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    Summary
    EudraCT Number:2013-004622-29
    Sponsor's Protocol Code Number:101MS408
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-12-04
    Trial results View 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 ConcernedDenmark - DHMA
    A.2EudraCT number2013-004622-29
    A.3Full title of the trial
    A Multicenter, Randomized, Open-Label Study to Assess the Impact of Natalizumab versus Fingolimod on Central Nervous System Tissue Damage and Recovery in Active Relapsing-Remitting Multiple Sclerosis Subjects
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Impact of Natalizumab versus Fingolimod on Central Nervous System (CNS) Tissue Damage and Recovery in Active Relapsing-Remitting Multiple Sclerosis (RRMS) Subjects
    A.4.1Sponsor's protocol code number101MS408
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    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 pointN/A
    B.5.3 Address:
    B.5.3.1Street AddressInnovation House, 70 Norden Road
    B.5.3.2Town/ cityMaidenhead, Berkshire
    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 Yes
    D.2.1.1.1Trade name Tysabri®
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Limited
    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 nameAN100226, BG00002
    D.3.4Pharmaceutical form Concentrate and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNATALIZUMAB
    D.3.9.1CAS number 189261-10-7
    D.3.9.4EV Substance CodeSUB22282
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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.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 Gilenya
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    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 nameFingolimod
    D.3.4Pharmaceutical form 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 INNfingolimod
    D.3.9.1CAS number 162359-56-0
    D.3.9.3Other descriptive nameFINGOLIMOD HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB30967
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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.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
    Multiple Sclerosis (MS)
    E.1.1.1Medical condition in easily understood language
    Multiple Sclerosis (MS)
    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 19.0
    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 primary objective of the study is to assess the effect of natalizumab compared to fingolimod on the evolution of
    new on-treatment T1-gadolinium-enhancing (Gd+) lesions to persistent black holes (PBH) over 52 weeks.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to assess the effect of natalizumab compared to fingolimod on:
    • MRI measures of CNS tissue destruction as measured by the number of new T1-Gd+ lesions.
    • Various other MRI measures of disease activity.
    • No Evidence of Disease Activity (NEDA)
    • Relapse on treatment over 52 weeks.
    • The change in information processing speed as measured by the Symbol Digit Modalities Test (SDMT).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The Diffusion Tensor Imaging (DTI) substudy, the structural changes in brain tissue within lesions and normal appearing white matter (NAWM) by measuring through voxel-wise analysis the extent and severity of fractional anisotrophy (FA)- and diffusivity-measured tissue damage of natalizumab- and fingolimodtreated subjects over 52 weeks compared to healthy volunteer cohort.
    E.3Principal inclusion criteria
    Inclusion Criteria for MS Patients:
    - Must have a documented diagnosis of relapsing MS (McDonald 2010 Criteria [Polman 2011]) at study screening.
    - for subjects with a previous history of treatment with BRACE-TA he/she must have:
    • Been on therapy for at least 6 months (unless experiencing highly active disease; see #6 below)
    • At least 9 T2-hyperintense lesions on a brain MRI scan, and
    • Experienced ≥1 relapse while on therapy within the last 6 months prior to study screening and either:
    * ≥1 new T1-Gd+ lesion or ≥2 new T2 lesions on a brain MRI scan performed ≤6 months prior to study screening
    or
    * ≥2 new T2 lesions on a brain MRI scan performed ≤6 months prior to study screening, with comparison made to a T2
    MRI scan performed up to 18 months before study screening.
    - For subjects with highly active disease (defined by the criteria below), regardless of whether they are disease-modifying therapy (DMT)-naïve or had previous exposure to BRACE TA, he/she must have had:
    • ≥2 disabling relapses in the 12 months prior to study screening and either:
    * ≥1 new T1 Gd+ lesion on a brain MRI scan performed ≤6 months prior to study screening
    or
    * ≥2 new T2 lesions on a brain MRI scan performed ≤6 months prior to study screening with comparison made to a T2
    MRI scan performed up to 18 months before study screening
    - Willing to take natalizumab or fingolimod as the only DMTs for the duration of the study treatment period.
    - Must have an EDSS score from 0 to 5.5 inclusive at study screening.

    Inclusion Criteria for Healthy Volunteers:
    - Subjects who are generally healthy as demonstrated by physical examination and by medical history, with no history or evidence of major illnesses, diseases, or disorders.
    - Subjects of childbearing potential must practice effective contraception and be willing and able to continue contraception for duration of the study.
    - No history of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening.
    - Willing and able to comply with scheduled visits and imaging services.

