    Completed
    68
    97
    Not completed
    42
    13
         Consent withdrawn by subject
    4
    2
         Adverse event, non-fatal
    26
    7
         Lost to follow-up
    2
    2
         Lack of efficacy
    6
    2
         Protocol deviation
    4
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 253 subjects were screened of which 30 subjects were screen failures. Out of the 223 subjects selected for randomization, 3 subjects were not randomized due to the withdrawal of consent before treatment allocation. The overall population consisted of 220 subjects randomized in the study, 110 subjects in each treatment group.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Masitinib
    Reporting group description
    		 Subjects received daily doses of masitinib at the dose of 6 mg/kg/day, taken twice daily (morning, evening) with a meal (breakfast, dinner).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received daily doses of matching placebo, taken twice daily (morning, evening) with a meal (breakfast, dinner).

    Reporting group values
    		 Masitinib Placebo Total
    Number of subjects
    		 110 110 220
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 105 99 204
        From 65-84 years
    		 5 10 15
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.71 ± 11.29 47.24 ± 13.20 -
    Gender categorical
    Units: Subjects
        Female
    		 78 76 154
        Male
    		 32 34 66
    Mastocytosis disease characteristics: c-Kit mutation status
    C-Kit mutation status was classified in 2 subgroups: 1. Clonal: Subjects with D816V c-Kit mutation in at least one organ in which c-Kit sequencing was performed. Several sequencing procedures could be performed for a given patient and for the same organ. D816V c-Kit mutation found in all the organs in which c-Kit sequencing was done were classified as D816V “pure”. Subjects with D816V variant found in one organ and the WT allele in a second organ were classified as D816V “chimeric”. 2. Wild-type: Subjects with no D816V c-Kit mutation in the organ(s) in which c-Kit sequencing was performed
    Units: Subjects
        Clonal:D816V pure
    		 83 85 168
        Clonal: D816V chimeric
    		 12 10 22
        Not Clonal: WT
    		 11 12 23
        Unknown status
    		 4 3 7
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population was defined as all randomized patients with systemic mastocytosis, based on the CDR classification. Only patients with indolent systemic mastocytosis meeting the prospectively declared inclusion criteria specified in this amendment were included for final analysis—ie, the ITT population. Patients were classified according to the treatment-arm to which they were randomized, irrespective of the actual treatment received.

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT population is the population that was designated for the primary analysis, across all version of the protocol. The mITT dataset included all ITT patients with exclusion of patients withdrawing prematurely from the study during the protocol period (week 0 to week 24) for a well-documented non–failure cause. Six patients from the ITT population were excluded from the mITT population based on this definition.

    Subject analysis sets values
    		 ITT mITT
    Number of subjects
    135
    129
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    127
    122
        From 65-84 years
    7
    6
        85 years and over
    1
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.10 ± 12.16
    47.14 ± 12.00
    Gender categorical
    Units: Subjects
        Female
    95
    91
        Male
    40
    38
    Mastocytosis disease characteristics: c-Kit mutation status
    C-Kit mutation status was classified in 2 subgroups: 1. Clonal: Subjects with D816V c-Kit mutation in at least one organ in which c-Kit sequencing was performed. Several sequencing procedures could be performed for a given patient and for the same organ. D816V c-Kit mutation found in all the organs in which c-Kit sequencing was done were classified as D816V “pure”. Subjects with D816V variant found in one organ and the WT allele in a second organ were classified as D816V “chimeric”. 2. Wild-type: Subjects with no D816V c-Kit mutation in the organ(s) in which c-Kit sequencing was performed
    Units: Subjects
        Clonal:D816V pure
    104
    100
        Clonal: D816V chimeric
    17
    16
        Not Clonal: WT
    9
    8
        Unknown status
    5
    5

    End points

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    End points reporting groups
    Reporting group title
    Masitinib
    Reporting group description
    		 Subjects received daily doses of masitinib at the dose of 6 mg/kg/day, taken twice daily (morning, evening) with a meal (breakfast, dinner).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received daily doses of matching placebo, taken twice daily (morning, evening) with a meal (breakfast, dinner).

