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    Clinical Trial Results:
    A 96-week, prospective, multicenter, randomised, double-blind, placebo-controlled, 2-parallel groups, Phase 3 study to compare efficacy and safety of masitinib 4.5 mg/kg/day versus placebo in the treatment of patients with primary progressive or relapse-free secondary progressive multiple sclerosis

    Summary
    EudraCT number
    		 2010-021219-17
    Trial protocol
    		 ES   DE   SK   GR   BG  
    Global end of trial date
    11 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 May 2022
    First version publication date
    26 May 2022
    Other versions
    Summary report(s)
    		 Vermersch P, et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial. Neurol Neuroimmunol Neuroinflamm. 2022;9(3):e1148.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AB07002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01433497
    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, 33 0147200014, clinical@ab-science.com
    Scientific contact
    Clinical Study Coordinator, AB Science, 33 0147200014, 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
    10 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether masitinib can decrease progression of disability, measured by the Expanded Disability Status Scale (EDSS), in adults with primary progressive MS (PPMS) or patients with nonactive secondary progressive MS (nSPMS) (with no exacerbations in the last 2 years).
    Protection of trial subjects
    The study protocol and amendments were approved by the institutional review board or ethics committee at each participating clinical site and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent. An independent Data Safety Monitoring Committee monitored safety throughout the study protocol period. Dose reduction or treatment interruption was allowed for moderate or severe toxicity according to predefined criteria.
    Background therapy
    		 Multiple sclerosis (MS) is an inflammatory, demyelinating, and degenerative disease of the CNS. The clinical course of MS is heterogeneous with patients falling into 2 core categories from a pharmacotherapy perspective. The first category, relapsing disease, is associated with processes of inflammatory demyelination, resulting in relapses followed by remissions. The second category, progressive disease, is associated with processes of progressive neurodegeneration resulting in a gradual accrual of neurologic disability. Additional MS phenotype descriptors are based on disease activity (determined by clinical relapses and/or MRI activity) and disease progression (measured by clinical evaluation). Hence, progressive MS can be described as active and with/without progression or not active and with/without progression. The vast majority of MS drugs primarily benefit active/relapsing forms of MS with limited efficacy in the progressive forms. This therapeutic divide is consistent with the growing opinion that active/relapsing MS and progressive MS are primarily driven by different disease mechanisms; the former characterized by activity of the peripheral adaptive immune system and the latter by an additional, predominant activity of the innate immune system, compartmentalized within the CNS. Masitinib is a selective oral tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive MS. Clinical proof of concept that masitinib slows disability progression in patients with progressive MS was previously demonstrated in a small phase 2 trial [Vermersch P, et al. BMC Neurol. 2012;12:36]. Masitinib has also demonstrated neuroprotective action in amyotrophic lateral sclerosis (ALS) and Alzheimer disease, via inhibition of microglia, macrophage, and mast cell activity. These are types of innate immune cells that are present in the CNS and are involved in the pathophysiology of progressive MS.
    Evidence for comparator
    		 Study AB07002 was a placebo-controlled trial, therefore, no active comparator drug was used.
    Actual start date of recruitment
    25 Aug 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
    France: 12
    Country: Number of subjects enrolled
    Algeria: 1
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 1
    Country: Number of subjects enrolled
    Bulgaria: 19
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Germany: 65
    Country: Number of subjects enrolled
    Greece: 27
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    India: 1
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Poland: 188
    Country: Number of subjects enrolled
    Romania: 31
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Slovakia: 26
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    Spain: 87
    Country: Number of subjects enrolled
    Tunisia: 32
    Country: Number of subjects enrolled
    Ukraine: 91
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    656
    EEA total number of subjects
    467
    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)
    627
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Date of first randomization: 25 August 2011 Date of last randomization: 10 March 2017 Date of completion: 11 February 2019 (last patient last visit) The study was conducted at 108 sites from 20 countries

    Pre-assignment
    Screening details
    		 Eligibility criteria were an age of 18–75 years, MS diagnosis according to the revised McDonald criteria of PPMS or nSPMS without relapse for at least 2 years prior to inclusion, and a baseline score on the EDSS of 2.0–6.0 inclusive. Clinical evidence of disability progression over the preceding 2 years (increase in EDSS score of at least 1.0).

    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, Monitor, Carer, Assessor
    Blinding implementation details
    Patients were centrally randomized using a computerized central randomization system and minimization method according to the covariates of MS phenotype (PPMS or nSPMS), baseline EDSS score, baseline MSFC subscale scores, and geographical region.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Masitinib arm from the 4.5 mg/kg/d parallel group
    Arm description
    		 Masitinib treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    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 4.5 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.

    Arm title
    		 Masitinib arm from the fixed 6.0 mg/kg/d parallel group
    Arm description
    		 Masitinib treatment-arm from the fixed masitinib 6.0 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    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 4.5 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.

    Arm title
    		 Masitinib arm from the titrated 6.0 mg/kg/d parallel group
    Arm description
    		 Masitinib treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group, wherein patients were randomly assigned to receive masitinib (administered orally as 2 daily intakes) at an initial dose of 4.5 mg/kg/d for 12 weeks which was then up-titrated (escalated) to a planned dose of 6.0 mg/kg/d. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    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 (taken twice daily (morning, evening) with a meal (breakfast, dinner).at an initial dose of 4.5 mg/kg/d for 12 weeks that was then up-titrated (escalated) to a planned dose of 6.0 mg/kg/d. 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.

    Arm title
    		 Placebo arm from the 4.5 mg/kg/d parallel group
    Arm description
    		 Placebo treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    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
    Subjects received daily doses of matched placebo, taken twice daily (morning, evening) with a meal (breakfast, dinner).

    Arm title
    		 Placebo arm from the fixed 6.0 mg/kg/d parallel group
    Arm description
    		 Placebo treatment-arm from the fixed masitinib 6.0 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    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
    Subjects received daily doses of matched placebo, taken twice daily (morning, evening) with a meal (breakfast, dinner).

    Arm title
    		 Placebo arm from the titrated 6.0 mg/kg/d parallel group
    Arm description
    		 Matched placebo treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group, wherein patients were randomly assigned to receive masitinib (administered orally as 2 daily intakes) at an initial dose of 4.5 mg/kg/d for 12 weeks which was then up-titrated (escalated) to a planned dose of 6.0 mg/kg/d. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    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
    Subjects received daily doses of matched placebo, taken twice daily (morning, evening) with a meal (breakfast, dinner).

