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    Summary
    EudraCT Number:2007-005450-23
    Sponsor's Protocol Code Number:MS-LAQ-302
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-05-27
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2007-005450-23
    A.3Full title of the trial
    A Multinational, Multicenter, Randomized, Parallel-Group study performed in subjects with Relapsing-Remitting Multiple Sclerosis (RRMS) to assess the efficacy, safety and tolerability of laquinimod over placebo in a double-blind design and of a reference arm of Interferon β-1a (Avonex®) in a rater-blinded design
    A.3.2Name or abbreviated title of the trial where available
    BRAVO
    A.4.1Sponsor's protocol code numberMS-LAQ-302
    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 SponsorTeva Pharmaceutical Industries Ltd
    B.1.3.4CountryIsrael
    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 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 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 nameLaquinimod Capsules 0.6 mg
    D.3.2Product code TV-5600
    D.3.4Pharmaceutical form Capsule*
    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 INNLaquinimod
    D.3.9.1CAS number 248282-07-7
    D.3.9.2Current sponsor codeTV-5600
    D.3.9.3Other descriptive nameLaquinimod Sodium (USAN)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.6
    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 No
    D.3.11.8Extractive medicinal product No
    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.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 30 microgram/0.5 ml Solution for Injection
    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.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntramuscular use
    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) 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 No
    D.3.11.8Extractive medicinal product No
    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 Yes
    D.3.11.13.1Other medicinal product typebeta-1a Interferon is produced from Chinese Hamster Ovary (CHO) cells which contain the gene for human interferon beta.
    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 placeboCapsule*
    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
    Relapsing Remitting Multiple Sclerosis (RRMS)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10063399
    E.1.2Term Relapsing-remitting multiple sclerosis
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of 0.6 mg daily dose of laquinimod in patients with RRMS, as measured by the number of confirmed relapses during the treatment period.
    E.2.2Secondary objectives of the trial
    To assess the effect of 0.6 mg daily dose of laquinimod on the accumulation of disability, as assessed by the MSFC score at the end of the treatment period.

    To assess the effect of 0.6 mg daily dose of laquinimod on the development of brain atrophy as defined by the percent brain volume change from baseline at the end of the treatment period.

    To assess the effect of 0.6 mg daily dose of laquinimod on the accumulation of physical disability as measured by the time to confirmed progression of EDSS during the treatment period.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacogenetic (PGt) ancillary study:
    This ancillary study is planned to be performed in all sites.
    Ojective:
    Relationship between PGt and response to laquinimod or to Avonex® in terms of clinical, MRI and safety parameters.
    Pharmacogenetic (PGt) assessment: Blood samples for PGt parameters will be collected from all subjects at month -1 (screening).

    Second ancillary study which will be performed in all subjects from US sites only:

    The effect of general health and symptom severity on work will be
    assessed by the work productivity and activities impairment –
    General Health (WPAI-GH) questionnaire (Appendix 16) at
    months 0 (baseline) and every 3 months thereafter, until month 24
    (termination/ early discontinuation) visit (this assessment will be
    performed in all subjects from US sites only).
    E.3Principal inclusion criteria
    1.Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria [Ann Neurol 2005: 58:840-846], with a relapsing-remitting disease course.
    2.Subjects must be ambulatory with Converted EDSS score of 0-5.5 in both screening and baseline visits.
    3.Subjects must be in a stable neurological condition and free of corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os (PO)] 30 days prior to screening (month -1) and between screening (month -1) and baseline (month 0) visits.
    4.Subjects must have had experienced one of the following:
    At least one documented relapse in the 12 months prior to screening, or
    At least two documented relapses in the 24 months prior to screening or
    One documented relapse between 12 and 24 months prior to screening
    with at least one documented T1-Gd enhancing lesion in an MRI performed
    within 12 months prior to screening.
    5.Subjects must be between 18 and 55 years of age, inclusive.
    6.Subjects must have disease duration of at least 6 months (from the first symptom) prior to screening.
    7.Women of child-bearing potential must practice an acceptable method of birth control [acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner’s vasectomy or a double-protection method (condom or diaphragm with spermicide)].
    8.Subjects must be able to sign and date a written informed consent prior to entering the study.
    9.Subjects must be willing and able to comply with the protocol requirements for the duration of the study.
    E.4Principal exclusion criteria
    1. An onset of relapse or any treatment with corticosteroids (intravenous [IV],
    intramuscular [IM] and/or per os [PO]) or ACTH between month -1 (screening)
    and 0 (baseline).
    2. Subjects with progressive forms of MS.
    3. Use of experimental or investigational drugs, and/or participation in drug clinical
    studies within the 6 months prior to screening.
    4. Use of immunosuppressive (including Mitoxantrone (Novantrone®) or cytotoxic
    agents within 6 months prior to the screening visit.
    5. Previous use of either of the following: natalizumab (Tysabri®), cladribine,
    laquinimod, Interferon beta-1a (Avonex® or Rebif®), Interferon beta-1b
    (Betaseron®/Betaferon®) or any other experimental Interferon-beta for MS.
    6. Previous treatment with glatiramer acetate (Copaxone®) or IVIG within 2 months
    prior to screening visit.
    7. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid
    treatment within 2 months prior to screening visit.
    8. Previous total body irradiation or total lymphoid irradiation.
    9. Previous stem-cell treatment, autologous bone marrow transplantation or
    allogenic bone marrow transplantation.
    10. A known history of tuberculosis.
    11. Acute infection within 2 weeks prior to baseline visit.
    12. Major trauma or surgery within 2 weeks prior to baseline visit.
    13. A history of vascular thrombosis (excluding catheter-site superficial venous
    thrombophlebitis).
    14. A carrier state of factor V Leiden mutation (either homo- or heterozygous) by
    history or as disclosed at screening.
    15. Positive screening test for Hepatitis B surface antigen or Hepatitis C antibody as
    disclosed at screening visit.
    16. Known human immunodeficiency virus (HIV) positive status.
    17. Use of inhibitors of CYP3A4 within 2 weeks prior to baseline visit
    18. Use of amiodarone within 2 years prior to screening visit.
    19. Pregnancy or breastfeeding.
    20. Subjects with a clinically significant or unstable medical or surgical condition that,
    in the Investigator's opinion, would preclude safe and complete study
    participation, as determined by medical history, physical examinations, ECG,
    laboratory tests or chest X-ray.
    21. A known history of sensitivity to Gadolinium.
    22. Inability to successfully undergo MRI scanning.
    23. A known drug hypersensitivity that would preclude administration of
    laquinimod, such as hypersensitivity to: mannitol, meglumine or sodium stearyl
    fumarate.
    24. A known history of hypersensitivity to natural or recombinant interferon beta,
    human albumin, or any other component of the formulation of Avonex®.
    E.5 End points
    E.5.1Primary end point(s)
    The number of confirmed relapses during the treatment period.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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 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 Yes
    E.8.1.7.1Other trial design description
    Third arm comparator, rater-blinded
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Avonex 30 microgram/0.5 ml Solution for Injection
    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 concerned13
    E.8.5The trial involves multiple Member States Information not present in EudraCT
    E.8.5.1Number of sites anticipated in the EEA69
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    Last visit of the three-arm phase will be visit 12 (month 24).

    Subjects successfully completing the study will be offered the opportunity to enter into a 1-year open-label extension in which laquinimod 0.6 mg/d will be administered.
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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) Information not present in EudraCT
    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 state162
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 650
    F.4.2.2In the whole clinical trial 1200
    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 Decision2008-05-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-03-20
    P. End of Trial
    P.End of Trial StatusCompleted
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