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    Clinical Trial Results:
    A phase II, multicentre, randomised, double-blind, parallel group, placebo-controlled, dose-finding study to evaluate the safety and efficacy of three different oral doses of MT-1303 administered for a period of 24 weeks in subjects with relapsing remitting multiple sclerosis

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2012-002470-31
    Trial protocol
    		 GB   LT   CZ   HU   FI   BE   IT   PL   BG   ES  
    Global end of trial date
    23 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jul 2016
    First version publication date
    27 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MT-1303-E04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01742052
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Momentum Study: MT-1303-E04
    Sponsors
    Sponsor organisation name
    Mitsubishi Tanabe Pharma Corporation
    Sponsor organisation address
    17-10, Nihonbashi-Koamicho, Chuo-ku, Tokyo, Japan, 103-8405
    Public contact
    General Information, Mitsubishi Tanabe Pharma Europe Ltd., regulatory@mt-pharma-eu.com
    Scientific contact
    General Information, Mitsubishi Tanabe Pharma Europe Ltd., regulatory@mt-pharma-eu.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
    17 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to evaluate the effects of three oral doses of MT-1303 compared to placebo given for a period of 24 weeks in subjects with relapsing-remitting multiple sclerosis (RRMS) on MRI parameters. It is also to evaluate the safety and tolerability of three oral doses of MT-1303 compared to placebo given for a period of 24 weeks in subjects with RRMS.
    Protection of trial subjects
    Subjects will be permanently withdrawn from study medication in the following circumstances: • Confirmed absolute lymphocyte count values <200/μL, on 2 consecutive occasions • Documented relapse of MS symptoms; or new or exacerbation of pre-existing conditions requiring treatment with one or more prohibited medications • Development of any clinically significant abnormalities on ECG, including but not limited to: Symptomatic bradycardia; New onset 2nd degree AV block, Mobitz Type II; New onset 3rd degree AV block; Confirmed QTcF interval prolongation >500msec and/or QTcF interval increase from baseline >60msec • Development of any clinically significant liver dysfunction as follows: o ALT or AST > 8 × ULN, or o ALT or AST >5 × ULN and persists for more than 2 consecutive visits, or o ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or o ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%) • Development of macular oedema during the study • Recurrence of the abnormality at re-challenge • Interruption to study medication lasting more than 14 days. In addition, a subject may voluntarily withdraw or be permanently withdrawn from the study at any time for reasons including, but not limited to, the following: • The subject wishes to withdraw from further participation • The subject is non-compliant with the protocol • The treatment blind is broken for the subject for the reasons other than regulatory reporting • Continuation in the study would be detrimental to the subject’s safety in the opinion of the Investigator • Pregnancy • The Investigator or the Sponsor, for any reason, stops the study
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2013
    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
    Poland: 84
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Bulgaria: 64
    Country: Number of subjects enrolled
    Czech Republic: 59
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    Serbia: 30
    Country: Number of subjects enrolled
    Turkey: 21
    Country: Number of subjects enrolled
    Ukraine: 30
    Worldwide total number of subjects
    415
    EEA total number of subjects
    304
    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)
    415
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 415 subjects randomised across 84 sites in 17 countries (BEL, BUL, CAN, HRZ, CZE, FIN, GER, HUN, ITA, LIT, POL, RUS, SER, ESP, TUR, UKR, GBR). FSFV (screen) 31 Jan 13, LSI (screen) 24 Dec 13. FSFV (randomised) 01 Mar 13. LSI (randomised) 15 Feb 14. Conducted in university/public/private hospitals and specialised multiple sclerosis care practices.

    Pre-assignment
    Screening details
    		 Up to 6 week screening period

    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, Assessor
    Blinding implementation details
    Lymphotcyte count and WBC differential were not provided to any site/study personel except the Unblinded Independent Monitor to maintain the study medication blind. PK results were not provided by the PK lab until after database lock. MT-1303/placebo capsules appeared the same and same number of capsules were given.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Once daily oral placebo capsules taken from Baseline Week 0 to End of Treatment
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule, containing placebo taken orally daily for 24 weeks.

    Arm title
    		 MT-1303 0.1 mg
    Arm description
    		 Once daily oral MT-1303 0.1mg capsules taken from Baseline Week 0 to End of Treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-1303
    Investigational medicinal product code
    MT-1303
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule, containing MT-1303 0.1mg taken orally daily for 24 weeks.

