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

Phase 3

Completed

Conditions: Bipolar Disorder

Interventions: Drug: BW430C (lamotrigine)

Registration Number: NCT00566020

Lead Sponsor: GlaxoSmithKline

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 92

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Lamotrigine	BW430C (lamotrigine)	study drug

Primary Outcome Measures

Name	Time	Method
Number of Participants With Any Serious Adverse Event (SAE) and Any Non Serious Adverse Event	From baseline (Week 0) until 2 weeks after the end of treatment (Week 54)	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.
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)	Baseline (Week 0) and Weeks 6, 16, 28, 40, and 52/Early Withdrawal (EW)	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.
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	Baseline (Week 0) and Weeks 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.
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	Baseline (Week 0) and Weeks 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.
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	Baseline (Week 0) and Weeks 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.
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	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.
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	Baseline (Week 0) and Weeks 0, 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.
Number of Participants With the Indicated Electrocardiogram (ECG) Findings at Weeks 0, 6, 28, and 52/EW	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.
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	Baseline (Week 0) and Weeks 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.
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	Baseline (Week 0) and Weeks 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.
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	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+).
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	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.
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	Baseline (Week 0) 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.

Secondary Outcome Measures

Name	Time	Method
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	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).
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	Baseline (Week 0) and 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).
Hamilton Rating Scale for Depression (HAM-D) Scale Total Score at Weeks 6, 16, 28, 40, and 52/EW	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 in the Hamilton Rating Scale for Depression (HAM-D) Scale Total Score at Weeks 6, 16, 28, 40, and 52/EW	Baseline (Week 0) and 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).
Young Mania Rating Scale (YMRS) Total Score at Weeks 6, 16, 28, 40, and 52/EW	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).
Change From Baseline in the Young Mania Rating Scale (YMRS) Total Score at Weeks 6, 16, 28, 40, and 52/EW	Baseline (Week 0) and 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).
Median Serum Lamotrigine 200 mg Concentration Among Participants With Concomitant Use of Inducer and Without Inhibitor (at the Timing of Blood Sample Collection)	from Week 6 to Week 52/EW	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.
Median Serum Lamotrigine 100 mg and 200 mg Concentration Among Participants With Concomitant Use of Inhibitor (at the Timing of Blood Sample Collection)	from Week 6 to Week 52/EW	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.
Median Serum Lamotrigine 25, 100, 125, 150, 200, 225, 300, and 400 mg Concentrations Among Participants Without Concomitant Use of Inhibitor and Inducer	from Week 6 to Week 52/EW	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.