Olanzapine Treatment of Patients With Bipolar I Disorder

Study Overview
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Brief Summary
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The purpose of this study is to assess whether olanzapine is superior to placebo in patients with bipolar depression.

Detailed Description
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Dose range and administration mode: Oral Olanzapine 5mg - 20mg/day Duration: Screening phase is 2-28 days. Double-blind treatment phase is 6 weeks Open-label extension phase is 18 weeks

Official Title
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Efficacy and Safety of Olanzapine in the Treatment of Patients With Bipolar I Disorder, Depressed: A Randomized, Double-Blind Comparison With Placebo

Conditions
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Depression, Bipolar

Intervention / Treatment
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* Drug: Olanzapine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each patient must be reliable, have a level of understanding sufficient to perform all tests and examinations required by the protocol, and must understand the nature of the study and have provided informed consent All female patients must test negative for pregnancy and females of breast-feeding potential must agree not to breastfeed an infant during the study and for 1 month following the last dose of study drug Patients must fulfill the criteria for a major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) as well as criteria for bipolar I disorder, depressed, as defined in the DSM-IV-TR, based on clinical assessment and confirmed by the structured diagnostic interview, the Mini International Neuropsychiatric Interview (MINI), at study entry Patients must have a current 17-item Hamilton Depression Rating Scale (HAMD-17) score greater than or equal to 18 at Visit 1 and Visit 2 Patients must have a current Young Mania Rating Scale (YMRS) total score less than or equal to 8 at Visit 2. Exclusion Criteria: Has received treatment within the past 30 days with a drug (not including study drug) that has not received regulatory approval for any indication at the time of study entry Has participated in a clinical trial of another investigational drug, including olanzapine, within 1 month (30 days) before study entry Was previously treated with olanzapine and had bipolar depression considered to be treatment-resistant to olanzapine or to olanzapine in combination with an available selective serotonin reuptake inhibitor (SSRI) Is experiencing (at the time of study entry) a current episode of bipolar depression that is greater than 90 days in duration Has been treatment-resistant to any therapy prescribed for bipolar depression when olanzapine alone or with an SSRI prescribed at an appropriate dose and duration