    Arm title
    		 MT-1303 0.2mg
    Arm description
    		 Once daily oral MT-1303 0.2mg capsules taken from Baseline Week 0 to End of Treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-1303
    Investigational medicinal product code
    MT-1303
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule, containing MT-1303 0.2mg taken orally daily for 24 weeks.

    Arm title
    		 MT-1303 0.4mg
    Arm description
    		 Once daily oral MT-1303 0.4mg capsules taken from Baseline Week 0 to End of Treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    MT-1303
    Investigational medicinal product code
    MT-1303
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule, containing MT-1303 0.4mg taken orally daily for 24 weeks.

    Number of subjects in period 1
    		Placebo MT-1303 0.1 mg MT-1303 0.2mg MT-1303 0.4mg
    Started
    103
    105
    103
    104
    Completed
    96
    96
    95
    94
    Not completed
    7
    9
    8
    10
         Consent withdrawn by subject
    1
    4
    4
    2
         Adverse event, non-fatal
    2
    2
    1
    4
         Other
    1
    1
    1
    1
         Protocol Specified
    3
    2
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Once daily oral placebo capsules taken from Baseline Week 0 to End of Treatment

    Reporting group title
    MT-1303 0.1 mg
    Reporting group description
    		 Once daily oral MT-1303 0.1mg capsules taken from Baseline Week 0 to End of Treatment

    Reporting group title
    MT-1303 0.2mg
    Reporting group description
    		 Once daily oral MT-1303 0.2mg capsules taken from Baseline Week 0 to End of Treatment

    Reporting group title
    MT-1303 0.4mg
    Reporting group description
    		 Once daily oral MT-1303 0.4mg capsules taken from Baseline Week 0 to End of Treatment

    Reporting group values
    		 Placebo MT-1303 0.1 mg MT-1303 0.2mg MT-1303 0.4mg Total
    Number of subjects
    		 103 105 103 104 415
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 103 105 103 104 415
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.2 ( 8.54 ) 37.2 ( 9.42 ) 38 ( 9.61 ) 37.6 ( 8.66 ) -
    Gender categorical
    Units: Subjects
        Female
    		 67 69 73 72 281
        Male
    		 36 36 30 32 134
    Baseline EDSS Score
    Expanded Disability Status Scale (EDSS) score taken during screening
    Units: No Unit
        arithmetic mean (standard deviation)
    		 2.7 ( 1.309 ) 2.88 ( 1.296 ) 2.77 ( 1.272 ) 2.61 ( 1.338 ) -
    Subject analysis sets

    Subject analysis set title
    Evaluable Population-placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects that received at least one dose of study medication (Placebo) who do not have any major protocol deviations, do not discontinue study medication prematurely and have at least 3 valid post-dose MRI scans

    Subject analysis set title
    Evaluable Population-0.1 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects that received at least one dose of study medication (MT-1303 0.1mg) who do not have any major protocol deviations, do not discontinue study medication prematurely and have at least 3 valid post-dose MRI scans

    Subject analysis set title
    Evaluable Population-0.2 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects that received at least one dose of study medication (MT-1303 0.2mg) who do not have any major protocol deviations, do not discontinue study medication prematurely and have at least 3 valid post-dose MRI scans

    Subject analysis set title
    Evaluable Population-0.4 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects that received at least one dose of study medication (MT-1303 0.4mg) who do not have any major protocol deviations, do not discontinue study medication prematurely and have at least 3 valid post-dose MRI scans

    Subject analysis set title
    ITT-placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of study medication (placebo) and have at least one post-dose efficacy assessment. Subjects will be analyzed according to treatment assignment regardless of whether the subject receives any study treatment or the wrong treatment.

    Subject analysis set title
    ITT-0.1 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of study medication (MT-1303 0.1mg) and have at least one post-dose efficacy assessment. Subjects will be analyzed according to treatment assignment regardless of whether the subject receives any study treatment or the wrong treatment.

    Subject analysis set title
    ITT-0.2 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of study medication (MT-1303 0.2mg) and have at least one post-dose efficacy assessment. Subjects will be analyzed according to treatment assignment regardless of whether the subject receives any study treatment or the wrong treatment.