    Number of subjects in period 1
    		Masitinib arm from the 4.5 mg/kg/d parallel group Masitinib arm from the fixed 6.0 mg/kg/d parallel group Masitinib arm from the titrated 6.0 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group Placebo arm from the fixed 6.0 mg/kg/d parallel group Placebo arm from the titrated 6.0 mg/kg/d parallel group
    Started
    200
    27
    203
    101
    18
    107
    Completed
    99
    3
    127
    67
    5
    74
    Not completed
    101
    24
    76
    34
    13
    33
         Adverse event, serious fatal
    -
    -
    1
    1
    -
    -
         Cancer
    2
    -
    1
    -
    -
    -
         IMP non compliance
    -
    -
    -
    -
    -
    2
         Travel
    -
    -
    -
    4
    -
    1
         Consent withdrawn by subject
    12
    -
    2
    6
    -
    3
         Adverse event, non-fatal
    33
    10
    40
    2
    -
    4
         Prohibited treatment
    -
    -
    -
    -
    -
    1
         Regulatory suspension
    8
    11
    -
    3
    7
    -
         Not related Adverse Event
    3
    1
    3
    -
    1
    2
         Unknown
    5
    -
    4
    4
    -
    2
         Eligibility criteria not respected
    -
    -
    -
    -
    1
    3
         Lost to follow-up
    1
    -
    1
    1
    1
    -
         Protocol deviation
    12
    2
    8
    1
    -
    -
         Lack of efficacy
    25
    -
    16
    12
    3
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Masitinib arm from the 4.5 mg/kg/d parallel group
    Reporting group description
    		 Masitinib treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Masitinib arm from the fixed 6.0 mg/kg/d parallel group
    Reporting group description
    		 Masitinib treatment-arm from the fixed masitinib 6.0 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Masitinib arm from the titrated 6.0 mg/kg/d parallel group
    Reporting group description
    		 Masitinib treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group, wherein patients were randomly assigned to receive masitinib (administered orally as 2 daily intakes) at an initial dose of 4.5 mg/kg/d for 12 weeks which was then up-titrated (escalated) to a planned dose of 6.0 mg/kg/d. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Placebo arm from the 4.5 mg/kg/d parallel group
    Reporting group description
    		 Placebo treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Placebo arm from the fixed 6.0 mg/kg/d parallel group
    Reporting group description
    		 Placebo treatment-arm from the fixed masitinib 6.0 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Placebo arm from the titrated 6.0 mg/kg/d parallel group
    Reporting group description
    		 Matched placebo treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group, wherein patients were randomly assigned to receive masitinib (administered orally as 2 daily intakes) at an initial dose of 4.5 mg/kg/d for 12 weeks which was then up-titrated (escalated) to a planned dose of 6.0 mg/kg/d. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Masitinib arm from the fixed 6.0 mg/kg/d parallel group Masitinib arm from the titrated 6.0 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group Placebo arm from the fixed 6.0 mg/kg/d parallel group Placebo arm from the titrated 6.0 mg/kg/d parallel group Total
    Number of subjects
    		 200 27 203 101 18 107 656
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 189 25 197 94 18 104 627
        From 65-84 years
    		 11 2 6 7 0 3 29
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.8 ± 9.63 53.0 ± 9.67 48.6 ± 10.10 49.7 ± 10.19 51.6 ± 7.43 48.8 ± 9.68 -
    Gender categorical
    Units: Subjects
        Female
    		 111 17 122 54 8 65 377
        Male
    		 89 10 81 47 10 42 279
    EDSS Category
    Expanded Disability Status Scale (EDSS), range, 0 to 10.0 in 0.5-point increments, with higher scores indicating greater disability
    Units: Subjects
        At least 6
    		 98 9 100 48 6 51 312
        5 and 5.5
    		 41 6 49 21 6 21 144
        Less than 5
    		 61 12 54 32 6 35 200
    MS phenotype
    Patients with primary progressive MS (PPMS) or patients with nonactive secondary progressive MS (nSPMS) (with no exacerbations in the last 2 years). MS phenotype descriptors are based on disease activity (determined by clinical relapses and/or MRI activity) and disease progression (measured by clinical evaluation). Hence, progressive MS can be described as primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS).
    Units: Subjects
        PPMS
    		 79 17 81 45 9 46 277
        nSPMS
    		 121 10 122 56 9 61 379
    EDSS Score
    Expanded Disability Status Scale (EDSS), range, 0 to 10.0 in 0.5-point increments, with higher scores indicating greater disability
    Units: point
        arithmetic mean (standard deviation)
    		 5.2 ± 1.07 4.8 ± 1.14 5.5 ± 0.95 5.1 ± 1.06 5.0 ± 1.02 5.5 ± 1.01 -
    Disease Duration from Onset
    Disease duration from onset of MS symptom at the time of randomization
    Units: Years
        arithmetic mean (standard deviation)
    		 14.0 ± 9.14 13.7 ± 9.56 14.2 ± 9.96 12.6 ± 7.96 12.2 ± 7.06 12.5 ± 8.81 -
    Disease Duration from MS Diagnosis
    Disease Duration from MS diagnosis at the time of randomization
    Units: Years
        arithmetic mean (standard deviation)
    		 9.1 ± 7.77 10.4 ± 8.84 10.0 ± 8.62 9.0 ± 8.17 8.8 ± 7.78 8.3 ± 8.26 -
    MSFC Timed 25-Foot Walk Test
    Multiple Sclerosis Functional Composite (MSFC) raw score for its component measurement of timed 25-foot walk test (T25FW, averaged time from 2 tests). MSFC is a composite instrument of disability.
    Units: seconds
        arithmetic mean (standard deviation)
    		 22.8 ± 31.52 11.2 ± 13.34 19.2 ± 24.18 22.7 ± 37.91 11.9 ± 13.36 18.8 ± 24.07 -
    MSFC 9-HPT
    MSFC 9-hole peg test (9-HPT), averaged time from 2 tests on each hand (raw score). Multiple Sclerosis Functional Composite (MSFC) is a composite instrument of disability.
    Units: seconds
        arithmetic mean (standard deviation)
    		 34.0 ± 18.63 31.4 ± 18.02 32.9 ± 14.3 34.2 ± 20.55 29.5 ± 6.96 35.1 ± 25.53 -
    MSFC PASAT-3
    Paced Auditory Serial Addition Test–3 (PASAT-3) (raw score). Multiple Sclerosis Functional Composite (MSFC) is a composite instrument of disability.
    Units: points
        arithmetic mean (standard deviation)
    		 41.6 ± 13.36 46.4 ± 11.02 41.9 ± 13.29 40.1 ± 14.47 42.9 ± 13.71 42.2 ± 12.36 -
    Subject analysis sets

    Subject analysis set title
    Masitinib arm from the 4.5 mg/kg/d parallel group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Masitinib treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm. 1 patient was excluded from the ITT data set because of no study drug intake,

    Subject analysis set title
    Placebo arm from the 4.5 mg/kg/d parallel group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Subject analysis set title
    Masitinib arm from titrated 6.0 mg/kg/d parallel group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Masitinib treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group.

