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    Clinical Trial Results:
    Open-Label, Multicenter, Multiple-Dose Study of the Effect of BG00012 on MRI Lesions and Pharmacokinetics in Pediatric Subjects With Relapsing-Remitting Multiple Sclerosis Aged 10 to 17 Years

    Summary
    EudraCT number
    2014-005003-24
    Trial protocol
    LV   DE   CZ   BG   PL   BE  
    Global end of trial date
    23 Sep 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    14 Oct 2017
    First version publication date
    05 Apr 2017
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Global amendment information included in error.

    Trial information

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    Trial identification
    Sponsor protocol code
    109MS202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02410200
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the effect of BG00012 (dimethyl fumarate) on brain magnetic resonance imaging (MRI) lesions in pediatric participants with relapsing-remitting multiple sclerosis (RRMS). The secondary objectives of this study are to characterize the pharmacokinetics of BG00012 in pediatric participants with RRMS and to evaluate the safety and tolerability of BG00012 in pediatric participants with RRMS.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Kuwait: 3
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Lebanon: 2
    Country: Number of subjects enrolled
    Poland: 5
    Worldwide total number of subjects
    22
    EEA total number of subjects
    14
    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)
    22
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subject eligibility for the study was determined within 4 weeks prior to the Baseline Period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    BG00012
    Arm description
    BG00012 taken orally at a dose of 120 mg twice daily (BID) for the first 7 days and at a dose of 240 mg BID thereafter for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    Other name
    dimethyl fumarate DMF
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Directions for Handling and Administration were followed.

    Number of subjects in period 1
    BG00012
    Started
    22
    Completed
    20
    Not completed
    2
         Adverse event, non-fatal
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BG00012
    Reporting group description
    BG00012 taken orally at a dose of 120 mg twice daily (BID) for the first 7 days and at a dose of 240 mg BID thereafter for 24 weeks.

    Reporting group values
    BG00012 Total
    Number of subjects
    22 22
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    22 22
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    15.8 ± 1.18 -
    Gender, Male/Female
    Units: Subjects
        Female
    14 14
        Male
    8 8

    End points

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    End points reporting groups
    Reporting group title
    BG00012
    Reporting group description
    BG00012 taken orally at a dose of 120 mg twice daily (BID) for the first 7 days and at a dose of 240 mg BID thereafter for 24 weeks.

    Primary: Change in the Number of New or Newly Enlarging T2 Hyperintense Lesions on Brain Magnetic Resonance Imaging (MRI) Scans From the Baseline Period to On-Treatment Assessment Period

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    End point title
    Change in the Number of New or Newly Enlarging T2 Hyperintense Lesions on Brain Magnetic Resonance Imaging (MRI) Scans From the Baseline Period to On-Treatment Assessment Period [1]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline Period (Week -8 to Day 0), On-Treatment Assessment Period (Week 16 to Week 24)
    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: Statistical analysis is provided in V1 document attached to this endpoint presentation. (Analysis could not be entered into EudraCT due to system limitations.)
    End point values
    BG00012
    Number of subjects analysed
    15
    Units: lesions
        arithmetic mean (standard deviation)
    -7.9 ± 16.23
    Attachments
    Untitled (Filename: Statistical Analysis for Primary Endpoint.docx)
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax)

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    End point title
    Maximum Observed Plasma Concentration (Cmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8
    End point values
    BG00012
    Number of subjects analysed
    21
    Units: ng/mL
        arithmetic mean (standard deviation)
    1998.62 ± 1286.467
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax)

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    End point title
    Time to Reach Maximum Observed Plasma Concentration (Tmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8
    End point values
    BG00012
    Number of subjects analysed
    21
    Units: hours
        arithmetic mean (standard deviation)
    4.2 ± 1.543
    No statistical analyses for this end point

    Secondary: Apparent Clearance (CL/F)

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    End point title
    Apparent Clearance (CL/F)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8
    End point values
    BG00012
    Number of subjects analysed
    17
    Units: L/h
        arithmetic mean (standard deviation)
    74.45 ± 30.185
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution (V/F)

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    End point title
    Apparent Volume of Distribution (V/F)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8
    End point values
    BG00012
    Number of subjects analysed
    14
    Units: liters
        arithmetic mean (standard deviation)
    98.19 ± 91.679
    No statistical analyses for this end point

    Secondary: Half-Life Lambda z

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    End point title
    Half-Life Lambda z
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8
    End point values
    BG00012
    Number of subjects analysed
    14
    Units: hours
        arithmetic mean (standard deviation)
    0.84 ± 0.408
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve from Time 0 to Infinity (AUC0-inf)

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    End point title
    Area Under the Concentration-Time Curve from Time 0 to Infinity (AUC0-inf)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8
    End point values
    BG00012
    Number of subjects analysed
    14
    Units: h*mcg/mL
        arithmetic mean (standard deviation)
    3630.52 ± 1153.768
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced Treatment-Emergent Adverse Events (AEs) and Serious Adverse events (SAEs)

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    End point title
    Number of Participants Who Experienced Treatment-Emergent Adverse Events (AEs) and Serious Adverse events (SAEs)
    End point description
    AE: any untoward medical occurrence that does not necessarily have a causal relationship with treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above.
    End point type
    Secondary
    End point timeframe
    Up to Week 28
    End point values
    BG00012
    Number of subjects analysed
    22
    Units: participants
        Any event
    20
        Moderate or severe event
    7
        Severe event
    1
        Event related to BG00012
    16
        Serious event
    5
        Serious event related to BG00012
    0
        Discontinued treatment due to an event
    2
        Withdrew from study due to an event
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through end of treatment period (Week 24 ±7 days) plus 4 weeks follow-up.
    Adverse event reporting additional description
    Treatment-emergent events are presented.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    BG00012
    Reporting group description
    BG00012 taken orally at a dose of 120 mg BID for the first 7 days and at a dose of 240 mg BID thereafter for 24 weeks.

    Serious adverse events
    BG00012
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 22 (22.73%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BG00012
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 22 (86.36%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    10 / 22 (45.45%)
         occurrences all number
    51
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    7 / 22 (31.82%)
         occurrences all number
    8
    Headache
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    6
    Abdominal pain upper
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    5
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2

    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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