    Subject analysis set title
    ITT-0.4 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of study medication (MT-1303 0.4mg) and have at least one post-dose efficacy assessment. Subjects will be analyzed according to treatment assignment regardless of whether the subject receives any study treatment or the wrong treatment.

    Subject analysis sets values
    		 Evaluable Population-placebo Evaluable Population-0.1 mg Evaluable Population-0.2 mg Evaluable Population-0.4 mg ITT-placebo ITT-0.1 mg ITT-0.2 mg ITT-0.4 mg
    Number of subjects
    94
    95
    94
    94
    103
    105
    103
    104
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    94
    95
    94
    94
    103
    105
    103
    104
        From 65-84 years
    0
    0
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.6 ( 8.52 )
    37.3 ( 9.66 )
    38.2 ( 9.81 )
    37.3 ( 8.53 )
    37.2 ( 8.54 )
    37.2 ( 9.42 )
    38 ( 9.61 )
    37.6 ( 8.66 )
    Gender categorical
    Units: Subjects
        Female
    62
    67
    65
    64
    67
    69
    73
    72
        Male
    32
    28
    29
    30
    36
    36
    30
    32
    Baseline EDSS Score
    Expanded Disability Status Scale (EDSS) score taken during screening
    Units: No Unit
        arithmetic mean (standard deviation)
    2.68 ( 1.287 )
    2.85 ( 1.303 )
    2.74 ( 1.315 )
    2.52 ( 1.29 )
    2.7 ( 1.309 )
    2.88 ( 1.296 )
    2.77 ( 1.272 )
    2.61 ( 1.338 )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Once daily oral placebo capsules taken from Baseline Week 0 to End of Treatment

    Reporting group title
    MT-1303 0.1 mg
    Reporting group description
    		 Once daily oral MT-1303 0.1mg capsules taken from Baseline Week 0 to End of Treatment

    Reporting group title
    MT-1303 0.2mg
    Reporting group description
    		 Once daily oral MT-1303 0.2mg capsules taken from Baseline Week 0 to End of Treatment

    Reporting group title
    MT-1303 0.4mg
    Reporting group description
    		 Once daily oral MT-1303 0.4mg capsules taken from Baseline Week 0 to End of Treatment

    Subject analysis set title
    Evaluable Population-placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects that received at least one dose of study medication (Placebo) who do not have any major protocol deviations, do not discontinue study medication prematurely and have at least 3 valid post-dose MRI scans

    Subject analysis set title
    Evaluable Population-0.1 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects that received at least one dose of study medication (MT-1303 0.1mg) who do not have any major protocol deviations, do not discontinue study medication prematurely and have at least 3 valid post-dose MRI scans

    Subject analysis set title
    Evaluable Population-0.2 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects that received at least one dose of study medication (MT-1303 0.2mg) who do not have any major protocol deviations, do not discontinue study medication prematurely and have at least 3 valid post-dose MRI scans

    Subject analysis set title
    Evaluable Population-0.4 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects that received at least one dose of study medication (MT-1303 0.4mg) who do not have any major protocol deviations, do not discontinue study medication prematurely and have at least 3 valid post-dose MRI scans

    Subject analysis set title
    ITT-placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of study medication (placebo) and have at least one post-dose efficacy assessment. Subjects will be analyzed according to treatment assignment regardless of whether the subject receives any study treatment or the wrong treatment.

    Subject analysis set title
    ITT-0.1 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of study medication (MT-1303 0.1mg) and have at least one post-dose efficacy assessment. Subjects will be analyzed according to treatment assignment regardless of whether the subject receives any study treatment or the wrong treatment.

    Subject analysis set title
    ITT-0.2 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of study medication (MT-1303 0.2mg) and have at least one post-dose efficacy assessment. Subjects will be analyzed according to treatment assignment regardless of whether the subject receives any study treatment or the wrong treatment.

    Subject analysis set title
    ITT-0.4 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of study medication (MT-1303 0.4mg) and have at least one post-dose efficacy assessment. Subjects will be analyzed according to treatment assignment regardless of whether the subject receives any study treatment or the wrong treatment.