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olanzapine<br>During double-blind treatment, participants receive olanzapine at a dose of 5 milligram (mg) which is increased to 10 mg per day no later than 3-7 days after randomization (Baseline). Subsequent dose increases above 10 mg (up to a maximum of 20 mg per day) are permitted in 5 mg per day increments, based upon tolerability and symptoms. Dosing may be decreased by any number of decrements, however dosing below 5 mg requires study discontinuation. | Drug: Olanzapine<br>* 5-20 mg, oral, once daily, for 24 weeks (participants randomized to olanzapine in double-blind treatment period) or 18 weeks (participants randomized to placebo in double-blind treatment period).<br>* Other names: Zyprexa;|
| Placebo Comparator: Placebo<br>Matching placebo administered once daily, by mouth during double-blind treatment. | Drug: Placebo<br>* placebo tablets, oral, once daily at bedtime, 6 weeks<br>|
| Experimental: Olanzapine (open-label treatment period)<br>During open-label treatment, participants randomized to placebo in double-blind period will receive olanzapine 5 mg starting at Week 6. Participants randomized to olanzapine must be at a 5 mg olanzapine dose at Week 7. Those on higher doses will be reduced between Week 6 and Week 7 (10 mg reduced to 5 mg; 15 mg reduced to 10 mg and then to 5 mg at Week 7; 20 mg reduced to 15 mg and then 10 mg to dosing at 5 mg at Week 7). Dose increases beyond Week 7 are permitted and at the investigator's discretion. | Drug: Olanzapine<br>* 5-20 mg, oral, once daily, for 24 weeks (participants randomized to olanzapine in double-blind treatment period) or 18 weeks (participants randomized to placebo in double-blind treatment period).<br>* Other names: Zyprexa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Endpoint in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (Acute Phase) | The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). | Baseline, Endpoint (Week 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Symptomatic Response at Endpoint (Acute Phase) | Response is defined as a reduction (from baseline to endpoint) of 50% or more in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). | Endpoint (Week 6) | 
| Percentage of Participants With Symptomatic Remission At Any Time (Acute Phase) | Percentage of participants with symptomatic remission at any time as defined as a score of less than or equal to 12 in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). | Baseline through Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Clinical Global Improvement- Bipolar (CGI-BP) Severity of Illness Scores-Mania, Depression, Overall Bipolar Illness Scores (Acute Phase) | CGI-BP is a measure of illness severity especially adapted for bipolar illness. It allows rating of mania, depression, and overall illness. The score ranges from 1 (normal, not ill) to 7 (very seriously ill). | Baseline, Endpoint (Week 6) | 
| Percentage of Participants With Recovery (Acute Phase) | Percentage of participants with recovery defined as a value of less than or equal to 12 in the MADRS total score for at least 4 weeks of post-baseline treatment. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). | Baseline through Endpoint (Week 6 ) | 
| Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Score (Acute Phase) | 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, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Hamilton Depression Rating Scale-17 (HAMD-17) Total Score (Acute Phase) | The 17-item HAMD measures depression severity. Each item was evaluated and scored using either a 5-point scale (e.g. absent, mild, moderate, severe, very severe) or a 3-point scale (e.g. absent, mild, marked). The total score of HAMD-17 may range from 0 (normal) to 52 (severe). | Baseline, Endpoint (Week 6) | 
| Percentage of Participants With Major Depressive Episode at Endpoint on Mini International Neuropsychiatric Interview (MINI), Depressive Episode Module (Acute Phase) | In the MINI Major Depressive Episode module, participants are asked a series of Yes/No questions to determine whether or not they are experiencing a major depressive episode or a major depressive episode with melancholic features. | Endpoint (Week 6) | 
| Percentage of Participants With Current Hypomanic Episode at Endpoint on MINI Manic Episode Module (Acute Phase) | In the MINI Manic Episode module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing hypomanic or manic episodes. | Endpoint (Week 6) | 
| Percentage of Participants With Psychotic Disorders and Mood Disorders With Psychotic Features at Endpoint on MINI Psychotic Disorders Module (Acute Phase) | In the MINI Psychotic Features Episode module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing mood disorder with psychotic features or current psychotic disorders. | Endpoint (Week 6) | 
| Percentage of Participants With Alcohol Dependence and Abuse at Endpoint on MINI Alcohol Dependence/Abuse Module (Acute Phase) | In the MINI Alcohol Abuse and Dependence Module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing symptoms indicating current alcohol dependence or abuse. | Endpoint (Week 6) | 
| Percentage of Participants With Non-Alcohol Psychoactive Substance Use Disorder at Endpoint on MINI Substance Dependence/Abuse Module (Acute Phase) | In the MINI Substance Dependence and Abuse Module, participants are asked a series of Yes/No questions to determine whether or not they are currently experiencing symptoms indicating current non-alcohol substance use dependence or abuse. | Endpoint (Week 6) | 
| Percentage of Participants With Emergence of Mania During the Study (Acute Phase) | Emergence of mania is defined as first occurrence of score of >=15 in the YMRS total score in the post-baseline period of Acute Phase. 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 Endpoint (Week 6) | 
