Study of the Effect of Dosing on Clozapine Levels (PK-CLZ)

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

The objectives of this 15-day study are:

1. 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)

2. To determine if frequency of clozapine administration has an effect on:

   1. Symptoms of schizophrenia
   2. Adverse effects of clozapine
   3. Fasting blood glucose, lipids, creatinine, and urea
   4. Weight and waist circumference

Study Overview

• Status: Withdrawn
• Conditions: Psychotic Disorders; Schizophrenia
• Intervention / Treatment: Drug: Clozapine

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2A1
      • UBC Hospital - Detwiller Pavilion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clozapine bid; 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; 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); Other Names: Clozaril; FazaClo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of British Columbia
• Investigators: Principal Investigator: Ric M. Procyshyn, Ph.D, University of British Columbia; Study Director: Alasdair Barr, Ph.D, University of British Columbia; Study Director: William Honer, MD, University of British Columbia; Study Director: Randall White, MD, University of British Columbia

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: November 4, 2014
• First Submitted That Met QC Criteria: November 4, 2014
• First Posted (Estimate): November 7, 2014

Study Record Updates

• Last Update Posted (Actual): October 8, 2021
• Last Update Submitted That Met QC Criteria: October 1, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Schizophrenia; Clozapine; Antipsychotic Agents; Psychotic Disorders; Psychotropic Drugs; Drug Monitoring; Adverse Effects
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Mental Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; GABA Agents; GABA Antagonists; Clozapine
• Other Study ID Numbers: H14-01644

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No