A Clinical Evaluation Of BW430C (Lamotrigine) In Bipolar I Disorder- Long-term Extension Of Study SCA104779 (NCT00550407) -

Study Overview
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Brief Summary
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This study is planned to assess the long-term safety of lamotrigine in Japanese patients with bipolar I disorder who will continue into the 52-week extension upon completion of a double-blind comparative study (Study No.: SCA104779 (NCT00550407)), i.e. the patients who receive the addition of any additional treatment to intervene in a mood episode in the double-blind phase or the patients completing the double-blind phase.

Official Title
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Study SCA106052, a Clinical Evaluation of BW430C (Lamotrigine) in Bipolar I Disorder- Long-term Extension Study (Extension of Study SCA104779 (NCT00550407))

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: BW430C (lamotrigine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Of subjects participating in the preceding double-blind study, those who are judged by the investigator/sub-investigator to have well tolerated the double-blind treatment and to be eligible for the 52-week extension treatment 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 start of this study, 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 start of this study until the end of the follow-up examination: Abstinence Oral contraceptive, either combined or progestogen alone (except during the Dosage Adjustment Phase) Injectable progestogen Implants of levonorgestrel Estrogenic vaginal ring (except during the Dosage Adjustment Phase) Percutaneous contraceptive patches (except during the Dosage Adjustment Phase) 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) In/Out patient: Either Informed consent: the subject capable of giving written informed consent Exclusion Criteria: 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 Has a history of severe rash or rash due to anti-epileptic drugs 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) 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) Patients with chronic hepatitis typeB and /or typeC which is positive of hepatitis B surface antigen （HBsAg）and/or hepatitis C antibody 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 Female patients who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study Has a history or current diagnosis of epilepsy Has received an investigational drug within 30 days of screening Patients with a history of drug allergy to any ingredient of the test-drug Patients whom the investigator or sub-investigator considers ineligible for the study

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lamotrigine<br>study drug | Drug: BW430C (lamotrigine)<br>* lamotrigine 50mg/day-400mg/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Serious Adverse Event (SAE) and Any Non Serious Adverse Event | An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of medicinal product, which does not necessarily have a causal relationship with the treatment. An SAE is any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or causes its prolongation, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. A complete list of all SAEs and AEs experienced in the study can be found in the SAE/AE section. | From baseline (Week 0) until 2 weeks after the end of treatment (Week 54) | 
| Number of Participants With the Indicated Clinical Laboratory Test Values for Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Gamma Glutamyl Transferase (GGT), and Lactate Dehydrogenase (LDH) | Participants in the study were evaluated for the following clinical laboratory parameters at the indicated time points: ALP, ALT, AST, GGT, and LDH. Participants were categorized as High for laboratory values above normal (reference) and as Low for laboratory values below normal ranges used by the central laboratory. Normal ranges: ALP, 104-338 International Units per liter (IU/L); ALT, 5-45 IU/L; AST, 10-40 IU/L; GGT, Male: 0-79 IU/L, Female: 0-48 IU/L; LDH 120-245 IU/L. | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/Early Withdrawal (EW) | 
| Number of Participants With Clinical Laboratory Test Values Out of the Normal Range and in the Normal Range for Total Bilirubin and Creatinine at Weeks 0, 6, 16, 28, 40, and 52/EW | Participants in the study were evaluated for the following clinical laboratory parameters at the indicated time points: total bilirubin and creatinine. Participants were categorized as High for laboratory values above normal (reference) and as Low for laboratory values below normal ranges used by the central laboratory. Normal ranges: total bilirubin, 3.42-17.1 micromoles per liter (UMOL/L); creatinine, Male: 57.46-96.356 UMOL/L, Female: 40.664-72.488 UMOL/L. | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | 
| Number of Participants With Clinical Laboratory Test Values Out of the Normal Range and in the Normal Range for Calcium, Cholesterol, Chloride, Potassium, Sodium, Triglycerides, and Urea/Blood Urea Nitrogen (BUN) at Weeks 0, 6, 16, 28, 40, and 52/EW | Participants were evaluated for the following clinical laboratory parameters for blood chemistry at the indicated time points: electrolytes (calcium, chloride, potassium, sodium), cholesterol, triglycerides, and urea/BUN. Participants were categorized as High for laboratory values above normal (reference) and as Low for laboratory values below normal ranges used by the central laboratory. Normal ranges (micromoles per liter [MMOL/L]): calcium, 2.0459-2.495; chloride, 98-108; potassium, 3.5-5; sodium, 135-145; cholesterol, 3.879-5.66334; triglycerides, 0.565-1.6837; urea/BUN, 2.856-7.14. | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | 