    Primary: Total Number of Gd-Enhanced T1-weighted Lesions across Weeks 8-24

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    End point title
    		 Total Number of Gd-Enhanced T1-weighted Lesions across Weeks 8-24
    End point description
    This endpoint is regarded as a countable end point however in order to present the summary statistics in the database it has been entered as a measurable endpoint. The measure type should be Incidence Rate and the point estimate parameter type should be Incidence Rate Ratio however the database does not allow these options.
    End point type
    Primary
    End point timeframe
    Week 8 - Week 24
    End point values
    		 Evaluable Population-placebo Evaluable Population-0.1 mg Evaluable Population-0.2 mg Evaluable Population-0.4 mg
    Number of subjects analysed
    94
    95
    94
    94
    Units: number of lesions
        least squares mean (confidence interval 95%)
    5.04 (3.6 to 7)
    2.69 (1.9 to 3.7)
    1.97 (1.4 to 2.8)
    1.16 (0.8 to 1.7)
    Statistical analysis title
    		 No. T1-weighted lesions 8-24 wks 0.1mg vs placebo
    Statistical analysis description
    "P-values based on Negative Binomial model using log link with total (cumulative) Gd-enhanced T1-weighted lesions over Wks 8 -24 as the response variable. The independent variables are baseline number of Gd-enhanced T1-weighted lesions, treatment and pooled centre.
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.1 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.8
    Statistical analysis title
    		 No. T1-weighted lesions 8-24 wks 0.2mg vs placebo
    Statistical analysis description
    "P-values based on Negative Binomial model using log link with total (cumulative) Gd-enhanced T1-weighted lesions over Wks 8 -24 as the response variable. The independent variables are baseline number of Gd-enhanced T1-weighted lesions, treatment and pooled centre.
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.2 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.6
    Statistical analysis title
    		 No. T1-weighted lesions 8-24 wks 0.4mg vs placebo
    Statistical analysis description
    "P-values based on Negative Binomial model using log link with total (cumulative) Gd-enhanced T1-weighted lesions over Wks 8 -24 as the response variable. The independent variables are baseline number of Gd-enhanced T1-weighted lesions, treatment and pooled centre.
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.4 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.4

    Secondary: Total Numbers of Gd-Enhanced T1-weighted Lesions across Weeks 4-24

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    End point title
    		 Total Numbers of Gd-Enhanced T1-weighted Lesions across Weeks 4-24
    End point description
    This endpoint is regarded as a countable end point however in order to present the summary statistics in the database it has been entered as a measurable endpoint. The measure type should be Incidence Rate and the point estimate parameter type should be Incidence Rate Ratio however the database does not allow these options.
    End point type
    Secondary
    End point timeframe
    Weeks 4 - 24
    End point values
    		 Evaluable Population-placebo Evaluable Population-0.1 mg Evaluable Population-0.2 mg Evaluable Population-0.4 mg
    Number of subjects analysed
    94
    95
    94
    94
    Units: number of lesions
        least squares mean (confidence interval 95%)
    5.8 (4.2 to 8)
    3.54 (2.6 to 4.9)
    3.28 (2.4 to 4.6)
    1.93 (1.4 to 2.7)
    Statistical analysis title
    		 No. T1-weighted lesions 4-24 wks 0.1mg vs placebo
    Statistical analysis description
    "P-values are based on a Negative Binomial model using log link with total (cumulative) Gd-enhanced T1-weighted lesions over weeks 4, 8, 12, 16, 20, and 24 as the response variable. The independent variables are baseline number of Gd-enhanced T1-weighted lesions, treatment and pooled centre
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.1 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1
    Statistical analysis title
    		 No. T1-weighted lesions 4-24 wks 0.2mg vs placebo
    Statistical analysis description
    "P-values are based on a Negative Binomial model using log link with total (cumulative) Gd-enhanced T1-weighted lesions over weeks 4, 8, 12, 16, 20, and 24 as the response variable. The independent variables are baseline number of Gd-enhanced T1-weighted lesions, treatment and pooled centre
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.2 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.018
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.9
    Statistical analysis title
    		 No. T1-weighted lesions 4-24 wks 0.4mg vs placebo
    Statistical analysis description
    "P-values are based on a Negative Binomial model using log link with total (cumulative) Gd-enhanced T1-weighted lesions over weeks 4, 8, 12, 16, 20, and 24 as the response variable. The independent variables are baseline number of Gd-enhanced T1-weighted lesions, treatment and pooled centre
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.4 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.5

