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    Clinical Trial Results:
    A phase II, multicentre study to evaluate the long-term safety and efficacy of MT-1303 in subjects with relapsing-remitting multiple sclerosis who have completed the MT-1303-E04 study

    Summary
    EudraCT number
    		 2012-002639-27
    Trial protocol
    		 GB   HU   ES   FI   BE   LT   CZ   PL   BG   IT  
    Global end of trial date
    15 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2017
    First version publication date
    16 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MT-1303-E05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01890655
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MOMENTUM extention study: MT-1303-E05
    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
    02 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to evaluate the long-term safety and tolerability of MT-1303 in subjects with relapsing-remitting multiple sclerosis (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    Subjects will be permanently withdrawn from study medication in the following circumstances: • Confirmed absolute lymphocyte count values 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 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 (during Part 1 only) • 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
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    31 Jan 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 21 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 78
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Bulgaria: 54
    Country: Number of subjects enrolled
    Czech Republic: 54
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Serbia: 25
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    Ukraine: 25
    Worldwide total number of subjects
    367
    EEA total number of subjects
    274
    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)
    367
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Part 1-Double Blind: subjects were randomised to receive 0.1mg, 0.2mg or 0.4mg of MT-1303. Part 2-Open Label: subjects with a minimum of 12 weeks left in the DB Period received OL treatment with the effective dose(s) for the remainder of the 18-month treatment period. Safety Follow Up: subjects then entered a 12-week Safety Follow Up Period

    Pre-assignment
    Screening details
    		 After providing the informed consent former MT-1303-E04 subjects could enter the MT-1303-E05 Double Blind period once all eligibility criteria were validated. There was no screening period.

    Period 1
    Period 1 title
    Double-Blind 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
    During the double-blind part (part 1/2) of the E05 study lymphocyte counts, subsets and WBC were not provided to any site/study personnel to maintain the study medication blind. Also all subjects underwent recommended monitoring of cardiovascular safety within the clinic for at least 6 h following the first dose of study medication at E05 Visit 1. All 3 doses of MT-1303 capsules were identical in appearance, taste and smell and the same number of capsules were given.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 MT-1303 0.1 mg (Safety Population)
    Arm description
    		 MT-1303 0.1 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during double-blind period of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo and during the double-blind period of MT-1303-E05. (Overall Summary all Treatments)
    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 18 months.

    Arm title
    		 MT-1303 0.2 mg (Safety Population)
    Arm description
    		 MT-1303 0.2 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)
    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 18 months.

    Arm title
    		 MT-1303 0.4 mg (Safety Population)
    Arm description
    		 MT-1303 0.4 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)
    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 18 months.

    Number of subjects in period 1
    		MT-1303 0.1 mg (Safety Population) MT-1303 0.2 mg (Safety Population) MT-1303 0.4 mg (Safety Population)
    Started
    123
    123
    121
    Completed
    108
    115
    107
    Not completed
    15
    8
    14
         Protocol Specific
    2
    -
    3
         Consent withdrawn by subject
    6
    1
    1
         Protocol-specific reason
    -
    2
    -
         Adverse event, non-fatal
    1
    -
    1
         Other
    -
    2
    5
         Completed during E05 DB period
    6
    3
    4
    Period 2
    Period 2 title
    Open-Label Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 MT-1303 0.2 mg (Safety Population)
    Arm description
    		 MT-1303 0.2 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods or taken only from start of open-label period in MT-1303-E05 after switching from MT-1303 0.1 mg then throughout the MT-1303-E05 open label treatment period. (Overall Summary all Treatments)
    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 18 months.

    Arm title
    		 MT-1303 0.4 mg (Safety Population)
    Arm description
    		 MT-1303 0.4 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods or taken only from start of open-label period in MT-1303-E05 after switching from MT-1303 0.1 mg then throughout the MT-1303-E05 open label treatment period. (Overall Summary all Treatments)
    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 18 months.