| Number of Participants With Clinical Laboratory Test Values Out of the Normal Range and in the Normal Range for Platelet Count and White Blood Cell Count at Weeks 0, 6, 16, 28, 40, and 52/EW | Participants in the study were evaluated for the following clinical laboratory parameters of hematology at the indicated time points: platelet count and white blood cell count. Participants were categorized as High for laboratory values above normal (reference) and as Low for laboratory values below normal ranges used by the central laboratory. Normal ranges: platelet count, 140-379 GI (gibi; 10^9) per liter (GI/L); white blood cell count, 3.5-9.7 GI/L. | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | 
| Number of Participants With Clinical Laboratory Test Values Out of the Normal Range and in the Normal Range for Total Protein, Hemoglobin, and Hematocrit at Weeks 0, 6, 16, 28, 40, and 52/EW | Participants in the study were evaluated for total protein, hemoglobin, and hematocrit at the indicated time points. Participants were categorized as High for laboratory values above normal (reference) and as Low for laboratory values below normal ranges used by the central laboratory. Normal ranges: total protein, 65-82 grams per liter (G/L); hemoglobin, Male: 136-183 G/L, Female: 112-152 G/L; hematocrit (proportion of 1), Male: 0.404-0.519, Female: 0.343-0.452. | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | 
| Number of Participants With Clinical Laboratory Test Values Out of the Normal Range and in the Normal Range for Red Blood Cell Count at Weeks 0, 6, 16, 28, 40, and 52/EW | Red blood cell count was measured in participants at the indicated time points. Participants were categorized as High for laboratory values above normal (reference) and as Low for laboratory values below normal ranges used by the central laboratory. Normal ranges: red blood cell count, Male: 4.38-5.77 TI (tebi; 10^12)/L, Female: 3.76-5.16 TI/L. | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | 
| Number of Participants in the Indicated Category for Urine Glucose, Urine Protein, and Urine Urobilinogen at Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | Urine glucose, urine protein, and urine urobilinogen were measured in participants at the indicated time points. In this dipstick (qualitative) test, the level of glucose, protein, and urobilinogen in urine samples was recorded as negative (NEG [-]), trace (TRA [+/-]), 1+, 2+, 3+, 4+, and 5+ (the plus sign increases with a higher level of glucose, protein, or urobilinogen in the urine: 1+=slightly positive, 2+=positive, 3+=high positive, 4+=very high positive, 5+=more positive than 4+). | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | 
| Mean Systolic Blood Pressure and Diastolic Blood Pressure of Participants at Baseline (Week 0) and Weeks 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | Systolic and diastolic blood pressure was measured in participants at the indicated time points. | Baseline (Week 0) and Weeks 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | 
| Mean Heart Rate of Participants at Week 0 (Baseline) and Weeks 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | Heart rate was measured in participants at the indicated time points. | Baseline (Week 0) and Weeks 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | 
| Mean Weight of Participants at Baseline (Week 0) and Weeks 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | The weight of participants was recorded at the indicated time points. | Baseline (Week 0) and Weeks 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | 
| Mean Body Mass Index (BMI) of All Participants at Week 0 (Baseline) and Weeks 6, 8, 12, 16, 20, 24, 28, 32,36, 40, 44, 48, and 52/EW | The BMI for participants was calculated at the indicated time points as body weight in kilograms divided by height in meters squared. | Baseline (Week 0) and Weeks 0, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | 
| Number of Participants With the Indicated Electrocardiogram (ECG) Findings at Weeks 0, 6, 28, and 52/EW | ECGs were recorded in participants at the indicated time points. ECG findings, as determined by the physicians, were reported as normal, abnormal but not clinically significant (NCS), abnormal but clinically significant (CS), and no result. Specific definitions of ECG categorizations were not provided; physicians were expected to apply reasonable standards of clinical judgment. | Weeks 0, 6, 28, and 52/EW | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impressions of Severity (CGI-S) Total Score at Weeks 0, 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | The CGI-S is a standardized assessment tool that uses a 7-point scale to assess a participant's severity of illness. The total score ranges from 0 to 7: 0=not assessed, 1=normal, 2=borderline ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severly ill, 7=extremely ill. Higher scores reflect a higher severity of current illness states. The number of participants with an assessment varied depending on the number of assessments completed at each visit (indicated time points). | Weeks 0, 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | 
