Clozapine for Schizophrenia

(REVISIT-C Trial)

Recruiting at 6 trial locations

Overseen By Ragy Girgis

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: New York State Psychiatric Institute

Must be taking: Antipsychotics

Must not be taking: Clozapine, Long-acting injectables

Disqualifiers: Unstable medical condition, Pregnancy, Suicide risk, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

280 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing whether clozapine can reduce violent behavior more effectively than usual treatments in adults with schizophrenia who have recently been violent. Clozapine helps by balancing brain chemicals to manage symptoms. The study will last for several months and include regular medical check-ups. Clozapine has been shown to reduce violent and aggressive behavior in patients with schizophrenia, especially those who are treatment-resistant.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you can participate if you are currently medication-free or on any antipsychotic, except clozapine or long-acting injectables with a dosing interval of more than 30 days.

Is clozapine safe for use in humans?

Clozapine is generally safe for humans when used carefully, but it can have serious side effects like blood problems, heart issues, and seizures. Regular monitoring of blood cells and other health checks are important to manage these risks. ^{1 2 3 4 5}

What makes the drug clozapine unique for treating schizophrenia?

Clozapine is unique because it is the only antipsychotic drug specifically approved for treatment-resistant schizophrenia, meaning it is used when other treatments have failed. It is also known for having fewer movement-related side effects compared to traditional antipsychotic drugs. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Clozapine for schizophrenia?

Clozapine is considered the most effective drug for managing treatment-resistant schizophrenia, showing significant improvement in symptoms compared to other second-generation antipsychotic drugs, especially in patients who have not responded well to at least two other antipsychotic medications. ^{7 11 12 13 14}

Who Is on the Research Team?

Ragy R Girgis, MD

Principal Investigator

New York State Psychiatric Institute

Are You a Good Fit for This Trial?

This trial is for adults with schizophrenia or schizoaffective disorder who have been violent recently. They must be medically stable, able to consent, and not on certain long-term medications. Pregnant women, those intolerant to clozapine, with serious medical conditions or high suicide risk are excluded.

Inclusion Criteria

Diagnostic and Statistical Manual-5 (DSM-5) diagnosis of schizophrenia or schizoaffective disorder by the Structured Clinical Interview for DSM-5 (SCID-5)

medically stable in judgment of physician providing study treatment

You have committed a violent act in the past six months, as determined by the MCVI assessment.

Exclusion Criteria

A history of intolerance/allergy to clozapine (e.g., agranulocytosis, small bowel obstruction, or myocarditis)

I do not have a serious condition affecting my blood or nervous system.

I tried clozapine without success or had side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive treatment with clozapine or treatment as usual (TAU) for 24 weeks

24 weeks

Regular visits for assessments and medical monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Clozapine
• Treatment as Usual

Trial Overview The study compares the effectiveness of clozapine versus usual antipsychotic treatments in reducing violence among individuals with schizophrenia over a 24-week period across seven sites. Participants will be randomly assigned to one of the two treatment groups.

How Is the Trial Designed?

Group I: Clozapine Experimental Treatment 1 Intervention

treatment with clozapine naturalistically administered (as per clinical guideline).

Group II: Treatment as usual Active Control 1 Intervention

open label naturalistic treatment as usual with any antipsychotic other than clozapine

Clozapine is already approved in United States, European Union for the following indications:

Approved in United States as Clozaril for:

• Schizophrenia
• Borderline Personality Disorder
• Paranoid Disorder

Approved in European Union as Clozapine for:

• Schizophrenia
• Treatment-resistant schizophrenia

Who Is Running the Clinical Trial?

New York State Psychiatric Institute

Lead Sponsor

Trials

481

Recruited

154,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

Clozapine is ineffective for over 50% of treatment-resistant schizophrenia patients, and while adjunctive treatments like amisulpride, aripiprazole, and mirtazapine show some evidence of efficacy, overall data on safety and effectiveness for these strategies is limited.

