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    Clinical Trial Results:
    Multicenter, Randomised, Double-blind, Placebo-controlled, Parallel Group, Phase 2/3 Study to Compare the Efficacy and Safety of Masitinib

    Summary
    EudraCT number
    		 2010-024423-24
    Trial protocol
    		 ES   GR   SK   IT   HU   PT   IE   NL  
    Global end of trial date
    01 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2021
    First version publication date
    16 Dec 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AB10015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02588677
    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, 0033 147200014, clinical@ab-science.com
    Scientific contact
    Clinical Study Coordinator, AB Science, 0033 147200014, 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
    05 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess masitinib as an add-on to riluzole in the treatment of ALS
    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
    		 In the European Union a drug called riluzole is the only authorized medicinal product for Amyotrophic Lateral Sclerosis (ALS). In this study, masitinib is investigated as an add-on therapy to riluzole in patients with ALS. the Investigational Medicinal Product (IMP) consisted of masitinib and its matching placebo IMP was supplied to the study Investigators or pharmacies by the Sponsor. Riluzole was not considered as being an IMP in this study and as such was not be provided by the Sponsor. A key patient inclusion criterion was that patients should be treated with a stable dose of riluzole (100 mg/day) for at least 30 days prior to screening. Thus, all patients received riluzole tablet 50 mg twice a day. The product was prepared, handled, used and stored according to standard practices and the Summary of Product Characteristics (SPC).
    Evidence for comparator
    		 In the European Union a drug called riluzole is the only authorized medicinal product for ALS. A comprehensive review by Miller and colleagues on the use of riluzole for ALS considered evidence from four randomized clinical trials involving 1477 ALS treated patients [Miller, R. G., Mitchell, J. D., Lyon, M., & Moore, D. H. (2003). Amyotrophic lateral sclerosis and other motor neuron disorders: official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases, 4(3), 191-206]. Results from this meta-analysis indicated that riluzole 100 mg probably prolongs median survival in people with ALS by 2 to 3 months with respect to participants taking placebo and the safety of the drug is not a major concern. There are no data that directly measured quality of life from the published trials. Additionally, there was no beneficial effect of riluzole on patient function in any of the randomized trials considered separately.
    Actual start date of recruitment
    08 Apr 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 155
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Argentina: 119
    Country: Number of subjects enrolled
    Italy: 75
    Country: Number of subjects enrolled
    Slovakia: 13
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Mexico: 3
    Worldwide total number of subjects
    394
    EEA total number of subjects
    264
    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)
    311
    From 65 to 84 years
    83
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were randomly assigned (1:1:1) to receive riluzole (100 mg/day) plus placebo or masitinib at 4.5 or 3.0 mg/kg/day (bis in die), with the high-dose cohort being predefined for primary analysis.

    Pre-assignment
    Screening details
    		 Eligible patients were aged 18–75 years with a laboratory-supported probable, probable, or definite diagnosis of ALS (revised El Escorial criteria), had less than 36 months duration of disease from the first ALS symptom (i.e. any progressive focal weakness or atrophy) and forced vital capacity (FVC) of at least 60% at baseline.

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    Patients were randomised using a computerised central randomization system and minimization method according to the covariates (i.e. prognostic factors) of: site of onset (spinal versus bulbar), ALSFRS-R score, age, geographical region, and post-onset ΔFS.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Masitinib 3.0 mg/kg/d
    Arm description
    		 masitinib 3 mg/kg/d administered as an add-on to riluzole
    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 3.0 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 4.5 mg/kg/d
    Arm description
    		 masitinib 4.5 mg/kg/d administered as an add-on to riluzole
    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
    		 Placebo
    Arm description
    		 placebo administered as an add-on to riluzole
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Riluzole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received daily doses of placebo, taken twice daily (morning, evening) with a meal (breakfast, dinner).