    Subject analysis set title
    Placebo arm from titrated 6.0 mg/kg/d parallel group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Subject analysis sets values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group Masitinib arm from titrated 6.0 mg/kg/d parallel group Placebo arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects
    199
    101
    203
    107
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    188
    188
    197
    104
        From 65-84 years
    11
    11
    6
    3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.8 ± 9.63
    49.7 ± 10.19
    48.6 ± 10.10
    48.8 ± 9.68
    Gender categorical
    Units: Subjects
        Female
    111
    54
    122
    65
        Male
    88
    47
    81
    42
    EDSS Category
    Expanded Disability Status Scale (EDSS), range, 0 to 10.0 in 0.5-point increments, with higher scores indicating greater disability
    Units: Subjects
        At least 6
    98
    48
    100
    51
        5 and 5.5
    41
    21
    49
    21
        Less than 5
    60
    32
    54
    35
    MS phenotype
    Patients with primary progressive MS (PPMS) or patients with nonactive secondary progressive MS (nSPMS) (with no exacerbations in the last 2 years). MS phenotype descriptors are based on disease activity (determined by clinical relapses and/or MRI activity) and disease progression (measured by clinical evaluation). Hence, progressive MS can be described as primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS).
    Units: Subjects
        PPMS
    79
    45
    81
    46
        nSPMS
    120
    56
    122
    61
    EDSS Score
    Expanded Disability Status Scale (EDSS), range, 0 to 10.0 in 0.5-point increments, with higher scores indicating greater disability
    Units: point
        arithmetic mean (standard deviation)
    5.2 ± 1.1
    5.1 ± 1.06
    5.5 ± 0.95
    5.5 ± 1.01
    Disease Duration from Onset
    Disease duration from onset of MS symptom at the time of randomization
    Units: Years
        arithmetic mean (standard deviation)
    14.0 ± 9.1
    12.6 ± 7.96
    14.2 ± 9.96
    12.5 ± 8.81
    Disease Duration from MS Diagnosis
    Disease Duration from MS diagnosis at the time of randomization
    Units: Years
        arithmetic mean (standard deviation)
    9.2 ± 7.8
    9.0 ± 8.17
    10.0 ± 8.62
    8.3 ± 8.26
    MSFC Timed 25-Foot Walk Test
    Multiple Sclerosis Functional Composite (MSFC) raw score for its component measurement of timed 25-foot walk test (T25FW, averaged time from 2 tests). MSFC is a composite instrument of disability.
    Units: seconds
        arithmetic mean (standard deviation)
    22.9 ± 31.6
    22.7 ± 37.91
    19.2 ± 24.18
    18.8 ± 24.07
    MSFC 9-HPT
    MSFC 9-hole peg test (9-HPT), averaged time from 2 tests on each hand (raw score). Multiple Sclerosis Functional Composite (MSFC) is a composite instrument of disability.
    Units: seconds
        arithmetic mean (standard deviation)
    34.2 ± 18.6
    34.2 ± 20.55
    32.9 ± 14.3
    35.1 ± 25.53
    MSFC PASAT-3
    Paced Auditory Serial Addition Test–3 (PASAT-3) (raw score). Multiple Sclerosis Functional Composite (MSFC) is a composite instrument of disability.
    Units: points
        arithmetic mean (standard deviation)
    41.5 ± 13.4
    40.1 ± 14.47
    41.9 ± 13.29
    42.2 ± 12.36

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Masitinib arm from the 4.5 mg/kg/d parallel group
    Reporting group description
    		 Masitinib treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Masitinib arm from the fixed 6.0 mg/kg/d parallel group
    Reporting group description
    		 Masitinib treatment-arm from the fixed masitinib 6.0 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Masitinib arm from the titrated 6.0 mg/kg/d parallel group
    Reporting group description
    		 Masitinib treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group, wherein patients were randomly assigned to receive masitinib (administered orally as 2 daily intakes) at an initial dose of 4.5 mg/kg/d for 12 weeks which was then up-titrated (escalated) to a planned dose of 6.0 mg/kg/d. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Placebo arm from the 4.5 mg/kg/d parallel group
    Reporting group description
    		 Placebo treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Placebo arm from the fixed 6.0 mg/kg/d parallel group
    Reporting group description
    		 Placebo treatment-arm from the fixed masitinib 6.0 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Reporting group title
    Placebo arm from the titrated 6.0 mg/kg/d parallel group
    Reporting group description
    		 Matched placebo treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group, wherein patients were randomly assigned to receive masitinib (administered orally as 2 daily intakes) at an initial dose of 4.5 mg/kg/d for 12 weeks which was then up-titrated (escalated) to a planned dose of 6.0 mg/kg/d. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Subject analysis set title
    Masitinib arm from the 4.5 mg/kg/d parallel group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Masitinib treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm. 1 patient was excluded from the ITT data set because of no study drug intake,

    Subject analysis set title
    Placebo arm from the 4.5 mg/kg/d parallel group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo treatment-arm from the masitinib 4.5 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Subject analysis set title
    Masitinib arm from titrated 6.0 mg/kg/d parallel group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Masitinib treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group.

    Subject analysis set title
    Placebo arm from titrated 6.0 mg/kg/d parallel group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo treatment-arm from the titrated masitinib 6.0 mg/kg/d parallel group. Each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.

