Efficacy and Safety of Olanzapine in the Extended Treatment for Manic or Mixed Episode of Bipolar I Disorder

Study Overview
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Brief Summary
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The efficacy and safety of the extended treatment to patients with most recent episode manic or mixed who completed previous double blind study (F1D-JE-BMAC [Study BMAC]) will be examined.

Official Title
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Efficacy and Safety of Olanzapine in the Extended Treatment for Manic or Mixed Episode of Bipolar I Disorder

Conditions
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Manic or Mixed Episode Associated With Bipolar I Disorder

Intervention / Treatment
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* Drug: olanzapine
* Drug: lithium
* Drug: valproate
* Drug: carbamazepine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Enrolled in and completed Study BMAC (NCT00129220), or those who discontinued Study BMAC at Visit 4 or Visit 5 due to lack of efficacy and for whom the Young Mania Rating Scale (YMRS) total score at the time of discontinuation was not lower than that at baseline of Study BMAC Are diagnosed as 294.4x Bipolar I Disorder, Most Recent Episode Manic or 296.6x Bipolar I Disorder, Most Recent Episode Mixed, as determined by the Mini-International Neuropsychiatric Interview (MINI) Exclusion Criteria: Have a diagnosis of diabetes mellitus Significant protocol deviation in Study BMAC The actual date of the final visit of Study BMAC is 4 days or more later than the scheduled date of first visit in Study BMEX

