Clozapine Plasma Levels and the Relationship to the Genetic Polymorphism in Shizophrenic Patients

This study is not yet open for participant recruitment.
Verified July 2012 by Tirat Carmel Mental Health Center
Sponsor:
Collaborators:
Technion, Israel Institute of Technology
Ben-Gurion University of the Negev
Beersheva Mental Health Center
Sha’ar Menashe Mental Health Center
HaEmek Medical Center, Israel
The Nazareth Hospital, Israel
Information provided by (Responsible Party):
Anatoly Dr. Kreinin, Tirat Carmel Mental Health Center
ClinicalTrials.gov Identifier:
NCT01663077
First received: July 25, 2012
Last updated: August 8, 2012
Last verified: July 2012
  Purpose

Approximately 30-60% of all schizophrenia patients who fail to respond to typical antipsychotics may respond to Clozapine. Clozapine has long been considered the "gold standard" within the atypical neuroleptic spectrum, backed by years of clinical experience and research, but uncertainties remain in some aspects of this drug. One such question is the link between dose, blood levels and patient clinical response. The Clozapine therapeutic plasma levels range between 250 - 450 ng/mL creating difficulties in using these results in routine clinical practice. Approximately 30% - 51% of "treatment-resistant schizophrenia" patients do not fully respond to Clozapine, a poorly understood phenomenon. Factors relevant to Clozapine-resistance include co-morbidity, drug misuse, poor adherence, inadequate duration of treatment and inadequate dose/plasma-levels. Pharmacogenetic factors such as different polymorphisms in involved genes may play a role. Pharmacodynamic and genetic data appear important in determining the clinical response to Clozapine. Clozapine-treated patients possessing different 3A4 polymorphisms, may respond differently as compared to other patients having normal 3A4 alleles. Recently, the CYP2D6 has also been involved in this drug metabolic pathway. Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. This pharmacogenetic explanation/hypothesis may explain Clozapine- resistance in schizophrenics.

The high variability in plasma levels requires a large study in order to be able to determine correlation between clinical efficacy and plasma levels and genotyping. A preliminary study will enable power analysis and adequate determination of sample size.


Condition Intervention Phase
Schizophrenia
Drug: Clozapine
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Clozapine Fixed Dose Steady State Plasma Levels and the Relationship to the Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in Clinically Stable Schizophrenic Adult Patients

Resource links provided by NLM:


Further study details as provided by Tirat Carmel Mental Health Center:

Primary Outcome Measures:
  • Clozapine steady state plasma level [ Time Frame: 3 month ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in clinically stable schizophrenic adult patients [ Time Frame: Once ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 20
Study Start Date: October 2012
Estimated Study Completion Date: October 2013
Estimated Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Clozapine
Clozapine tablet 150 mg at the day and 150 mg in the evening by mouth per day for 3 month
Drug: Clozapine
A fixed dose of Clozapine 300 mg/day (150 mg x 2)for 3 month
Other Name: Leponex

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • DSM-IV criteria for schizophrenia (American Psychiatric Association 2000)
  • All clozapine mono-therapy patients (only 300 mg/day) who respond to treatment and achieved symptomatic remission (45, 46) and were stable for at least 3 month will be included
  • No change in benzodiazepine medications for the trial period.
  • Legal ability and willingness to sign an informed consent form for participation in the study.

Exclusion Criteria:

  • Evidence of serious neurologic or endocrine disorder, for example severe head trauma, seizure disorder, dementia, Cushing's disease, thyroid disorder, mental retardation, alcohol or drug abuse, substance dependence (other than nicotine dependence), or presenting symptoms likely substance- induced, as judged by a study physician.
  • Unstable medical illness or neurologic illness (seizures, CVA); breast, uterine, or ovarian cancer.
  • Pregnant women, use of oral contraceptives or other hormonal supplementation such as estrogen. [Female patients will also have a pregnancy test.].
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01663077

Contacts
Contact: Anatoly Kreinin, MD, PhD +97248559325 ANATOLY.KREININ@PSTIRA.HEALTH.GOV.IL

Locations
Israel
Tirat Carmel Mental Health Center Not yet recruiting
Tirat Carmel, Israel, 30200
Contact: Anatoly Kreinin, MD, PhD         
Principal Investigator: Anatoly Kreinin, MD, PhD         
Sponsors and Collaborators
Tirat Carmel Mental Health Center
Technion, Israel Institute of Technology
Ben-Gurion University of the Negev
Beersheva Mental Health Center
Sha’ar Menashe Mental Health Center
HaEmek Medical Center, Israel
The Nazareth Hospital, Israel
Investigators
Study Director: Anatoly Kreinin, MD, Phd Tirat Carmel Mental Health Center
Principal Investigator: Yedidia Bentur, MD Rambam Health Care Campus, Haifa
Principal Investigator: Norberto Krivoy, MD Rambam Health Care Campus, Haifa
Principal Investigator: David Rabinowitz, MD Rambam Health Care Campus, Haifa
Principal Investigator: Kamal Farhat, MD The Nazareth Hospital-EMM
Principal Investigator: Vladimir Lerner, MD, Phd Beersheva Mental Health Center
Principal Investigator: Boaz Bloch, MD Haemek Hospital, Afula
Principal Investigator: Alexander Grinshpoon, MD, MHA, PhD Shaar Menashe MHC
  More Information

No publications provided

Responsible Party: Anatoly Dr. Kreinin, Director of Psychiatric Department, Tirat Carmel Mental Health Center
ClinicalTrials.gov Identifier: NCT01663077     History of Changes
Other Study ID Numbers: KBK2012, 03/11
Study First Received: July 25, 2012
Last Updated: August 8, 2012
Health Authority: Israel: Ministry of Health

Keywords provided by Tirat Carmel Mental Health Center:
Clozapine
Schizophrenia
Remissia
polymorphism

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia and Disorders with Psychotic Features
Mental Disorders
Clozapine
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
GABA Antagonists
GABA Agents

ClinicalTrials.gov processed this record on April 16, 2014