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    Summary
    EudraCT Number:2007-003226-19
    Sponsor's Protocol Code Number:MS-LAQ-301
    National Competent Authority:Latvia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-09-12
    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 ConcernedLatvia - SAM
    A.2EudraCT number2007-003226-19
    A.3Full title of the trial
    Study Title: A multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, to evaluate the safety, tolerability and efficacy of daily oral administration of laquinimod 0.6 mg in subjects with relapsing remitting multiple sclerosis (RRMS)
    A.3.2Name or abbreviated title of the trial where available
    Allegro
    A.4.1Sponsor's protocol code numberMS-LAQ-301
    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 nameABR-215062 sodium salt
    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.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 PT
    E.1.2Classification code 10028245
    E.1.2Term 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 compared to placebo in RRMS subjects, as measured by the number of confirmed relapses during the core study period.
    E.2.2Secondary objectives of the trial
    Accumulation of physical disability measured by the time to confirmed
    progression of EDSS during the double blind study period (A confirmed
    progression of EDSS is defined as a 1 point increase from baseline on EDSS
    score if baseline EDSS was between 0 and 5.0, or a 0.5 point increase if
    baseline EDSS was 5.5, confirmed 3 months later. Progression can not be
    confirmed during a relapse). EDSS changes relate to converted EDSS scores.
    ! To asses the cumulative number of enhancing lesions on T1-weighted images
    taken on months 12, and 24 (and 30 in case of extending the study for 6 months).
    ! To asses the cumulative number of new hypointense lesions on enhanced T1
    scans at months 12, and 24 (and 30 in case of extending the study for 6 months).
    ! To asses the cumulative number of new T2 lesions on scans taken on months 12
    and 24 (and 30 in case of extending the study for 6 months).
    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 following ancillary studies will be performed in a subset of countries and sites:
     Frequent MRI: The cumulative number of T1-Gd enhancing lesions taken from scans obtained at months 0, 3, 6, 12, 18 and 24. In case the study will be extended also in month 30.
     MT: The change from baseline to month 12 and 24/30 months in magnetization transfer MRI.
     MRS: Change from baseline to 24/30 in Magnetic Resonance Spectroscopy (NAA:Cr ratio in lesions, normally-appearing white matter).
     Brain atrophy, as defined by the percentage of change from one scan to the subsequent scan in brain volume, in addition to the measurements done in the (Frequent MRI Cohort).
     Serum samples will be collected from all subjects in order to investigate the potential mechanism of action of laquinimod and additional biomarkers of inflammation and potential biomarkers of MS disease. These samples will be collected at months: 0 (baseline), 1, 12 and 24 (even if the study is extended to month 30).
     Whole blood and serum samples will be collected for evaluation of the immunological response to treatment with laquinimod and further investigation of the potential mechanism of action. The whole blood samples will be collected at months: 0 (baseline), 1, 3, 6, 12 and 24 (even if the study is extended to month 30) (in selected countries and sites).
     The serum samples will be collected at months: 0 (baseline), 1, 6, 12 and 24 (in selected countries and sites).
    The following ancillary studies will be performed in all sites:
     Relationship between PGx and response to laquinimod in terms of clinical, MRI and safety parameters.
     Population PK – fitness of a population model to different covariates will be evaluated. (covariates such as: gender, age, concomitant medications, weight, AE profile, habits)

    In Latvia only the following substudies will be performed:
    - Genetic Markers (PGx)
    - Population PK
    - Investigation of potential pathways of Laquinimod’s mechanism of action
    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 Kurtzke EDSS score of 0-5.5.
    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).
    4. Subjects must have had experienced one of the following:
     At least one documented relapse in the 12 months prior to screening
     At least two documented relapses in the 24 months prior to screening
     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 methods 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 double-barrier 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. Subjects with progressive forms of MS
    2. An onset of relapse, unstable neurological condition or any treatment with corticosteroids [intravenous (iv), intramuscular (im) and/or per os (po)] or ACTH between month -1 (screening) and 0 (baseline).
    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.
    6. Previous treatment with glatiramer acetate (Copaxone®) Interferon-β (either 1a or 1b) or IVIG within 2 months prior to screening visit.
    7. Systemic corticosteroid treatment of ≥30 consecutive days duration 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 two weeks prior to baseline visit.
    12. Major trauma or surgery two weeks prior to baseline
    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) as disclosed at screening.
    15. Positive screening test for Hepatitis B surface antigen, Hepatitis C antibody, or HIV antibody as disclosed at screening visit.
    16. Use of potent inhibitors of CYP3A4 within 2 weeks prior to baseline visit (1 month for fluoxetine) see detailed list in Appendix 5
    17. Use of amiodarone within 2 years prior to screening visit.
    18. Pregnancy or breastfeeding.
    19. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests or chest X-ray. Such conditions may include:
     A cardiovascular or pulmonary disorder that cannot be well-controlled by standard treatment permitted by the study protocol.
     A gastrointestinal disorder that may affect the absorption of study medication.
     Renal or metabolic diseases.
     Any form of chronic liver disease, including known non-alcoholic steatohepatitis.
     A ≥2xULN serum elevation of either of the following at screening: ALT, AST or direct bilirubin
     A QTC interval (obtained from either 2 ECG recordings at screening or from the mean value calculated from 3 measurements at baseline visit) which is >450msec.
     A family history of Long- QT syndrome.
     A history of drug and/or alcohol abuse.
     Major psychiatric disorder.
    20. A known history of sensitivity to Gd.
    21. Inability to successfully undergo MRI scanning.
    22. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.
    E.5 End points
    E.5.1Primary end point(s)
    The study's primary endpoint is the number of confirmed relapses during the double blind treatment phase.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 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
    an open label extension is foreseen
    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.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA106
    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 double blind phase will be visit 10 (month 24). The protocol includes a blinded variance and power reassessment, carried out few months prior to FPO. According to its results, the trial might be prolonged by 6 months (total 30 months). In addition a 12 months open label extension is foreseen.
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 610
    F.4.2.2In the whole clinical trial 1000
    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 Decision2007-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-09-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2010-11-08
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