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population was defined as all randomized patients with systemic mastocytosis, based on the CDR classification. Only patients with indolent systemic mastocytosis meeting the prospectively declared inclusion criteria specified in this amendment were included for final analysis—ie, the ITT population. Patients were classified according to the treatment-arm to which they were randomized, irrespective of the actual treatment received.

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The mITT population is the population that was designated for the primary analysis, across all version of the protocol. The mITT dataset included all ITT patients with exclusion of patients withdrawing prematurely from the study during the protocol period (week 0 to week 24) for a well-documented non–failure cause. Six patients from the ITT population were excluded from the mITT population based on this definition.

    Primary: Cumulative response on four handicaps (4H75%)

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    End point title
    		 Cumulative response on four handicaps (4H75%)
    End point description
    Cumulative response in at least one of 4 severe baseline handicaps from among pruritus, flushes, depression, or asthenia (referred to as 4H75) was equal to number of actual responses divided by total number of possible responses, between weeks 8 & 24. Missing data were considered as failure (MDF) and the p-value was obtained via a re-randomization (10,000 replicate) test. Response on a handicap defined as: an improvement with respect to the baseline values of ≥ 75% for pruritus, flushes, depression and asthenia, with handicaps at baseline being defined as pruritus score ≥ 9, number of flushes/week ≥ 8, HAMD-17 score ≥ 19, and Fatigue Impact Scale ≥ 75. To account for handicap imbalances between groups, observations for each handicap were weighted based on total number of patients with handicap and between-group difference in that handicap. Hence, total number of possible handicap observations for each group was equivalent. Population analysed : mITT (129 subjects)
    End point type
    Primary
    End point timeframe
    Up to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [1]
    62 [2]
    Units: percent
    number (not applicable)
        Main analysis
    18.7
    7.4
        Sensitivity of main analysis
    18.7
    7.5
    Notes
    [1] - mITT population
    [2] - mITT population
    Statistical analysis title
    		 Re-randomization p-value
    Statistical analysis description
    Main analysis: The difference between treatment groups (masitinib vs placebo) was tested using a Generalized Estimating Equations (GEE) model using Logit as the link function. This statistical model included all the responses (yes/no) on handicaps observed from week 8 to week 24; thus, from 5 to 20 responses per patient. Correlations between measurements within a subject were taken into account by using an exchangeable correlation matrix structure as hypothesized in the sample size calculation.
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0076
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 10.83
    Statistical analysis title
    		 Re-randomization p-value
    Statistical analysis description
    Sensitivity analysis: Same as main analysis but with Last Observation Carried Forward (LOCF) then with Observed Cases (data remain missing) instead of missing = failure if data are not available for assessment at a visit because a patient left the study prematurely or had no measurement at the visit.
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0079
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 10.84

    Secondary: Cumulative response on 3 handicaps (Pruritus or Flush or Depression): 3H75%

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    End point title
    		 Cumulative response on 3 handicaps (Pruritus or Flush or Depression): 3H75%
    End point description
    The analysis on response 3 handicaps (pruritus + flushes + depression) was done on the patients with handicap on pruritus and/or flushes and/or depression at baseline. The cumulative response by patient*handicap on pruritus and/or flushes and/or depression, among patients with at least one of these handicaps at baseline. 1. Response on a handicap defined as an improvement with respect to the baseline values ≥ 75% for pruritus and/or flushes and/or depression. 2. Handicaps at baseline defined as: pruritus score ≥ 9, number of flushes per week ≥ 8, and HAMD-17 score ≥ 19. For every patient the response at each study visit (5 visits from week 8 to week 24) was calculated on each handicap present at baseline. Thus, from 5 to 15 responses were calculated per patient: 5 if the patient presented only 1 handicap at baseline (corresponding to the 5 visits) and 15 if the patient presented all 3 handicaps at baseline. Population analysed : mITT population (129 subjects)
    End point type
    Secondary
    End point timeframe
    From Week 8 to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [3]
    62 [4]
    Units: percent
    number (not applicable)
        Main Analysis
    24.7
    9.8
        Sensitivity analysis
    32.4
    10.4
    Notes
    [3] - mITT population
    [4] - mITT population
    Statistical analysis title
    		 Observed p-value (GEE Model)
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0071
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.36
         upper limit
    		 6.92