    Number of subjects in period 1
    		Masitinib 3.0 mg/kg/d Masitinib 4.5 mg/kg/d Placebo
    Started
    131
    130
    133
    Completed
    89
    83
    92
    Not completed
    42
    47
    41
         Adverse event, serious fatal
    9
    6
    9
         Adverse event, non-fatal
    7
    12
    1
         Prohibited Concomitant treatment
    2
    -
    1
         Non compliance
    2
    3
    -
         Cancer not related
    -
    1
    2
         Lost to follow-up
    -
    1
    -
         Procedure
    -
    -
    3
         Lack of efficacy
    19
    19
    15
         Protocol deviation
    2
    1
    2
         Travel
    1
    4
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Masitinib 3.0 mg/kg/d
    Reporting group description
    		 masitinib 3 mg/kg/d administered as an add-on to riluzole

    Reporting group title
    Masitinib 4.5 mg/kg/d
    Reporting group description
    		 masitinib 4.5 mg/kg/d administered as an add-on to riluzole

    Reporting group title
    Placebo
    Reporting group description
    		 placebo administered as an add-on to riluzole

    Reporting group values
    		 Masitinib 3.0 mg/kg/d Masitinib 4.5 mg/kg/d Placebo Total
    Number of subjects
    		 131 130 133 394
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 105 103 103 311
        From 65-84 years
    		 26 27 30 83
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.7 ± 10.2 55.5 ± 10.6 55.2 ± 10.6 -
    Gender categorical
    Units: Subjects
        Female
    		 50 47 53 150
        Male
    		 81 83 80 244
    ΔFS<1.1 before randomisation
    Proportion of patients with Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised progression rate (ΔFS) from disease-onset to baseline of less than 1.1 points/month
    Units: Subjects
        Yes
    		 110 103 114 327
        No
    		 21 27 19 67
    Site of onset
    Site of ALS onset (spinal versus bulbar)
    Units: Subjects
        Bulbar
    		 21 23 24 68
        Spinal
    		 110 107 109 326
    ΔFS before randomisation
    Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) progression rate from disease-onset to baseline
    Units: points/month
        arithmetic mean (standard deviation)
    		 0.65 ± 0.48 0.73 ± 0.63 0.71 ± 0.53 -
    ALSFRS-R score at baseline
    Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score at baseline
    Units: points
        arithmetic mean (standard deviation)
    		 37.4 ± 5.7 37.5 ± 5.5 38.1 ± 5.5 -
    Subject analysis sets

    Subject analysis set title
    'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    ‘Normal and Fast Progressor’ Masitinib 4.5 mg/kg/d cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    Control (placebo) for the 'Normal and Fast' M4.5 cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    ‘Normal Progressor’ Masitinib 3.0 mg/kg/d cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    Control (placebo) for the 'Normal Progressor' M3.0 cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    ‘Normal and Fast Progressor’ Masitinib 3.0 mg/kg/d cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    Control (placebo) for the 'Normal and Fast' M3.0 cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis sets values
    		 'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) Control (placebo) for the 'Normal Progressor' M4.5 cohort ‘Normal and Fast Progressor’ Masitinib 4.5 mg/kg/d cohort Control (placebo) for the 'Normal and Fast' M4.5 cohort ‘Normal Progressor’ Masitinib 3.0 mg/kg/d cohort Control (placebo) for the 'Normal Progressor' M3.0 cohort ‘Normal and Fast Progressor’ Masitinib 3.0 mg/kg/d cohort Control (placebo) for the 'Normal and Fast' M3.0 cohort
    Number of subjects
    106
    114
    130
    133
    110
    114
    131
    133
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.8 ± 10.8
    55.4 ± 10.5
    55.5 ± 10.6
    55.2 ± 10.6
    54.9 ± 10.3
    55.4 ± 10.5
    55.7 ± 10.2
    55.2 ± 10.6
    Gender categorical
    Units: Subjects
        Female
    37
    45
    47
    53
    40
    45
    50
    53
        Male
    69
    69
    83
    80
    70
    69
    81
    80
    ΔFS<1.1 before randomisation
    Proportion of patients with Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised progression rate (ΔFS) from disease-onset to baseline of less than 1.1 points/month
    Units: Subjects
        Yes
    106
    114
    106
    114
    110
    114
    110
    114
        No
    0
    0
    24
    19
    0
    0
    21
    19
    Site of onset
    Site of ALS onset (spinal versus bulbar)
    Units: Subjects
        Bulbar
    21
    24
    23
    24
    18
    24
    21
    24
        Spinal
    85
    90
    107
    109
    92
    90
    110
    109
    ΔFS before randomisation
    Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) progression rate from disease-onset to baseline
    Units: points/month
        arithmetic mean (standard deviation)
    0.49 ± 0.25
    0.49 ± 0.24
    0.73 ± 0.63
    0.71 ± 0.69
    0.48 ± 0.25
    0.49 ± 0.24
    0.65 ± 0.48
    0.71 ± 0.69
    ALSFRS-R score at baseline
    Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score at baseline
    Units: points
        arithmetic mean (standard deviation)
    38.3 ± 5.3
    39.3 ± 4.6
    37.5 ± 5.5
    38.1 ± 5.5
    38.6 ± 5.1
    39.3 ± 4.6
    37.4 ± 5.7
    38.1 ± 5.5