    Primary: δEDSS (repeated-measures EDSS change)

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    End point title
    		 δEDSS (repeated-measures EDSS change)
    End point description
    Change from baseline on the EDSS, calculated using repeated measures methodology (i.e., generalized estimating equation [GEE]) based on all time points measured every 12 weeks over 96 weeks (δEDSS); i.e., a population-averaged score comprising 8 consecutive data points from each patient. Results were expressed as least-squares mean (LSM) change on the EDSS from baseline (δEDSS, wherein a positive value indicates disability progression), with treatment effect (masitinib vs placebo) reported as the between treatment-arm difference (LSM difference, wherein a negative value favors masitinib). The change on the EDSS from baseline was calculated using a GEE model with normal distribution and identity link function, 97.04% CIs, and 2-sided comparison at an overall alpha level of 0.030 (adjusted for a single interim analysis). Missing data imputed via last observation carried forward methodology for those patients discontinuing before week 96 because of a safety event or lack of efficacy
    End point type
    Primary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group Masitinib arm from titrated 6.0 mg/kg/d parallel group Placebo arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    203
    107
    Units: points
        least squares mean (standard error)
    0.001 ± 0.034
    0.098 ± 0.041
    0.009 ± 0.0352
    -0.005 ± 0.009
    Statistical analysis title
    		 LSM difference (4.5 mg/kg/d Parallel Group)
    Statistical analysis description
    Between treatment-arm difference in dEDSS, wherein a negative value favors masitinib (i.e., masitinib arm minus its related placebo arm). NOTE that each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0257
    Method
    		 ANCOVA GEE model
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.097
    Confidence interval
         level
    		 97%
         sides
    2-sided
         lower limit
    		 -0.192
         upper limit
    		 -0.002
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0435
    Statistical analysis title
    		 LSM difference (titrated 6 mg/kg/d Parallel Group)
    Statistical analysis description
    Between treatment-arm difference in dEDSS, wherein a negative value favors masitinib (i.e., masitinib arm minus its related placebo arm). NOTE that each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    Comparison groups
    Masitinib arm from titrated 6.0 mg/kg/d parallel group v Placebo arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8019
    Method
    		 ANCOVA GEE model
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.014
    Confidence interval
         level
    		 97%
         sides
    2-sided
         lower limit
    		 -0.111
         upper limit
    		 0.1399
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0577

    Secondary: Ordinal EDSS Analysis

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    End point title
    		 Ordinal EDSS Analysis
    End point description
    Consistency of the primary analysis was tested using predefined sensitivity analyses (EDSS-related secondary endpoints), including change from baseline in ordinal EDSS score averaged for all time points over 96 weeks; a 3-level ordinal EDSS model (GEE [W12–W96]) wherein values of +1, 0, or −1 were assigned for improved, stable, or worsening condition, respectively. This approach simultaneously measures intrasubject and intragroup incidence of positive and negative outcomes over duration of treatment. A worsening condition was defined as an increase from baseline in the EDSS of ≥1.0 point for a baseline score of ≤5.5 or of ≥0.5 points for a baseline score of >5.5 points. Likewise, an improving condition was defined by a decrease from baseline in the EDSS of the aforementioned values. NOTE
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group Masitinib arm from titrated 6.0 mg/kg/d parallel group Placebo arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    203
    107
    Units: points
        number (not applicable)
    199
    101
    203
    107
    Statistical analysis title
    		 Ordinal EDSS (4.5 mg/kg/d Parallel Group)
    Statistical analysis description
    Change from baseline in ordinal EDSS score averaged for all time points over 96 weeks; a 3-level ordinal EDSS model (GEE [W12–W96]) wherein values of +1, 0, or −1 were assigned for improved, stable, or worsening condition, respectively. NOTE that each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0444
    Method
    		 ANCOVA GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.376
         upper limit
    		 0.988
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1501
    Statistical analysis title
    		 Ordinal EDSS (titrated 6 mg/kg/d Parallel Group)
    Statistical analysis description
    Change from baseline in ordinal EDSS score averaged for all time points over 96 weeks; a 3-level ordinal EDSS model (GEE [W12–W96]) wherein values of +1, 0, or −1 were assigned for improved, stable, or worsening condition, respectively. NOTE that each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    Comparison groups
    Masitinib arm from titrated 6.0 mg/kg/d parallel group v Placebo arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6756
    Method
    		 ANCOVA GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.134
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.629
         upper limit
    		 2.044
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3408

    Secondary: Time-to-Confirmed (12 weeks) EDSS progression

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    End point title
    		 Time-to-Confirmed (12 weeks) EDSS progression
    End point description
    Time-to-confirmed (TTC) EDSS progression. Predefined time-to-event analysis of risk of EDSS progression confirmed at week 12, wherein a worsening condition was defined as an increase from baseline in the EDSS of .1.0 point for a baseline score of .5.5 or of .0.5 points for a baseline score of >5.5 points. NOTE that each parallel group was effectively run as a separate study, distinct in matters of statistical analysis and control arm.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group Masitinib arm from titrated 6.0 mg/kg/d parallel group Placebo arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    203
    107
    Units: events
    22
    18
    25
    17
    Statistical analysis title
    		 TTC EDSS progression (4.5 mg/kg/d parallel group)
    Statistical analysis description
    Time-to-confirmed (TTC) EDSS progression in the 4.5 mg/kg/d parallel arm. Kaplan-Meier analysis
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.159 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.327
    Notes
    [1] - Log-rank p-value is adjusted for baseline MSFC components, baseline EDSS and Region
    Statistical analysis title
    		 TTC EDSS progression (titrated parallel group)
    Statistical analysis description
    Time-to-confirmed (TTC) EDSS progression in the titrated 6.0 mg/kg/d parallel arm. Kaplan-Meier analysis
    Comparison groups
    Masitinib arm from titrated 6.0 mg/kg/d parallel group v Placebo arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2935 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [2] - Log-rank p-value is adjusted for baseline MSFC components, baseline EDSS and Region

    Secondary: Time-to-first EDSS progression

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    End point title
    		 Time-to-first EDSS progression
    End point description
    Time-to-first EDSS progression. Predefined time-to-event analysis of risk of EDSS progression (unconfirmed), wherein a worsening condition was defined as an increase from baseline in the EDSS of .1.0 point for a baseline score of .5.5 or of .0.5 points for a baseline score of >5.5 points.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group Masitinib arm from titrated 6.0 mg/kg/d parallel group Placebo arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    203
    107
    Units: events
    34
    31
    42
    25
    Statistical analysis title
    		 TTF EDSS progression (4.5 mg/kg/d parallel group)
    Statistical analysis description
    Time-to-first (TTF) EDSS progression in the 4.5 mg/kg/d parallel arm. Kaplan-Meier analysis
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0342 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.254
    Notes
    [3] - Log-rank p-value is adjusted for baseline MSFC components, baseline EDSS and Region
    Statistical analysis title
    		 TTF EDSS progression (titrated parallel group)
    Statistical analysis description
    Time-to-first (TTF) EDSS progression in the titrated 6.0 mg/kg/d parallel arm. Kaplan-Meier analysis
    Comparison groups
    Placebo arm from titrated 6.0 mg/kg/d parallel group v Masitinib arm from titrated 6.0 mg/kg/d parallel group
    Number of subjects included in analysis
    310
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7153 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.264
    Notes
    [4] - Log-rank p-value is adjusted for baseline MSFC components, baseline EDSS and Region

