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    Summary
    EudraCT Number:2005-001949-42
    Sponsor's Protocol Code Number:BRD50
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-07-04
    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 ConcernedUK - MHRA
    A.2EudraCT number2005-001949-42
    A.3Full title of the trial
    A randomised controlled trial of neuroprotection with lamotrigine in secondary progressive multiple sclerosis
    A.3.2Name or abbreviated title of the trial where available
    Neuroprotection with lamotrigine in multiple sclerosis
    A.4.1Sponsor's protocol code numberBRD50
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberN/A
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Information not present in EudraCT
    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 nameLamotrigine extended release tablets
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Modified-release tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNLamotrigine
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeN/A
    D.3.9.3Other descriptive nameN/A
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number400
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Multiple sclerosis
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The clinical trial we are proposing directly addresses the problem that at the moment there is no treatment that can stop people with multiple sclerosis (MS) from becoming permanently disabled in the long term by their illness: this usually occurs when people develop the secondary progressive form of MS, where it is believed that the disability arises because of permanent damage to the nerve fibres (axons) in the brain and spinal cord. We propose to test the possibility that the drug lamotrigine has the ability to protect axons from damage in people with secondary progressive MS, and that it can thereby prevent the accumulation of disability.
    E.2.2Secondary objectives of the trial
    To assess whether treatment of patients with lamotrigine is well tolerated over a period of two years, and to assess the utility of several magnetic resonance imaging techniques for measuring the degeneration of axons in patients with secondary progressive multiple sclerosis.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    a) Age 18−60 years. The lower limit has been chosen to enable informed consent, and the upper limit to avoid the possible inclusion of patients with cerebrovascular disease, which would potentially influence the cerebral volumes and white matter lesion numbers and thereby affect the MR outcome measures.

    b) Sex. Men and women will be included, but women of childbearing age would be required to use appropriate methods of contraception to avoid any teratogenic effects of lamotrigine.

    c) Patients with a diagnosis of secondary progressive MS where steady progression rather than relapse is the major cause of increased disability in the preceding 2 years, and who are therefore not eligible for treatment with disease modifying therapies according to the criteria of the Association of British Neurologists (available at www.theabn.org/downloads/msdoc.pdf) that are used as the current standard for practice in the UK National Health Service. Evidence of progression can be from either 1) clinical documentation of steadily increasing disability, or 2) an increase of at least 1 point in disability as measured using the EDSS.

    d) EDSS 4.0−6.5. Disability progresses at a relatively stable rate within this range of disability.
    E.4Principal exclusion criteria
    a) Secondary progressive MS with very rapid deterioration of disability, if eligible for treatment with mitoxantrone at the National Hospital for Neurology and Neurosurgery using a protocol recently approved by the Trust’s Pharmaceutical Committee, making it unethical to offer an alternative, experimental treatment in a clinical trial.

    b) Use of sodium or calcium channel blockers in the previous 2 weeks, corticosteroids in the previous 2 months, or immunosuppressive drugs in the previous 6 months (12 months for mitoxantrone), as these have potential neuroprotective properties which may interact with the effects of lamotrigine and therefore dilute the power of the trial.

    c) Evidence of significant hepatic or renal abnormalities, either in the clinical history or in blood tests prior to entry into the trial. Patients with other major systemic diseases will also be excluded.

    d) Past untoward reactions to lamotrigine, or disabling temperature−dependent symptoms related to MS, which may render participants vulnerable to side−effects of lamotrigine.

    e) Contraindications to magnetic resonance imaging.
    E.5 End points
    E.5.1Primary end point(s)
    Based on the assumption that axonal loss is a key mechanism of progressive cerebral atrophy in MS, the primary outcome will be the rate of reduction of partial cerebral volume over two years. We have chosen a method that has very good reproducibility, is sensitive in detecting progressive cerebral atrophy in secondary progressive MS and has been used effectively in a previous multi−centre placebo controlled trial in secondary progressive MS. Data using the method were also available to allow sample size calculations to be generated in designing the present trial. Imaging studies will be carried out on a 1.5 Tesla scanner at the Institute of Neurology. Measurements will be made from all five scans (baseline, 6, 12, 18 and 24 months). The primary outcome will be measured from the 6 x 3mm thick axial slices that are located immediately rostral to the velum interpositum. These slices will be selected from a 2D T1−weighted spin echo sequence (TR 550ms, TE 15ms) acquired through the whole brain with 3mm thick, axial, contiguous slices oriented to the bicallosal line. On each of

    the selected slices, the brain will be segmented from surrounding tissues and CSF using an automated segmentation ("Losseff cerebral method”), which has a scan−reposition−rescan reproducibility of 0.5%.
    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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Information not present in EudraCT
    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
    The end point will be the last visit of the last subject undergoing the trail.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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 state120
    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)
    We do not intend to offer to continue lamotrigine between the treatment phase and the completion of analysis, as this is a phase II trial and we will not know until the data has been analysed whether the therapy is beneficial. If it is beneficial, we will negotiate funding for continued prescription through the normal health commissioning process at each Centre.
    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 Decision2005-09-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-07-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2008-12-29
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