An Evaluation Of BW430C (Lamotrigine) Versus Placebo In The Prevention Of Mood Episodes In Bipolar I Disorder Patients
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Intervention: lamotrigine; Placebo
Intervention description: lamotrigine 100mg/day or 200mg/day; placebo once daily
Intervention MeSH terms: Lamotrigine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 215.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No
Keywords: Lamotrigine; Prevention of relapse or recurrence of a mood episode; Bipolar I disorder

Summary:

      This study is planned to objectively assess the efficacy and safety of lamotrigine
      maintenance therapy after symptoms of mood episode had been stabilised by open-label
      treatment with lamotrigine alone or in combination with other psychotropic medication in
      patients with bipolar I disorder.
    

Eligibility criteria:

        Inclusion Criteria:

        At Screening Disease to be studied: Has a diagnosis of following disease as defined by
        DSM-IV-TR criteria.

          -  Bipolar I Disorder, most recent episode depressed（296.5x）

          -  Bipolar I Disorder, most recent episode hypomanic（296.40）

          -  Bipolar I Disorder, most recent episode manic（296.4x） The diagnosis of mood episode
             will be made with reference to Mini International Neuropsychiatric Interview: M.I.N.I,
             Japanese Version.

        At Screening

        The subject who has a diagnose of bipolar I disorder, most recent episode depressed
        (296.5x) must meet the following criteria:

          -  Is currently experiencing a major depressive episode or has had a major depressive
             episode as defined by DSM-IV-TR criteria within 60 days of the screening visit and at
             least one additional major depressive episode and one manic or hypomanic episode, as
             defined by DSM-IV-TR criteria, within 3 years of enrolment. A well documented history
             of a mixed episode that meets DSM-IV-TR criteria may be counted as a previous
             episode.All subjects must have experienced at least one well-documented manic or mixed
             episode in the past.

          -  Has a duration of the most recent/current depressive episode of at least 2 weeks but
             not longer than 12 months prior to enrolment.

          -  The subject without current major depressive episode must have a major depressive
             episode within 60 days of screening and has depressive symptoms at screening or is
             under treatment for depressive symptoms, which can be confirmed by medical record,
             etc.

          -  If the subject is currently experiencing a major depressive episode, the subject must
             have a minimum total score on the HAM-D (17-item scale) of 18 at the screening. This
             criterion will not apply to the subject with recent depressive episode.

        At Screening

        The subject who has a diagnose of bipolar I disorder, most recent episode hypomanic（296.4x）
        or bipolar I disorder, most recent episode manic（296.5x） must meet the following criteria:

          -  Has experienced a recent manic or hypomanic episode (current or within 60 days of the
             Screening Visit) and has had at least one additional manic or hypomanic episode and
             one depressed episode, as defined by DSM-IV-TR criteria, within three years of
             enrolment. A well documented history of a mixed episode that meets DSM-IV-TR criteria
             may be counted as a previous episode. All subjects must have experienced at least one
             well-documented manic or mixed episode in the past.

          -  Has a duration of the index manic episode of at least 1 week (unless hospitalised) or
             hypomanic episode of at least 4 days. In neither case should the index episode be more
             than 12 months in duration.

          -  The subject current experiencing hypomania episode or without current episode must
             have a manic episode which can be confirmed by medical record, etc. The subject
             without current episode must have a episode within 60 days of screening and has manic
             or hypomanic symptomatology is under treatment for manic or hypomanic symptoms.

          -  If the subject's index episode is subject initial manic mood event, subject must have
             a minimum score of 10 (moderate severity) on the first 11 items of the YMRS at the
             screening. A threshold YMRS score that indicates significant manic symptoms is not
             required for patients who previously experienced well-documented DSM-IV-level mania or
             when the index episode is hypomania or when a subject's index manic or hypomanic
             episode is documented to have occurred within 60 days of the screening Visit.

        At Screening Age: Is at least 20 years of age (at the time of informed consent). At
        Screening Sex: either sex. Female of child-bearing potential will be eligible for inclusion
        in this study. However they have to have a negative pregnancy test at the screening visit,
        agree to further pregnancy testing at the time points determined in study assessments and
        procedures and practice one of the following methods of contraception from the screening
        visit until the end of the follow-up examination.

          -  Abstinence

          -  Injectable progestogen

          -  Implants of levonorgestrel

          -  Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP
             effectiveness criteria as stated in the product label

          -  Male partner sterilization (vasectomy with documentation of azoospermia) prior to the
             female subject's entry into the study, and this male is the sole partner for that
             subject

          -  Double barrier method: condom or occlusive cap (diaphragm or cervical / vault caps)
             plus spermicidal agent (foam /gel / film / cream / suppository) At Screening In/Out
             patient: Either At Screening Informed consent: the subject capable of giving written
             informed consent. At Week 0 of First Phase (titration) If the subject is currently
             experiencing a major depressive episode, the subject must have a minimum total score
             at baseline on the HAM-D (17-item scale) of 18 at the start of First Phase. This
             criterion will not apply to the subject with recent depressive episode.