    Secondary: Multiple Sclerosis Functional Composite (MSFC) Score

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    End point title
    		 Multiple Sclerosis Functional Composite (MSFC) Score
    End point description
    Change from baseline on the MSFC raw scores averaged for all time points over 96 weeks, calculated using repeated measures methodology (mixed-effect model repeated measure, timeframe [W12–W96]). The Multiple Sclerosis Functional Composite (MSFC) is a standardized, three-part tool used to assess the degree of disability in patients with MS. The MSFC was created for use in clinical studies and measures three key areas of MS disability—leg function/walking, arm and hand function, and cognitive function.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    Units: points
        least squares mean (standard error)
    0.031 ± 0.0221
    0.042 ± 0.0271
    Statistical analysis title
    		 MSFC Difference (4.5 mg/kg/d parallel group)
    Statistical analysis description
    Between treatment-arm difference in MSFC (i.e., masitinib arm minus its related placebo arm).
    Comparison groups
    Placebo arm from the 4.5 mg/kg/d parallel group v Masitinib arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.729
    Method
    		 Logrank
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.074
         upper limit
    		 0.052
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0318

    Secondary: MSFC T25FW

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    End point title
    		 MSFC T25FW
    End point description
    Change from baseline on the MSFC component measure of timed 25-foot walk test (T25FW, averaged time from 2 tests) The T25-FW is a quantitative mobility and leg function performance test based on a timed 25-walk
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    Units: seconds
        least squares mean (standard error)
    1.345 ± 1.3582
    3.042 ± 1.6661
    Statistical analysis title
    		 MSFC T25FW Difference (4.5 mg/kg/d parallel group)
    Statistical analysis description
    Between treatment-arm difference in MSFC T25FW (i.e., masitinib arm minus its related placebo arm).
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3848
    Method
    		 Logrank
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.697
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.534
         upper limit
    		 2.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9498

    Secondary: MSFC 9-HPT

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    End point title
    		 MSFC 9-HPT
    End point description
    Change from baseline on the MSFC component measure of 9-hole peg test (9-HPT, averaged time from 2 tests on each hand) The 9-HPT is a brief, standardized, quantitative test of upper extremity function.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    Units: seconds
        least squares mean (standard error)
    -1.027 ± 1.4455
    3.256 ± 1.7704
    Statistical analysis title
    		 MSFC 9-HPT Difference (4.5 mg/kg/d parallel group)
    Statistical analysis description
    Between treatment-arm difference in MSFC 9-HPT (i.e., masitinib arm minus its related placebo arm).
    Comparison groups
    Placebo arm from the 4.5 mg/kg/d parallel group v Masitinib arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0388
    Method
    		 Logrank
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.283
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.344
         upper limit
    		 -0.221
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.0644

    Secondary: MSFC PASAT-3

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    End point title
    		 MSFC PASAT-3
    End point description
    Change from baseline on the MSFC component measure of Paced Auditory Serial Addition Test–3 (PASAT-3) The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    Units: points
        least squares mean (standard error)
    2.209 ± 0.4758
    2.806 ± 0.5826
    Statistical analysis title
    		 MSFC PASAT Difference (4.5 mg/kg/d parallel group)
    Statistical analysis description
    Between treatment-arm difference in MSFC PASAT-3 (i.e., masitinib arm minus its related placebo arm).
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3807
    Method
    		 Logrank
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.597
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.935
         upper limit
    		 0.741
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.68

    Secondary: MSQOL-54 Physical Health

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    End point title
    		 MSQOL-54 Physical Health
    End point description
    Change from baseline in the MS quality of life (MSQOL-54) subscale of Physical Health, calculated using repeated measures methodology (mixed-effect model repeated measure, timeframe [W12–W96]). The MSQOL-54 is a multidimensional health-related quality of life measure that combines both generic and MS-specific items into a single instrument. This 54-item instrument generates 12 subscales along with two summary scores (Physical Health and Mental Health) and two additional single-item measures.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    Units: points
        least squares mean (standard error)
    -0.976 ± 0.7663
    -1.221 ± 0.9411
    Statistical analysis title
    		 MSQOL-54 PH Difference (4.5mg/kg/d parallel group)
    Statistical analysis description
    Between treatment-arm difference in MSQOL-54 Physical Health (PH) (masitinib arm minus its related placebo arm)
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8234
    Method
    		 Logrank
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.246
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.918
         upper limit
    		 2.409
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.0996

    Secondary: MSQOL-54 Mental Health

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    End point title
    		 MSQOL-54 Mental Health
    End point description
    Change from baseline in the MS quality of life (MSQOL-54) subscale of Mental Health, calculated using repeated measures methodology (mixed-effect model repeated measure, timeframe [W12–W96]). The MSQOL-54 is a multidimensional health-related quality of life measure that combines both generic and MS-specific items into a single instrument. This 54-item instrument generates 12 subscales along with two summary scores (Physical Health and Mental Health) and two additional single-item measures.
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    Units: points
        least squares mean (standard error)
    -1.863 ± 0.9436
    -1.107 ± 1.1580
    Statistical analysis title
    		 MSQOL-54 MH Difference (4.5mg/kg/d parallel group)
    Statistical analysis description
    Between treatment-arm difference in MSQOL-54 Mental Health (MH) (masitinib arm minus its related placebo arm)
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5776
    Method
    		 Logrank
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.755
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.421
         upper limit
    		 1.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.3555

    Secondary: Health State Visual Analogue Scale (EQ-VAS)

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    End point title
    		 Health State Visual Analogue Scale (EQ-VAS)
    End point description
    Change from baseline in the Health State Visual Analogue Scale (EQ-VAS) (Quality of life instrument consisting of a vertical visual analog scale wherein a score of 0 indicates worst imaginable health and 100 indicates best imaginable health).
    End point type
    Secondary
    End point timeframe
    96 weeks
    End point values
    		 Masitinib arm from the 4.5 mg/kg/d parallel group Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects analysed
    199
    101
    Units: points
        least squares mean (standard error)
    0.877 ± 0.9329
    -1.495 ± 1.1148
    Statistical analysis title
    		 EQ-VAS Difference (4.5 mg/kg/d parallel group)
    Statistical analysis description
    Between treatment-arm difference in EQ-VAS (masitinib arm minus its related placebo arm)
    Comparison groups
    Masitinib arm from the 4.5 mg/kg/d parallel group v Placebo arm from the 4.5 mg/kg/d parallel group
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0753
    Method
    		 Logrank
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.372
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.243
         upper limit
    		 4.987
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.3294

