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    Summary
    EudraCT Number:2004-000114-40
    Sponsor's Protocol Code Number:CLIC477D2303
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2006-07-24
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2004-000114-40
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety and tolerability of licarbazepine 750-2000 mg/d as adjunctive therapy to lithium or valproate in the treatment of manic episodes of bipolar I disorder over 6 weeks
    A.3.2Name or abbreviated title of the trial where available
    D2303
    A.4.1Sponsor's protocol code numberCLIC477D2303
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) Numbernot applicable
    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 SponsorNovartis Pharma AG
    B.1.3.4CountrySwitzerland
    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 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 nameLicarbazepine
    D.3.2Product code LIC477
    D.3.4Pharmaceutical form Film-coated 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 INNLicarbazepine
    D.3.9.1CAS number 29331-92-8
    D.3.9.2Current sponsor codeLIC477
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250, 500
    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 placeboFilm-coated tablet
    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
    Bipolar I disorder, manic or mixed episodes
    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
    To demonstrate the efficacy of licarbazepine 750-2000 mg/d added to lithium or valproate in the treatment of manic episodes of bipolar I disorder by testing the following hypothesis:
    Licarbazepine added to lithium or valproate is superior to placebo combined with lithium or valproate in the reduction of the mean total score of the Young Mania Rating Scale (Y-MRS) from baseline to endpoint (Week 6).
    E.2.2Secondary objectives of the trial
    • To study the safety and tolerability of licarbazepine 750-2000 mg/d added to lithium or valproate in patients with manic episodes of bipolar I disorder by comparing licarbazepine added to lithium or valproate to placebo added to lithium or valproate with respect to the rates of adverse events and serious adverse events, as well as changes in laboratory values, ECGs and vital signs during the 6-week treatment.
    • To determine the efficacy of licarbazepine 750-2000 mg/d added to lithium or valproate in the treatment of manic episodes of bipolar I disorder by testing the following hypothesis:
    Licarbazepine added to lithium or valproate is superior to placebo added to lithium or valproate in the proportion of patients with a ≥50% reduction of the baseline Y-MRS at endpoint.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. males and females, 18 through 70 years of age;
    2. diagnosis of bipolar disorder type I, manic or mixed episodes according to DSM-IV
    criteria (i.e., 296.0, 296.4 or 296.6), including patients with/without psychotic features or with/without a history of rapid cycling;
    3. total score of at least 20 on the Young Mania Rating Scale (Y-MRS) at screening and at least 18 at baseline;
    4. need of psychiatric treatment;
    5. cooperation and willingness to complete all aspects of the study, including hospitalization;
    6. written informed consent provided prior to participation in the study.
    E.4Principal exclusion criteria
    1. current DSM-IV Axis-I diagnosis other than bipolar I disorder;
    2. history of schizophrenia or schizoaffective disorder;
    3. concomitant use of psychoactive medication other than lorazepam, lithium or valproate, whereby the washout time between the last dose of prior medication and the beginning of the Pre-randomization Treatment Phase (Day -7) is dependent on the medication:
    • oral antipsychotics, mood stabilizers (carbamazepine, lamotrigine, etc.), antidepressants and sedatives (benzodiazepines, zolpidem, zopliclone): 5 half lives.
