Study of the Effect of Dosing on Clozapine Levels

Study Overview
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Brief Summary
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The objectives of this 15-day study are: To compare steady-state trough plasma concentrations of clozapine and its metabolite norclozapine when given once daily and twice daily (at the same total daily dose) To determine if frequency of clozapine administration has an effect on: Symptoms of schizophrenia Adverse effects of clozapine Fasting blood glucose, lipids, creatinine, and urea Weight and waist circumference

Detailed Description
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It is important that clinicians do everything possible to optimize the use of clozapine in individuals with treatment-resistant schizophrenia. To our knowledge, there are no published studies evaluating whether twice daily administration of clozapine is better than once daily administration in terms of effectiveness and tolerability. Although this may seem trivial at first, when we consider that clozapine has a relatively short half-life and dissociates quickly from the dopamine D2 receptor, it justifies further consideration. It takes on even more significance knowing that the established threshold clozapine plasma concentration for therapeutic response (i.e., 350-420 ng/ml) was determined using steady-state trough plasma samples (i.e., approximately 12 hours after the evening dose) in patients administered clozapine twice rather than once daily.

Official Title
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A Pilot Study to Determine How Frequency of Administration Modifies Steady-State Plasma Concentrations of Orally Administered Clozapine

Conditions
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Psychotic Disorders, Schizophrenia

Intervention / Treatment
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* Drug: Clozapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be between the ages of 19 - 65 Participants must be fluent in English Participants must have a psychiatric diagnosis and are currently treated with clozapine once daily in the evening Participants must be on a stable dose of clozapine for at least one week to ensure steady-state has been achieved Exclusion Criteria: Participants who are hypersensitive to clozapine Participants who are pregnant or lactating Participants who are of childbearing age and not using reliable contraception Participants who have postsurgical complications of the gastrointestinal tract that might impair absorption Participants who have any clinically relevant abnormalities of laboratory parameters Participants who have had a potent CYP1A2 metabolic inducer (e.g., carbamazepine; rifampin) or inhibitor (e.g., amiodarone; cimetidine; efavirenz; fluoroquinolone antibiotics; ticlopidine) added to and/or removed from their medication regimen in the past two weeks

Ages Eligible for Study
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Minimum Age: 19 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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clozapine bid<br>Participants have been taking clozapine once daily and have reached steady-state prior to the start of this study. Intervention: Days 1-14 | Drug: Clozapine<br>* One-half baseline dose po bid (or one-third baseline dose po qam and two-thirds baseline dose po qhs at the discretion of the treating clinicians and principal investigator)<br>* Other names: FazaClo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in steady-state trough plasma concentrations of clozapine and norclozapine at Days 7 and 14. | Steady-state trough plasma concentrations of clozapine and norclozapine will be measured on Days 7 and 14 and compared to those obtained on Day 0 (baseline). | Days 0 (baseline), 7, and 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in symptoms at Day 14. | As assessed by structured clinical interviews for the Positive and Negative Syndrome Scale (PANSS) | Day 0 (baseline) and 14 | 
| Change from baseline in side effect burden at Day 14 | As assessed by the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale | Days 0 (baseline) and 14 | 
| Changes from baseline in laboratory measures at Day 14. | Laboratory measures include fasting blood glucose, fasting lipid profile, creatinine, and urea. | Days 0 (baseline) and 14 | 
| Change from baseline in weight and waist circumference at Day 14. |  | Days 0 (baseline) and 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clozapine, Psychotropic Drugs, Antipsychotic Agents, Psychotic Disorders, Schizophrenia, Adverse Effects, Drug Monitoring