    End points

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    End points reporting groups
    Reporting group title
    Masitinib 3.0 mg/kg/d
    Reporting group description
    		 masitinib 3 mg/kg/d administered as an add-on to riluzole

    Reporting group title
    Masitinib 4.5 mg/kg/d
    Reporting group description
    		 masitinib 4.5 mg/kg/d administered as an add-on to riluzole

    Reporting group title
    Placebo
    Reporting group description
    		 placebo administered as an add-on to riluzole

    Subject analysis set title
    'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    ‘Normal and Fast Progressor’ Masitinib 4.5 mg/kg/d cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    Control (placebo) for the 'Normal and Fast' M4.5 cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    ‘Normal Progressor’ Masitinib 3.0 mg/kg/d cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    Control (placebo) for the 'Normal Progressor' M3.0 cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    ‘Normal and Fast Progressor’ Masitinib 3.0 mg/kg/d cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Subject analysis set title
    Control (placebo) for the 'Normal and Fast' M3.0 cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    An important prognostic factor in ALS is the ALSFRS-R progression rate from disease-onset to baseline (ΔFS) (i.e., speed of functional deterioration). Four efficacy population were therefore predefined according to masitinib dose and ΔFS, using the cut-off < 1.1 points/month to define ‘Normal Progressors’ and ≥ 1.1 points/month to define ‘Fast Progressors’. The high-dose (masitinib 4.5 mg/kg/d) ‘Normal Progressor’ cohort, and associated control cohort, was prospectively declared as the primary efficacy population (subject analysis set). The broader ‘Normal and Fast Progressor’ masitinib 4.5 mg/kg/d cohort, and corresponding ΔFS-tiered low-dose (masitinib 3.0 mg/kg/d) cohorts were predefined as secondary subject analysis sets.

    Primary: ∆ALSFRS-R (primary efficacy population of ‘Normal Progressor’ patients receiving masitinib 4.5 mg/kg/d versus Control)

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    End point title
    		 ∆ALSFRS-R (primary efficacy population of ‘Normal Progressor’ patients receiving masitinib 4.5 mg/kg/d versus Control)
    End point description
    The primary endpoint was decline in ALSFRS-R from baseline to week-48 (∆ALSFRS-R). Missing data were imputed via last observation carried forward (LOCF) methodology for those patients discontinuing because of toxicity or lack of efficacy before week 48. Any patient dying after randomization had an ALSFRS-R score of zero imputed. ∆ALSFRS-R was calculated using a model of analysis of covariance (ANCOVA), adjusted on the baseline covariates (site of onset, ALSFRS-R score, age, geographical region, and ΔFS ), expressing results as difference of least-squares means (∆LSM) between treatments (masitinib versus placebo) with corresponding 95% two-sided confidence intervals (CI) and statistical test P-value.
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Number of subjects analysed
    99 [1]
    102 [2]
    Units: points
        least squares mean (standard error)
    -9.24 ± 1.357
    -12.63 ± 1.371
    Notes
    [1] - Assessable patients for primary endpoint according to rules for missing data imputation
    [2] - Assessable patients for primary endpoint according to rules for missing data imputation
    Statistical analysis title
    		 Least squares mean difference (LSMD)
    Statistical analysis description
    Between treatment-arm difference of least-squares means difference from baseline
    Comparison groups
    'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) v Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0158
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 6.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.391
    Statistical analysis title
    		 LSMD using Jump to Reference method
    Statistical analysis description
    Sensitivity analysis on the primary efficacy endpoint using the recommended technique of jump-to-reference. This multiple imputation Jump to Reference approach imputed missing data for reason of discontinuation due to lack of efficacy or toxicity, using estimates from the control group. This is justifiable under the assumption that patients who stop taking therapy for lack of efficacy will no longer benefit from it in the future, and thus will tend to have outcomes similar to the control.
    Comparison groups
    'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) v Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Number of subjects included in analysis
    201
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0386
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 5.46
    Statistical analysis title
    		 LSMD using Multiple Imputation method
    Statistical analysis description
    Sensitivity analysis on the primary efficacy endpoint using the recommended techniques of multiple imputation and jump-to-reference. Multiple imputation is the most widely used sensitivity analysis technique and is highly recommended by all health authorities. The multiple imputation approach used is based on factors the explained maximum variability in primary endpoint.
    Comparison groups
    'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) v Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Number of subjects included in analysis
    201
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.436
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 6.33

