Once-Daily vs Twice-Daily Clozapine for Schizophrenia

Overseen By Carol Borlido, BSc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Centre for Addiction and Mental Health

Must be taking: Clozapine

Disqualifiers: Significant medical, neurological illnesses, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether taking clozapine, a medication for schizophrenia, once a day is as effective and tolerable as taking it twice a day. Researchers aim to determine if a simpler dosing schedule can work as well for individuals already stable on a twice-daily routine. Those who have taken clozapine twice daily, with one dose in the evening or at bedtime for at least three months, and have schizophrenia or schizoaffective disorder, might be suitable for this study. Participants will either switch to a once-daily dose or continue their usual twice-daily dosing to compare outcomes. As a Phase 4 trial, this study involves an FDA-approved treatment and seeks to understand how it can benefit more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that you have been taking clozapine twice a day for at least 3 months. It seems you will continue with clozapine, but the dosing schedule might change.

What is the safety track record for switching from twice-daily to once-daily clozapine dosing?

Research has shown that taking clozapine once a day is as safe for people with schizophrenia as taking it twice a day. Studies found no major safety differences between the two schedules, indicating that once-daily dosing is generally as safe as twice-daily dosing.

People who switched to taking clozapine once a day often reported feeling and functioning better in their daily lives. This suggests that once-daily dosing might not only be safe but also more convenient and effective for some individuals.

Multiple studies support these findings, providing strong evidence for the safety of once-daily clozapine. For those considering joining a trial or changing their dosing schedule, this information may help ease any safety concerns. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about the once-daily clozapine dosing because it offers a simpler regimen for managing schizophrenia. Most treatments for schizophrenia, like the standard twice-daily clozapine, require multiple doses throughout the day, which can be challenging for patients to maintain. By reducing the frequency to just once at evening or bedtime, this approach could improve adherence and make life easier for patients. Additionally, the convenience of a once-daily dosing schedule may enhance the overall effectiveness of the treatment by ensuring more consistent medication intake.

What evidence suggests that switching from twice-daily to once-daily clozapine dosing could be effective for schizophrenia?

This trial will compare once-daily and twice-daily dosing of clozapine for schizophrenia. Research has shown that taking clozapine once a day is as effective and safe as taking it multiple times a day. Studies found no major differences in efficacy or safety for people with treatment-resistant schizophrenia between once-daily and multiple doses. Some research even suggests that once-daily dosing might reduce symptoms and improve daily functioning. Thus, taking clozapine once a day could effectively manage symptoms without compromising effectiveness. ^{1 2 3 4 6}

Who Is on the Research Team?

Gary Remington, MD, PhD

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

This trial is for adults over 18 with schizophrenia or schizoaffective disorder, currently taking clozapine twice daily. They must be outpatients, fluent in English, and able to consent. It's not for those with serious medical conditions or women who are pregnant or breastfeeding.

Inclusion Criteria

I have been taking clozapine twice daily, including bedtime, at the same dose for 3 months.

I have been diagnosed with schizophrenia or schizoaffective disorder.

I am not currently admitted to a hospital.

Exclusion Criteria

Having significant medical or neurological illnesses

Pregnant or lactating

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are switched from twice-daily to once-daily clozapine dosing or continue with twice-daily dosing

12 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Switching From Twice-Daily to Once-Daily Clozapine Dosing

Trial Overview

The study tests if taking clozapine once a day is as effective and tolerable as the standard twice-daily dose for schizophrenia treatment. Participants will be randomly assigned to one of the dosing schedules in a controlled environment.

How Is the Trial Designed?

Group I: Switch group Experimental Treatment 1 Intervention

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.

Group II: Maintenance group Active Control 1 Intervention

Participants will continue to take clozapine twice daily throughout the study period.

Switching From Twice-Daily to Once-Daily Clozapine Dosing is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Clozaril for:

• Schizophrenia
• Recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder

Approved in European Union as Clozaril for:

• Schizophrenia
• Recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder

Approved in Canada as Clozaril for:

• Schizophrenia
• Recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Published Research Related to This Trial

In a study involving 2810 clozapine-treated individuals, patients on multiple-daily dosing exhibited more severe clinical symptoms and a higher risk of adverse drug reactions (ADRs) compared to those on once-daily dosing, suggesting that multiple dosing may be linked to worse outcomes.

The analysis indicated that patients on multiple-daily dosing were often prescribed higher doses and more co-medications, which could contribute to the increased severity of symptoms and ADRs, highlighting the importance of considering patient preferences and adherence when choosing a dosing regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine once- versus multiple-daily dosing: a two-center cross-sectional study, systematic review and meta-analysis. Kuzo, N., Haen, E., Ho, DM., et al.[2023]

In a study of 55 treatment-resistant schizophrenia patients, 85% continued clozapine treatment, with significant improvements in BPRS scores observed after 1 month, indicating its efficacy as a long-term treatment option.

Clozapine should be administered as a monotherapy with a gradual dosage increase to minimize side effects, as it was discontinued in a few cases due to adverse effects like leukopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical experience with clozapine in 55 cases of treatment-resistant schizophrenia]. Enomoto, T., Ito, T., Sekine, K., et al.[2013]

In an 18-week study involving 147 patients with treatment-resistant schizophrenia, olanzapine showed similar efficacy to clozapine, with no significant differences in key measures of schizophrenia symptoms or response rates.

Both olanzapine and clozapine were well tolerated, with no significant safety concerns, making olanzapine a viable and safer alternative for patients who cannot tolerate clozapine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Bitter, I., Dossenbach, MR., Brook, S., et al.[2018]

In a study of 159 participants with treatment-resistant schizophrenia, once-daily dosing of clozapine was linked to younger age, better cognitive performance, and lower clinical symptom severity compared to divided dosing regimens.

The once-daily dosing group also had lower trough plasma concentrations of clozapine and norclozapine, suggesting that this regimen may be effective without increasing the risk of severe symptoms or side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily versus divided dosing regimens of clozapine: A cross-sectional study in Singapore. Yang, Z., Takeuchi, H., Yee, JY., et al.[2023]

A study involving 118 patients with treatment-resistant schizophrenia found no significant difference in all-cause discontinuation rates between once-daily and divided dosing of clozapine, suggesting both methods are equally effective.

The safety profiles were also similar for both dosing regimens, indicating that patients can be prescribed either method without increased risk of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the Effectiveness and Safety of Clozapine Between Once-Daily and Divided Dosing Regimen in Patients With Treatment-Resistant Schizophrenia. Sathienluckana, T., Jansing, T., Srisuriyakamon, S., et al.[2023]

In a study of 108 participants, there were no significant differences in the plasma concentrations of clozapine between once-daily and divided dosing regimens, suggesting that once-daily dosing may be just as effective.

Psychiatric symptoms and subjective adverse effects were similar for both dosing strategies, indicating that once-daily dosing could be a feasible alternative in clinical practice for patients on clozapine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan. Kitagawa, K., So, R., Nomura, N., et al.[2022]

Clozapine is the most effective treatment for resistant schizophrenia, but its pharmacokinetic properties suggest it should ideally be administered twice daily due to its short half-life and quick dissociation from the dopamine D2 receptor.

Current practices often prescribe clozapine once daily to manage side effects and simplify regimens, but this may not provide optimal therapeutic outcomes, indicating a need for reevaluation of dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine administered once versus twice daily: does it make a difference? Procyshyn, RM., Vila-Rodriguez, F., Honer, WG., et al.[2014]

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