Manic or Mixed Episode Associated With Bipolar I Disorder
Conditions
Brief summary
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.
Interventions
DRUGolanzapine
oral, daily
DRUGlithium
Dose adjusted according to local package insert
DRUGvalproate
Dose adjusted according to local package insert
DRUGcarbamazepine
Dose adjusted according to local package insert
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Scores - Olanzapine Monotherapy Arm Only | baseline through 18 weeks | 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. |
| Number of Participants With Response of Manic Symptoms - Olanzapine Monotherapy Arm Only | baseline through 18 weeks | 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. |
| Number of Participants With Remission of Mania - Olanzapine Monotherapy Arm Only | baseline through 18 weeks | 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. |
| Number of Participants With Relapse of Manic Symptoms - Olanzapine Monotherapy Arm Only | baseline through 18 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Remission of Bipolar Disorder | Week 18 | 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). |
| Positive and Negative Syndrome Scale Positive Scores - Visit Data | baseline, Weeks 1, 2, 4, 6, 10, 14, 18 | 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. |
| Number of Participants Who Switched to Syndromic Depression | baseline through 18 weeks | 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. |
| Maximum Change From Baseline to Endpoint on the Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) - Total Score | baseline through 18 weeks | 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. |
| Number of Participants With Treatment-Emergent Parkinsonism Based on DIEPSS Scores | baseline through 18 weeks | 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. |
| Number of Participants With Treatment-Emergent Akathisia Based on DIEPSS Scores | baseline through 18 weeks | 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). |
| Change From Baseline to Endpoint on the YMRS Total Score - Olanzapine + Mood Stabilizer Only | baseline through 18 weeks | 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. |
| Number of Participants With Treatment-Emergent Dyskenisia Based on DIEPSS Scores | baseline through 18 weeks | 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). |
| Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | baseline through 18 weeks | 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. |
| Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | baseline through 18 weeks | 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%; |
| Number of Participants With Potentially Clinically Significant Changes in Electrocardiograms - High Fridericia Corrected QT Interval (QTcF) | baseline through 18 weeks | High QTcF: more than or equal to 450 milliseconds (msec) for males; more than or equal to 470 milliseconds (msec) for females |
| Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | baseline through 18 weeks | 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%. |
| Number of Participants With Treatment-Emergent Dystonia Based on DIEPSS Scores | baseline through 18 weeks | 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). |
| Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | baseline, Weeks 1, 2, 4, 6, 10, 14, 18 | Measures severity of the patient's overall severity of bipolar symptoms (1=normal, not at all ill; 7=among the most extremely ill patients). |
| Number of Participants Who Experienced Switch to Symptomatic Depression as Measured by the Hamilton Depression Scale - 17 Item Version (HAMD-17) | baseline through 18 weeks | 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). |
| Number of Participants With Relapse of Depressive Symptoms | baseline through 18 weeks | 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). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Olanzapine Monotherapy Olanzapine extension for Study BMAC patients who completed Visit 8. Patients received olanapine 5-20 mg for 18 weeks. | 100 |
| Olanzapine + Mood Stabilizer 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. | 39 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 6 |
| Overall Study | Entry Criteria not met | 1 | 0 |
| Overall Study | Lack of Efficacy | 1 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other | 19 | 11 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Withdrawal by Subject | 10 | 2 |
Baseline characteristics
| Characteristic | Total | Olanzapine Monotherapy | Olanzapine + Mood Stabilizer |
|---|---|---|---|
| Age Continuous | 42.2 years STANDARD_DEVIATION 11.6 | 41.8 years STANDARD_DEVIATION 11.7 | 43.2 years STANDARD_DEVIATION 11.1 |
| Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) overall | 2.7 units on a scale STANDARD_DEVIATION 1.6 | 1.9 units on a scale STANDARD_DEVIATION 1 | 4.7 units on a scale STANDARD_DEVIATION 0.8 |
| Current Episode - Mixed or Manic Manic | 127 participants | 88 participants | 39 participants |
| Current Episode - Mixed or Manic Mixed | 12 participants | 12 participants | 0 participants |
| Current Episode - Psychotic or Nonpsychotic Nonpsychotic | 117 participants | 87 participants | 30 participants |
| Current Episode - Psychotic or Nonpsychotic Psychotic | 22 participants | 13 participants | 9 participants |
| Hamilton Depression Scale - 17 item version (HAMD-17) Total Score | 2.5 units on a scale STANDARD_DEVIATION 3.5 | 1.8 units on a scale STANDARD_DEVIATION 3.1 | 4.4 units on a scale STANDARD_DEVIATION 3.9 |
| Length of Current Episode | 33.9 days STANDARD_DEVIATION 24.6 | 33.5 days STANDARD_DEVIATION 23.9 | 35.0 days STANDARD_DEVIATION 26.7 |
| Mean Age at Onset of Illness | 31.0 years STANDARD_DEVIATION 10.8 | 31.5 years STANDARD_DEVIATION 11.6 | 29.8 years STANDARD_DEVIATION 8.4 |
| Race/Ethnicity, Customized Japanese | 139 participants | 100 participants | 39 participants |
| Rapid Cyclers Non-Rapid Cyclers | 129 participants | 93 participants | 36 participants |
| Rapid Cyclers Rapid Cyclers | 10 participants | 7 participants | 3 participants |
| Region of Enrollment Japan | 139 participants | 100 participants | 39 participants |
| Sex: Female, Male Female | 80 Participants | 59 Participants | 21 Participants |
| Sex: Female, Male Male | 59 Participants | 41 Participants | 18 Participants |
| Young Mania Rating Scale (YMRS) Total Score | 13.4 units on a scale STANDARD_DEVIATION 13.9 | 5.7 units on a scale STANDARD_DEVIATION 6.4 | 33.2 units on a scale STANDARD_DEVIATION 6.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 59 / 100 | 31 / 39 |
| serious Total, serious adverse events | 1 / 100 | 0 / 39 |
Outcome results
Primary
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.