| Percentage of Participants With Extra-Pyramidal Symptoms (EPS) At Endpoint As Measured by Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) (Acute Phase) | EPS symptoms measured by DIEPSS are grouped into 4 categories: parkinsonism, akathisia, dystonia, and dyskinesia. Severity is assessed at 5 levels, from level 0 (none, normal) to level 4 (severe). For Parkinsonism, normal baseline is defined as a score not >=3 on 1 item nor >=2 on 2 items; abnormal endpoint is defined as a score >=3 on 1 item or >=2 on 2 items, or an increase of 3 on Parkinsonism total. Baseline akathisia, dystonia and dyskinesia is defined as a score <2; abnormal endpoint is a score >=2 or an increase >= 2 from that baseline score. | Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Blood Pressure (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Weight (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Glucose and Lipids (Cholesterol, Triglycerides, HDL Cholesterol, LDL Cholesterol) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Albumin (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Alanine Amino Transferase/Serum Glutamate Pyruvate Transaminase (ALT/SGPT), Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT), Gamma Glutamyl Transferase (GGT) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Direct Bilirubin, Total Bilirubin, Uric Acid (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Erythrocyte Count (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Hematocrit (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Hemoglobin A1c (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Hemoglobin (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Prolactin (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Urinalysis (UA)- Specific Gravity (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change in Electrocardiogram (ECG) From Baseline to Endpoint (Acute Phase) | Time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole, fixed correction factor (QTcF interval); Bazett-Corrected QT Interval (QTcB interval). | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in Heart Rate (Acute Phase) |  | Baseline, Endpoint (Week 6) | 
| Change From Baseline to Endpoint in MINI Suicidality Total Scores (Acute Phase) | The MINI module C (MINI-C) is a rating scale for severity of suicidal thoughts and behaviors. The MINI-C is composed of 12 Yes/No questions with variable scores assigned to each question. The scale ranges from 0 to 52 with higher scores indicating a greater presence of suicidal thoughts and/or behaviors. | Baseline, Endpoint (Week 6) | 
| Number of Participants With Adverse Events (Acute Phase) | Please refer to the Adverse Event overview for details regarding adverse events and serious adverse events. | Baseline through Week 6 (Acute Phase) | 
| Percentage of Participants With Symptomatic Response in Montgomery-Asberg Depression Rating (MADRS) Depression Rating (Open-Label Phase) | The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). Response is defined as a reduction (from baseline to endpoint) of 50% or more in the MADRS total score. | Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24) | 
| Percentage of Participants With Symptomatic Remission in the MADRS Total Score (Open-Label Phase) | Percentage of participants with symptomatic remission at any time as defined as a score of less than or equal to 12 in the MADRS total score. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). | Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24) | 
| Percentage of Participants With Recovery (Open-Label Phase) | Percentage of participants with recovery defined as a value of less than or equal to 12 in the MADRS total score for at least 4 weeks of post-baseline treatment. The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). | Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Young Mania Rating Scale (YMRS) Total Score (Open-Label Phase) | 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 (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Percentage of Participants With Emergence of Mania During the Study (Open-Label Phase) | Emergence of mania is defined as first occurrence of score of >=15 in the YMRS total score in the Open-Label Extension. 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 (End of Acute Phase/Week 6) through Endpoint (Week 24) | 
| Percentage of Participants With Extra-Pyramidal Symptoms (EPS) at Endpoint As Measured by Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) (Open-Label Phase) | EPS symptoms measured by DIEPSS are grouped into 4 categories: parkinsonism, akathisia, dystonia, and dyskinesia. Severity is assessed at 5 levels, from level 0 (none, normal) to level 4 (severe). For Parkinsonism, normal baseline is defined as a score not >=3 on 1 item nor >=2 on 2 items; abnormal endpoint is defined as a score >=3 on 1 item or >=2 on 2 items, or an increase of 3 on Parkinsonism total. Baseline akathisia, dystonia and dyskinesia is defined as a score <2; abnormal endpoint is a score >=2 or an increase >= 2 from that baseline score. | Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Blood Pressure (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Weight (Open-Label Phase) |  | Baseline (End of Acute Phase/ Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Albumin and Total Protein (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Alkaline Phosphatase, Creatinine Phosphokinase (CPK), GGT (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Chloride (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Creatinine (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Erythrocyte Count (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Hemoglobin (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Platelet Count (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Prolactin (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Uric Acid (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Glucose and Lipids (Cholesterol, Triglycerides, HDL Cholesterol, LDL Cholesterol) (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in ECG (Open-Label Phase) | Time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole, fixed correction factor (QTcF interval); Bazett-Corrected QT Interval (QTcB interval). | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Change From Baseline to Endpoint in Heart Rate (Open-Label Phase) |  | Baseline (End of Acute Phase/Week 6), Endpoint (Week 24) | 
| Percentage of Participants With High Suicidality at Endpoint (Open-Label Phase) | The MINI module C (MINI-C) is a rating scale for severity of suicidal thoughts and behaviors. The MINI-C is composed of 12 Yes/No questions with variable scores assigned to each question. The scale ranges from 0 to 52 with higher scores indicating a greater presence of suicidal thoughts and/or behaviors. Based upon scores, suicidality is defined as Low (1-8), Medium (9-16), and High (>=17). | Endpoint (Week 24) | 
| Number of Participants With Adverse Events (Open-Label Phase) | Please refer to the Adverse Event overview for details regarding adverse events and serious adverse events. | Baseline (End of Acute Phase/Week 6) through Endpoint (Week 24) |