    Secondary: Cumulative response on 2 handicaps (Pruritus or Flush): 2H75%

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    End point title
    		 Cumulative response on 2 handicaps (Pruritus or Flush): 2H75%
    End point description
    The analysis on response 2 handicaps was done on the patients with handicap on pruritus and/or flushes at baseline. The response on 2 handicaps (pruritus + flushes) is the cumulative response by patient*handicap on pruritus and/or flushes, among patients with either of these handicaps at baseline. - Response was defined as an improvement with respect to the baseline values ≥ 75% for pruritus and/or flushes. - Handicap at baseline was defined as: pruritus score ≥ 9 and flushes per week ≥ 8. For every patient the response at each study visit (5 visits from week 8 to week 24) was calculated on each handicap present at baseline (from among pruritus and flushes) as defined above. Thus, from 5 to 10 responses were calculated per patient: 5 if the patient presented only 1 handicap at baseline (corresponding to the 5 visits) and 10 if the patient presented both handicaps at baseline (corresponding to the 2 handicaps * the 5 visits). Population analysed : mITT population (129 subjects)
    End point type
    Secondary
    End point timeframe
    Week 8 to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [5]
    62 [6]
    Units: percent
        number (not applicable)
    27.2
    10.7
    Notes
    [5] - mITT population
    [6] - mITT population
    Statistical analysis title
    		 Observed p-value (GEE Model)
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.038
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 6.55

    Secondary: Cumulative response on pruritus among patients with this handicap at baseline

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    End point title
    		 Cumulative response on pruritus among patients with this handicap at baseline
    End point description
    The pruritus score analysis endpoint is the cumulative response on pruritus among patients with this handicap at baseline/ - Response was defined as an improvement with respect to the baseline values ≥ 75% for pruritus. - Handicap at baseline was defined as: pruritus score ≥ 9. For patients presenting this handicap at baseline (i.e. pruritus score ≥ 9), the response at each study visit (5 visits from week 8 to week 24) was calculated. Thus, 5 responses were calculated per patient. Population analysed : mITT population (129 subjects)
    End point type
    Secondary
    End point timeframe
    Week 8 to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [7]
    62 [8]
    Units: percent
        number (not applicable)
    22.0
    7.3
    Notes
    [7] - mITT population
    [8] - mITT population
    Statistical analysis title
    		 Observed p-value (GEE Model)
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0322
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 8.88

    Secondary: Long-term efficacy: Cumulative response rates (4H75%, 3H75% and pruritus) from W8 to W96

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    End point title
    		 Long-term efficacy: Cumulative response rates (4H75%, 3H75% and pruritus) from W8 to W96
    End point description
    This endpoint evaluated the sustainability of response in the long term, including the extension period. The following responses by patient*handicap were analyzed on the extension period up to W96 (2 years). - Response on 4 handicaps (4H75%) up to week 96 (2 years) - Response on 3 handicaps (3H75%) up to week 96 (2 years) - Response on pruritus up to week 96 (2 years) Population analysed : mITT population (129 subjects)
    End point type
    Secondary
    End point timeframe
    Week 8 to Week 96
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [9]
    62 [10]
    Units: percent
    number (not applicable)
        4H75%
    16.8
    6.8
        3H75%
    21.8
    8.3
        Pruritus
    19.2
    6.2
    Notes
    [9] - mITT population
    [10] - mITT population
    Statistical analysis title
    		 Observed p-value (GEE Model): 4H75%
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0156
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.27
         upper limit
    		 9.7
    Statistical analysis title
    		 Observed p-value (GEE Model): 3H75%
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0031
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.47
         upper limit
    		 6.81
    Statistical analysis title
    		 Observed p-value (GEE Model): pruritis
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0338
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 8.59

