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    Summary
    EudraCT Number:2013-002318-11
    Sponsor's Protocol Code Number:109MS306
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-04-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2013-002318-11
    A.3Full title of the trial
    Open-Label, Randomized, Multicenter, Multiple-Dose, Active Controlled, Parallel-Group, Efficacy and Safety Study of BG00012 in Children From 10 to Less Than 18 Years of Age With Relapsing-Remitting Multiple Sclerosis, With Optional Open-Label Extension
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Subjects With relapsing-remitting multiple sclerosis (RRMS).
    A.3.2Name or abbreviated title of the trial where available
    CONNECT
    A.4.1Sponsor's protocol code number109MS306
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/027/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBiogen Idec Research Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBiogen Idec Research Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBiogen Idec Research Limited
    B.5.2Functional name of contact pointMedical Director
    B.5.3 Address:
    B.5.3.1Street AddressInnovation House, 70 Norden Road
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 4AY
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailclinicaltrials@biogen.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBG00012
    D.3.2Product code BG00012
    D.3.4Pharmaceutical form Gastro-resistant capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDIMETHYL FUMARATE
    D.3.9.1CAS number 624-49-7
    D.3.9.2Current sponsor codeBG00012
    D.3.9.3Other descriptive nameDIMETHYL FUMARATE
    D.3.9.4EV Substance CodeSUB13608MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name AVONEX
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAvonex
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNInterferon beta-1a
    D.3.9.1CAS number 220581-49-7
    D.3.9.3Other descriptive nameINTERFERON BETA-1A
    D.3.9.4EV Substance CodeSUB12440MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number7.5 to 30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsing-Remitting Multiple Sclerosis
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level SOC
    E.1.2Classification code 10029205
    E.1.2Term Nervous system disorders
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10063399
    E.1.2Term Relapsing-remitting multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objectives of Part 1 are as follows:
    • To evaluate the safety, tolerability, and effect on the disease course of
    BG00012 (dimethyl fumarate) in pediatric participants with RRMS, as
    compared with a disease modifying treatment.
    • To assess pharmacokinetic (PK) and pharmacodynamic (PD)
    parameters in a representative subset of pediatric participants
    • To assess health outcomes and evolution of disability

    The primary objective of Part 2 is to evaluate the long-term safety of BG00012 in subjects who completed Part1 of Study 109MS306.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    key inclusion criteria:
    - Must have a body weight of ≥30 kg.
    - Must have a diagnosis of RRMS (consensus definition for pediatric
    RRMS [Krupp 2007]).
    - Must be ambulatory with a baseline EDSS score between 0 and 5.5,
    inclusive.
    - Must have experienced at least 1 relapse within the last 12 months
    prior to Day 1, or at least 2 relapses within the last 24 months prior to
    Day 1, with a prior brain MRI demonstrating lesions consistent with MS,
    or show evidence of Gd enhancing lesions of the brain on an MRI
    performed within the 6 weeks prior to Day 1.
    - Must be neurologically stable, with no evidence of relapse within 50
    days prior to Day 1 and no evidence of corticosteroid treatment within
    30 days prior to Day 1.
    - Subjects of childbearing potential who are sexually active must be
    willing to practice effective contraception during the study and be willing
    - Must be neurologically stable, with no evidence of relapse within 50
    days prior to Day 1 and no evidence of corticosteroid treatment within
    30 days prior to Day 1.
    - Subjects of childbearing potential who are sexually active must be
    willing to practice effective contraception during the study and be willing
    and able to continue contraception for at least 30 days after their final
    dose of study treatment.

    Part 2;
    -Subjects who have completed Part 1

    NOTE: Other protocol defined inclusion criteria may apply
    E.4Principal exclusion criteria
    Key exclusion criteria:
    - Primary progressive, secondary progressive, or progressive relapsing
    MS (as defined by [Lublin and Reingold 1996]). These conditions require
    the presence of continuous clinical disease worsening over a period of at
    least 3 months. Subjects with these conditions may also have
    superimposed relapses but are distinguished from relapsing remitting
    subjects by the lack of clinically stable periods or clinical improvement.
    - Disorders mimicking MS, such as other demyelinating disorders (e.g.,
    acute disseminated encephalomyelitis), systemic autoimmune disorders
    (e.g., Sjögren disease, lupus erythematosus), metabolic disorders (e.g.,
    dystrophies), and infectious disorders.
    - History of premalignant or malignant disease. Subjects with basal cell
    carcinoma that has been completely excised prior to screening will
    remain eligible.
    - History of severe allergic or anaphylactic reactions, or known drug
    hypersensitivity to DMF or fumaric acid esters.
    - History of abnormal laboratory results indicative of any significant
    endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic,
    renal, and/or any other major disease that would preclude participation
    in a clinical study.
    - History of clinically significant cardiovascular, pulmonary, GI,
    dermatologic, growth, developmental, psychiatric (including
    depression), neurologic (other than MS), and/or other major disease
    that would preclude participation in a clinical study.
    - History of human immunodeficiency virus.
    - An MS relapse that has occurred within 50 days prior to Day 1 AND/OR
    the subject has not stabilized from a previous relapse prior to Day 1.
    - Other unspecified reasons that, in the opinion of the Investigator or
    Biogen Idec, make the subject unsuitable for enrollment.
    - For the PD/PK subset of subjects: subjects unable to swallow the
    BG00012 capsule whole.
    Key Treatment history
    - Any previous treatment with Fumaderm (fumaric acid esters) or
    BG00012.
    - Prior treatment with any of the following: total lymphoid irradiation,
    cladribine, T-cell or T-cell receptor vaccination, any therapeutic
    monoclonal antibody, with the exception of rituximab or natalizumab
    - Prior treatment with any of the following medications within the 12
    months prior to Day 1: mitoxantrone, cyclophosphamide, rituximab
    - Prior treatment with any of the following medications or procedures
    within 6 months prior to Day 1: fingolimod, teriflunomide, natalizumab,
    cyclosporine, azathioprine, methotrexate, mycophenolate mofetil,
    laquinimod, IV immunoglobulin, plasmapheresis or cytapheresis
    - Prior treatment with any of the following within 3 months prior to Day
    1: glatiramer acetate, interferon-alpha, interferon β (subjects who are
    positive for neutralizing antibodies to interferon-β may receive
    interferon-β treatment up to 2 weeks prior to Day 1)
    - Treatment with any of the following medications within 30 days prior
    to Day 1:
    - steroids (IV or oral corticosteroid treatment, including agents that may
    act through the corticosteroid pathway [e.g., low dose naltrexone]), 4-
    aminopyridine or related products (except subjects on a stable dose of
    controlled-release fampridine for 3 months)

