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    Clinical Trial Results:
    A Multicenter Extension Study to Determine the Long-Term Safety and Efficacy of BG00012 in Pediatric Subjects With Relapsing-Remitting Multiple Sclerosis

    Summary
    EudraCT number
    2015-003282-29
    Trial protocol
    DE   BE   CZ   LV   BG  
    Global end of trial date
    24 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Apr 2019
    First version publication date
    11 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    109MS311
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02555215
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 Binney Street, Cambridge, United States, 02142
    Public contact
    Medical Director, Overall Study Officials, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Medical Director, Overall Study Officials, 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
    27 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the long-term safety of BG00012 in subjects who completed Study 109MS202 (NCT02410200). Secondary objectives were to evaluate the long-term efficacy of BG00012 and to describe the long-term Multiple Sclerosis (MS) outcomes in subjects who completed Study 109MS202 (NCT02410200).
    Protection of trial subjects
    Written informed consent was obtained from each subject, prior to evaluations 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. Subjects were provided with a copy of the signed and dated informed consent form (ICF).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Feb 2016
    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: 5
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Kuwait: 3
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Lebanon: 2
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    20
    EEA total number of subjects
    13
    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)
    14
    Adults (18-64 years)
    6
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The number of subjects who were eligible for this study was determined by the number of subjects who had completed Study 109MS202 as per protocol.

    Pre-assignment
    Screening details
    A total of 20 subjects who completed Study 109MS202 were enrolled at 12 study sites in 10 countries.

    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
    Dimethyl Fumarate
    Arm description
    Participants received 240 mg dimethyl fumarate oral capsules daily for 96 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    dimethyl fumarate
    Investigational medicinal product code
    Other name
    Tecfidera, BG000012
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 240 mg dimethyl fumarate oral capsules daily for 96 weeks.

    Number of subjects in period 1
    Dimethyl Fumarate
    Started
    20
    Completed
    17
    Not completed
    3
         Investigator Decision
    2
         Not Specified
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dimethyl Fumarate
    Reporting group description
    Participants received 240 mg dimethyl fumarate oral capsules daily for 96 weeks.

    Reporting group values
    Dimethyl Fumarate Total
    Number of subjects
    20 20
    Age Categorical
    Units: Subjects
        <=18 years
    14 14
        Between 18 and 65 years
    6 6
        >=65 years
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    16.7 ± 1.31 -
    Sex: Female, Male
    Units: Subjects
        Female
    13 13
        Male
    7 7
    Race/Ethnicity, Customized
    Units: Subjects
        Asian|
    1 1
        Black or African American|
    0 0
        White|
    5 5
        Not Reported Due to Confidentiality Regulations|
    13 13
        Other|
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Dimethyl Fumarate
    Reporting group description
    Participants received 240 mg dimethyl fumarate oral capsules daily for 96 weeks.

    Primary: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An AE is any untoward medical occurrence that does not necessarily have a causal relationship with treatment. An SAE is any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the subject 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 subject or may require intervention to prevent one of the other outcomes listed in the definition above.
    End point type
    Primary
    End point timeframe
    Baseline to Week 96
    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: No statistical analyses are reported for this endpoint.
    End point values
    Dimethyl Fumarate
    Number of subjects analysed
    20
    Units: Subjects
        Adverse Event
    18
        Serious Adverse Event
    2
    No statistical analyses for this end point

    Primary: Number of Subjects Discontinuing Treatment Due to an Adverse Event

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    End point title
    Number of Subjects Discontinuing Treatment Due to an Adverse Event [2]
    End point description
    An AE is any untoward medical occurrence that does not necessarily have a causal relationship with treatment.
    End point type
    Primary
    End point timeframe
    Baseline to Week 96
    Notes
    [2] - 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: No statistical analyses are reported for this endpoint.
    End point values
    Dimethyl Fumarate
    Number of subjects analysed
    20
    Units: Subjects
    0
    No statistical analyses for this end point

    Secondary: Total Number of New or Newly Enlarging T2 Hyperintense Lesions from Week 16 to Week 24

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    End point title
    Total Number of New or Newly Enlarging T2 Hyperintense Lesions from Week 16 to Week 24
    End point description
    T2 hyperintense lesions were measured by MRI brain scans.
    End point type
    Secondary
    End point timeframe
    Week 16 to Week 24
    End point values
    Dimethyl Fumarate
    Number of subjects analysed
    17
    Units: Subjects
        0 lesions
    12
        1 lesion
    2
        2 lesions
    1
        3 lesions
    1
        4 lesions
    0
        5 or more lesions
    1
    No statistical analyses for this end point