    Secondary: Efficacy evaluation based on objective markers of mast cell activity: Change from baseline in tryptase level

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    End point title
    		 Efficacy evaluation based on objective markers of mast cell activity: Change from baseline in tryptase level
    End point description
    Tryptase is a measure of the burden of mast cells and of the activity of mast cells that can change in a 6-month period. It was analyzed for patients with a baseline level of greater than 20 µg/L. The absolute change from baseline in serum tryptase level to last visit ([W0-W24 period]) in the mITT population is presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    40 [11]
    42 [12]
    Units: microgram(s)/litre
        arithmetic mean (standard deviation)
    -10 ± 46.9
    2.7 ± 20.0
    Notes
    [11] - Only subjects with tryptase level ≥ 20 micro/L at baseline and Week 24 data (mITT population).
    [12] - Only subjects with tryptase level ≥ 20 micro/L at baseline and Week 24 data (mITT population).
    Statistical analysis title
    		 Absolute change from baseline
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0267
    Method
    		 GEE model
    Confidence interval

    Other pre-specified: Cumulative response on flushes among patients with the handicap at baseline

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    End point title
    		 Cumulative response on flushes among patients with the handicap at baseline
    End point description
    For patients presenting this handicap at baseline (i.e. number of flushes per week ≥ 8), the response at each study visit (5 visits from week 8 to week 24) was calculated. Thus, 5 responses were calculated per patient. Response was defined as an improvement ≥ 75% at the visit. Population analysed : mITT population (129 subjects)
    End point type
    Other pre-specified
    End point timeframe
    Week 8 to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [13]
    62 [14]
    Units: percent weight/weight
        number (not applicable)
    39.9
    19.0
    Notes
    [13] - mITT population
    [14] - mITT population
    Statistical analysis title
    		 Odds ration (GEE model)
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 10.68

    Other pre-specified: Cumulative response on depression among patients with this handicap at baseline

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    End point title
    		 Cumulative response on depression among patients with this handicap at baseline
    End point description
    For patients presenting this handicap at baseline (i.e. HAMD-17 ≥ 19), the response at each study visit (5 visits from week 8 to week 24) was calculated. Thus, 5 responses were calculated per patient. Response was defined as an improvement ≥ 75% at the visit. Population analysed : mITT population (129 subjects)
    End point type
    Other pre-specified
    End point timeframe
    Week 8 to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [15]
    62 [16]
    Units: percent
        number (not applicable)
    18.6
    7.6
    Notes
    [15] - mITT population
    [16] - mITT population
    Statistical analysis title
    		 Odds ratio (GEE Model)
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 11.08

    Other pre-specified: Cumulative response on asthenia (FIS) among patients with this handicap at baseline

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    End point title
    		 Cumulative response on asthenia (FIS) among patients with this handicap at baseline
    End point description
    For patients presenting this handicap (asthenia) at baseline (i.e. FIS ≥ 75), the response at each study visit (5 visits from week 8 to week 24) was calculated. Thus, 5 responses were calculated per patient. Response was defined as an improvement ≥ 75% at the visit. Population analysed : mITT population (129 subjects)
    End point type
    Other pre-specified
    End point timeframe
    Week 8 to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [17]
    62 [18]
    Units: percent
        number (not applicable)
    7.7
    3.2
    Notes
    [17] - mITT population
    [18] - mITT population
    Statistical analysis title
    		 Observed p-value (GEE Model)
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 23.44

    Other pre-specified: Quality of life: 75% improvement on the OPA score

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    End point title
    		 Quality of life: 75% improvement on the OPA score
    End point description
    OPA score corresponds to the 53rd question of the AFIRMM questionnaire. For the patients presenting the handicap at Baseline (ie. OPA “severe” or “intolerable”), the response at each study visit (5 visits from week 0 to week 24) was calculated. Response being defined as an OPA “normal” or “light” at the visit. If data were not available for assessment at a visit because a patient left the study prematurely or had no measurement at the visit, missing data were considered as failure (missing = failure as primary analysis). So, 5 responses were calculated by patient. Improvement on quality of life was measured by a decrease by ≥75% in the OPA score (exploratory analysis). OPA score is a unidimensional questionnaire on the patient's assessment of pain, general health status and impact on life. Population analysed: mITT population (129 subjects)
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Week 0) to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    67 [19]
    62 [20]
    Units: percent
        number (not applicable)
    3.7
    0.6
    Notes
    [19] - mITT population
    [20] - mITT population
    Statistical analysis title
    		 Response rate for OPA score
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 56.13