    NOTE: Other protocol defined Inclusion criteria may apply
    E.4Principal exclusion criteria
    Exclusion Criteria for MS Patients:
    - History of or positive test result at study screening for HIV
    - History or positive test result at study screening for HCV antibody or current hepatitis B infection (defined as positive for HBsAg and/or HBcAb). Subjects with immunity to hepatitis B from either active vaccination (defined as negative HBsAg, positive HBsAb and negative HBcAb) or from previous natural infection (defined as negative HBsAg, positive HBsAb immunoglobulin G, and positive HBcAb) are eligible to participate in the study
    - Prior treatment with natalizumab or fingolimod
    - Diagnosis of PPMS and/or SPMS
    - History of or known active malignant disease, including solid tumors and hematologic malignancies (subjects with cutaneous basal and squamous cell carcinoma that has been completely excised and considered cured prior to study screening remain eligible)
    - History of opportunistic infections (including PML) or any clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic,metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal condition, or other major disease
    - A clinically significant infectious illness (eg, pneumonia, septicemia) within the 1 mth prior to study screening
    - History of drug or alcohol abuse within 1 yr prior to study screening
    - Exposure to IVIg, monoclonal antibodies, cytokines, growth factors, soluble receptors, other recombinant products, or fusion proteins within 1 yr prior to study screening
    - History of immunosuppressant use (eg, mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, cladribine, rituximab) in the last 12 mths prior to study screening. Treatment with IV and/or oral corticosteroids (topical corticosteroids are acceptable) within 4 wks of baseline DTI-MRI assessment
    - An MS relapse that has occurred within the 30 days prior to randomization and/or the subject has not stabilized from a previous relapse prior to randomization
    - Current/previous participation in investigational drug studies
    - Subject has any contraindications to fingolimod or natalizumab, as described in the respective Prescribing Information or has any medical condition as described in the warnings and precautions of the respective Prescribing Information that makes the subject unsuitable for participation in the study
    - Subject treated with teriflunomide who did not undergo an accelerated elimination procedure prior to study screening.
    - History or evidence of macular edema on ophthalmologic exam
    - History of congenital QT prolongation, unexplained hypokalemia, myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure in last 6 mths
    - Mobitz type II second degree or third degree AV block or sick sinus syndrome, symptomatic bradycardia, recurrent syncope, or severe untreated sleep apnea
    - Baseline corrected QTc (Fridericia [QTcF] or Bazett's [QTcB] formula) interval ≥470 ms in females and ≥450 ms in males
    - Treatment with Class Ia (e.g., procainamide, quinidine, ajmaline, disopyramide) or Class III (amiodarone, bretylium, dofelitide, sotalol, ibulitide, azilimide) anti-arrhythmic drugs
    - Concurrent therapy with drugs that slow heart rate (eg, beta-blockers, heart-rate lowering calcium channel blockers such as diltiazem, verapamil or digoxin), prolong the QTc interval, or are potent inducers of CYP450
    - Hypertension not controlled with prescribed medications
    - History of severe respiratory disease, pulmonary fibrosis or class III or IV chronic obstructive pulmonary disease
    - Subjects without immunity to VZV from either active vaccination or from previous natural infection (defined as negative IgG antibodies) at study screening
    - The use of live or live attenuated vaccination within 4 wks of study screening
    - Presence of a metal device affected by MRI (eg, electronic or magnetic implant, cardiac pacemaker or defibrillator) or potential ferromagnetic foreign body (metal slivers, shavings, other metal objects), which would be a contraindication for MRI
    - Claustrophobia sufficient to interfere with generating reliable MRI scans in MS subjects in the DTI sub-study
    - Women who are breastfeeding, pregnant, or planning to become pregnant; not postmenopausal or surgically sterile and are unwilling to practice contraception

    Exclusion Criteria for Healthy Volunteers:
    - Claustrophobia sufficient to interfere with generating reliable MRI scans
    - History of other major illness including neurological disorders
    - Presence of a metal device affected by MRI (eg, electronic or magnetic implant, cardiac pacemaker or defibrillator) or potential ferromagnetic foreign body (metal slivers, metal shavings, other metal objects), which would be a contraindication for MRI
    - Women who are currently pregnant or breastfeeding, or who have a positive pregnancy test result at screening

    NOTE: Other protocol defined Exclusion criteria may apply
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the cumulative number of ≥6-month confirmed T1-hypointense lesions (i.e., PBH) arising from new on-treatment T1-Gd+ lesions.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Weeks 4, 8, 12, 16, 20, 24
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are the follwoing:
    • MRI endpoints:
    o Cumulative number of new T1-Gd+ lesions .
    o Change in total T1-hypointense and total T2-hyperintense lesion volumes.
    o Cumulative number of new or enlarging T2 lesions.
    • Proportion of subjects with NEDA according to the following definition:
    o No relapses.
    o No 12-week confirmed disability progression based on EDSS.*
    o No new T1-Gd+ lesions on brain MRI.
    o No new or enlarging T2-hyperintense lesions.
    • Time to first relapse, cumulative risk of relapses and time to complete recovery from first relapse. **
    • Change in information processing speed as measured by the SDMT from baseline to Week 24 and Week 52.

    * Increase of 1.0 or more on the EDSS from a baseline score of 1.0 or more, or an increase of 1.5 or more from a baseline score of 0 that was sustained for 12 weeks (progression could not be confirmed during a relapse).
    ** 12-week confirmed complete Expanded Disability Status Scale (EDSS) recovery from first on-treatment relapse is defined as an EDSS score that is equal to or lower than the last pre-relapse EDSS score and sustained for at least 12 week
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 4, 8, 12, 16, 20, 24, 52
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Australia
    Czech Republic
    Denmark
    France
    Germany
    Italy
    Spain
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 540
    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 Yes
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 327
    F.4.2.2In the whole clinical trial 540
    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)
    None
    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 Decision2015-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-29
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2016-05-17
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