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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of BG00012 in Delaying Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis

    Summary
    EudraCT number
    2014-003021-18
    Trial protocol
    SE   IT   SK   NL   CZ   BE   DE   PL   AT   DK   FI  
    Global end of trial date
    05 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Dec 2016
    First version publication date
    28 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    109MS308
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02430532
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to investigate whether treatment with BG00012 (dimethyl fumarate) compared with placebo slows the accumulation of disability not related to relapses in participants with secondary progressive multiple sclerosis (SPMS). The secondary objective of the study is to assess the effect of BG00012 compared with placebo on patient-reported outcomes, brain atrophy, and cognitive function.
    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
    14 May 2015
    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: 44
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Slovakia: 1
    Worldwide total number of subjects
    58
    EEA total number of subjects
    49
    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)
    58
    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 study entry.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Protocol-specified measures were put in place to maintain the study blind. Sites were selected based on their ability to comply with these requirements.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    BG00012 120 mg capsule orally once a day (QD) supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    BG00012
    Other name
    dimethyl fumarate, DMF, Tecfidera
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in the Placebo Group received BG00012 120 mg QD randomly in the morning or evening for the first 4 weeks of treatment as an additional blinding measure, and matched placebo only thereafter.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in the Placebo Group received 1 BG00012 120 mg capsule+1 matching placebo capsule in the morning AND 2 matching placebo capsules in the evening; or, 2 matching placebo capsules in the morning AND 1 BG00012 120 mg capsule+1 matching placebo capsule in the evening for Weeks 1-4. Subjects received 2 matching placebo capsules BID thereafter.

    Arm title
    Tecfidera 240 mg BID
    Arm description
    BG00012 120 mg (1 BG00012 120 mg capsule + 1 matching placebo capsule) orally twice daily (BID) for 1 week, followed by BG00012 240 mg orally BID thereafter.
    Arm type
    Experimental

    Investigational medicinal product name
    BG00012
    Investigational medicinal product code
    BG00012
    Other name
    dimethyl fumarate, DMF, Tecfidera
    Pharmaceutical forms
    Gastro-resistant capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in the BG00012 Treatment Group received BG00012 120 mg BID for 1 week, and an increased dose of BG00012 240 mg BID beginning on Day 8.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in the Tecfidera 240 mg Group received 1 matching placebo capsule BID during Week 1 only.

    Number of subjects in period 1
    Placebo Tecfidera 240 mg BID
    Started
    30
    28
    Completed
    0
    0
    Not completed
    30
    28
         Sponsor Decision to Stop Study Early
    30
    25
         Consent Withdrawn
    -
    2
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    BG00012 120 mg capsule orally once a day (QD) supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.

    Reporting group title
    Tecfidera 240 mg BID
    Reporting group description
    BG00012 120 mg (1 BG00012 120 mg capsule + 1 matching placebo capsule) orally twice daily (BID) for 1 week, followed by BG00012 240 mg orally BID thereafter.

    Reporting group values
    Placebo Tecfidera 240 mg BID Total
    Number of subjects
    30 28 58
    Age Categorical
    Units: Subjects
        < 20 years
    0 0 0
        20 to 29 years
    0 0 0
        30 to 39 years
    1 4 5
        40 to 49 years
    10 8 18
        >= 50 years
    19 16 35
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.7 ± 6.67 49.6 ± 8.05 -
    Gender, Male/Female
    Units: Subjects
        Female
    19 17 36
        Male
    11 11 22

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    BG00012 120 mg capsule orally once a day (QD) supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.

    Reporting group title
    Tecfidera 240 mg BID
    Reporting group description
    BG00012 120 mg (1 BG00012 120 mg capsule + 1 matching placebo capsule) orally twice daily (BID) for 1 week, followed by BG00012 240 mg orally BID thereafter.