    Other pre-specified: Long-term measures of mast cell activity nullification: Response on UP assessment: “Darier’s sign” disappearance

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    End point title
    		 Long-term measures of mast cell activity nullification: Response on UP assessment: “Darier’s sign” disappearance
    End point description
    “Darier’s sign” disappearance (Yes/No) for subjects with “Darier’s sign” at baseline, was analysed at different time points (Up to Week 24). The percentage of subjects in whom the Darier’s sign disappeared is presented for the mITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Week 0) to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    37 [21]
    37 [22]
    Units: percent
        number (not applicable)
    18.9
    2.7
    Notes
    [21] - Only subjects from mITT population with Darier's sign at baseline are included.
    [22] - Only subjects from mITT population with Darier's sign at baseline are included.
    Statistical analysis title
    		 Observed p-value (GEE Model)
    Comparison groups
    Placebo v Masitinib
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0187
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 41.45

    Other pre-specified: Long-term measures of mast cell activity nullification: Response on urticaria pigmentosa (UP)

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    End point title
    		 Long-term measures of mast cell activity nullification: Response on urticaria pigmentosa (UP)
    End point description
    Masitinib demonstrated activity on the objective long-term markers of mast cell activation including urticaria pigmentosa (UP) is presented here. Relative change from baseline in the body surface area covered by the UP corrected with Wallace formula is summarized for the mITT population (129 subjects). The data are presented as percent change from baseline for the overall period (up to Week 24).
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Week 0) to Week 24
    End point values
    		 Masitinib Placebo
    Number of subjects analysed
    33 [23]
    36 [24]
    Units: percent
        number (not applicable)
    -12.3
    15.9
    Notes
    [23] - Only those subjects from mITT population with values at Baseline and at Week 24 are included.
    [24] - Only those subjects from mITT population with values at Baseline and at Week 24 are included.
    Statistical analysis title
    		 Observed p-value
    Comparison groups
    Masitinib v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.021
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 56.13

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Main period (up to Week 24)
    Adverse event reporting additional description
    Adverse events have been reported for Overall population (safety population + Others) which includes all patients with severe systemic mastocytosis as well as other mastocytosis patients (non severe systemic mastocytosis and cutaneous mastocytosis), who took at least one dose of study medication (masitinib or placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13
    Reporting groups
    Reporting group title
    Masitinib
    Reporting group description
    		 Subjects received daily doses of masitinib at the dose of 6 mg/kg/day, taken once daily (morning) or twice daily (morning/evening) with a meal (breakfast/dinner).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received daily doses of matching placebo, taken once daily (morning) or twice daily (morning/evening) with a meal (breakfast/dinner).