| Change From Baseline in the Clinical Global Impressions of Severity (CGI-S) Total Score at Weeks 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | The CGI-S is a standardized assessment tool that uses a 7-point scale to assess a participant's severity of illness. The total score ranges from 0 to 7: 0=not assessed, 1=normal, 2=borderline ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severly ill, 7=extremely ill. Higher scores reflect a higher severity of current illness states. Change from baseline was calculated as the values at Weeks 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52 (or EW) minus the baseline value (Week 0). | Baseline (Week 0) and Weeks 2, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52/EW | 
| Hamilton Rating Scale for Depression (HAM-D) Scale Total Score at Weeks 6, 16, 28, 40, and 52/EW | The HAMD-17 is a 17-item questionnaire that detects change and measures illness severity. Individual items were rated on a scale of 0-4 and 0-2, with the total HAMD-17 score ranging from 0 (not ill) to 52 (severely ill). | Weeks 6, 16, 28, 40, and 52/EW | 
| Change From Baseline in the Hamilton Rating Scale for Depression (HAM-D) Scale Total Score at Weeks 6, 16, 28, 40, and 52/EW | The HAMD-17 is a 17-item questionnaire that detects change and measures illness severity. Individual items were rated on a scale of 0-4 and 0-2, with the total HAMD-17 score ranging from 0 (not ill) to 52 (severely ill). Change from baseline was calculated as the values at Week 6, 16, 28, 40, and 52 (or EW) minus the baseline value (Week 0). | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | 
| Young Mania Rating Scale (YMRS) Total Score at Weeks 6, 16, 28, 40, and 52/EW | The YMRS is an 11-item, multiple-choice diagnostic questionnaire used to measure the severity of disease in participants. Individual items (1=elevated mood, 2=increased motor activity, 3=sexual interest, 4=sleep, 5=irritability, 6=speech, 7=language thought disorder, 8=content, 9=disruptive aggressive behaviour, 10=appearance, 11=insight) were rated on a scale of 0-4 and 0-8. For all items, 0 is the best rating and 4 or 8 is the worst rating. YMRS total score was computed as the sum of the scores for the 11 items on the scale. The possible total scores range from 0 (best) to 60 (worst). | Weeks 6, 16, 28, 40, and 52/EW | 
| Change From Baseline in the Young Mania Rating Scale (YMRS) Total Score at Weeks 6, 16, 28, 40, and 52/EW | The YMRS is an 11-item, multiple-choice diagnostic questionnaire used to measure the severity of disease in participants. Individual items (1=elevated mood, 2=increased motor activity, 3=sexual interest, 4=sleep, 5=irritability, 6=speech, 7=language thought disorder, 8=content, 9=disruptive aggressive behaviour, 10=appearance, 11=insight) were rated on a scale of 0-4 and 0-8. YMRS total score (range of 0-60) was computed as sum of the scores for the 11 items on the scale. Change from baseline was calculated as the values at Week 6, 16, 28, 40, and 52 (or EW) minus the baseline value (Week 0). | Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/EW | 
| Median Serum Lamotrigine 200 mg Concentration Among Participants With Concomitant Use of Inducer and Without Inhibitor (at the Timing of Blood Sample Collection) | Pharmacokinetic (PK) samples were collected at Weeks 6, 16, 28, 40, 52/EW, and the plasma lamotrigine concentrations were measured. Participants were required to visit the study site without taking the investigational product on the morning of the PK blood sampling. Inhibitors are defined as drugs that inhibit lamotrigine glucuronidation (i.e., valproate). Inducers are defined as drugs that induce lamotrigine glucuronidation (e.g., carbamazepine). The median value presented is the median of all samples collected at Weeks 6, 16, 28, 40, and 52/EW. | from Week 6 to Week 52/EW | 
| Median Serum Lamotrigine 100 mg and 200 mg Concentration Among Participants With Concomitant Use of Inhibitor (at the Timing of Blood Sample Collection) | PK samples were collected at Weeks 6, 16, 28, 40, 52/EW, and the plasma lamotrigine concentrations were measured. Participants were required to visit the study site without taking the investigational product on the morning of the PK blood sampling. Inhibitors are defined as drugs that inhibit lamotrigine glucuronidation (i.e., valproate). The median value presented is the median of all samples collected at Weeks 6, 16, 28, 40, and 52/EW. | from Week 6 to Week 52/EW | 
| Median Serum Lamotrigine 25, 100, 125, 150, 200, 225, 300, and 400 mg Concentrations Among Participants Without Concomitant Use of Inhibitor and Inducer | PK samples were collected at Weeks 6, 16, 28, 40, 52/EW, and the plasma lamotrigine concentrations were measured. Participants were required to visit the study site without taking the investigational product on the morning of the PK blood sampling. Inhibitors are defined as drugs that inhibit lamotrigine glucuronidation (i.e., valproate). Inducers are defined as drugs that induce lamotrigine glucuronidation (e.g., carbamazepine). The median value presented is the median of all samples collected at Weeks 6, 16, 28, 40, and 52/EW. | from Week 6 to Week 52/EW | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open-label extension, Tolerability, Lamotrigine, Safety, Bipolar I disorder