Meta-analyses indicated that risperidone and lamotrigine do not support their use as adjuncts to clozapine, highlighting the need for further research due to small sample sizes and variability in study designs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine resistance: augmentation strategies. Porcelli, S., Balzarro, B., Serretti, A.[2022]

A study involving 28 Korean patients with schizophrenia found that the generic formulation of clozapine (Clzapine) is bioequivalent to the brand name formulation (Clozaril), showing similar pharmacokinetic profiles in terms of peak concentration and overall drug exposure.

Both formulations had comparable safety profiles, with no significant differences in adverse events, vital signs, or laboratory tests, suggesting that Clzapine can be a safe alternative to Clozaril for treating refractory schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence of Generic and Brand Name Clozapine in Korean Schizophrenic Patients: A Randomized, Two-Period, Crossover Study. Woo, YS., Wang, HR., Yoon, BH., et al.[2020]

A study involving 26 Chinese patients with schizophrenia found that the generic formulation of clozapine is bioequivalent to the brand-name Clozaril, meaning they produce similar plasma drug concentrations after multiple doses.

Both formulations resulted in a comparable number of adverse events, indicating that the safety profile of the generic clozapine is similar to that of the brand-name version.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of bioequivalence between generic and brand-name clozapine in Chinese schizophrenic patients: A randomized, two-period, crossover study. Yang, X., Yan, Q., Yang, L., et al.[2021]

In a study of 187 patients treated with clozapine, 39% were found to carry the CYP2C19*17 polymorphism, which was associated with higher levels of norclozapine and lower fasting glucose and HbA1c levels, indicating a reduced risk of diabetes.

Patients with the CYP2C19*17 polymorphism not only had a lower prevalence of diabetes but also showed a greater likelihood of clinical improvement in their schizophrenia symptoms, suggesting that this genetic variant may offer protective benefits during clozapine treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CYP2C19*17 protects against metabolic complications of clozapine treatment. Piatkov, I., Caetano, D., Assur, Y., et al.[2022]

Clozapine is more effective than other second-generation antipsychotic drugs in improving symptoms for patients with schizophrenia who have not responded to two or more previous treatments, as shown by a significant reduction in the PANSS total score in a study of 136 participants over one year.

While clozapine did not show a significant advantage in Quality of Life scores compared to other SGAs, it was associated with fewer extrapyramidal side effects and reported better mental health by participants at 12 weeks, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Lewis, SW., Barnes, TR., Davies, L., et al.[2022]

Clozapine is the only approved treatment for resistant schizophrenia, but it is often underprescribed due to concerns about its adverse drug events (ADEs) and monitoring requirements.

Despite the risks, the benefits of clozapine generally outweigh its risks, as most ADEs can be managed with careful patient assessment and monitoring, including regular checks of neutrophil levels and gradual dosage adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine is the approved option in treatment-resistant schizophrenia and requires careful management. Fenton, C., Kang, C.[2023]

Clozapine is an effective treatment for resistant schizophrenia but is often underused due to serious side effects and the need for regular monitoring of white blood cell counts.

The article advocates for expanded monitoring practices beyond the mandatory requirements to enhance patient safety and encourage clinicians to use clozapine more confidently.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine Monitoring in Clinical Practice: Beyond the Mandatory Requirement. Kar, N., Barreto, S., Chandavarkar, R.[2022]

Clozapine is an effective antipsychotic with a unique clinical profile, but it carries significant safety risks, including potentially life-threatening conditions like neutropenia, seizures, and myocarditis.

A thorough understanding of clozapine's safety profile is essential for maximizing its benefits while minimizing risks, making careful monitoring crucial during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of clozapine safety. Fitzsimons, J., Berk, M., Lambert, T., et al.[2013]

Clozapine is an effective antipsychotic with unique clinical benefits, but it poses serious safety risks, particularly hematological issues, requiring strict monitoring protocols for patients.