    Serious adverse events
    		 Masitinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 110 (29.09%)
    15 / 110 (13.64%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 110 (2.73%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic oedema
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type I hypersensitivity
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactoid reaction
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food allergy
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Investigation
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    3 / 110 (2.73%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 110 (2.73%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glossitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (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 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis ulcerative
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 110 (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 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichenoid keratosis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital oedema
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis acute
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         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
    109 / 110 (99.09%)
    109 / 110 (99.09%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    10 / 110 (9.09%)
    2 / 110 (1.82%)
         occurrences all number
    13
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    29 / 110 (26.36%)
    20 / 110 (18.18%)
         occurrences all number
    36
    22
    Oedema peripheral
         subjects affected / exposed
    20 / 110 (18.18%)
    8 / 110 (7.27%)
         occurrences all number
    26
    10
    Face oedema
         subjects affected / exposed
    14 / 110 (12.73%)
    2 / 110 (1.82%)
         occurrences all number
    15
    2
    Fatigue
         subjects affected / exposed
    13 / 110 (11.82%)
    20 / 110 (18.18%)
         occurrences all number
    19
    22
    Pyrexia
         subjects affected / exposed
    10 / 110 (9.09%)
    1 / 110 (0.91%)
         occurrences all number
    12
    1
    Oedema
         subjects affected / exposed
    6 / 110 (5.45%)
    1 / 110 (0.91%)
         occurrences all number
    8
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 110 (10.00%)
    6 / 110 (5.45%)
         occurrences all number
    12
    6
    Dyspnoea
         subjects affected / exposed
    7 / 110 (6.36%)
    6 / 110 (5.45%)
         occurrences all number
    7
    7
    Psychiatric disorders
    Depression
         subjects affected / exposed
    11 / 110 (10.00%)
    7 / 110 (6.36%)
         occurrences all number
    11
    7
    Insomnia
         subjects affected / exposed
    11 / 110 (10.00%)
    10 / 110 (9.09%)
         occurrences all number
    11
    11
    Sleep disorder
         subjects affected / exposed
    4 / 110 (3.64%)
    6 / 110 (5.45%)
         occurrences all number
    4
    7
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    24 / 110 (21.82%)
    9 / 110 (8.18%)
         occurrences all number
    43
    15
    Blood glucose increased
         subjects affected / exposed
    23 / 110 (20.91%)
    19 / 110 (17.27%)
         occurrences all number
    31
    28
    Blood triglycerides increased
         subjects affected / exposed
    20 / 110 (18.18%)
    23 / 110 (20.91%)
         occurrences all number
    22
    35
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 110 (19.09%)
    6 / 110 (5.45%)
         occurrences all number
    33
    8
    Blood phosphorus decreased
         subjects affected / exposed
    21 / 110 (19.09%)
    6 / 110 (5.45%)
         occurrences all number
    29
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 110 (17.27%)
    5 / 110 (4.55%)
         occurrences all number
    26
    7
    White blood cell count decreased
         subjects affected / exposed
    15 / 110 (13.64%)
    6 / 110 (5.45%)
         occurrences all number
    27
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    15 / 110 (13.64%)
    10 / 110 (9.09%)
         occurrences all number
    24
    11
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    15 / 110 (13.64%)
    16 / 110 (14.55%)
         occurrences all number
    19
    23
    Lymphocyte count decreased
         subjects affected / exposed
    11 / 110 (10.00%)
    6 / 110 (5.45%)
         occurrences all number
    15
    6
    Blood bilirubin increased
         subjects affected / exposed
    12 / 110 (10.91%)
    8 / 110 (7.27%)
         occurrences all number
    15
    14
    Weight decreased
         subjects affected / exposed
    11 / 110 (10.00%)
    2 / 110 (1.82%)
         occurrences all number
    11
    2
    Neutrophil count decreased
         subjects affected / exposed