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    96 weeks
    Adverse event reporting additional description
    Treatment Emergent Adverse Events (TEAEs) is defined as Adverse Events (AEs) begin after the administration of study drug and/or within 28 days after the last dose and/or worsening after the date of the first study drug. Safety dataset excluded 1 patient from ITT because of no intake of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Pooled Placebo
    Reporting group description
    		 Safety for each masitinib dose level was compared against a pooled placebo population

    Reporting group title
    Masitinib 4.5 mg/kg/d
    Reporting group description
    		 Patients were randomly assigned to receive masitinib at 4.5 mg/kg/d (administered orally as 2 daily intakes) or equivalent placebo.

    Reporting group title
    Masitinib 6.0 mg/kg/d (fixed dose)
    Reporting group description
    		 Patients were randomly assigned to receive masitinib at a fixed dose of 6.0 mg/kg/d (administered orally as 2 daily intakes) or equivalent placebo.

    Reporting group title
    Titrated masitinib 6.0 mg/kg/d
    Reporting group description
    		 An independent parallel group was introduced as an amendment in which patients were randomly assigned to receive masitinib (administered orally as 2 daily intakes) at an initial dose of 4.5 mg/kg/d for 12 weeks that was then up-titrated (escalated) to a planned dose of 6.0 mg/kg/d or equivalent placebo.