A new consensus statement recommends enhanced monitoring for additional adverse effects, including cardiovascular and metabolic risks, based on practices from five major psychiatric hospitals in Victoria, Australia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring the safe use of clozapine: a consensus view from Victoria, Australia. Berk, M., Fitzsimons, J., Lambert, T., et al.[2018]

A 5-year study involving 21 patients with treatment-resistant schizophrenia showed that continuous clozapine use did not significantly affect psychiatric symptoms or social performance, indicating its long-term efficacy in managing TRS.

The study also highlighted that with proper dietary and clinical monitoring, clozapine can be safely managed, as evidenced by a significant decrease in body mass index (BMI) and stable hematological parameters, except for a decrease in red blood cell count over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine Management in Schizophrenia Inpatients: A 5-Year Prospective Observational Study of Its Safety and Tolerability Profile. de Filippis, R., Gaetano, R., Schoretsanitis, G., et al.[2022]

Clozapine (CLOZ) is an effective treatment for some patients with treatment-resistant schizophrenia, showing fewer extrapyramidal side effects compared to traditional antipsychotics, making it a valuable option for difficult cases.

Further research is needed to clarify optimal dosing, treatment duration, and the potential use of CLOZ for other conditions like schizoaffective disorder and Parkinson's disease, as well as to better understand neuroleptic intolerance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on the clinical efficacy and side effects of clozapine. Safferman, A., Lieberman, JA., Kane, JM., et al.[2022]

Clozapine is an atypical antipsychotic introduced in the UK in the early 1990s, specifically designed for treating intractable schizophrenia, and is notable for its minimal extrapyramidal side effects.

The drug is effective in addressing negative symptoms of schizophrenia, distinguishing it from conventional neuroleptics, and requires special monitoring and dispensing protocols to ensure safe use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine. Launer, M.[2016]

Clozapine serum levels are significantly correlated with increased heart rate, triglycerides, and overall adverse drug reactions (ADRs), indicating that monitoring these parameters could be important for patient safety.

Norclozapine levels are associated with higher triglycerides, total cholesterol, and weight gain, suggesting that both clozapine and its metabolite may contribute to metabolic side effects in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions. Tan, MSA., Honarparvar, F., Falconer, JR., et al.[2021]

Patients with treatment-resistant schizophrenia experienced a significant average delay of 47.7 months before starting clozapine, highlighting a gap in timely treatment despite its effectiveness.

Before initiating clozapine, a notable percentage of patients (36.2%) were on multiple antipsychotics and 34.2% were receiving high doses, indicating that current treatment practices often do not align with established guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Howes, OD., Vergunst, F., Gee, S., et al.[2021]

Citations

1. Netherlands pubmed.ncbi.nlm.nih.gov

Clozapine resistance: augmentation strategies. [2022]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Bioequivalence of Generic and Brand Name Clozapine in Korean Schizophrenic Patients: A Randomized, Two-Period, Crossover Study. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

Evaluation of bioequivalence between generic and brand-name clozapine in Chinese schizophrenic patients: A randomized, two-period, crossover study. [2021]

4. England pubmed.ncbi.nlm.nih.gov

CYP2C19*17 protects against metabolic complications of clozapine treatment. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Clozapine is the approved option in treatment-resistant schizophrenia and requires careful management. [2023]

7. Korea (South) pubmed.ncbi.nlm.nih.gov

Clozapine Monitoring in Clinical Practice: Beyond the Mandatory Requirement. [2022]

8. England pubmed.ncbi.nlm.nih.gov

A review of clozapine safety. [2013]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Monitoring the safe use of clozapine: a consensus view from Victoria, Australia. [2018]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Clozapine Management in Schizophrenia Inpatients: A 5-Year Prospective Observational Study of Its Safety and Tolerability Profile. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Update on the clinical efficacy and side effects of clozapine. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Clozapine. [2016]

13. Germany pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. [2021]