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

Phase 4

Recruiting

• Conditions: Schizoaffective Disorder; Schizophrenia
• Interventions: Drug: Clozapine

• Registration Number: NCT02639702
• Lead Sponsor: Centre for Addiction and Mental Health

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2015-12-18
• Study First Submitted QC: 2015-12-22
• Study First Posted: 2015-12-24
• Study Start: 2016-08
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-03
• Last Update Posted: 2023-09-07
• Primary Completion: 2026-12
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Switch group	Clozapine	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.

Primary Outcome Measures

Name	Time	Method
Brief Psychiatric Rating 18 item Scale (BPRS 18 item scale)	0 and 12 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS-C)	0 and 12 weeks	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)
Change in the Visual Analogue Scale for Distress Associated with Symptoms (VAS-DAS) scores from baseline to 12 weeks	0 and 12 weeks	Assess changes in level of distress associated with symptoms from no distress to worst distress (i.e., 0-100)
Brief Evaluation of Psychosis Symptom Domains (BE-PSD)	0 and 12 weeks	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)
Brief Neurocognitive Assessment (BNA)	0 and 12 weeks	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.
Subjective Well-being under Neuroleptics scale - Short form (SWNS)	0 and 12 weeks	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
Personal and Social Performance scale (PSP)	0 and 12 weeks	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.
Clinical Global Impression - Severity of Illness (CGI-S)	0 and 12 weeks	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)

Trial Locations

Locations (1)

Centre for Addiction and Mental Health; 🇨🇦 Toronto, Ontario, Canada