Time frame: baseline through 18 weeks
Population: The primary objective was only interested in the effects in the olanzapine monotherapy arm, thus the results for the olanzapine + mood stabilizer arm are presented as secondary outcomes. Analyzed were all participants in the olanzapine monotherapy arm who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine Monotherapy | Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Scores - Olanzapine Monotherapy Arm Only | -3.0 units on a scale | Standard Deviation 5.6 |
95% CI: [-4.1, -1.9]
Primary
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.
Time frame: baseline through 18 weeks
Population: Analyzed were all participants in the olanzapine monotherapy group who were in remission at baseline (end of Study BMAC) with 12 points or less in YMRS total score and 7 points or less in the 17-item Hamilton Depression Rating Scale total score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Relapse of Manic Symptoms - Olanzapine Monotherapy Arm Only | 3 participants |
Primary
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.
Time frame: baseline through 18 weeks
Population: Analyzed were all participants in the olanzapine monotherapy arm who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Remission of Mania - Olanzapine Monotherapy Arm Only | 93 participants |
Primary
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.
Time frame: baseline through 18 weeks
Population: Analyzed were all participants in the olanzapine monotherapy arm who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Response of Manic Symptoms - Olanzapine Monotherapy Arm Only | 97 participants |
Secondary
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.
Time frame: baseline through 18 weeks
Population: Analyzed were all participants who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine Monotherapy | Change From Baseline to Endpoint on the YMRS Total Score - Olanzapine + Mood Stabilizer Only | -19.8 units on a scale | Standard Deviation 17.8 |
95% CI: [-25.58, -14.06]
Secondary
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).
Time frame: baseline, Weeks 1, 2, 4, 6, 10, 14, 18
Population: Analyzed were all participants who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine Monotherapy | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | baseline | 1.9 units on a scale | Standard Deviation 1 |
| Olanzapine Monotherapy | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 1 week | 1.8 units on a scale | Standard Deviation 1 |
| Olanzapine Monotherapy | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 2 weeks | 1.8 units on a scale | Standard Deviation 1 |
| Olanzapine Monotherapy | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 4 weeks | 1.7 units on a scale | Standard Deviation 1 |
| Olanzapine Monotherapy | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 6 weeks | 1.7 units on a scale | Standard Deviation 1.1 |
| Olanzapine Monotherapy | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 10 weeks | 1.7 units on a scale | Standard Deviation 1.1 |
| Olanzapine Monotherapy | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 14 weeks | 1.8 units on a scale | Standard Deviation 1.2 |
| Olanzapine Monotherapy | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 18 weeks endpoint | 1.7 units on a scale | Standard Deviation 1.2 |
| Olanzapine + Mood Stabilizer | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 18 weeks endpoint | 2.9 units on a scale | Standard Deviation 2 |
| Olanzapine + Mood Stabilizer | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | baseline | 4.7 units on a scale | Standard Deviation 0.8 |
| Olanzapine + Mood Stabilizer | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 6 weeks | 3.4 units on a scale | Standard Deviation 1.7 |
| Olanzapine + Mood Stabilizer | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 1 week | 4.1 units on a scale | Standard Deviation 1.2 |
| Olanzapine + Mood Stabilizer | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 14 weeks | 3.0 units on a scale | Standard Deviation 1.9 |
| Olanzapine + Mood Stabilizer | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 2 weeks | 3.7 units on a scale | Standard Deviation 1.3 |
| Olanzapine + Mood Stabilizer | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 10 weeks | 3.0 units on a scale | Standard Deviation 1.8 |
| Olanzapine + Mood Stabilizer | Clinical Global Impressions - Bipolar Version, Severity of Illness (CGI-BP) Overall, Visit Data | 4 weeks | 3.5 units on a scale | Standard Deviation 1.6 |
Secondary
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.