    Secondary: Progression free survival (PFS) on the primary efficacy population of ‘Normal Progressor’ patients receiving masitinib 4.5 mg/kg/d versus Control

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    End point title
    		 Progression free survival (PFS) on the primary efficacy population of ‘Normal Progressor’ patients receiving masitinib 4.5 mg/kg/d versus Control
    End point description
    Time-to-event analysis, defined here as a deterioration of 9 points from baseline in ALSFRS-R or death. This endpoint is driven by both death and a fixed disease progression on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scale.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Number of subjects analysed
    105 [3]
    113 [4]
    Units: months
        median (confidence interval 95%)
    20 (14 to 30)
    16 (11 to 19)
    Notes
    [3] - Assessable patients for above referenced endpoint according to rules for missing data imputation
    [4] - Assessable patients for above referenced endpoint according to rules for missing data imputation
    Statistical analysis title
    		 Delay in disease progression
    Comparison groups
    'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) v Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0159
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: ΔALSAQ-40

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    End point title
    		 ΔALSAQ-40
    End point description
    Change from baseline in ALS Assessment Questionnaire 40-item (ALSAQ-40) score. (Jenkinson C, Fitzpatrick R, Brennan C, Swash M. Evidence for the validity and reliability of the ALS assessment questionnaire: the ALSAQ-40. Amyotroph Lateral Scler Other Motor Neuron Disord 1999; 1: 33–40)
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Number of subjects analysed
    99
    102
    Units: points
        least squares mean (standard error)
    19.42 ± 2.818
    27.18 ± 2.847
    Statistical analysis title
    		 Least squares mean difference (LSMD)
    Statistical analysis description
    Between treatment-arm difference of least-squares means difference from baseline
    Comparison groups
    'Normal Progressor' Masitinib 4.5 mg/kg/d (Primary Population) v Control (placebo) for the 'Normal Progressor' M4.5 cohort
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0078
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.45
         upper limit
    		 -2.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.888

    Other pre-specified: ∆ALSFRS-R (secondary analysis set of ‘Normal and Fast Progressor’ patients receiving masitinib 4.5 mg/kg/d versus Control)

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    End point title
    		 ∆ALSFRS-R (secondary analysis set of ‘Normal and Fast Progressor’ patients receiving masitinib 4.5 mg/kg/d versus Control)
    End point description
    ∆ALSFRS-R for predefined secondary analysis set (step 2: efficacy analyses conducted using a stepwise fixed sequence method to control the global family-wise error rate at the 0.05 level for the primary analysis). Missing data were imputed via last observation carried forward (LOCF) methodology for those patients discontinuing because of toxicity or lack of efficacy before week 48. Any patient dying after randomization had an ALSFRS-R score of zero imputed. ∆ALSFRS-R was calculated using a model of analysis of covariance (ANCOVA), adjusted on the baseline covariates (site of onset, ALSFRS-R score, age, geographical region, and ΔFS), expressing results as difference of least-squares means (∆LSM) between treatments (masitinib versus placebo) with corresponding 95% two-sided confidence intervals (CI) and statistical test P-value.
    End point type
    Other pre-specified
    End point timeframe
    48 weeks
    End point values
    		 ‘Normal and Fast Progressor’ Masitinib 4.5 mg/kg/d cohort Control (placebo) for the 'Normal and Fast' M4.5 cohort
    Number of subjects analysed
    120 [5]
    119 [6]
    Units: points
        least squares mean (standard error)
    -10.89 ± 1.411
    -12.97 ± 1.42
    Notes
    [5] - Assessable patients for above referenced endpoint according to rules for missing data imputation
    [6] - Assessable patients for above referenced endpoint according to rules for missing data imputation
    Statistical analysis title
    		 Least squares mean difference
    Statistical analysis description
    Between treatment-arm difference of least-squares means difference from baseline
    Comparison groups
    Control (placebo) for the 'Normal and Fast' M4.5 cohort v ‘Normal and Fast Progressor’ Masitinib 4.5 mg/kg/d cohort
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1202
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 4.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.339