    Secondary: Total Number of New or Newly Enlarging T2 Hyperintense Lesions from Week 64 to Week 72

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    End point title
    Total Number of New or Newly Enlarging T2 Hyperintense Lesions from Week 64 to Week 72
    End point description
    T2 hyperintense lesions were measured by MRI brain scans.
    End point type
    Secondary
    End point timeframe
    Week 64 to Week 72
    End point values
    Dimethyl Fumarate
    Number of subjects analysed
    10
    Units: Subjects
        0 lesions
    8
        1 lesion
    1
        2 lesions
    1
        3 lesions
    0
        4 lesions
    0
        5 or more lesions
    0
    No statistical analyses for this end point

    Secondary: Average Annualized Relapse Rate (ARR)

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    End point title
    Average Annualized Relapse Rate (ARR)
    End point description
    Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Investigator. New or recurrent neurologic symptoms that evolved gradually over months were considered disability progression, not an acute relapse, and were not treated with steroids. The ARR was calculated as the total number of relapses that occurred during the previous 12 months and during the 120 weeks on treatment for subjects in Study 109MS202 that continued into Study 109MS311, divided by the total number of person-years followed prior to the study and by the total number of person-years followed during the study, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    Dimethyl Fumarate
    Number of subjects analysed
    20
    Units: Annualized relapse rate
        number (not applicable)
    0.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Experiencing One or More Relapses

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    End point title
    Percentage of Subjects Experiencing One or More Relapses
    End point description
    Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Investigator. New or recurrent neurologic symptoms that evolved gradually over months were considered disability progression, not an acute relapse, and were not treated with steroids.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    Dimethyl Fumarate
    Number of subjects analysed
    20
    Units: Percentage of subjects
    10
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Degree of Disability

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    End point title
    Change from Baseline in the Degree of Disability
    End point description
    The Expanded Disability Status Scale (EDSS) measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. Scoring is based on measures of impairment in eight functional systems on examination by a neurologist.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    Dimethyl Fumarate
    Number of subjects analysed
    20
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    1.00 ± 1.026
        Change from Baseline at Week 12|
    0.15 ± 0.718
        Change from Baseline at Week 24|
    0.29 ± 0.508
        Change from Baseline at Week 36|
    0.27 ± 0.832
        Change from Baseline at Week 48|
    0.50 ± 0.791
        Change from Baseline at Week 72|
    0.71 ± 1.010
        Change from Baseline at Week 96|
    0.21 ± 0.964
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing Disability Progression

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    End point title
    Number of Subjects Experiencing Disability Progression
    End point description
    Measured by at least a 1.0-point increase on the EDSS from baseline EDSS ≥1.0 that is sustained for 24 weeks, or at least a 1.5-point increase on the EDSS from baseline EDSS = 0 that is sustained for 24 weeks.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 96
    End point values
    Dimethyl Fumarate
    Number of subjects analysed
    20
    Units: Subjects
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    **Timeframe description needed**
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    BG00012
    Reporting group description
    -

    Serious adverse events
    BG00012
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
         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
    18 / 20 (90.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    5 / 20 (25.00%)
         occurrences all number
    21
    Immune system disorders
    Dust allergy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Seasonal allergy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Smoke sensitivity
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Influenza like illness
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Somatic symptom disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    7
    Menstruation irregular
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ovarian cyst
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Uterine inflammation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cardiac disorders
    Wolff-parkinson-white syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Hyperventilation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    7
    Productive cough
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Paranasal cyst
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nervous system disorders
    Demyelination
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    12
    Hypoaesthesia
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Multiple sclerosis relapse
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Migraine
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Presyncope
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Abdominal pain
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    6
    Abdominal pain upper
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    4
    Vomiting
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Hypertonic bladder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Micturition urgency
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Urinary retention
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Alopecia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Alopecia areata
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dermatitis allergic
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Limb discomfort
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Herpes zoster
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mastoiditis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Root canal infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Salpingo-oophoritis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jan 2016
    Removed the paragraph on resumption of study treatment for subjects with <LLN; Removed the section on central assessment of MRI scans.
    24 Apr 2018
    There were no major changes to the protocol.

    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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