Time frame: baseline through 18 weeks
Population: Analyzed were all participants who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine Monotherapy | Maximum Change From Baseline to Endpoint on the Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) - Total Score | Baseline | 0.35 units on a scale | Standard Deviation 1.01 |
| Olanzapine Monotherapy | Maximum Change From Baseline to Endpoint on the Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) - Total Score | Maximum Change from baseline to endpoint | 0.05 units on a scale | Standard Deviation 1.21 |
| Olanzapine + Mood Stabilizer | Maximum Change From Baseline to Endpoint on the Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) - Total Score | Baseline | 0.18 units on a scale | Standard Deviation 0.6 |
| Olanzapine + Mood Stabilizer | Maximum Change From Baseline to Endpoint on the Drug Induced Extra-Pyramidal Symptoms Scale (DIEPSS) - Total Score | Maximum Change from baseline to endpoint | 0.64 units on a scale | Standard Deviation 1.51 |
Secondary
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).
Time frame: Week 18
Population: Analyzed were all participants who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants Who Experienced Remission of Bipolar Disorder | 54 participants |
| Olanzapine + Mood Stabilizer | Number of Participants Who Experienced Remission of Bipolar Disorder | 12 participants |
Secondary
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).
Time frame: baseline through 18 weeks
Population: Analyzed were all participants who had equal to or less than 7 points on the HAMD-17 total score at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants Who Experienced Switch to Symptomatic Depression as Measured by the Hamilton Depression Scale - 17 Item Version (HAMD-17) | 4 participants |
| Olanzapine + Mood Stabilizer | Number of Participants Who Experienced Switch to Symptomatic Depression as Measured by the Hamilton Depression Scale - 17 Item Version (HAMD-17) | 1 participants |
Secondary
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.
Time frame: baseline through 18 weeks
Population: Analyzed were all participants who had a manic episode at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants Who Switched to Syndromic Depression | 8 participants |
| Olanzapine + Mood Stabilizer | Number of Participants Who Switched to Syndromic Depression | 4 participants |
Secondary
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
Time frame: baseline through 18 weeks
Population: Analyzed were all participants who had baseline and post-baseline measurements and no abnormal values in the direction at baseline (e.g. participants with an abnormally low value for a given parameter at baseline who showed an abnormally low value for the same parameter at a later visit were not included). Last observation carried forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Electrocardiograms - High Fridericia Corrected QT Interval (QTcF) | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Electrocardiograms - High Fridericia Corrected QT Interval (QTcF) | 0 participants |
Secondary
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.
Time frame: baseline through 18 weeks
Population: Analyzed were all participants without an abnormal value in the direction at baseline (for example, participants with an abnormally low value at baseline who experienced an abnormally low value at any time post baseline were not included, but were included if they experienced an abnormally high value at any time post baseline).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | High triglycerides; n=100, n=38 | 5 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | High glucose (non-fasting); n=64, n=28 | 0 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | Low glucose (non-fasting); n=64, n=28 | 0 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | High glucose (fasting); n=40, n=6 | 3 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | Low glucose (fasting); n=40, n=6 | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | High glucose (fasting); n=40, n=6 | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | Low glucose (fasting); n=40, n=6 | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | High triglycerides; n=100, n=38 | 2 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | Low glucose (non-fasting); n=64, n=28 | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Laboratory Analytes | High glucose (non-fasting); n=64, n=28 | 0 participants |
Secondary
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%;
Time frame: baseline through 18 weeks
Population: Analyzed were all study participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | High diastolic blood pressure | 1 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low systolic blood pressure | 6 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low weight | 3 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | High pulse | 0 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | High weight | 17 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | High systolic blood pressure | 0 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low pulse | 0 participants |
| Olanzapine Monotherapy | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low diastolic blood pressure | 4 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low pulse | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | High pulse | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low systolic blood pressure | 2 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low diastolic blood pressure | 1 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | High diastolic blood pressure | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | Low weight | 1 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | High weight | 10 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Potentially Clinically Significant Changes in Vital Signs and Weight | High systolic blood pressure | 0 participants |
Secondary
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).
Time frame: baseline through 18 weeks
Population: Analyzed were all participants in the olanzapine monotherapy group who had 12 points or less in the YMRS total score and 7 points or less in the HAMD-17 total score at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Relapse of Depressive Symptoms | 4 participants |
Secondary
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%.