    8 / 110 (7.27%)
    3 / 110 (2.73%)
         occurrences all number
    14
    3
    Blood cholesterol increased
         subjects affected / exposed
    7 / 110 (6.36%)
    16 / 110 (14.55%)
         occurrences all number
    8
    25
    Blood calcium decreased
         subjects affected / exposed
    7 / 110 (6.36%)
    3 / 110 (2.73%)
         occurrences all number
    8
    3
    Lymphocyte count increased
         subjects affected / exposed
    4 / 110 (3.64%)
    6 / 110 (5.45%)
         occurrences all number
    4
    7
    Blood sodium decreased
         subjects affected / exposed
    1 / 110 (0.91%)
    6 / 110 (5.45%)
         occurrences all number
    1
    7
    Blood calcium increased
         subjects affected / exposed
    2 / 110 (1.82%)
    10 / 110 (9.09%)
         occurrences all number
    2
    13
    Neutrophil count increased
         subjects affected / exposed
    0 / 110 (0.00%)
    6 / 110 (5.45%)
         occurrences all number
    0
    7
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    7 / 110 (6.36%)
    5 / 110 (4.55%)
         occurrences all number
    7
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 110 (22.73%)
    31 / 110 (28.18%)
         occurrences all number
    28
    39
    Paraesthesia
         subjects affected / exposed
    8 / 110 (7.27%)
    3 / 110 (2.73%)
         occurrences all number
    11
    7
    Dizziness
         subjects affected / exposed
    5 / 110 (4.55%)
    8 / 110 (7.27%)
         occurrences all number
    6
    10
    Sciatica
         subjects affected / exposed
    1 / 110 (0.91%)
    6 / 110 (5.45%)
         occurrences all number
    1
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    22 / 110 (20.00%)
    12 / 110 (10.91%)
         occurrences all number
    36
    19
    Lymphopenia
         subjects affected / exposed
    16 / 110 (14.55%)
    8 / 110 (7.27%)
         occurrences all number
    31
    14
    Neutropenia
         subjects affected / exposed
    12 / 110 (10.91%)
    13 / 110 (11.82%)
         occurrences all number
    17
    16
    Leukopenia
         subjects affected / exposed
    6 / 110 (5.45%)
    6 / 110 (5.45%)
         occurrences all number
    7
    6
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 110 (3.64%)
    7 / 110 (6.36%)
         occurrences all number
    4
    7
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    28 / 110 (25.45%)
    7 / 110 (6.36%)
         occurrences all number
    32
    8
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    51 / 110 (46.36%)
    26 / 110 (23.64%)
         occurrences all number
    63
    34
    Diarrhoea
         subjects affected / exposed
    50 / 110 (45.45%)
    26 / 110 (23.64%)
         occurrences all number
    67
    31
    Abdominal pain
         subjects affected / exposed
    24 / 110 (21.82%)
    17 / 110 (15.45%)
         occurrences all number
    27
    19
    Vomiting
         subjects affected / exposed
    24 / 110 (21.82%)
    15 / 110 (13.64%)
         occurrences all number
    28
    19
    Abdominal pain upper
         subjects affected / exposed
    7 / 110 (6.36%)
    10 / 110 (9.09%)
         occurrences all number
    7
    10
    Constipation
         subjects affected / exposed
    4 / 110 (3.64%)
    11 / 110 (10.00%)
         occurrences all number
    4
    11
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    23 / 110 (20.91%)
    14 / 110 (12.73%)
         occurrences all number
    30
    15
    Rash
         subjects affected / exposed
    15 / 110 (13.64%)
    4 / 110 (3.64%)
         occurrences all number
    18
    6
    Dry skin
         subjects affected / exposed
    10 / 110 (9.09%)
    1 / 110 (0.91%)
         occurrences all number
    11
    1
    Eczema
         subjects affected / exposed
    6 / 110 (5.45%)
    2 / 110 (1.82%)
         occurrences all number
    7
    2
    Urticaria
         subjects affected / exposed
    6 / 110 (5.45%)
    2 / 110 (1.82%)
         occurrences all number
    7
    2
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    8 / 110 (7.27%)
    5 / 110 (4.55%)
         occurrences all number
    9
    6
    Haematuria
         subjects affected / exposed
    7 / 110 (6.36%)
    7 / 110 (6.36%)
         occurrences all number
    8
    7
    Leukocyturia
         subjects affected / exposed
    5 / 110 (4.55%)
    7 / 110 (6.36%)
         occurrences all number
    6
    8
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    29 / 110 (26.36%)
    8 / 110 (7.27%)
         occurrences all number
    33
    13
    Arthralgia
         subjects affected / exposed
    15 / 110 (13.64%)
    18 / 110 (16.36%)
         occurrences all number
    19
    21
    Back pain
         subjects affected / exposed
    9 / 110 (8.18%)
    12 / 110 (10.91%)
         occurrences all number
    10
    12
    Bone pain