    Other pre-specified: ∆ALSFRS-R (secondary analysis set of ‘Normal Progressor’ patients receiving masitinib 3.0 mg/kg/d versus Control)

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    End point title
    		 ∆ALSFRS-R (secondary analysis set of ‘Normal Progressor’ patients receiving masitinib 3.0 mg/kg/d versus Control)
    End point description
    ∆ALSFRS-R for predefined secondary analysis set (step 3: efficacy analyses conducted using a stepwise fixed sequence method to control the global family-wise error rate at the 0.05 level for the primary analysis). Missing data were imputed via last observation carried forward (LOCF) methodology for those patients discontinuing because of toxicity or lack of efficacy before week 48. Any patient dying after randomization had an ALSFRS-R score of zero imputed. ∆ALSFRS-R was calculated using a model of analysis of covariance (ANCOVA), adjusted on the baseline covariates (site of onset, ALSFRS-R score, age, geographical region, and ΔFS), expressing results as difference of least-squares means (∆LSM) between treatments (masitinib versus placebo) with corresponding 95% two-sided confidence intervals (CI) and statistical test P-value.
    End point type
    Other pre-specified
    End point timeframe
    48 weeks
    End point values
    		 ‘Normal Progressor’ Masitinib 3.0 mg/kg/d cohort Control (placebo) for the 'Normal Progressor' M3.0 cohort
    Number of subjects analysed
    106 [7]
    102 [8]
    Units: points
        least squares mean (standard error)
    -8.61 ± 1.478
    -11.34 ± 1.430
    Notes
    [7] - Assessable patients for above referenced endpoint according to rules for missing data imputation
    [8] - Assessable patients for above referenced endpoint according to rules for missing data imputation
    Statistical analysis title
    		 Least squares mean difference
    Statistical analysis description
    Between treatment-arm difference of least-squares means difference from baseline
    Comparison groups
    ‘Normal Progressor’ Masitinib 3.0 mg/kg/d cohort v Control (placebo) for the 'Normal Progressor' M3.0 cohort
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0661
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 5.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.478

    Other pre-specified: ∆ALSFRS-R (secondary analysis set of ‘Normal and Fast Progressor’ patients receiving masitinib 3.0 mg/kg/d versus Control)

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    End point title
    		 ∆ALSFRS-R (secondary analysis set of ‘Normal and Fast Progressor’ patients receiving masitinib 3.0 mg/kg/d versus Control)
    End point description
    ∆ALSFRS-R for predefined secondary analysis set (step 4: efficacy analyses conducted using a stepwise fixed sequence method to control the global family-wise error rate at the 0.05 level for the primary analysis). Missing data were imputed via last observation carried forward (LOCF) methodology for those patients discontinuing because of toxicity or lack of efficacy before week 48. Any patient dying after randomization had an ALSFRS-R score of zero imputed. ∆ALSFRS-R was calculated using a model of analysis of covariance (ANCOVA), adjusted on the baseline covariates (site of onset, ALSFRS-R score, age, geographical region, and ΔFS), expressing results as difference of least-squares means (∆LSM) between treatments (masitinib versus placebo) with corresponding 95% two-sided confidence intervals (CI) and statistical test P-value.
    End point type
    Other pre-specified
    End point timeframe
    48 weeks
    End point values
    		 ‘Normal and Fast Progressor’ Masitinib 3.0 mg/kg/d cohort Control (placebo) for the 'Normal and Fast' M3.0 cohort
    Number of subjects analysed
    119 [9]
    126 [10]
    Units: points
        least squares mean (standard error)
    -10.27 ± 1.448
    -12.07 ± 1.409
    Notes
    [9] - Assessable patients for above referenced endpoint according to rule for missing data imputation
    [10] - Assessable patients for above referenced endpoint according to rules for missing data imputation
    Statistical analysis title
    		 Least squares mean difference
    Statistical analysis description
    Between treatment-arm difference of least-squares means difference from baseline
    Comparison groups
    ‘Normal and Fast Progressor’ Masitinib 3.0 mg/kg/d cohort v Control (placebo) for the 'Normal and Fast' M3.0 cohort
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1918
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 4.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.375