    Number of subjects in period 2
    		MT-1303 0.2 mg (Safety Population) MT-1303 0.4 mg (Safety Population)
    Started
    169
    161
    Completed
    157
    152
    Not completed
    12
    9
         Protocol Specific
    2
    1
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    4
    2
         Adverse event, non-fatal
    3
    4
         Other
    2
    1
         Pregnancy
    1
    -
    Period 3
    Period 3 title
    Safety Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 MT-1303 0.1 mg (Safety Population)
    Arm description
    		 MT-1303 0.1 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during double-blind period of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo and during the double-blind period of MT-1303-E05. (Overall Summary all Treatments)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 MT-1303 0.2 mg (Safety Population)
    Arm description
    		 MT-1303 0.2 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 MT-1303 0.4 mg (Safety Population)
    Arm description
    		 MT-1303 0.4 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		MT-1303 0.1 mg (Safety Population) MT-1303 0.2 mg (Safety Population) MT-1303 0.4 mg (Safety Population)
    Started
    121
    119
    117
    Completed
    116
    116
    114
    Not completed
    5
    3
    3
         Consent withdrawn by subject
    2
    1
    1
         Other
    2
    2
    2
         Lost to follow-up
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MT-1303 0.1 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.1 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during double-blind period of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo and during the double-blind period of MT-1303-E05. (Overall Summary all Treatments)

    Reporting group title
    MT-1303 0.2 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.2 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)

    Reporting group title
    MT-1303 0.4 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.4 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)

    Reporting group values
    		 MT-1303 0.1 mg (Safety Population) MT-1303 0.2 mg (Safety Population) MT-1303 0.4 mg (Safety Population) Total
    Number of subjects
    		 123 123 121 367
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 123 123 121 367
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37 ( 9.27 ) 38.1 ( 9.56 ) 37.5 ( 8.53 ) -
    Gender categorical
    Units: Subjects
        Female
    		 83 87 82 252
        Male
    		 40 36 39 115
    Baseline EDSS Score
    Expanded Disability Status Scale (EDSS) score taken during enrollment into the MT-1303-E05 study
    Units: No units
        arithmetic mean (standard deviation)
    		 2.8 ( 1.3 ) 2.7 ( 1.3 ) 2.5 ( 1.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    MT-1303 0.1 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.1 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during double-blind period of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo and during the double-blind period of MT-1303-E05. (Overall Summary all Treatments)

    Reporting group title
    MT-1303 0.2 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.2 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)

    Reporting group title
    MT-1303 0.4 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.4 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)
    Reporting group title
    MT-1303 0.2 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.2 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods or taken only from start of open-label period in MT-1303-E05 after switching from MT-1303 0.1 mg then throughout the MT-1303-E05 open label treatment period. (Overall Summary all Treatments)

    Reporting group title
    MT-1303 0.4 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.4 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods or taken only from start of open-label period in MT-1303-E05 after switching from MT-1303 0.1 mg then throughout the MT-1303-E05 open label treatment period. (Overall Summary all Treatments)
    Reporting group title
    MT-1303 0.1 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.1 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during double-blind period of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo and during the double-blind period of MT-1303-E05. (Overall Summary all Treatments)

    Reporting group title
    MT-1303 0.2 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.2 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)

    Reporting group title
    MT-1303 0.4 mg (Safety Population)
    Reporting group description
    		 MT-1303 0.4 mg (oral capsules) taken from Wk 0 up to Wk 24 in MT-1303-E04 and during both double-blind and open-label periods of MT-1303-E05 or taken only from Wk 0 in MT-1303-E05 after switching from placebo then throughout the MT-1303-E05 treatment periods. (Overall Summary all Treatments)