        At Week 0 of First Phase (titration) If the subject's index episode is subject initial
        manic mood event, subject must have a minimum total score at baseline of 10 (moderate
        severity) on the first 11 items of the YMRS at the start of First Phase (titration). A
        threshold YMRS score that indicates significant manic symptoms is not required for patients
        who previously experienced well-documented DSM-IV-level mania or when the index episode is
        hypomania or when a subject's index manic or hypomanic episode is documented to have
        occurred within 60 days of the screening Visit.

        At Week 0 of Second Phase (maintenance therapy) Each subject completing 8 to 16 weeks of
        open-label lamotrigine treatment in the First Phase must meet all of the following
        inclusion criteria to be eligible for entry into the Second Phase (maintenance therapy,
        randomization phase).

        At Week 0 of Second Phase (maintenance therapy) Has no tolerability problem with
        lamotrigine at a minimum dosage of 100 mg/day during the final 2 weeks of the First Phase
        (titration).

        At Week 0 of Second Phase (maintenance therapy) Has improved/stabilised during the First
        Phase (titration) as indicated by a CGI-S score of ≤3 (mildly ill). Once improved, the
        subject must also demonstrate sustained improvement by achieving a CGI-S score of ≤3
        (mildly ill) for at least 4 consecutive weeks of treatment immediately prior to the Second
        Phase (maintenance therapy) (randomization).

        At Week 0 of Second Phase (maintenance therapy) Has demonstrated adequate compliance with
        the study treatment in the First Phase (titration) (compliance rate: at least 70%).

        At Week 0 of Second Phase (maintenance therapy) In/Out patient: Either

        Exclusion Criteria:

        At Screening Has a DSM-IV-TR diagnosis of rapid cycling and has had more than six mood
        episodes including depression, mania, hypomania or mixed, in the 12-month period prior to
        screening. Note: while 4 or more episodes in the past 12 months constitute rapid cycling up
        to six episodes in the past 12 months are allowed in this protocol.

        At Screening Has a DSM-IV-TR diagnosis of bipolar I disorder, most recent episode mixed
        (296.6x).

        At Screening Has a DSM-IV-TR diagnosis of Axis II which would suggest non-responsiveness to
        pharmacotherapy for bipolar disorder.

        At Screening Has a DSM-IV-TR diagnosis of or has received treatment for major depressive
        disorder, panic disorder, obsessive-compulsive disorder, social phobia, bulimia nervosa,
        schizophrenia or schizoaffective disorder within 12 months of screening.

        At Screening Has a history of substance (including alcohol and drugs) dependence within 12
        months of screening or abuse within 1 month of screening according to DSM-IV-TR.

        At Screening Patients whose mood episode is due to direct physiological effects of a
        general medical condition (for example, hypothyroidism, hyperthyroidism) At Screening Has a
        score of 3 or more on item of the HAM-D related to suicide or is at a high suicidal risk in
        the judgment of the investigator/sub-investigator.

        At Screening Has a history of severe rash or rash due to anti-epileptic drugs. At Screening
        Patients with severe hepatic/renal/cardiac/pulmonary disorder or hematopoietic disorder.
        The severity refers to Grade 3 according to the Classification of the Severity of Adverse
        Experiences (PAB/SD Notification No. 80, dated 29 June 1992).

        At Screening Patients have less than 5 years of remission history from clinically
        significant malignancy (other than e.g. basal cell or squamous cell skin cancer, in-situ
        carcinoma of cervix or prostate CA in situ).

        At Screening Patients with chronic hepatitis typeB and /or typeC which is positive of
        hepatitis B surface antigen （HBsAg）and/or hepatitis C antibody.

        At Screening Has an acute or chronic illness likely to impair drug absorption,
        distribution, metabolism or excretion or has any unstable physical symptoms likely to
        require hospitalisation during participation in the study.

        At Screening Female patients who are pregnant or lactating, who may be pregnant, or who
        plan for pregnancy during the study.

        At Screening Has a history or current diagnosis of epilepsy. At Screening Has a history of
        treatment with lamotrigine. At Screening Patients with a history of drug allergy to any
        ingredient of the test-drug. At Screening Has received an investigational drug within 30
        days of screening. At Screening Is morbidly obese (Body Mass Index [BMI] >40) BMI = body
        weight (kg)/height (m2).

        At Screening Patients whom the investigator or sub-investigator considers ineligible for
        the study.

        At Week 0 of First Phase (titration) Has a score of 3 or more on item of the HAM-D related
        to suicide or is at a high suicidal risk in the judgment of the
        investigator/sub-investigator and continues .to meet the criteria at the screening visit.

        At Week 0 of Second Phase (maintenance therapy) Has signs or symptoms of psychosis. At Week
        0 of Second Phase (maintenance therapy) Has a score of 3 or more on item of the HAM-D
        related to suicide or is at a high suicidal risk in the judgment of the
        investigator/sub-investigator.

        At Week 0 of Second Phase (maintenance therapy) Has had a change in lamotrigine dosage
        during the final week of the First Phase (titration).

        At Week 0 of Second Phase (maintenance therapy) Has a diagnosis of bipolar I disorder, most
        recent episode of depressed (296.5x) and has experienced manic, hypomanic or mixed
        symptoms; Has a diagnosis of bipolar I disorder, most recent episode hypomanic (296.40) or
        most recent episode manic (296.4x) and has experienced depressive symptoms, that require
        treatment during the First Phase (titration).