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to week-48
    Adverse event reporting additional description
    Adverse events (AE) were recorded until 28 days after treatment interruption with any AE not resolved at the death of the patients recorded as an AE leading to death. 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
    Placebo
    Reporting group description
    		 Placebo plus riluzole

    Reporting group title
    Masitinib 4.5 mg/kg/d
    Reporting group description
    		 Masitinib 4.5 mg/kg/day plus riluzole

    Reporting group title
    Masitinib 3.0 mg/kg/d
    Reporting group description
    		 Masitinib 3.0 mg/kg/day plus riluzole

    Serious adverse events
    		 Placebo Masitinib 4.5 mg/kg/d Masitinib 3.0 mg/kg/d
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 133 (27.07%)
    50 / 129 (38.76%)
    28 / 131 (21.37%)
         number of deaths (all causes)
    12
    10
    11
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural Mesothelioma
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Wisdom Teeth Removal
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Euthanasia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory Failure
         subjects affected / exposed
    6 / 133 (4.51%)
    13 / 129 (10.08%)
    8 / 131 (6.11%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 13
    0 / 9
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    0 / 4
    Dyspnoea
         subjects affected / exposed
    1 / 133 (0.75%)
    4 / 129 (3.10%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Chronic Respiratory Failure
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Obstructive Airways Disorder
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory Arrest
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Increased Bronchial Secretion
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic Attack
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Transaminases Increased
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 129 (1.55%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 129 (0.78%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration Bronchial
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin T Increased
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urine Cytology Abnormal
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 129 (1.55%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face Injury
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scapula Fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 129 (0.78%)
    4 / 131 (3.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Myocardial Infarction
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain Oedema
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amyotrophic Lateral Sclerosis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain Injury
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cauda Equina Syndrome
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle Spasticity
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercapnic Coma
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Microcytic Anaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normochromic Normocytic Anaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    9 / 133 (6.77%)
    11 / 129 (8.53%)
    14 / 131 (10.69%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal Haemorrhage
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 133 (2.26%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis Bacterial
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection Viral
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug Reaction With Eosinophilia And Systemic Symptoms
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dry Skin
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical Urticaria
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pruritus Generalised
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash Generalised
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash Maculo-Papular
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seborrhoeic Dermatitis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic Skin Eruption
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 129 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 129 (1.55%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 133 (1.50%)
    2 / 129 (1.55%)
    2 / 131 (1.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis Haemophilus
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral Candidiasis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal Candidiasis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 129 (0.78%)
    0 / 131 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Masitinib 4.5 mg/kg/d Masitinib 3.0 mg/kg/d
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 133 (57.89%)
    114 / 129 (88.37%)
    30 / 131 (22.90%)
    Investigations
    Weight Decreased
         subjects affected / exposed
    10 / 133 (7.52%)
    11 / 129 (8.53%)
    12 / 131 (9.16%)
         occurrences all number
    10
    11
    12
