An Evaluation Of BW430C (Lamotrigine) Versus Placebo In The Prevention Of Mood Episodes In Bipolar I Disorder Patients

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).