    Secondary: Total Number of New or Enlarged T2-weighted Lesions across Weeks 4-24

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    End point title
    		 Total Number of New or Enlarged T2-weighted Lesions across Weeks 4-24
    End point description
    This endpoint is regarded as a countable end point however in order to present the summary statistics in the database it has been entered as a measurable endpoint. The measure type should be Incidence Rate and the point estimate parameter type should be Incidence Rate Ratio however the database does not allow these options.
    End point type
    Secondary
    End point timeframe
    Weeks 4 -24
    End point values
    		 Evaluable Population-placebo Evaluable Population-0.1 mg Evaluable Population-0.2 mg Evaluable Population-0.4 mg
    Number of subjects analysed
    94
    95
    94
    94
    Units: number of lesions
        least squares mean (confidence interval 95%)
    10.08 (7.1 to 14.3)
    7.62 (5.3 to 10.9)
    4.57 (3.2 to 6.5)
    3.13 (2.2 to 4.5)
    Statistical analysis title
    		 No. T2-weighted lesions 4-24 wks 0.1mg vs placebo
    Statistical analysis description
    "Total number of new or enlarged T2 weighted lesions across weeks 4-24 versus placebo. P-values are based on a Negative Binomial model using log link with total (cumulative) number of new or enlarged T2-weighted lesions over weeks 4, 8, 12, 16, 20, and 24 as the response variable. The independent variables are treatment and pooled centre.
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.1 mg
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.272
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.2
    Statistical analysis title
    		 No. T2-weighted lesions 4-24 wks 0.2mg vs placebo
    Statistical analysis description
    "Total number of new or enlarged T2 weighted lesions across weeks 4-24 versus placebo. P-values are based on a Negative Binomial model using log link with total (cumulative) number of new or enlarged T2-weighted lesions over weeks 4, 8, 12, 16, 20, and 24 as the response variable. The independent variables are treatment and pooled centre.
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.2 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.7
    Statistical analysis title
    		 No. T2-weighted lesions 4-24 wks 0.4mg vs placebo
    Statistical analysis description
    "Total number of new or enlarged T2 weighted lesions across weeks 4-24 versus placebo. P-values are based on a Negative Binomial model using log link with total (cumulative) number of new or enlarged T2-weighted lesions over weeks 4, 8, 12, 16, 20, and 24 as the response variable. The independent variables are treatment and pooled centre.
    Comparison groups
    Evaluable Population-placebo v Evaluable Population-0.4 mg
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.5

    Secondary: Annualised Relapse Rate (ARR) at Week 24

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    End point title
    		 Annualised Relapse Rate (ARR) at Week 24
    End point description
    This endpoint is regarded as a countable end point however in order to present the summary statistics in the database it has been entered as a measurable endpoint. The measure type should be Incidence Rate and the point estimate parameter type should be Incidence Rate Ratio however the database does not allow these options.
    End point type
    Secondary
    End point timeframe
    Week 0 - 24
    End point values
    		 ITT-placebo ITT-0.1 mg ITT-0.2 mg ITT-0.4 mg
    Number of subjects analysed
    103
    105
    103
    104
    Units: Relapses/year
        least squares mean (confidence interval 95%)
    0.42979 (0.2104 to 0.8778)
    0.35467 (0.1732 to 0.7263)
    0.42316 (0.1977 to 0.9059)
    0.07834 (0.0311 to 0.1975)
    Statistical analysis title
    		 Annualised Relapse Rate MT-1303 0.1mg vs placebo
    Statistical analysis description
    "P-values are based on a Negative Binomial model using log link with individual annualised relapse rate as the response variable. The independent variables are number of relapses in the 12 months prior to the study, treatment and pooled centre.
    Comparison groups
    ITT-placebo v ITT-0.1 mg
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.706
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.82521
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3044
         upper limit
    		 2.2368
    Statistical analysis title
    		 Annualised Relapse Rate MT-1303 0.2mg vs placebo
    Statistical analysis description
    "P-values are based on a Negative Binomial model using log link with individual annualised relapse rate as the response variable. The independent variables are number of relapses in the 12 months prior to the study, treatment and pooled centre.
    Comparison groups
    ITT-placebo v ITT-0.2 mg
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.977
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.98457
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3382
         upper limit
    		 2.866
    Statistical analysis title
    		 Annualised Relapse Rate MT-1303 0.4mg vs placebo
    Statistical analysis description
    "P-values are based on a Negative Binomial model using log link with individual annualised relapse rate as the response variable. The independent variables are number of relapses in the 12 months prior to the study, treatment and pooled centre.
    Comparison groups
    ITT-placebo v ITT-0.4 mg
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Negative Binomial Regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    0.18227
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0559
         upper limit
    		 0.5938