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    9 / 133 (6.77%)
    11 / 129 (8.53%)
    8 / 131 (6.11%)
         occurrences all number
    10
    12
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 133 (6.02%)
    9 / 129 (6.98%)
    6 / 131 (4.58%)
         occurrences all number
    10
    10
    7
    Blood and lymphatic system disorders
    Iron Deficiency Anaemia
         subjects affected / exposed
    1 / 133 (0.75%)
    9 / 129 (6.98%)
    3 / 131 (2.29%)
         occurrences all number
    1
    9
    3
    General disorders and administration site conditions
    Oedema Peripheral
         subjects affected / exposed
    1 / 133 (0.75%)
    9 / 129 (6.98%)
    7 / 131 (5.34%)
         occurrences all number
    1
    10
    8
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 133 (4.51%)
    16 / 129 (12.40%)
    9 / 131 (6.87%)
         occurrences all number
    6
    17
    10
    Diarrhoea
         subjects affected / exposed
    6 / 133 (4.51%)
    10 / 129 (7.75%)
    10 / 131 (7.63%)
         occurrences all number
    6
    12
    12
    Dyspepsia
         subjects affected / exposed
    3 / 133 (2.26%)
    9 / 129 (6.98%)
    3 / 131 (2.29%)
         occurrences all number
    3
    10
    4
    Abdominal Pain Upper
         subjects affected / exposed
    3 / 133 (2.26%)
    8 / 129 (6.20%)
    4 / 131 (3.05%)
         occurrences all number
    3
    9
    5
    Dysphagia
         subjects affected / exposed
    7 / 133 (5.26%)
    6 / 129 (4.65%)
    4 / 131 (3.05%)
         occurrences all number
    7
    6
    4
    Skin and subcutaneous tissue disorders
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 133 (0.00%)
    11 / 129 (8.53%)
    6 / 131 (4.58%)
         occurrences all number
    0
    14
    7
    Rash
         subjects affected / exposed
    4 / 133 (3.01%)
    10 / 129 (7.75%)
    2 / 131 (1.53%)
         occurrences all number
    4
    10
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    9 / 133 (6.77%)
    11 / 129 (8.53%)
    12 / 131 (9.16%)
         occurrences all number
    9
    11
    12
    Insomnia
         subjects affected / exposed
    6 / 133 (4.51%)
    5 / 129 (3.88%)
    9 / 131 (6.87%)
         occurrences all number
    6
    5
    9
    Anxiety
         subjects affected / exposed
    1 / 133 (0.75%)
    7 / 129 (5.43%)
    5 / 131 (3.82%)
         occurrences all number
    1
    7
    5
    Infections and infestations
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 133 (4.51%)
    7 / 129 (5.43%)
    9 / 131 (6.87%)
         occurrences all number
    6
    7
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jul 2013
    Protocol amendments were implemented during the study with data remaining blinded throughout, i.e. no changes were data-driven. There were two key amendments: including a non-premeditated passage from a phase 2 to a demonstrative phase 2/3 design, requiring appropriate adjustment in sample size and statistical hypothesis (amendment dated 02 July 2013 following recruitment of 34/394 (9%) patients, of which none had completed the 48-week treatment period).
    08 Oct 2014
    Protocol amendments were implemented during the study with data remaining blinded throughout, i.e. no changes were data-driven. There were two key amendments including implementation of a prospectively tiered design based on aggressiveness phenotype (amendment dated 08 October 2014 following recruitment of 142/394 (36%) patients, of which 46/394 (12%) had completed the 48-week treatment period). This amendment involved categorization of patients according to ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised) progression rate (ΔFS), calculated from disease-onset to baseline with a dichotomizing cut-off at 1.1 points/month. Accordingly, patients receiving masitinib 4.5 mg/kg/day with post-onset ΔFS<1.1 points/month (comprising an estimated 84% of the ALS population) were predefined as the primary efficacy population. All necessary information was available from patient records, meaning no retrospective data-collection was necessary, with stratification (minimization algorithm) implemented for the remaining (64%) patient recruitment to ensure balanced treatment-arms. This prospectively defined two-tiered approach defines a more homogenous target population (primary analysis), reducing variability and therefore sample size requirements, while concurrently permitting evaluation (secondary analysis) of the broader, more heterogeneous population. The rationale for this amendment assumed that heterogeneity in ALS disease aggressiveness reflects differing disease mechanisms, with dysregulated immunity being one possibly factor, leading to an unpredictable and likely divergent treatment-effect across the overall population. Furthermore, the right-skewed (positive-skew) characteristic of ΔFS histogram distributions was a common observation in clinical practice.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31280619
    http://www.ncbi.nlm.nih.gov/pubmed/34457038
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