    Primary: Not Applicable - none reported as safety is primary endpoint

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    End point title
    		 Not Applicable - none reported as safety is primary endpoint [1]
    End point description
    No primary endpoints were defined for efficacy or PD variables. Safety was the only primary endpoint.
    End point type
    Primary
    End point timeframe
    Not applicable
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There was no formal statistical analysis performed as safety was the primary endpoint
    End point values
    		 MT-1303 0.1 mg (Safety Population) MT-1303 0.2 mg (Safety Population) MT-1303 0.4 mg (Safety Population) MT-1303 0.2 mg (Safety Population) MT-1303 0.4 mg (Safety Population)
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    Units: n/a
    Notes
    [2] - There are no pre-defined study endpoints. Safety was the only parameter measured
    [3] - There are no pre-defined study endpoints. Safety was the only parameter measured
    [4] - There are no pre-defined study endpoints. Safety was the only parameter measured
    [5] - There are no pre-defined study endpoints. Safety was the only parameter measured
    [6] - There are no pre-defined study endpoints. Safety was the only parameter measured
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were considered to be treatment-emergent if they started or worsened on or after the first dose of MT-1303-E04 or MT-1303-E05 study medication.
    Adverse event reporting additional description
    For summaries by treatment period (E04 study period, E05 study periods, overall), data for AEs were assigned to the treatment period (and therefore study treatment) they started in each period. Subjects were carefully monitored by the Investigator for AEs, including regular questioning of the subject, although no leading questions were asked.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    MT-1303 0.2 mg only (Selected Treatment Sequences)
    Reporting group description
    		 MT-1303 0.2 mg (oral capsules) taken from Wk 0 in MT-1303-E04 study and throughout both treatment periods of MT-1303-E05 (Overall for Selected Treatment Sequences)

    Reporting group title
    MT-1303 0.4 mg only (Selected Treatment Sequences)
    Reporting group description
    		 MT-1303 0.4 mg (oral capsules) taken from Wk 0 in MT-1303-E04 study and throughout both treatment periods of MT-1303-E05 (Overall for Selected Treatment Sequences)

    Reporting group title
    Placebo to MT-1303 0.2 mg (Selected Treatment Sequences)
    Reporting group description
    		 MT-1303 0.2 mg (oral capsules) taken throughout both treatment periods in MT-1303-E05 after switching from Placebo administered during the complete treatment period of MT-1303-E04 (Overall for Selected Treatment Sequences)

    Reporting group title
    Placebo to MT-1303 0.4 mg (Selected Treatment Sequences)
    Reporting group description
    		 MT-1303 0.4 mg (oral capsules) taken throughout both treatment periods in MT-1303-E05 after switching from Placebo administered during the complete treatment period of MT-1303-E04 (Overall for Selected Treatment Sequences)