    Part 2;
    -Any significant changes in medical history occurring after enrollment in
    Part 1
    -Subjects who could not tolerate BG00012 in Part 1

    NOTE: Other protocol-defined inclusion/exclusion criteria may apply
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of Part 1 of the study is the proportion of participants free
    of new/newly enlarging T2 hyperintense lesions on brain MRI scans at
    Week 96.

    The primary endpoint of the Part 2 is the incidence of adverse events, serious adverse events and discontinuations of study treatment due to an adverse event.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1 - Day 1 (baseline visit), weeks 24, 48, 72, 96

    part 2-up to week 240
    E.5.2Secondary end point(s)
    The secondary endpoints of Part 1 are as follows:
    • Number of new/newly enlarging T2 hyperintense lesions on brain MRI
    scans at Weeks 24 and 96
    • Proportion of participants free of new/newly enlarging T2
    hyperintense lesions on brain MRI scans at Weeks 24 and 48
    • Proportion of participants free of new MRI activity as measured by
    brain MRI scans (new MRI activity includes: Gd enhancing MRI lesion on
    brain MRI scans; new T2 MRI lesions on brain MRI scans and newly
    enlarging LRI lesions on brain MRI scans) at Weeks 24, 48, and 96
    • Time to first relapse up to week 96
    • Proportion of participants who do not experience relapse up to Week
    96
    • Annualized relapse rate at Weeks 48 and 96
    • Number of participants that experience adverse events (AEs) and
    serious adverse events (SAEs), including prospective and follow up of
    flushing, nausea, abdominal pain, and diarrhea up to week 96
    • Participants receiving BG00012 who consent to participate in the
    PD/PK subset - PK parameters derived from PK subset data analysis:
    area under the concentration time curve from time 0 to 10 hours (AUC0
    10), maximum observed plasma concentration (Cmax), time to reach
    maximum observed plasma concentration (Tmax), lag time, elimination
    half-life (t½), apparent clearance (Cl/F), and apparent volume of
    distribution (V/F) up to week 4
    • Participants receiving BG00012 who consent to participate in the
    PD/PK subset - PD parameters, derived from PD subset data analysis:
    changes in the nuclear factor (erythroid derived 2) like 2 activation
    pathway markers quinone 1 (NQO 1) and heme oxygenase 1 (HO 1)up
    to week 4
    • Fatigue as measured by the Pediatric Quality of Life Inventory
    (PedsQL) Multidimensional Fatigue Scale scores (Multidimensional
    Fatigue Scale scores designed as a generic symptomspecific instrument
    to measure fatigue in patients with acute and chronic health conditions
    as well as healthy school and community populations.) up to week 96
    • Quality of Life as measured by the PedsQL up to week 96
    • Change from baseline to Week 96 in the Expanded Disability Status
    Scale (EDSS score; The EDSS measures the disability status of people
    with multiple sclerosis on a scale that ranges from 0 to 10. The first
    levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability
    and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory
    ability. The range of main categories include (0) = normal neurologic
    exam; to (5) = ambulatory without aid or rest for 200 meters; disability
    severe enough to impair full daily activities; to (10) = death due to MS.)
    up to week 96
    • Vital signs, electrocardiograms (ECGs) and changes in clinical
    laboratory data, including monitoring of liver function, renal function,
    hematologic and coagulation parameters up to week 96
    • Other pre-specified outcomes
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part 1 - The various secondary endpoints will be measured throughout the study as defined by the Schedule of Events. Specifically there are visits at Day 1 (baseline) weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 and a safety follow-up visit at week 100. There is also a safety telephone call at week2.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Part 2 is open label with all subjects receiving BG00012
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Bulgaria
    Canada
    Czech Republic
    Denmark
    France
    Hungary
    Israel
    Italy
    Poland
    Serbia
    Spain
    Sweden
    Turkey
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS: The end of study is last subject, last visit for final collection of data for the primary outcome
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 142
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 122
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 127
    F.4.2.2In the whole clinical trial 142
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects who choose not to enroll in the extension study will have a Safety Follow-Up Visit 4 weeks after taking the final dose. Subjects who withdraw prematurely will complete the Early Withdrawal Visit and the Safety Follow-Up Visit 4 weeks after taking their final dose.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-05-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-29
    P. End of Trial
    P.End of Trial StatusOngoing
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