Clozapine for the Prevention of Violence in Schizophrenia: a Randomized Clinical Trial (REVISIT-C)

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

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Clozapine; Drug: treatment as usual

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 280
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ragy Girgis; Phone Number: 646-774-5553; Email: ragy.girgis@nyspi.columbia.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90024
      • Not yet recruiting
      • University of California, Los Angeles
      • Contact: Alex Kopelowicz, MD; Phone Number: 818-837-8150; Email: akopel@ucla.edu
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Not yet recruiting
      • Augusta University Research Institute, Inc.
      • Contact: Joseph McEvoy, MD; Phone Number: 706-792-7021; Email: jmcevoy@augusta.edu
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Not yet recruiting
      • University of Maryland School of Medicine
      • Contact: Deanna Kelly, PharmD; Phone Number: 410-402-6861; Email: dlkelly@som.umaryland.edu
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • New York State Psychiatric Institute
      • Contact: Ragy R Girgis, MD; Phone Number: 646-774-5553; Email: rg2290@columbia.edu
      • Principal Investigator: Ragy R Girgis, MD
      • Principal Investigator: Scott Stroup, MD
    • New York, New York, United States, 10016
      • Not yet recruiting
      • NYU Langone Medical Center
      • Contact: Donald Goff; Phone Number: 646-754-4843; Email: donald.goff@nyulangone.org
    • New York, New York, United States, 10035
      • Not yet recruiting
      • Manhattan Psychiatric Center
      • Contact: Jean-Pierre Lindenmayer, MD; Phone Number: 212-249-2720; Email: jean-pierre.lindenmayer@nki.rfmh.org
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Not yet recruiting
      • University of North Carolina At Chapel Hill
      • Contact: Fred Jarskog, MD; Phone Number: 919-842-7683; Email: jarskog@med.unc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interventions to Prevent Violence	examine the effects of clozapine vs TAU on interventions to prevent violence based on a querying clinicians treating patients about interventions to prevent violence at weeks 4, 8, 16 and 24	Randomization to end of treatment (24 weeks)

Collaborators and Investigators

• Sponsor: New York State Psychiatric Institute
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Ragy Girgis, MD, New York State Psychiatric Institute

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2022
• Primary Completion (Estimated): January 23, 2027
• Study Completion (Estimated): February 28, 2027

Study Registration Dates

• First Submitted: January 12, 2022
• First Submitted That Met QC Criteria: January 12, 2022
• First Posted (Actual): January 26, 2022

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic 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: I20-02054; 1R01MH120317-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes