One-Year Trial of Oral Ziprasidone in Bipolar Patients With Metabolic Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to explore the impact of Ziprasidone HCl on the distribution of metabolic syndrome (MS) risk factors in a population of Bipolar patients presenting with glucose intolerance, dyslipidemia and/or elevated waist circumference associated with their current antipsychotic medication.

Detailed Description
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The trial was terminated prematurely on December 14, 2010, due to inability to recruit the planned number of subjects and shifting organizational priorities. The decision to terminate the trial was not based on any safety or efficacy concerns.

Official Title
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A One-year, Phase III, Open-label, Non-comparative Trial of the Effect of Ziprasidone HCl on Metabolic Syndrome Risk Factors in Patients With Bipolar Disorder

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Ziprasidone HCL (oral)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must present at least 2 of the following risk factors of MS at screening: Elevated waist circumference: >102 cm in men and >88 cm in women; Elevated triglycerides (TGs): ≥1.7 mmol/L (≥150 mg/dL); Reduced HDL-Cholesterol: <1.03 mmol/L (<40 mg/dL) in men and <1.3 mmol/L (<50 mg/dL) in women; Elevated fasting glucose: ≥ 5.6 mmol/L. According to the clinical judgment of the investigator, the risk factors for MS have developed in close temporal relationship to starting an antipsychotic medication. Substitution to a less metabolically disruptive antipsychotic medication is considered Exclusion Criteria: Subjects with contraindication(s) to the use of Ziprasidone according to Canadian prescribing information. Subjects with a history of treatment resistance. Subjects with any medical condition (e.g. pre-existing diabetes, pre-existing dyslipidemia, thyroid pathology) or taking any concomitant medication (e.g. topiramate or other weight loss-promoting agents, hypoglycemic agents, hypolipemic agents), that may confound the evaluation of the study drug. Body mass index ≥ 40 at baseline.

Ages Eligible for Study
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Minimum Age: 18 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: Active treatment (switch to oral Ziprasidone)<br> | Drug: Ziprasidone HCL (oral)<br>* Ziprasidone Hydrochloride 20 to 80 mg administered orally twice a day (40-160 mg total daily dose) for up to 1 year.<br>* Other names: Zeldox, Geodon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Reduction From Baseline of at Least 1 Risk Factor for Metabolic Syndrome (MS) at Week 52 or Premature Discontinuation | MS risks factors: elevated (el) waist circumference: ≥102 centimeters (cm) in men and ≥88 cm in women (Asian origin: ≥90 cm [men] and ≥80 cm [women]); el triglycerides: ≥1.7 millimoles per liter (mmol/L) (1≥50 milligrams per deciliter [mg/dL]); reduced high-density lipoprotein cholesterol (HDL-C): <1.03 mmol/L (<40 mg/dL) in men and <1.3 mmol/L (<50 mg/dL) in women; el fasting glucose: ≥5.6 mmol/L (≥100 mg/dL); and el systolic/diastolic blood pressure: systolic ≥130 millimeters of mercury (mmHg) and/or diastolic ≥85 mmHg. Responder = at least 1 less risk factor at endpoint than baseline. | Week 52 or Early Termination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Number of Risk Factors of Metabolic Syndrome (MS) | MS risks factors: elevated waist circumference: ≥102 cm in men and ≥88 cm in women (Asian origin: ≥90 cm [men] and ≥80 cm [women]); elevated triglycerides: ≥1.7 mmol/L (1≥50 mg/dL); reduced HDL-C: <1.03 mmol/L (<40 mg/dL) in men and <1.3 mmol/L (<50 mg/dL) in women; elevated fasting glucose: ≥5.6 mmol/L (≥100 mg/dL); and elevated systolic/diastolic blood pressure: systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥85 mm Hg. | Baseline, Week 52 | 
| Metabolic Syndrome (MS) Prevalence | Percentage of participants at each visit defined as having metabolic syndrome (MS) based on the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. MS = 3 or more of 5 characteristics: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, high blood pressure, and high fasting glucose. | Baseline through Week 52 | 
| Change From Baseline in the Percentage of Participants With Each Individual Metabolic Syndrome (MS) Risk Factor | MS risks factors: elevated waist circumference: ≥102 cm in men and ≥88 cm in women (Asian origin: ≥90 cm [men] and ≥80 cm [women]); elevated triglycerides: ≥1.7 mmol/L (1≥50 mg/dL); reduced HDL-C: <1.03 mmol/L (<40 mg/dL) in men and <1.3 mmol/L (<50 mg/dL) in women; elevated fasting glucose: ≥5.6 mmol/L (≥100 mg/dL); and elevated systolic/diastolic blood pressure: systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥85 mm Hg. | Baseline through Week 52 | 
| Percentage of Participants With Individual Metabolic Syndrome (MS) Risk Factors | MS risks factors = elevated waist circumference: ≥102 cm in men and ≥88 cm in women (Asian origin: ≥90 cm [men] and ≥80 cm [women]); elevated triglycerides: ≥1.7 mmol/L (1≥50 mg/dL); reduced HDL-C: <1.03 mmol/L (<40 mg/dL) in men and <1.3 mmol/L (<50 mg/dL) in women; elevated fasting glucose: ≥5.6 mmol/L (≥100 mg/dL); and elevated systolic/diastolic blood pressure: systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥85 mm Hg. | Baseline through Week 52 | 
| Change From Baseline in Individual Risk Factors of Metabolic Syndrome (MS): Elevated Waist Circumference | MS risk factor elevated waist circumference defined as ≥102 centimeters (cm) in men and ≥88 cm in women (Asian origin: ≥90 cm [men] and ≥80 cm [women]). | Baseline, Week 4, Week 12, Week 52 | 
| Change From Baseline in Individual Risk Factors of Metabolic Syndrome (MS): Elevated Systolic/Diastolic Blood Pressure | MS risk factor elevated systolic/diastolic blood pressure defined as systolic blood pressure ≥130 millimeters of mercury (mm Hg) and/or diastolic blood pressure ≥85 mm Hg. | Baseline, Week 4, Week 12, Week 52 | 
| Change From Baseline in Individual Risk Factors of Metabolic Syndrome (MS): Elevated Fasting Glucose | MS risk factor elevated fasting glucose defined as ≥5.6 millimoles per liter (mmol/L) (≥100 mg/dL). | Baseline, Week 4, Week 12, Week 52 | 
| Change From Baseline in Individual Risk Factors of Metabolic Syndrome (MS): Reduced High-density Lipoprotein Cholesterol (HDL-C) | MS risk factor reduced HDL-C defined as <1.03 millimoles per liter (mmol/L) (<40 mg/dL) in men and <1.3 mmol/L (<50 mg/dL) in women. | Baseline, Week 4, Week 12, Week 52 | 
| Change From Baseline in Individual Risk Factors of Metabolic Syndrome (MS): Elevated Triglycerides | MS risk factor elevated triglycerides defined as ≥1.7 millimoles per liter (mmol/L) (1≥50 mg/dL). | Baseline, Week 4, Week 12, Week 52 | 
| Change From Baseline in Ten-year Coronary Heart Disease (CHD) Risk According to Framingham Scoring System | Framingham scoring system risk factors: age (risk points range: -9 to 16), cholesterol (risk points range: 0 to 13), HDL cholesterol (risk points range: -1 to 2), smoking (risk points range: 0 to 9), and systolic blood pressure (risk points range: 0 to 6); total risk points range <0 to ≥25, higher score indicates higher 10 year risk (range <1% to ≥30% 10 year risk). | Baseline, Week 4, Week 52 | 
| Change From Baseline in Total Cholesterol and Low-density Lipoprotein (LDL) Cholesterol Levels |  | Baseline, Week 52 or Early Termination | 
| Change From Baseline in Weight |  | Baseline, Week 4, Week 12, Week 52 or Early Termination | 
| Change From Baseline in Body Mass Index (BMI) | Body mass index = weight in kilograms (kg) / height in meters (m)^2 . | Baseline, Week 4, Week 12, Week 52 or Early Termination | 
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) |  | Baseline, Week 52 or Early Termination | 
| Change From Baseline in Insulin Levels |  | Baseline, Week 52 or Early Termination | 
| Change From Baseline in Corrected QT Interval (QTc): Fridericia's Heart Rate Correction Formula (QTcF) | QT interval is the time between the start of the Q wave and the end of the T wave in the cardiac electrical cycle. QTc is the QT interval corrected for heart rate. Corrected QT interval using Fridericia's heart rate correction formula: QTcF = QT/RR^1/3, where RR=RR interval in seconds. | Baseline, Week 4, Week 52 or Early Termination | 
| Change From Baseline in Apolipoprotein B (ApoB) Levels |  | Baseline, Week 52 or Early Termination | 
| Change From Baseline in Leptin |  | Baseline, Week 52 or Early Termination | 
| Change From Baseline in Physical Activity Index | Physical activity (exercise) score derived for each participant based on the frequency and intensity of physical activities: regular walking, recreational activity, cycling, and sporting activity. Six categories of total score: inactive (range: 0-2), occasional (range: 3-5), light (range: 6-8), moderate (range: 9-12), moderately vigorous (range: 13-20), and vigorous (≥21). Higher score = higher frequency and intensity of physical activity. | Baseline, Week 28, Week 52 or Early Termination | 
| Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) - Total Score | Measures the overall severity of depressive 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, Week 4, Week 12, Week 28, Week 52 or Early Termination | 
| Change From Baseline in Young Mania Rating Scale (YMRS) | 11-item scale that measures the severity of manic episodes from subject reported symptoms over previous 48 hours and clinical observation during interview. Four items (irritability, speech, thought content, disruptive-aggressive behaviour) are rated on a scale from 0 (symptom not present) to 8 (symptom extremely severe). The remaining 7 items (elevated mood, increased motor activity-energy, sexual interest, sleep, language-thought disorder, appearance, insight) are rated on a scale from 0 (symptom not present) to 4 (symptom extremely severe). YMRS total score range = 0 to 60. | Baseline, Week 4, Week 12, Week 28, Week 52 or Early Termination | 
| Change From Baseline in Clinical Global Impression - Severity (CGI-S) Subscale | CGI-S: 7-point clinician rated scale to assess severity of participant's current illness state; range: 1 (normal - not ill at all) to 7 (among the most extremely ill patients). Higher score = more affected. | Baseline, Week 4, Week 12, Week 28, Week 52 or Early Termination | 
| Clinical Global Impression - Improvement (CGI-I) Subscale Score | CGI-I: 7-point clinician rated scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved), 2 (much improved), or 3 (minimally improved) on the scale. Higher score = more affected. | Week 52 or Early Termination | 
| Change From Baseline in Drug Attitude Inventory (DAI) | DAI, a 10-item scale to assess how the attitude of schizophrenia participants toward their medications may affect compliance. Respondents indicate 'true' or 'false' for each item. An overall calculated score ranged from -10 to 10, where a positive score indicated a positive subjective response (compliant), a negative score indicated non-compliance. Change: score at observation minus score at baseline. | Week 28, Week 52 or Early Termination | 
| Change From Baseline in Social and Occupational Functioning Assessment Scale (SOFAS) | 0-100 single score scale focusing exclusively on participant's level of social and occupational functioning; not directly influenced by overall severity of participant's psychological symptoms; higher score = higher level of functioning. 1 to 10 = persistent inability to maintain minimal personal hygiene; unable to function without harming self or others or without considerable external support; 91 to 100 = superior functioning in a wide range of activities. | Baseline, Week 28, Week 52 or Early Termination | 
| Change From Baseline in EuroQoL Index (EQ-I) | EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. | Baseline, Week 28, Week 52 or Early Termination | 
| Change From Baseline in European Quality of Life (EuroQol) Visual Analogue Scale (EQ-5D VAS): Current Health State Score | EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. | Baseline, Week 28, Week 52 or Early Termination | 
| Change From Baseline in Impact of Weight on Quality of Life-Lite Version (IWQOL-Lite) Scale | 31-item self report inventory to assess impact of weight on quality of life. Five subscales: physical functioning, self-esteem, sexual life, public distress, and work, with categories in each subscale scored 1 (no trouble or difficulty) to 5 (persistent trouble or difficulty). The rescaled IWQoL-Lite score is determined by the sum of scores on all 31 items and rescaling this sum to a 1 to 100 scoring with 0=the poorest and 100=the best quality of life. | Baseline, Week 28, Week 52 or Early Termination | 
| Number of Participants With Suicidal Tendencies (Columbian-Suicide Severity Rating Scale, [C-SSRS], Mapped to C-CASA [Columbia Classification Algorithm For Suicide Assessment]) | C-SSRS is a participant rated questionnaire to assess suicidal ideation, suicidal behavior, actual attempts (yes or no responses), and intensity of ideation (rated 1=low severity to 5=high severity). Yes/No responses are mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories: Completed suicide, suicide attempt, preparatory acts toward imminent suicidal behavior, suicidal ideation, and self-injurious behavior, or no suicidal intent. A participant could have a yes or no response in more than one category. | Baseline, Week 1 through Week 52 or Early Termination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ziprasidone, Bipolar Disorder, Metabolic Syndrome