    Primary: Time to Disability Progression Independent of Relapse

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    End point title
    Time to Disability Progression Independent of Relapse [1]
    End point description
    Time to onset of confirmed progression of disability is defined as 1 or more of the following criteria, confirmed at ≥ 6 months after start of treatment and at Week 108 using 1 or more of the following assessments: Expanded Disability Status Scale (EDSS) score increased from Baseline of ≥ 1 point if baseline EDSS ≤ 5.5, or ≥ 0.5 point if Baseline EDSS ≥ 6.0; Timed 25-Foot Walk (T25FW) ≥ 20% increase from Baseline in the time taken for the 25-foot walk; worsening on the 9-Hole Peg Test (9HPT; ≥ 20% increase from Baseline in the time taken for the 9HPT, confirmed in the same hand). The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. The 9HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs.
    End point type
    Primary
    End point timeframe
    Up to 108 weeks
    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: The endpoint was not analyzed due to early study termination.
    End point values
    Placebo Tecfidera 240 mg BID
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: days
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [2] - These data were not analyzed due to early study termination.
    [3] - These data were not analyzed due to early study termination.
    No statistical analyses for this end point

    Secondary: Change from Baseline to 2 Years on the 12-Item Multiple Sclerosis Walking Scale (MSWS-12)

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    End point title
    Change from Baseline to 2 Years on the 12-Item Multiple Sclerosis Walking Scale (MSWS-12)
    End point description
    MSWS-12 is a participant self-assessment of walking limitations due to multiple sclerosis (MS) during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater negative impact on walking.
    End point type
    Secondary
    End point timeframe
    Baseline, 2 years
    End point values
    Placebo Tecfidera 240 mg BID
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [4] - These data were not analyzed due to early study termination.
    [5] - These data were not analyzed due to early study termination.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 108 in ABILHAND Questionnaire Score

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    End point title
    Change from Baseline to Week 108 in ABILHAND Questionnaire Score
    End point description
    The ABILHAND Questionnaire measures the participant’s perceived difficulty in performing everyday manual activities in the last 3 months. Participants fill in the 56-item questionnaire by estimating their own difficulty or ease in performing each of the 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where high scores indicate greater impact on manual ability.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 108
    End point values
    Placebo Tecfidera 240 mg BID
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [6] - These data were not analyzed due to early study termination.
    [7] - These data were not analyzed due to early study termination.
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline to Week 108 in Whole Brain Volume

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    End point title
    Percentage Change from Baseline to Week 108 in Whole Brain Volume
    End point description
    Whole brain volume is measured by magnetic resonance imaging (MRI).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 108
    End point values
    Placebo Tecfidera 240 mg BID
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: percentage change
    Notes
    [8] - These data were not analyzed due to early study termination.
    [9] - These data were not analyzed due to early study termination.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 108 in Cognitive Function as Measured by the Symbol Digit Modalities Test (SDMT)

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    End point title
    Change from Baseline to Week 108 in Cognitive Function as Measured by the Symbol Digit Modalities Test (SDMT)
    End point description
    The SDMT measures the time to pair abstract geometric symbols with specific numbers. The score is the number of correctly coded items from 0-110 in 90 seconds. A higher score indicates a better outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 108
    End point values
    Placebo Tecfidera 240 mg BID
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [10] - These data were not analyzed due to early study termination.
    [11] - These data were not analyzed due to early study termination.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 24 weeks (overall mean time on study of 14.34, with an overall mean time on study treatment of 9.58 weeks).
    Adverse event reporting additional description
    Data summaries of adverse events are descriptive in nature and the comparison between treatment groups might not be appropriate due to the small number of participants and limited study follow-up duration.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Tecfidera 240 mg BID
    Reporting group description
    BG00012 120 mg orally twice daily (BID) for 1 week, followed by BG00012 240 mg orally BID beginning on Day 8 for up to 108 weeks.

    Reporting group title
    Placebo
    Reporting group description
    BG00012 120 mg capsule orally once a day (QD) supplemented with matching placebo capsules for the first 4 weeks of treatment. Matched placebo capsules only thereafter for up to 108 weeks.

    Serious adverse events
    Tecfidera 240 mg BID Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 28 (17.86%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Tecfidera 240 mg BID Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 28 (32.14%)
    9 / 30 (30.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    5 / 28 (17.86%)
    5 / 30 (16.67%)
         occurrences all number
    5
    5
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Vomiting
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 30 (10.00%)
         occurrences all number
    2
    4

    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.
    The study was terminated early by the sponsor for business reasons. Efficacy, patient-reported outcomes, and pharmacodynamic data were not analyzed.
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