Time frame: baseline through 18 weeks
Population: Analyzed were all participants who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | High high density lipoprotein (HDL); n=95, n=37 | 5 participants |
| Olanzapine Monotherapy | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | High hemoglobin A1C (HBA1C); n=97, n=38 | 2 participants |
| Olanzapine Monotherapy | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | Low low density lipoprotein (LDL); n=97; n=37 | 1 participants |
| Olanzapine Monotherapy | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | Low hemoglobin A1C (HBA1C); n=100, n=39 | 1 participants |
| Olanzapine Monotherapy | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | High low density lipoprotein (LDL); n=71, n=31 | 24 participants |
| Olanzapine Monotherapy | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | Low high density lipoprotein (HDL); n=93, n=36 | 10 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | High low density lipoprotein (LDL); n=71, n=31 | 11 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | Low high density lipoprotein (HDL); n=93, n=36 | 3 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | High high density lipoprotein (HDL); n=95, n=37 | 1 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | Low hemoglobin A1C (HBA1C); n=100, n=39 | 1 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | High hemoglobin A1C (HBA1C); n=97, n=38 | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-emergent Abnormal, High, or Low Laboratory Values | Low low density lipoprotein (LDL); n=97; n=37 | 1 participants |
Secondary
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).
Time frame: baseline through 18 weeks
Population: Included were all participants who did not have an abnormal value at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Treatment-Emergent Akathisia Based on DIEPSS Scores | 3 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-Emergent Akathisia Based on DIEPSS Scores | 2 participants |
Secondary
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).
Time frame: baseline through 18 weeks
Population: Included were all participants who did not have an abnormal value at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Treatment-Emergent Dyskenisia Based on DIEPSS Scores | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-Emergent Dyskenisia Based on DIEPSS Scores | 0 participants |
Secondary
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).
Time frame: baseline through 18 weeks
Population: Included were all participants who did not have an abnormal value at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Treatment-Emergent Dystonia Based on DIEPSS Scores | 0 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-Emergent Dystonia Based on DIEPSS Scores | 1 participants |
Secondary
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.
Time frame: baseline through 18 weeks
Population: Included were all participants who did not have an abnormal value at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olanzapine Monotherapy | Number of Participants With Treatment-Emergent Parkinsonism Based on DIEPSS Scores | 1 participants |
| Olanzapine + Mood Stabilizer | Number of Participants With Treatment-Emergent Parkinsonism Based on DIEPSS Scores | 3 participants |
Secondary
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.
Time frame: baseline, Weeks 1, 2, 4, 6, 10, 14, 18
Population: Analyzed were all participants who had baseline and post-baseline measurements. Last observation carried forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Olanzapine Monotherapy | Positive and Negative Syndrome Scale Positive Scores - Visit Data | baseline | 7.7 units on a scale | Standard Deviation 1.8 |
| Olanzapine Monotherapy | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 1 week | 7.5 units on a scale | Standard Deviation 1.6 |
| Olanzapine Monotherapy | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 2 weeks | 7.5 units on a scale | Standard Deviation 1.4 |
| Olanzapine Monotherapy | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 4 weeks | 7.4 units on a scale | Standard Deviation 1.4 |
| Olanzapine Monotherapy | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 6 weeks | 7.3 units on a scale | Standard Deviation 1.2 |
| Olanzapine Monotherapy | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 10 weeks | 7.4 units on a scale | Standard Deviation 1.7 |
| Olanzapine Monotherapy | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 14 weeks | 7.4 units on a scale | Standard Deviation 1.7 |
| Olanzapine Monotherapy | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 18 week endpoint | 7.4 units on a scale | Standard Deviation 1.7 |
| Olanzapine + Mood Stabilizer | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 18 week endpoint | 9.9 units on a scale | Standard Deviation 5.4 |
| Olanzapine + Mood Stabilizer | Positive and Negative Syndrome Scale Positive Scores - Visit Data | baseline | 12.5 units on a scale | Standard Deviation 5.7 |
| Olanzapine + Mood Stabilizer | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 6 weeks | 10.1 units on a scale | Standard Deviation 5.4 |
| Olanzapine + Mood Stabilizer | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 1 week | 10.5 units on a scale | Standard Deviation 4.1 |
| Olanzapine + Mood Stabilizer | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 14 weeks | 9.9 units on a scale | Standard Deviation 5.4 |
| Olanzapine + Mood Stabilizer | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 2 weeks | 10.1 units on a scale | Standard Deviation 3.9 |
| Olanzapine + Mood Stabilizer | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 10 weeks | 9.9 units on a scale | Standard Deviation 5.4 |
| Olanzapine + Mood Stabilizer | Positive and Negative Syndrome Scale Positive Scores - Visit Data | 4 weeks | 10.1 units on a scale | Standard Deviation 5.4 |