    Serious adverse events
    		 Pooled Placebo Masitinib 4.5 mg/kg/d Masitinib 6.0 mg/kg/d (fixed dose) Titrated masitinib 6.0 mg/kg/d
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 226 (11.95%)
    42 / 199 (21.11%)
    6 / 27 (22.22%)
    49 / 203 (24.14%)
         number of deaths (all causes)
    2
    0
    0
    2
         number of deaths resulting from adverse events
    2
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder Papilloma
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal Proliferative Breast Lesion
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine Tumour Of The Lung
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Venous Thrombosis Limb
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait Disturbance
         subjects affected / exposed
    2 / 226 (0.88%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    1 / 27 (3.70%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal Mucosal Ulcer
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal Ulceration
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Granuloma
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar I Disorder
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed Mood
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental Disorder
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric Symptom
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 199 (1.01%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytology Abnormal
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eosinophil Count Increased
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    1 / 27 (3.70%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm Fracture
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Column Injury
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Injury
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sternal Fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Left Ventricular Failure
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple Sclerosis Relapse
         subjects affected / exposed
    5 / 226 (2.21%)
    4 / 199 (2.01%)
    0 / 27 (0.00%)
    6 / 203 (2.96%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 4
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Sclerosis
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 199 (1.01%)
    0 / 27 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplegia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    1 / 27 (3.70%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Primary Progressive Multiple Sclerosis
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 199 (1.01%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain Stem Stroke
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radicular Syndrome
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Speech Disorder
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 199 (1.01%)
    1 / 27 (3.70%)
    4 / 203 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron Deficiency Anaemia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenic Purpura
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mouth Ulceration
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    1 / 27 (3.70%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic Disorder
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tongue Ulceration
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    1 / 27 (3.70%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Face Oedema
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    2 / 27 (7.41%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accidental Death
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Generalised Oedema
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis Acute
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis Cholestatic
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mixed Liver Injury
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 226 (0.00%)
    3 / 199 (1.51%)
    0 / 27 (0.00%)
    4 / 203 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema Multiforme
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 199 (1.01%)
    1 / 27 (3.70%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    1 / 27 (3.70%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 199 (1.01%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash Generalised
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    1 / 27 (3.70%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cutaneous Vasculitis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus Ulcer
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug Eruption
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pruritus Generalised
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash Macular
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Exfoliation
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Necrosis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Ulcer
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson Syndrome
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Swelling Face
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic Epidermal Necrolysis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    1 / 27 (3.70%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic Skin Eruption
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral Stenosis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Incontinence
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Spinal Stenosis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    2 / 226 (0.88%)
    2 / 199 (1.01%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Sepsis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis Bacterial
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Cystitis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal Skin Infection
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    1 / 27 (3.70%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis Aseptic
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral Viral Infection
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 199 (0.50%)
    0 / 27 (0.00%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    0 / 27 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pooled Placebo Masitinib 4.5 mg/kg/d Masitinib 6.0 mg/kg/d (fixed dose) Titrated masitinib 6.0 mg/kg/d
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    185 / 226 (81.86%)
    188 / 199 (94.47%)
    26 / 27 (96.30%)
    184 / 203 (90.64%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 226 (5.31%)
    3 / 199 (1.51%)
    1 / 27 (3.70%)
    3 / 203 (1.48%)
         occurrences all number
    13
    4
    1
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 226 (5.75%)
    14 / 199 (7.04%)
    2 / 27 (7.41%)
    9 / 203 (4.43%)
         occurrences all number
    13
    14
    2
    10
    Oedema Peripheral
         subjects affected / exposed
    1 / 226 (0.44%)
    14 / 199 (7.04%)
    4 / 27 (14.81%)
    9 / 203 (4.43%)
         occurrences all number
    1
    15
    4
    10
    Gait Disturbance
         subjects affected / exposed
    13 / 226 (5.75%)
    10 / 199 (5.03%)
    1 / 27 (3.70%)
    2 / 203 (0.99%)
         occurrences all number
    14
    10
    1
    2
    Pyrexia
         subjects affected / exposed
    2 / 226 (0.88%)
    7 / 199 (3.52%)
    3 / 27 (11.11%)
    9 / 203 (4.43%)
         occurrences all number
    2
    8
    3
    11
    Peripheral Swelling
         subjects affected / exposed
    0 / 226 (0.00%)
    5 / 199 (2.51%)
    0 / 27 (0.00%)
    12 / 203 (5.91%)
         occurrences all number
    0
    7
    0
    14
    Asthenia
         subjects affected / exposed
    4 / 226 (1.77%)
    6 / 199 (3.02%)
    2 / 27 (7.41%)
    8 / 203 (3.94%)
         occurrences all number
    4
    6
    2
    8
    Face Oedema
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 199 (0.00%)
    2 / 27 (7.41%)
    3 / 203 (1.48%)
         occurrences all number
    0
    0
    3
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 226 (2.21%)
    11 / 199 (5.53%)
    0 / 27 (0.00%)
    9 / 203 (4.43%)
         occurrences all number
    5
    12
    0
    9
    Investigations
    Blood Triglycerides Increased
         subjects affected / exposed
    24 / 226 (10.62%)
    18 / 199 (9.05%)
    1 / 27 (3.70%)
    16 / 203 (7.88%)
         occurrences all number
    39
    25
    1
    19
    Lymphocyte Count Decreased
         subjects affected / exposed
    11 / 226 (4.87%)
    22 / 199 (11.06%)
    3 / 27 (11.11%)
    17 / 203 (8.37%)
         occurrences all number
    12
    25
    3
    21
    Alanine Aminotransferase Decreased
         subjects affected / exposed
    15 / 226 (6.64%)
    14 / 199 (7.04%)
    0 / 27 (0.00%)
    9 / 203 (4.43%)
         occurrences all number
    27
    19
    0
    14
    Haemoglobin Decreased
         subjects affected / exposed
    7 / 226 (3.10%)
    21 / 199 (10.55%)
    1 / 27 (3.70%)
    15 / 203 (7.39%)
         occurrences all number
    11
    29
    1
    18
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    10 / 226 (4.42%)
    18 / 199 (9.05%)
    1 / 27 (3.70%)
    19 / 203 (9.36%)
         occurrences all number
    11
    21
    1
    22
    Protein Total Decreased
         subjects affected / exposed
    9 / 226 (3.98%)
    18 / 199 (9.05%)
    0 / 27 (0.00%)
    11 / 203 (5.42%)
         occurrences all number
    10
    24
    0
    17
    White Blood Cell Count Decreased
         subjects affected / exposed
    5 / 226 (2.21%)
    19 / 199 (9.55%)
    0 / 27 (0.00%)
    14 / 203 (6.90%)
         occurrences all number
    7
    25
    0
    18
    Blood Phosphorus Decreased
         subjects affected / exposed
    5 / 226 (2.21%)
    24 / 199 (12.06%)
    0 / 27 (0.00%)
    7 / 203 (3.45%)
         occurrences all number
    5
    32
    0
    8
    Haematocrit Decreased
         subjects affected / exposed
    4 / 226 (1.77%)
    15 / 199 (7.54%)
    1 / 27 (3.70%)
    9 / 203 (4.43%)
         occurrences all number
    6
    22
    2
    13
    Blood Bilirubin Decreased