         subjects affected / exposed
    9 / 110 (8.18%)
    6 / 110 (5.45%)
         occurrences all number
    9
    8
    Myalgia
         subjects affected / exposed
    9 / 110 (8.18%)
    8 / 110 (7.27%)
         occurrences all number
    10
    9
    Pain in extremity
         subjects affected / exposed
    8 / 110 (7.27%)
    5 / 110 (4.55%)
         occurrences all number
    10
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 110 (10.91%)
    7 / 110 (6.36%)
         occurrences all number
    12
    8
    Bronchitis
         subjects affected / exposed
    3 / 110 (2.73%)
    7 / 110 (6.36%)
         occurrences all number
    3
    8
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    19 / 110 (17.27%)
    18 / 110 (16.36%)
         occurrences all number
    25
    24
    Hypertriglyceridaemia
         subjects affected / exposed
    13 / 110 (11.82%)
    21 / 110 (19.09%)
         occurrences all number
    16
    26
    ANOREXIA
         subjects affected / exposed
    10 / 110 (9.09%)
    2 / 110 (1.82%)
         occurrences all number
    10
    2
    Hypophosphataemia
         subjects affected / exposed
    8 / 110 (7.27%)
    2 / 110 (1.82%)
         occurrences all number
    9
    2
    Hypercholesterolaemia
         subjects affected / exposed
    7 / 110 (6.36%)
    16 / 110 (14.55%)
         occurrences all number
    9
    17
    Hypoglycaemia
         subjects affected / exposed
    2 / 110 (1.82%)
    11 / 110 (10.00%)
         occurrences all number
    3
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2013
    To increase the benefit/risk ratio following discussion with EMA (Scientific advice) for indications in non-oncology, the protocol was amended to include only mastocytosis patients with smoldering systemic and indolent systemic mastocytosis. The inclusion criteria for Handicaps were strengthened (Pruritus score from ≥ 6 to ≥ 9; Flushes frequency per week from ≥ 7 to ≥ 8 ; Hamilton score from ≥ 14 to ≥ 19). Number of patients was changed to 150 with documented smoldering or indolent systemic mastocytosis with a severe handicap (75 patients per group). Limit of hemoglobin level was added to inclusion criteria in order to avoid enrolling anemic patients. The threshold of liver enzymes for the inclusion of the patients was modified to better stick to the CTCAE classification (mild / grade 1 liver enzymes increase is allowed at the inclusion). The threshold of albumin has been increased to avoid hypoalbuminia that could potentially interfere with PK of masitinib. The age limit has been set in order to avoid enrolling elderly patients in this indication. BMI level and minimal weight has been set. Subsequent dose reductions in case of occurrence of Adverse Event was allowed and specified. Specific surveillance for adverse events was clarified and risk management plans were updated.
    13 Feb 2015
    Protocol version 7.0 including amendment No. 6 incorporated the following changes: - Clarification of contraceptive methods that must be used by patients during the study and for 3 months after the last treatment intake was added for male and female patients. - Maximum IMP exposure duration was limited to 2 years. After 2 years, patients were allowed to continue the treatment on a case by case basis only if a documented favorable benefit/risk ratio is established by the investigator. - New safety rules: Chest X-ray removed from screening; if chest X-ray performed within 3 months prior to baseline, not required at baseline. Risk management plan/procedures for carcinogenicity as potential adverse events were supplemented with NMP test at the baseline visit, every 12 weeks, and at the final visit; frequency of urinary cytology was increased to every 12 weeks and specific search for transitional and/or malignant cells was emphasized. - Hormonal work up to address the risk of uterine carcinoma was added. - Prescription of broad-spectrum antibiotherapy was considered and executed by clinical study physicians in case subjects will present themselves with signs or symptoms suggesting the occurrence of severe neutropenia and/or severe skin toxicity. - Information about the AB Science pregnancy surveillance program (for confirmed pregnancy). - Frequency for (optional depending on patients` consent) semen analysis for male patients was increased to the baseline visit, every 12 weeks, and final visit. Live attenuated vaccines were added to prohibited concomitant treatments. - Pelvic ultrasound in women of childbearing potential added to safety assessment at baseline and final visit. A serum pregnancy test was added to screening procedures. Introduced rebound evaluation assessment of symptoms after treatment discontinuation. Updated severe skin toxicity questionnaire.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28069279
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