SchizophreniaPhase 4NCT02639702
Switching From Twice-Daily to Once-Daily Clozapine Dosing in Schizophrenia
A Phase 4 study testing Clozapine in people with Schizophrenia and Schizoaffective Disorder, run by Centre for Addiction and Mental Health at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Schizophrenia, Schizoaffective Disorder
- What is being tested?
- Clozapine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteCanada
- Study dates
- 15 Oct 2016to 31 Dec 2027
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- Having significant medical or neurological illnesses
- Pregnant or lactating
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
Centre for Addiction and Mental Health
Toronto, Ontario, M5T 1R8
Gary Remington, MD, PhD, 416-535-8501 ext. 34864, Gary.Remington@camh.ca
Gary Remington, MD, PhD
About this study
Official title: Switching From Twice-Daily to Once-Daily Clozapine Dosing in Schizophrenia: A Pilot, Double-Blind, Randomized Controlled Trial
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.
Read the 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.
- Conditions
- Schizophrenia, Schizoaffective Disorder
- Being tested
- Clozapine
- Keywords
- Clozapine, Dosing, Once daily, Regimen, Schizophrenia
- Medical subject headings
- Schizophrenia, Psychotic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ClozapineDrug
Also called Clozaril
Switching from twice-daily to once-daily clozapine dosing regimen
| Study group | Role | What they receive |
|---|---|---|
| Switch group | Experimental | 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. Receives: Drug: Clozapine |
| Maintenance group | No intervention | Participants will continue to take clozapine twice daily throughout the study period. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 0 and 12 weeks
Secondary outcomes (7)
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)
Measured: 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)
Measured: 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.
Measured: 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)
Measured: 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.
Measured: 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
Measured: 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)
Measured: 0 and 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2015 (estimated)
- Study start15 Oct 2016
- Primary completion30 Sep 2027 (estimated)
- Study completion31 Dec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre for Addiction and Mental Health
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Gary Remington, Centre for Addiction and Mental Health
- Investigators
- Gary Remington, MD, PhD, Principal investigator, Centre for Addiction and Mental Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02639702
- Sponsor's protocol ID
- 096/2015
- Status last verified
- Aug 2026
- First submitted
- 18 Dec 2015
- Last updated
- 25 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Takeuchi H, Fervaha G, Uchida H, Suzuki T, Bies RR, Gronte D, Remington G. Impact of once- versus twice-daily perphenazine dosing on clinical outcomes: an analysis of the CATIE data. J Clin Psychiatry. 2014 May;75(5):506-11. doi: 10.4088/JCP.13m08695.
PubMed 24569099Nair NP. Therapeutic equivalence of risperidone given once daily and twice daily in patients with schizophrenia. The Risperidone Study Group. J Clin Psychopharmacol. 1998 Apr;18(2):103-10. doi: 10.1097/00004714-199804000-00002.
PubMed 9555595Agarwal V, Chadda RK. Once daily risperidone in treatment of schizophrenia. Indian J Psychiatry. 2001 Jan;43(1):32-5.
PubMed 21407835Takeuchi H, Fervaha G, Lee J, Agid O, Remington G. Effectiveness of different dosing regimens of risperidone and olanzapine in schizophrenia. Eur Neuropsychopharmacol. 2015 Mar;25(3):295-302. doi: 10.1016/j.euroneuro.2014.12.008. Epub 2015 Jan 9.
PubMed 25649680Chengappa KN, Parepally H, Brar JS, Mullen J, Shilling A, Goldstein JM. A random-assignment, double-blind, clinical trial of once- vs twice-daily administration of quetiapine fumarate in patients with schizophrenia or schizoaffective disorder: a pilot study. Can J Psychiatry. 2003 Apr;48(3):187-94. doi: 10.1177/070674370304800307.
PubMed 12728743Sun X, Hamer R, McEvoy J. Asenapine once daily versus twice daily: impact on patient acceptance in a randomized, open-label, 14-day clinical trial. J Clin Psychiatry. 2015 Jul;76(7):992-3. doi: 10.4088/JCP.14l09206. No abstract available.
PubMed 26231009Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, Fric M, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, Jaquenoud Sirot E, Kirchherr H, Laux G, Lutz UC, Messer T, Muller MJ, Pfuhlmann B, Rambeck B, Riederer P, Schoppek B, Stingl J, Uhr M, Ulrich S, Waschgler R, Zernig G. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry. 2011 Sep;44(6):195-235. doi: 10.1055/s-0031-1286287. Epub 2011 Sep 27.
PubMed 21969060Takeuchi H, Powell V, Geisler S, DeSanti M, Fervaha G, Agid O, Kane JM, Remington G. Clozapine administration in clinical practice: once-daily versus divided dosing. Acta Psychiatr Scand. 2016 Sep;134(3):234-40. doi: 10.1111/acps.12593. Epub 2016 May 16.
PubMed 27182769