Switching From Twice-Daily to Once-Daily Clozapine Dosing in Schizophrenia

Study Overview
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Brief Summary
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Plasma half-life has routinely been used to establish the dosing schedule of antipsychotics; for example, it is recommended that agents with a short plasma half-life be administered multiple times per day. However, to date, several randomized controlled trials (RCTs) have shown no differences in clinical outcomes between once- and twice-daily dosing of various antipsychotics, suggesting that once-daily dosing of antipsychotics is a viable option regardless of plasma half-life. This would apply to clozapine as well; however, there have been no studies comparing once-daily vs. twice-daily dosing regimens of clozapine in terms of efficacy and tolerability. To address this gap in the literature, the investigators shall conduct a pilot, double-blind, RCT to examine efficacy and tolerability following a switch to once-daily dosing regimen of clozapine in patients with schizophrenia receiving clozapine twice a day.

Detailed Description
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Plasma half-life has routinely been used to establish the dosing schedule of antipsychotics; for example, it is recommended that agents with a short plasma half-life be administered multiple times per day. To date, however, several randomized controlled trials (RCTs) have shown that once-daily dosing of antipsychotics including perphenazine, risperidone, olanzapine, quetiapine, and asenapine is comparable to twice-daily dosing in terms of efficacy and tolerability, suggesting that once-daily dosing of antipsychotics is a viable option regardless of plasma half-life. This issue applies to clozapine as well, in that it has a relatively short plasma half-life of 12-16 hours; of note, the product monographs recommends that clozapine be administered more than once daily if the dose exceeds 200 mg/day in Canada. Despite this, in clinical practice clozapine is frequently administered once daily because of convenience and side effects such as a daytime sedation or somnolence, In support of this, a cross-sectional survey done at the investigators' own centre has revealed that clozapine was prescribed once daily in 75.1% of 676 patients, even though >200 mg/day was administered in 88.6%. However, there have been no studies comparing once-daily vs. twice-daily dosing regimens of clozapine in terms of efficacy and tolerability. To address this gap in the literature, the investigators shall conduct a pilot, double-blind, RCT to examine efficacy and tolerability following a switch to once-daily dosing regimen of clozapine in patients with schizophrenia receiving clozapine twice a day.

Official Title
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Switching From Twice-Daily to Once-Daily Clozapine Dosing in Schizophrenia: A Pilot, Double-Blind, Randomized Controlled Trial

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: Clozapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with schizophrenia or schizoaffective disorder based on DSM-IV criteria Outpatient status Ages 18 years or older Has received clozapine twice a day, one of which is in the evening/bedtime, at the same dose and dosing regimen for at least 3 months Fluent in English and competent to provide written informed consent Exclusion Criteria: Having significant medical or neurological illnesses Pregnant or lactating

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: Switch group<br>Participants will receive clozapine once daily at evening or bedtime throughout the study period. If a participant takes ≥200 mg of clozapine at a time other than evening/bedtime, half of this dose will be switched to an evening/bedtime regimen on day 0 (baseline), then another half dose will be switched on day 7 (week 1). Participants will receive placebo in place of the clozapine dose that was switched to evening/bedtime. | Drug: Clozapine<br>* Switching from twice-daily to once-daily clozapine dosing regimen<br>* Other names: Clozaril;|
| No Intervention: Maintenance group<br>Participants will continue to take clozapine twice daily throughout the study period. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brief Psychiatric Rating 18 item Scale (BPRS 18 item scale) | Change in BPRS total scores from baseline to 12 weeks Total scores range from 18-126, higher scores represent worse clinical outcomes: <31 = Illness not significant >=31 = Mildly ill >41 = Moderately ill >53 = Markedly ill. | 0 and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS-C) | Detect side effects related to Clozapine from baseline to 12 weeks Higher Scores indicating worse side-effects: 0-16 (absent/mild side-effects) 17-32 (moderate side-effects) 33-48 (severe side-effects) | 0 and 12 weeks | 
| Brief Evaluation of Psychosis Symptom Domains (BE-PSD) | Assess the overall severity of five symptom domains of BE-PSD with a total score in each domain scoring from absent to very severe (i.e. 0-6 with higher scores with worse outcomes) | 0 and 12 weeks | 
| Personal and Social Performance scale (PSP) | Change in patients social functioning scores from baseline to 12 weeks The PSP is a 100-point single item rating scale from 1-100, subdivided into 10 equal intervals with higher scores indicating better outcomes. The ratings are based on patient's functioning in four main areas: 1) socially useful activities, 2) personal and social relationships, 3) self-care; and 4) disturbing and aggressive behaviours. | 0 and 12 weeks | 
| Clinical Global Impression - Severity of Illness (CGI-S) | Assess severity of Illness in Schizophrenia CGI scores from baseline to 12 weeks Scores ranging from normal to the most ill (i.e., scores ranging from 1-7 with higher scores with illness worsening) | 0 and 12 weeks | 
| Brief Neurocognitive Assessment (BNA) | The BNA is a brief neurocognitive assessment that measures global cognitive impairment in patients with schizophrenia from baseline to 12 weeks. Negative Z scores (i.e., -0.5 to -2.0 ) indicate mild to severe cognitive impairment. | 0 and 12 weeks | 
| Subjective Well-being under Neuroleptics scale - Short form (SWNS) | Self report scale to measure well being. Study assess changes in subjective wellbeing in patients on a neuroleptic from baseline to Week 12. Higher total score indicating better outcomes | 0 and 12 weeks | 
| Change in the Visual Analogue Scale for Distress Associated with Symptoms (VAS-DAS) scores from baseline to 12 weeks | Assess changes in level of distress associated with symptoms from no distress to worst distress (i.e., 0-100) | 0 and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clozapine, Dosing, Once daily, Regimen, Schizophrenia