Safety and Maintenance of Effect of Ziprasidone Plus a Mood Stabilizer in Bipolar I Disorder (Manic or Mixed)

Study Overview
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Brief Summary
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The purpose of this study is to determine if ziprasidone plus a mood stabilizer will continue to be a safe and effective treatment regimen for adults with Bipolar I Disorder (manic or mixed symptoms) after they have achieved 8 consecutive weeks of symptom improvement on the regimen.

Official Title
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A Phase 3, Randomized, 6-Month, Double-Blind Trial in Subjects With Bipolar I Disorder to Evaluate the Continued Safety and Maintenance of Effect of Ziprasidone Plus a Mood Stabilizer (vs Placebo Plus a Mood Stabilizer) Following a Minimum of 2 Months of Response to Open-Label Treatment With Both Agents

Conditions
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Bipolar Mania, Bipolar Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: Ziprasidone Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults meeting DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for Bipolar I Disorder (currently with manic or mixed symptoms) Exclusion Criteria: Ultra rapid cyclers and subjects with significant cardiovascular disease including history of QT prolongation and/or congenital long QT syndrome

Ages Eligible for Study
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Minimum Age: 18 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: Ziprasidone<br>Active treatment, double-blind, randomized arm | Drug: Ziprasidone Oral Capsule<br>* Oral capsule formulation: Patients will be treated initially with open-label ziprasidone in the range of 40-80 mg BID for at least 10 weeks and up to 16 weeks. Patients who achieve a stable treatment regimen and whose symptoms stabilize for 8 consecutive weeks by Week 16 (Week 10 at the earliest) will be randomized. Patients randomized to ziprasidone will continue to receive the same stable treatment regimen achieved during the open-label treatment, ie, either 40 mg BID, 60 mg BID or 80 mg BID for up to 24 weeks of double-blind treatment.<br>* Other names: Geodon, Zeldox;|
| Placebo Comparator: Placebo<br>Placebo treatment, double-blind, randomized arm | Drug: Placebo<br>* Oral capsule formulation: Patients will be treated initially with open-label ziprasidone in the range of 40-80 mg BID (twice a day) for at least 10 weeks and up to 16 weeks. Patients who achieve a stable treatment regimen and whose symptoms stabilize for 8 consecutive weeks by Week 16 (Week 10 at the earliest) will be randomized. Patients randomized to placebo will be tapered off the open-label ziprasidone by 20 mg BID every 2 days (in a double-blinded manner) until they are completely off ziprasidone and are on matching placebo capsules for up to 24 weeks of double-blind treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Intervention for a Mood Episode During Double Blind Period | Time to Intervention for Mood Episode (TIME) while on randomized drug after at least 8 weeks of symptom reduction on open-label ziprasidone plus mood stabilizer. Mood episode considered to have occurred and subject discontinued if one or more of the following: Investigator (INV) decides discontinuation is in best interest of subject; loss of effect and/or change to treatment regimen (INV judgment); subject hospitalized for disease under study; Mania Rating Scale (MRS) and/or Montgomery-Asberg Rating Scale (MADRS) rating is ≥18 for 2 consecutive visits scheduled no more than 10 days apart. | Period 2: 24 weeks or time of early termination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Discontinuation for Any Reason During Double Blind Period 2 | Key Secondary endpoint is time to discontinuation for any reason. Profile of patients remaining in the trial over time. | Period 2: 24 weeks or time of early termination | 
| Modified Time to Intervention for a Mood Episode (TIME) | Time to intervention for a mood episode or time to discontinuation for treatment related adverse events, or death due to drug, or death due to disease. Mood episode considered to have occurred and subject discontinued if one or more of the following: Investigator (INV) decides discontinuation is in best interest of subject; loss of effect and/or change to treatment regimen (INV judgment); subject hospitalized for disease under study; Mania Rating Scale (MRS) and/or Montgomery-Asberg Rating Scale (MADRS) rating is ≥18 for 2 consecutive visits scheduled no more than 10 days apart. | Period 2: Week 24 or time of early termination | 
| Change From Baseline in Mania Rating Scale (MRS) by Visit During Double Blind Period | Period 2 Baseline = last observation in Period 1 to the start of Period 2. MRS is 11-item scale to measure mania; derived from Schedule for Affective Disorders and Schizophrenia-Change Behavior (SADS-CB). Subscales: Manic Syndrome (elevated mood, less need for sleep, excessive energy and activity, grandiosity), Behavior and Ideation (irritability, motor hyperactivity, accelerated speech, racing thoughts, poor judgment), and Impaired Insight. Racing thoughts range=0 to 2 (highest level of abnormal=2); all other items 0 to 5 (highest level of abnormal=5). Higher score = greater abnormality. | Period 2: Weeks 1 - 24 or time of early termination | 
| Change From Baseline in Clinical Global Impression Severity (CGI-S) Score by Visit During Double Blind Period | Baseline for Period 2 is the last observation in Period 1 to the start of Period 2. Clinical Global Impression Severity Score is 7-item scale rates severity of illness from 0=not assessed, 1= normal to 7=most extremely ill. | Period 2: Weeks 1 - 24 or time of early termination | 
| Clinical Global Impression - Improvement (CGI-I) Score by Visit During Double Blind Period | Clinical Global Impression measures 7 items in Global assessment of improvement in patient's condition; 0=not assessed, 1= very much improved to 7= very much worse. | Period 2: Weeks 1 - 24 or time of early termination | 
| Change From Baseline in Montgomery-Asberg Rating Scale (MADRS) Score by Visit During Double Blind Period | Baseline for Period 2 is the last observation in Period 1 to the start of Period 2. MADRS is 10-item instrument measuring depression: scales from 0=Normal to 6 = most abnormal. | Period 2: Weeks 1 - 24 or time of early termination | 
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score by Visit During Double Blind Period | Baseline for Period 2 is the last observation in Period 1 to the start of Period 2. Positive and Negative Syndrome Scale Total Score is 30-item scale measuring severity of psychopathology (16 items), positive symptoms (7 items) and negative symptoms (7 items); scale from 1 (absent) to 7 (extreme) | Period 2: Weeks 4 - 24 or time of early termination | 
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Postive Scale by Visit During Double Blind Period | Baseline for Period 2 is the last observation in Period 1 to the start of Period 2. Positive Scale is 7-items derived from PANSS; 1 (absent), 2 (minimal) to 7 (extreme). | Period 2: Weeks 4 - 24 or time of early termination | 
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Negative Scale by Visit During Double Blind Period | Baseline for Period 2 is the last observation in Period 1 to the start of Period 2. Negative Scale is 7 items derived from PANSS; scale is 1 (absent) to 7 (extreme). | Period 2: Weeks 4 - 24 or time of early termination |