    Serious adverse events
    		 MT-1303 0.2 mg only (Selected Treatment Sequences) MT-1303 0.4 mg only (Selected Treatment Sequences) Placebo to MT-1303 0.2 mg (Selected Treatment Sequences) Placebo to MT-1303 0.4 mg (Selected Treatment Sequences)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 90 (23.33%)
    11 / 92 (11.96%)
    9 / 33 (27.27%)
    7 / 28 (25.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 90 (3.33%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminortransferase increased
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    0 / 28 (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
    White blood cell count decreased
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (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
    Injury, poisoning and procedural complications
    Exposure via father
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    1 / 33 (3.03%)
    0 / 28 (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
    Fibula fracture
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    0 / 28 (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
    Joint injury
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (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
    Meniscus injury
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    1 / 28 (3.57%)
         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
    Upper limb fracture
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    0 / 28 (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 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (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
    Surgical and medical procedures
    Finger amputation
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    0 / 28 (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
    Hysterectomy
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (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
    Mammoplasty
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    1 / 33 (3.03%)
    0 / 28 (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
    Nervous system disorders
    Grand mal convulsion
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (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
    Multiple sclerosis relapse
         subjects affected / exposed
    11 / 90 (12.22%)
    3 / 92 (3.26%)
    6 / 33 (18.18%)
    5 / 28 (17.86%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 3
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculitis lumbosacral
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    0 / 28 (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
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    0 / 28 (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
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    0 / 28 (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
    Ovarian cyst
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine enlargement
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (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
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    1 / 28 (3.57%)
         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
    Confusional state
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    1 / 33 (3.03%)
    0 / 28 (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
    Mood disorder due to a general medical condition
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    1 / 33 (3.03%)
    0 / 28 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    1 / 33 (3.03%)
    0 / 28 (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
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    1 / 33 (3.03%)
    0 / 28 (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
    Infections and infestations
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    0 / 28 (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
    		 MT-1303 0.2 mg only (Selected Treatment Sequences) MT-1303 0.4 mg only (Selected Treatment Sequences) Placebo to MT-1303 0.2 mg (Selected Treatment Sequences) Placebo to MT-1303 0.4 mg (Selected Treatment Sequences)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 90 (78.89%)
    75 / 92 (81.52%)
    30 / 33 (90.91%)
    22 / 28 (78.57%)
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    15 / 90 (16.67%)
    24 / 92 (26.09%)
    6 / 33 (18.18%)
    1 / 28 (3.57%)
         occurrences all number
    16
    26
    7
    1
    Gamma glutamyltransferase increased
         subjects affected / exposed
    8 / 90 (8.89%)
    6 / 92 (6.52%)
    2 / 33 (6.06%)
    2 / 28 (7.14%)
         occurrences all number
    9
    6
    2
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 90 (4.44%)
    6 / 92 (6.52%)
    2 / 33 (6.06%)
    3 / 28 (10.71%)
         occurrences all number
    4
    6
    2
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 90 (2.22%)
    3 / 92 (3.26%)
    2 / 33 (6.06%)
    3 / 28 (10.71%)
         occurrences all number
    2
    3
    2
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    1
    3
    0
    2
    Blood triglycerides increased
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 92 (1.09%)
    1 / 33 (3.03%)
    2 / 28 (7.14%)
         occurrences all number
    3
    1
    1
    2
    Neutrophil count decreased
         subjects affected / exposed
    4 / 90 (4.44%)
    2 / 92 (2.17%)
    1 / 33 (3.03%)
    2 / 28 (7.14%)
         occurrences all number
    4
    3
    1
    2
    White blood cell count decreased
         subjects affected / exposed
    1 / 90 (1.11%)
    4 / 92 (4.35%)
    3 / 33 (9.09%)
    0 / 28 (0.00%)
         occurrences all number
    1
    5
    5
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 90 (5.56%)