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 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: Olanzapine Monotherapy<br>Olanzapine extension for Study BMAC patients who completed Visit 8. Patients received olanzapine 5-20 mg for 18 weeks. | Drug: olanzapine<br>* oral, daily<br>* Other names: Zyprexa;|
| Experimental: Olanzapine + Mood Stabilizer<br>Olanzapine extension for Study BMAC patients who discontinued at Visit 4 or 5. Patients received an initial dose of olanzapine 10 mg for 1 week and subsequent doses of olanzapine 5-20 mg for 17 weeks. Patients received one (1) mood stabilizer (lithium, valproate or carbamazepine) for 18 weeks. | Drug: olanzapine<br>* oral, daily<br>* Other names: Zyprexa;Drug: lithium<br>* Dose adjusted according to local package insert<br>Drug: valproate<br>* Dose adjusted according to local package insert<br>Drug: carbamazepine<br>* Dose adjusted according to local package insert<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Scores - Olanzapine Monotherapy Arm Only | The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60. The primary objective was only interested in the effects in the olanzapine monotherapy arm. | baseline through 18 weeks | 
| Number of Participants With Response of Manic Symptoms - Olanzapine Monotherapy Arm Only | Defined by a 50% or more reduction in YMRS total score from baseline in Study BMAC to endpoint. The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60. The primary objective was only interested in the effects in the olanzapine monotherapy arm. | baseline through 18 weeks | 
| Number of Participants With Remission of Mania - Olanzapine Monotherapy Arm Only | Remission of Mania was defined as a YMRS total score of less than or equal to 12 at endpoint. The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60. The primary objective was only interested in the effects in the olanzapine monotherapy arm. | baseline through 18 weeks | 
| Number of Participants With Relapse of Manic Symptoms - Olanzapine Monotherapy Arm Only | Patients achieved remission in Study BMAC (defined as YMRS total score <=12 and HAMD-17 total score <=7) and obtained YMRS total score of >=15 at any time during Study BMEX. The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60. The primary objective was only interested in the effects in the olanzapine monotherapy arm. | baseline through 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Endpoint on the YMRS Total Score - Olanzapine + Mood Stabilizer Only | The YMRS is an 11-item scale that measures the severity of manic episodes. Four items are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total score ranges from 0 to 60. | baseline through 18 weeks | 
| Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | Measures severity of the patient's overall severity of bipolar symptoms (1=normal, not at all ill; 7=among the most extremely ill patients). | baseline, Weeks 1, 2, 4, 6, 10, 14, 18 | 
| Number of Participants Who Experienced Switch to Symptomatic Depression as Measured by the Hamilton Depression Scale - 17 Item Version (HAMD-17) | Incidence of depressive symptoms was defined as a score of equal to or more than 13 points on the HAMD-17. The 17-item HAMD measures depression severity. Each item was evaluated and scored a 3-point scale (e.g. absent, mild, marked) or a 5-point scale (e.g. absent, mild, moderate, severe, very severe). The total score of HAMD-17 may range from 0 (normal) to 52 (severe). | baseline through 18 weeks | 
| Number of Participants With Relapse of Depressive Symptoms | Assessed were participants meeting remission criteria for bipolar disorder in Study BMAC and have a HAMD-17 total score greater than or equal to 13 at any time. The 17-item HAMD measures depression severity. Each item was evaluated and scored using a 3-point scale (e.g. absent, mild, marked) or a 5-point scale (e.g. absent, mild, moderate, severe, very severe). The total score of HAMD-17 may range from 0 (normal) to 52 (severe). | baseline through 18 weeks | 
| Number of Participants Who Experienced Remission of Bipolar Disorder | Participants who had equal to or less than 12 points in YMRS total score and equal to or less than 7 points in HAMD-17 total score at 18 weeks. YMRS: 11-item scale, measures the severity of manic episodes. 4 items are rated from 0 (symptom not present) to 8 (symptom extremely severe). The remaining items are rated from 0 (symptom not present) to 4 (symptom extremely severe). The YMRS total: 0 to 60. The 17-item HAMD measures depression severity. Each item was evaluated and scored using a 3-point scale or a 5-point scale. HAMD-17 total score: 0 (normal) to 52 (severe). | Week 18 | 
| Positive and Negative Syndrome Scale Positive Scores - Visit Data | Assesses positive symptoms associated with schizophrenia. 7 items make up the Positive scale. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Total Positive Subscale scores range from 7 to 49. For the analysis, the score was converted to 0 to 6 for each item range; hence, the total score ranges from 0 to 42. | baseline, Weeks 1, 2, 4, 6, 10, 14, 18 | 
| Number of Participants Who Switched to Syndromic Depression | As defined as a shift from a Manic Episode at baseline to a Major Depressive Episode, at any post baseline visit, based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision. | baseline through 18 weeks | 
| Maximum Change From Baseline to Endpoint on the Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) - Total Score | A scale used to assess the extrapyramidal symptoms attributable to antipsychotics. Consists of 9 items (8 to assess individual symptoms and 1 to assess global severity). Each item is assessed from 0 (none, normal) to 4 (severe). The total points of 8 items are defined as DIEPSS total (0 to 32 points). The items for the assessment of individual symptoms are classified into 4 categories of parkinsonism, akathisia, dystonia and dyskinesia. Parkinsonism is assessed by the total points of items 1 to 5; akathisia, dystonia and dyskinesia are assessed by the points given to the corresponding items. | baseline through 18 weeks | 
| Number of Participants With Treatment-Emergent Parkinsonism Based on DIEPSS Scores | DIEPSS assesses the extrapyramidal symptoms attributable to antipsychotics. Consists of 9 items (8 to assess individual symptoms and 1 to assess global severity). Each item is assessed from 0 (none, normal) to 4 (severe). The total points of 8 items are defined as DIEPSS total (0 to 32 points). Parkinsonism is assessed by the total points of items 1 to 5 (total score of 0 to 20). Treatment-emergent parkinsonism was defined as a score of equal or greater than 3 on 1 item, equal or greater than 2 on 2 items, or an increase of equal or greater than 3 from baseline on the parkinsonism total. | baseline through 18 weeks | 
| Number of Participants With Treatment-Emergent Akathisia Based on DIEPSS Scores | DIEPSS assesses the extrapyramidal symptoms attributable to antipsychotics. Consists of 9 items (8 to assess individual symptoms and 1 to assess global severity). Each item is assessed from 0 (none, normal) to 4 (severe). The total points of 8 items are defined as DIEPSS total (0 to 32 points). The items are classified into 4 categories of parkinsonism, akathisia, dystonia and dyskinesia. Treatment-emergent akathisia was defined as a score of equal or more than 2 or an increase of equal or more than 2 points from baseline on the akathisia item (total score possible 0 to 4 points). | baseline through 18 weeks | 
| Number of Participants With Treatment-Emergent Dystonia Based on DIEPSS Scores | DIEPSS assesses the extrapyramidal symptoms attributable to antipsychotics. Consists of 9 items (8 to assess individual symptoms and 1 to assess global severity). Each item is assessed from 0 (none, normal) to 4 (severe). The total points of 8 items are defined as DIEPSS total (0 to 32 points). The items are classified into 4 categories of parkinsonism, akathisia, dystonia and dyskinesia. Treatment-emergent dystonia was defined as a score equal or more than 2 or an increase of equal or more than 2 points from baseline on the dystonia item (total score possible 0 to 4 points). | baseline through 18 weeks | 
| Number of Participants With Treatment-Emergent Dyskenisia Based on DIEPSS Scores | DIEPSS assesses the extrapyramidal symptoms attributable to antipsychotics. Consists of 9 items (8 to assess individual symptoms and 1 to assess global severity). Each item is assessed from 0 (none, normal) to 4 (severe). The total points of 8 items are defined as DIEPSS total (0 to 32 points). The items are classified into 4 categories of parkinsonism, akathisia, dystonia and dyskinesia. Treatment-emergent dyskenisia was defined as a score of equal or more than 2 or an increase of equal to or more than 2 points from baseline on the dyskenisia item (total score possible 0 to 4 points). | baseline through 18 weeks | 
| Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | Triglycerides: high limit equal to or more than 500 milligram/deciliter (mg/dL); Glucose (non-fasting): low limit 2.4975 mmol/liter (L); high limit 13.875 mmol/L; Glucose (fasting): low limit 2.4975 mmol/L; high limit 6.993 mmol/L. | baseline through 18 weeks | 
| Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low systolic blood pressure (SBP): <=90 millimeter mercury (mmHg) and decrease of >=20 mmHg; High SBP: >=180 mmHg and increase of >=20 mmHg; Low diastolic blood pressure (DBP): <=50 mmHg and decrease of >=15 mmHg; High DBP: >=105 mmHg and increase of >=15 mmHg; Low pulse: <50 beats per minute (bpm) and decrease of >=15 bpm; High pulse: >120 bpm and an increase of >=15 bpm; Low weight: decrease of >=7%; High weight: increase of >=7%; | baseline through 18 weeks | 
| Number of Participants With Potentially Clinically Significant Changes in Electrocardiograms - High Fridericia Corrected QT Interval (QTcF) | High QTcF: more than or equal to 450 milliseconds (msec) for males; more than or equal to 470 milliseconds (msec) for females | baseline through 18 weeks | 
| Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | High density lipoprotein: males low 40 milligram/deciliter (mg/dL), high 80 mg/dL; females low 40 mg/dL, high 90 mg/dL. Low density lipoprotein (LDL): males and females low 70 mg/dL, high 139 mg/dL. Hemoglobin A1C (HBA1C): males and females low 4.3%, high 5.8%. | baseline through 18 weeks |