         subjects affected / exposed
    13 / 226 (5.75%)
    4 / 199 (2.01%)
    0 / 27 (0.00%)
    8 / 203 (3.94%)
         occurrences all number
    20
    6
    0
    11
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    13 / 226 (5.75%)
    9 / 199 (4.52%)
    1 / 27 (3.70%)
    9 / 203 (4.43%)
         occurrences all number
    14
    10
    1
    10
    Haematocrit Increased
         subjects affected / exposed
    14 / 226 (6.19%)
    3 / 199 (1.51%)
    0 / 27 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    20
    9
    0
    8
    Red Blood Cell Count Decreased
         subjects affected / exposed
    1 / 226 (0.44%)
    16 / 199 (8.04%)
    1 / 27 (3.70%)
    11 / 203 (5.42%)
         occurrences all number
    3
    18
    2
    13
    Alanine Aminotransferase Increased
         subjects affected / exposed
    7 / 226 (3.10%)
    8 / 199 (4.02%)
    1 / 27 (3.70%)
    16 / 203 (7.88%)
         occurrences all number
    7
    9
    1
    17
    Blood Cholesterol Increased
         subjects affected / exposed
    13 / 226 (5.75%)
    9 / 199 (4.52%)
    0 / 27 (0.00%)
    2 / 203 (0.99%)
         occurrences all number
    16
    14
    0
    2
    Blood Creatinine Decreased
         subjects affected / exposed
    12 / 226 (5.31%)
    10 / 199 (5.03%)
    0 / 27 (0.00%)
    6 / 203 (2.96%)
         occurrences all number
    13
    10
    0
    7
    Weight Decreased
         subjects affected / exposed
    2 / 226 (0.88%)
    9 / 199 (4.52%)
    4 / 27 (14.81%)
    10 / 203 (4.93%)
         occurrences all number
    3
    9
    4
    11
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    4 / 226 (1.77%)
    13 / 199 (6.53%)
    1 / 27 (3.70%)
    5 / 203 (2.46%)
         occurrences all number
    4
    15
    1
    6
    Blood Sodium Increased
         subjects affected / exposed
    3 / 226 (1.33%)
    11 / 199 (5.53%)
    0 / 27 (0.00%)
    4 / 203 (1.97%)
         occurrences all number
    3
    12
    0
    4
    Monocyte Count Increased
         subjects affected / exposed
    10 / 226 (4.42%)
    16 / 199 (8.04%)
    0 / 27 (0.00%)
    12 / 203 (5.91%)
         occurrences all number
    11
    19
    0
    13
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    16 / 226 (7.08%)
    13 / 199 (6.53%)
    1 / 27 (3.70%)
    6 / 203 (2.96%)
         occurrences all number
    25
    26
    1
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 226 (5.31%)
    14 / 199 (7.04%)
    2 / 27 (7.41%)
    11 / 203 (5.42%)
         occurrences all number
    21
    18
    3
    13
    Multiple Sclerosis Relapse
         subjects affected / exposed
    11 / 226 (4.87%)
    15 / 199 (7.54%)
    0 / 27 (0.00%)
    14 / 203 (6.90%)
         occurrences all number
    18
    16
    0
    17
    Muscle Spasticity
         subjects affected / exposed
    12 / 226 (5.31%)
    4 / 199 (2.01%)
    0 / 27 (0.00%)
    5 / 203 (2.46%)
         occurrences all number
    13
    4
    0
    5
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    3 / 226 (1.33%)
    11 / 199 (5.53%)
    1 / 27 (3.70%)
    13 / 203 (6.40%)
         occurrences all number
    3
    15
    2
    17
    Eosinophilia
         subjects affected / exposed
    4 / 226 (1.77%)
    5 / 199 (2.51%)
    3 / 27 (11.11%)
    5 / 203 (2.46%)
         occurrences all number
    4
    7
    3
    5
    Eye disorders
    Eyelid Oedema
         subjects affected / exposed
    1 / 226 (0.44%)
    10 / 199 (5.03%)
    5 / 27 (18.52%)
    12 / 203 (5.91%)
         occurrences all number
    1
    12
    6
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 226 (3.98%)
    29 / 199 (14.57%)
    5 / 27 (18.52%)
    17 / 203 (8.37%)
         occurrences all number
    12
    36
    8
    27
    Nausea
         subjects affected / exposed
    9 / 226 (3.98%)
    21 / 199 (10.55%)
    7 / 27 (25.93%)
    23 / 203 (11.33%)
         occurrences all number
    11
    24
    9
    29
    Vomiting
         subjects affected / exposed
    3 / 226 (1.33%)
    11 / 199 (5.53%)
    4 / 27 (14.81%)
    7 / 203 (3.45%)
         occurrences all number
    3
    14
    6
    8
    Dry Mouth
         subjects affected / exposed
    3 / 226 (1.33%)
    5 / 199 (2.51%)
    2 / 27 (7.41%)
    5 / 203 (2.46%)
         occurrences all number
    3
    5
    3
    6
    Upper Respiratory Tract Infection
         subjects affected / exposed
    11 / 226 (4.87%)
    7 / 199 (3.52%)
    0 / 27 (0.00%)
    15 / 203 (7.39%)
         occurrences all number
    11
    7
    0
    17
    Skin and subcutaneous tissue disorders
    Rash Maculo-Papular
         subjects affected / exposed
    2 / 226 (0.88%)
    15 / 199 (7.54%)
    3 / 27 (11.11%)
    15 / 203 (7.39%)
         occurrences all number
    5
    18
    5
    18
    Erythema
         subjects affected / exposed
    8 / 226 (3.54%)
    12 / 199 (6.03%)
    3 / 27 (11.11%)
    9 / 203 (4.43%)
         occurrences all number
    13
    17
    3
    10
    Rash
         subjects affected / exposed
    8 / 226 (3.54%)
    3 / 199 (1.51%)
    5 / 27 (18.52%)
    15 / 203 (7.39%)
         occurrences all number
    13
    16
    7
    18
    Pruritus
         subjects affected / exposed
    3 / 226 (1.33%)
    14 / 199 (7.04%)
    2 / 27 (7.41%)
    8 / 203 (3.94%)
         occurrences all number
    4
    17
    2
    15
    Skin Exfoliation
         subjects affected / exposed
    2 / 226 (0.88%)
    3 / 199 (1.51%)
    0 / 27 (0.00%)
    15 / 203 (7.39%)
         occurrences all number
    3
    3
    0
    22
    Rash Generalised
         subjects affected / exposed
    0 / 226 (0.00%)
    5 / 199 (2.51%)
    4 / 27 (14.81%)
    4 / 203 (1.97%)
         occurrences all number
    0
    7
    4
    4
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 199 (0.00%)
    2 / 27 (7.41%)
    0 / 203 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    14 / 226 (6.19%)
    13 / 199 (6.53%)
    1 / 27 (3.70%)
    13 / 203 (6.40%)
         occurrences all number
    15
    13
    1
    14
    Infections and infestations
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    19 / 226 (8.41%)
    28 / 199 (14.07%)
    0 / 27 (0.00%)
    19 / 203 (9.36%)
         occurrences all number
    22
    41
    0
    21
    Urinary Tract Infection
         subjects affected / exposed
    19 / 226 (8.41%)
    28 / 199 (14.07%)
    0 / 27 (0.00%)
    19 / 203 (9.36%)
         occurrences all number
    22
    41
    0
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2012
    Protocol amendments were implemented during the study with data remaining blinded throughout, i.e. no changes were data-driven. Study AB07002 initially planned to enrol patients into a 6 mg/kg/day (fixed dose) treatment-arm. However, following analysis of severe adverse event (AE) and discontinuation rates for all non-oncology clinical trials (not including the current AB07002 study), it was shown that single agent masitinib starting at a dose of 3 or 4.5 mg/kg/day had an incidence similar to placebo, whereas single agent masitinib starting at a dose of 6 mg/kg/day showed increased frequency of certain events (for example, neutropenia and skin toxicity) with respect to placebo (unpublished data). A related analysis also revealed that up-titrated (escalated) doses from 3 or 4.5 mg/kg/day to 6 mg/kg/day improved tolerability and minimized discontinuations during the first 3 months of treatment when compared with a stable starting dose of 6 mg/kg/day. Indeed, this titrated dose regimen showed a similar discontinuation rate as when maintaining a stable dose of 3 or 4.5 mg/kg/day during and after the first 3 months. An amendment to the protocol of study AB07002 was therefore an unavoidable consequence of these developments and was made with an objective to improve the benefit/risk balance. Change was implemented over two protocol versions. First, it was decided to terminate the 6 mg/kg/day (starting dose) treatment-arm (as per protocol version 5.0; May, 2012). Second, there was the addition of an independent parallel group in which patients were randomly assigned (1:2) to receive placebo or masitinib as a titrated treatment regimen, i.e. an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to a planned dose of 6.0 mg/kg/day (as per protocol version 6.0; August, 2013).
    15 Sep 2016
    Protocol amendments were implemented during the study with data remaining blinded throughout, i.e. no changes were data-driven. Study AB07002 initially planned to use the endpoint of Multiple Sclerosis Functional Composite (MSFC) for its primary analysis. However, during the study, the European Medicines Agency (EMA) ‘Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis’* was issued in which use of the Kurtzke’s Expanded Disability Status Scale (EDSS) as primary endpoint was clearly recommended. It was also stated that MSFC should be used as secondary measurement of disability. This guideline was adopted by Committee for Medicinal Products for Human Use (CHMP) in March 2015. Following this development, it was decided to change the primary analysis from an endpoint based on Multiple Sclerosis Functional Composite (MSFC) to an endpoint based on Expanded Disability Status Scale (EDSS). Analysis based on MSFC was consequently reassigned as a secondary endpoint. This change was implemented in the last protocol amendment (version 9; Sept 2016). * European Medicines Agency. Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. Committee for Medicinal Products for Human Use (CHMP). EMA/CHMP/771815/2011, Rev. 2. https://www.ema.europa.eu/en/clinical-investigation-medicinalproducts-treatment-multiple-sclerosis (accessed 09 September 2020).

    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.
    Validation of these positive findings via a confirmatory phase 3 study will be necessary, in part because neuroimaging data were not collected during the during the current study and also due to an absence of signal on secondary end points

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35190477
    http://www.ncbi.nlm.nih.gov/pubmed/22691628
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