Clozapine for the Prevention of Violence in Schizophrenia: a Randomized Clinical Trial

Study Overview
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Brief Summary
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Two-hundred and eighty individuals with schizophrenia who have a recent history of violent acts will be randomized in this 2-arm, parallel-group, 24-week, open-label, 7-site clinical trial to examine the effects of treatment with clozapine vs antipsychotic treatment as usual (TAU) for reducing the risk of violent acts in real-world settings

Detailed Description
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This is a single-blind, open-label, randomized, active comparator (TAU) controlled clinical trial to examine the effects of clozapine vs. TAU on the risk for violent acts as measured by the MacArthur Community Violence Interview (MCVI) and to examine the effects of clozapine vs. TAU on the Excitement Factor of the PANSS. Adults age 18-65 with schizophrenia or schizoaffective disorder who have committed a violent act within 6 months and are appropriate for treatment with clozapine or TAU will receive treatment for 24 weeks which will be naturalistically administered. Participants will also participate in assessments and appropriate medical monitoring which will include blood draws, pharmacokinetic blood samples, and physical exams, etc. Cox proportional hazards survival modeling will be used to test the association between treatment group and time until first violent act after randomization (i.e., number of weeks form randomization to violent act).

Official Title
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Clozapine for the Prevention of Violence in Schizophrenia: a Randomized Clinical Trial

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: Clozapine
* Drug: treatment as usual


Participation Criteria
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Eligibility Criteria
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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) commission of a minor or serious act of violence as measured by the MCVI in the last six months willing and able to provide informed consent medically stable in judgment of physician providing study treatment appropriate for treatment with either clozapine or TAU, i.e., that there is clinical equipoise between the two treatment options. Individuals who are currently medication free or on any antipsychotic, with the exception of clozapine or long-acting injectable medication with a dosing interval of more than 30 days will be eligible Exclusion Criteria: An unstable of serious medical or neurological condition including a myeloproliferative disorder or condition that surprises the bone marrow A history of intolerance/allergy to clozapine (e.g., agranulocytosis, small bowel obstruction, or myocarditis) A history of intellectual impairment pregnant or lactating women; women who are able to become pregnant but who are not willing to sue effective methods of birth control Individuals who score a 3, 4, or 5 within the previous month on the suicidal ideation section of the Columbia Suicide Severity Rating Scale (CSSRS), have any suicidal behavior (not including Not Suicidal Self Injury) within the previous 3 months, or are, in the opinion of the investigator, at too high of a risk for suicide to be safety treated in a randomized trial in which they may not be treated with clozapine Documented intolerance to or lack of any therapeutic benefit with clozapine after a full trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: single-blind, open-label, randomized, active comparator (TAU) controlled clinical trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clozapine<br>treatment with clozapine naturalistically administered (as per clinical guideline). | Drug: Clozapine<br>* treatment will occur naturalistically, as per standard clinical guidelines<br>* Other names: clozaril;|
| Active Comparator: Treatment as usual<br>open label naturalistic treatment as usual with any antipsychotic other than clozapine | Drug: treatment as usual<br>* naturalistic treatment with any other antipsychotic medication except clozapine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness outcome: Violent acts | violent acts as measured by the MacArthur Community Violence Interview | Time to violent act from randomization to treatment completion (24 weeks) | 
| Target engagement outcome: Excitement Factor of the Positive and Negative Syndrome Scale (PANSS) | a composite of the scores of excitement, uncooperativeness, poor impulse control, and hostility) | Randomization to end of study treatment (24 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect on aggression | examine the effects of clozapine vs TAU on aggression as measured by the Point Subtraction Aggression Paradigm | Randomization to end of treatment (24 weeks) | 
| Positive symptoms and substance use | explore effects of clozapine vs TAU on the positive symptom sub scale of the PANSS and alcohol and illicit substance use, how these effects influence the risk for violent acts, and the degree to which clozapine's effects on the Excitement Factor of the PANSS are independent of its effects on total positive symptoms and substance use. | Randomization to end of treatment (24 weeks) |