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start of double-blind treatment to end of 12 week follow-up period. Treatment-Emergent AEs were defined as those which started or worsened in severity after the first dose of double-blind study medication.
    Adverse event reporting additional description
    During the study visits regular questioning of each subject by study staff. No leading questions were asked. Data recorded under "Non-Serious Adverse Events" also includes serious adverse events as that is how data was reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Once daily oral placebo capsules taken from Baseline Week 0 to end of treatment

    Reporting group title
    MT-1303 0.1mg
    Reporting group description
    		 Once daily oral MT-1303 0.1mg capsules taken from Baseline Week 0 to end of treatment

    Reporting group title
    MT-1303 0.2mg
    Reporting group description
    		 Once daily oral MT-1303 0.2mg capsules taken from Baseline Week 0 to end of treatment

    Reporting group title
    MT-1303 0.4mg
    Reporting group description
    		 Once daily oral MT-1303 0.4mg capsules taken from Baseline Week 0 to end of treatment

    Serious adverse events
    		 Placebo MT-1303 0.1mg MT-1303 0.2mg MT-1303 0.4mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 103 (9.71%)
    8 / 105 (7.62%)
    7 / 103 (6.80%)
    6 / 104 (5.77%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 104 (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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 104 (0.96%)
         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
    Injury, poisoning and procedural complications
    Joint Injury
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 104 (0.96%)
         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
    Tendon Injury
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    0 / 104 (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
    Wrist Fracture
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 104 (0.96%)
         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
    Cardiac disorders
    Atrioventricular Block Second Degree
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 104 (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
    Ventricular Tachycardia
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 104 (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
    Surgical and medical procedures
    Mammoplasty
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    0 / 104 (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
    Additional description: Not all MS relapses are added as AEs/SAEs
         subjects affected / exposed
    7 / 103 (6.80%)
    5 / 105 (4.76%)
    4 / 103 (3.88%)
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular oedema
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    0 / 104 (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
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    1 / 103 (0.97%)
    0 / 104 (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
    Uterine Enlargement
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 104 (0.96%)
         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
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    0 / 104 (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
    Neurosis
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 104 (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
    Renal and urinary disorders
    Cystitis Noninfective
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 104 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo MT-1303 0.1mg MT-1303 0.2mg MT-1303 0.4mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 103 (64.08%)
    59 / 105 (56.19%)
    69 / 103 (66.99%)
    58 / 104 (55.77%)
    Nervous system disorders
    Headache
    Additional description: Number of occurrences were not reported
         subjects affected / exposed
    4 / 103 (3.88%)
    10 / 105 (9.52%)
    10 / 103 (9.71%)
    10 / 104 (9.62%)
         occurrences all number
    0
    0
    0
    0
    Multiple Sclerosis Relapse
    Additional description: Number of occurrences were not reported
         subjects affected / exposed
    8 / 103 (7.77%)
    7 / 105 (6.67%)
    4 / 103 (3.88%)
    3 / 104 (2.88%)
         occurrences all number
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Number of occurrences were not reported
         subjects affected / exposed
    3 / 103 (2.91%)
    6 / 105 (5.71%)
    0 / 103 (0.00%)
    4 / 104 (3.85%)
         occurrences all number
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
    Additional description: Number of occurrences were not reported
         subjects affected / exposed
    8 / 103 (7.77%)
    9 / 105 (8.57%)
    7 / 103 (6.80%)
    10 / 104 (9.62%)
         occurrences all number
    0
    0
    0
    0
    Influenza
    Additional description: Number of occurrences were not reported
         subjects affected / exposed
    3 / 103 (2.91%)
    1 / 105 (0.95%)
    6 / 103 (5.83%)
    4 / 104 (3.85%)
         occurrences all number
    0
    0
    0
    0
    Upper Respiratory Tract Infection
    Additional description: Number of occurrences were not reported
         subjects affected / exposed
    7 / 103 (6.80%)
    3 / 105 (2.86%)
    2 / 103 (1.94%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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