    The last dose of lorazepam must be at least 12 hours before screening and baseline assessments
    • depot antipsychotics, MAOIs: 4 weeks;
    4. use of warfarin, tolbutamide, iodide salts, or zidovudine during the study;
    5. drug dependence during the one month prior to screening. Drug dependence is defined by DSM-IV criteria;
    6. positive urine drug screen at screening visit (or at repeat screening within 1 week of initial drug screen failure) for amphetamines, cocaine, hallucinogens, or opiates;
    7. history of suicide attempt within the past one month prior to screening or immediate risk of harm to self or others at the time of screening, as judged by the Investigator;
    8. mental retardation according to DSM-IV criteria;
    9. female patients of childbearing potential who are not using effective contraception during the study, are breast feeding, or have a positive pregnancy test (β-hCG) at screening or baseline. Effective contraceptive measures are the following:
    • A hormonal oral, transdermal, or injectable contraceptive agent with a double-barrier method
    • An implantable contraceptive device for at least 3 months prior to screening with a double-barrier method
    • A triple barrier-method of contraception (condom, diaphragm and a spermicide);
    10. serum sodium ≤130 mmol/L or history of multiple episodes of hyponatremia (defined as serum Na ≤125 mmol/L);
    11. any sensory or motor deficits that may prevent the patient from completing any of the study assessments;
    12. any non-psychiatric coexistent illness (e.g., diabetes mellitus, hypothyroidism) that has not been maintained in a stable condition for at least 3 months prior to baseline;
    13. clinically significant abnormal conditions of the gastrointestinal system, liver, or kidneys, which could result in the possibility of altered absorption, excess accumulation, or impairment of metabolism or excretion of the double-blind or open-label study drug;
    14. The Investigator should be guided by evidence such as the following:
    • recent major gastrointestinal tract surgery (e.g., gastrectomy, gastroenterostomy, bowel resection, etc.)
    • currently active peptic ulcer, ulcerative colitis, or regional ileitis;
    15. history of serious dermatological reaction while being treated with an antiepileptic medication;
    16. twice the upper normal limit at screening and upon repeated measurement for any one of the following laboratory parameters: SGOT, SGPT, LDH, alkaline phosphatase, or bilirubin; BUN values ≥30 mg/dL or creatinine clearance <30 mL/min;
    17. any other clinically significant abnormal laboratory findings at screening which remain abnormal upon repeated measurement;
    • any of the following serological findings:
    • a positive hepatitis A antibody (IgM)
    • a positive hepatitis B surface antigen (HBsAg)
    • a positive hepatitis B core antibody (Anti-HBcAb), along with a negative hepatitis B surface antibody (Anti-HBsAb), in the setting of abnormal liver enzymes or recent clinical symptoms of hepatitis (within the last 2 months);
    18. current diagnosis or recent past history of epilepsy, major head trauma, or progressive neurological disease (e.g., Parkinson’s disease, ALS);
    19. known hypersensitivity to lithium or valproate or drugs chemically related to licarbazepine (e.g., oxcarbazepine, carbamezapine);
    20. exposure during the 30 days preceding screening to any drug not registered for use in the country where the study is being conducted;
    21. electroconvulsive therapy (ECT) within the 3 months preceding baseline;
    22. any form of psychotherapy within the one month preceding screening;
    23. hospitalization for mania due to a court order;
    24. patients who are under legal supervision or guardianship;
    25. a documented history of non-response to lithium or valproate, whereby non-response is defined by the treating physician who documented the history.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy: The primary efficacy variable is the change from baseline to endpoint (Week 6) in the total score of the Y-MRS score.

    Safety: The assessment of safety will be based mainly on the frequency of adverse events and on the number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. electrocardiogram, vital signs, and special tests) will be considered as appropriate.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Information not present in EudraCT
    E.6.2Prophylaxis Information not present in EudraCT
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Information not present in EudraCT
    E.6.7Pharmacodynamic Information not present in EudraCT
    E.6.8Bioequivalence Information not present in EudraCT
    E.6.9Dose response Information not present in EudraCT
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic Information not present in EudraCT
    E.6.12Pharmacoeconomic Information not present in EudraCT
    E.6.13Others Information not present in EudraCT
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Information not present in EudraCT
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Information not present in EudraCT
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Information not present in EudraCT
    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 Yes
    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 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
    Last visit of the last patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    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 months7
    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) Yes
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-07-24. Yes
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 106
    F.4.2.2In the whole clinical trial 430
    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)
    Patients who complete the study may enter an open-label extension study (CLIC477D2303E1) to receive licarbazepine for 12 months.
    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 Decision2006-09-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-09-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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