    2 / 92 (2.17%)
    1 / 33 (3.03%)
    2 / 28 (7.14%)
         occurrences all number
    5
    2
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 90 (20.00%)
    15 / 92 (16.30%)
    5 / 33 (15.15%)
    3 / 28 (10.71%)
         occurrences all number
    40
    91
    12
    4
    Multiple sclerosis relapse
         subjects affected / exposed
    4 / 90 (4.44%)
    3 / 92 (3.26%)
    2 / 33 (6.06%)
    0 / 28 (0.00%)
         occurrences all number
    6
    3
    2
    0
    Dizziness
         subjects affected / exposed
    4 / 90 (4.44%)
    6 / 92 (6.52%)
    4 / 33 (12.12%)
    1 / 28 (3.57%)
         occurrences all number
    10
    7
    4
    2
    Paraesthesia
         subjects affected / exposed
    2 / 90 (2.22%)
    7 / 92 (7.61%)
    2 / 33 (6.06%)
    1 / 28 (3.57%)
         occurrences all number
    2
    7
    2
    1
    Sciatica
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 92 (2.17%)
    2 / 33 (6.06%)
    1 / 28 (3.57%)
         occurrences all number
    0
    2
    2
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 90 (4.44%)
    2 / 92 (2.17%)
    1 / 33 (3.03%)
    2 / 28 (7.14%)
         occurrences all number
    6
    2
    1
    3
    Pain
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 92 (1.09%)
    2 / 33 (6.06%)
    0 / 28 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Pyrexia
         subjects affected / exposed
    2 / 90 (2.22%)
    5 / 92 (5.43%)
    0 / 33 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    2
    6
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 92 (0.00%)
    2 / 33 (6.06%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    2
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 90 (4.44%)
    7 / 92 (7.61%)
    1 / 33 (3.03%)
    1 / 28 (3.57%)
         occurrences all number
    5
    11
    1
    1
    Vomiting
         subjects affected / exposed
    0 / 90 (0.00%)
    5 / 92 (5.43%)
    3 / 33 (9.09%)
    0 / 28 (0.00%)
         occurrences all number
    0
    6
    5
    0
    Nausea
         subjects affected / exposed
    5 / 90 (5.56%)
    3 / 92 (3.26%)
    1 / 33 (3.03%)
    1 / 28 (3.57%)
         occurrences all number
    5
    3
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    4 / 90 (4.44%)
    9 / 92 (9.78%)
    1 / 33 (3.03%)
    0 / 28 (0.00%)
         occurrences all number
    6
    15
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 90 (8.89%)
    1 / 92 (1.09%)
    2 / 33 (6.06%)
    1 / 28 (3.57%)
         occurrences all number
    8
    1
    3
    2
    Arthralgia
         subjects affected / exposed
    4 / 90 (4.44%)
    5 / 92 (5.43%)
    3 / 33 (9.09%)
    1 / 28 (3.57%)
         occurrences all number
    4
    9
    3
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 90 (0.00%)
    0 / 92 (0.00%)
    2 / 33 (6.06%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Neck pain
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 92 (0.00%)
    0 / 33 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    0
    2
    Pain in extremity
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 92 (1.09%)
    0 / 33 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    6
    4
    0
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 90 (15.56%)
    13 / 92 (14.13%)
    5 / 33 (15.15%)
    2 / 28 (7.14%)
         occurrences all number
    18
    16
    10
    2
    Urinary tract infection
         subjects affected / exposed
    8 / 90 (8.89%)
    9 / 92 (9.78%)
    6 / 33 (18.18%)
    2 / 28 (7.14%)
         occurrences all number
    14
    13
    8
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 90 (4.44%)
    5 / 92 (5.43%)
    4 / 33 (12.12%)
    2 / 28 (7.14%)
         occurrences all number
    8
    6
    9
    3
    Influenza
         subjects affected / exposed
    6 / 90 (6.67%)
    10 / 92 (10.87%)
    1 / 33 (3.03%)
    1 / 28 (3.57%)
         occurrences all number
    12
    12
    1
    2
    Bronchitis
         subjects affected / exposed
    4 / 90 (4.44%)
    1 / 92 (1.09%)
    2 / 33 (6.06%)
    0 / 28 (0.00%)
         occurrences all number
    4
    1
    2
    0
    Cystitis
         subjects affected / exposed
    5 / 90 (5.56%)
    2 / 92 (2.17%)
    2 / 33 (6.06%)
    0 / 28 (0.00%)
         occurrences all number
    8
    3
    2
    0
    Gastroenteritis
         subjects affected / exposed
    6 / 90 (6.67%)
    2 / 92 (2.17%)
    2 / 33 (6.06%)
    1 / 28 (3.57%)
         occurrences all number
    6
    2
    2
    1
    Oral herpes
         subjects affected / exposed
    2 / 90 (2.22%)
    5 / 92 (5.43%)
    0 / 33 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    5
    10
    0
    2
    Sinusitis
         subjects affected / exposed
    1 / 90 (1.11%)
    5 / 92 (5.43%)
    0 / 33 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    8
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 92 (2.17%)
    2 / 33 (6.06%)
    0 / 28 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 90 (0.00%)
    6 / 92 (6.52%)
    1 / 33 (3.03%)
    0 / 28 (0.00%)
         occurrences all number
    0
    7
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2013
    Inclusion of two additional safety monitoring visits, between Visit 1 (Week 0) and Visit 2 (Week 12) to ensure consistent review of safety parameters for all patients in transit from the MT-1303-E04 study to the MT-1303-E05 study. Visit 1a and 1b at Week 4 and Week 8 respectively.
    24 Mar 2015
    In light of the increasing evidence from recent research for other disease-modifying therapies (DMTs) in MS, an amendment was made to allow patients to receive DMT during the Safety Follow-up Period if this was considered appropriate.

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

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