<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01663077</url>
  </required_header>
  <id_info>
    <org_study_id>KBK2012</org_study_id>
    <secondary_id>03/11</secondary_id>
    <nct_id>NCT01663077</nct_id>
  </id_info>
  <brief_title>Clozapine Plasma Levels and the Relationship to the Genetic Polymorphism in Shizophrenic Patients</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tirat Carmel Mental Health Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Technion, Israel Institute of Technology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ben-Gurion University of the Negev</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beersheva Mental Health Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sha'ar Menashe Mental Health Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>HaEmek Medical Center, Israel</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Nazareth Hospital, Israel</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Tirat Carmel Mental Health Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Approximately 30-60% of all schizophrenia patients who fail to respond to typical&#xD;
      antipsychotics may respond to Clozapine. Clozapine has long been considered the &quot;gold&#xD;
      standard&quot; within the atypical neuroleptic spectrum, backed by years of clinical experience&#xD;
      and research, but uncertainties remain in some aspects of this drug. One such question is the&#xD;
      link between dose, blood levels and patient clinical response. The Clozapine therapeutic&#xD;
      plasma levels range between 250 - 450 ng/mL creating difficulties in using these results in&#xD;
      routine clinical practice. Approximately 30% - 51% of &quot;treatment-resistant schizophrenia&quot;&#xD;
      patients do not fully respond to Clozapine, a poorly understood phenomenon. Factors relevant&#xD;
      to Clozapine-resistance include co-morbidity, drug misuse, poor adherence, inadequate&#xD;
      duration of treatment and inadequate dose/plasma-levels. Pharmacogenetic factors such as&#xD;
      different polymorphisms in involved genes may play a role. Pharmacodynamic and genetic data&#xD;
      appear important in determining the clinical response to Clozapine. Clozapine-treated&#xD;
      patients possessing different 3A4 polymorphisms, may respond differently as compared to other&#xD;
      patients having normal 3A4 alleles. Recently, the CYP2D6 has also been involved in this drug&#xD;
      metabolic pathway. Population pharmacokinetics of clozapine evaluated with the nonparametric&#xD;
      maximum likelihood method. This pharmacogenetic explanation/hypothesis may explain Clozapine-&#xD;
      resistance in schizophrenics.&#xD;
&#xD;
      The high variability in plasma levels requires a large study in order to be able to determine&#xD;
      correlation between clinical efficacy and plasma levels and genotyping. A preliminary study&#xD;
      will enable power analysis and adequate determination of sample size.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">December 2016</completion_date>
  <primary_completion_date type="Actual">November 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clozapine steady state plasma level</measure>
    <time_frame>3 month</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in clinically stable schizophrenic adult patients</measure>
    <time_frame>Once</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Schizophrenia</condition>
  <arm_group>
    <arm_group_label>Clozapine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Clozapine tablet 150 mg at the day and 150 mg in the evening by mouth per day for 3 month</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clozapine</intervention_name>
    <description>A fixed dose of Clozapine 300 mg/day (150 mg x 2)for 3 month</description>
    <arm_group_label>Clozapine</arm_group_label>
    <other_name>Leponex</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  DSM-IV criteria for schizophrenia (American Psychiatric Association 2000)&#xD;
&#xD;
          -  All clozapine mono-therapy patients (only 300 mg/day) who respond to treatment and&#xD;
             achieved symptomatic remission (45, 46) and were stable for at least 3 month will be&#xD;
             included&#xD;
&#xD;
          -  No change in benzodiazepine medications for the trial period.&#xD;
&#xD;
          -  Legal ability and willingness to sign an informed consent form for participation in&#xD;
             the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Evidence of serious neurologic or endocrine disorder, for example severe head trauma,&#xD;
             seizure disorder, dementia, Cushing's disease, thyroid disorder, mental retardation,&#xD;
             alcohol or drug abuse, substance dependence (other than nicotine dependence), or&#xD;
             presenting symptoms likely substance- induced, as judged by a study physician.&#xD;
&#xD;
          -  Unstable medical illness or neurologic illness (seizures, CVA); breast, uterine, or&#xD;
             ovarian cancer.&#xD;
&#xD;
          -  Pregnant women, use of oral contraceptives or other hormonal supplementation such as&#xD;
             estrogen. [Female patients will also have a pregnancy test.].&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anatoly Kreinin, MD, Phd</last_name>
    <role>Study Director</role>
    <affiliation>Tirat Carmel Mental Health Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Yedidia Bentur, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rambam Health Care Campus, Haifa</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Norberto Krivoy, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rambam Health Care Campus, Haifa</affiliation>
  </overall_official>
  <overall_official>
    <last_name>David Rabinowitz, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rambam Health Care Campus, Haifa</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kamal Farhat, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Nazareth Hospital-EMM</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Vladimir Lerner, MD, Phd</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beersheva Mental Health Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Boaz Bloch, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Haemek Hospital, Afula</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Alexander Grinshpoon, MD, MHA, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shaar Menashe MHC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Tirat Carmel Mental Health Center</name>
      <address>
        <city>Tirat Carmel</city>
        <zip>30200</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>July 25, 2012</study_first_submitted>
  <study_first_submitted_qc>August 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2012</study_first_posted>
  <last_update_submitted>October 11, 2017</last_update_submitted>
  <last_update_submitted_qc>October 11, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 12, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tirat Carmel Mental Health Center</investigator_affiliation>
    <investigator_full_name>Anatoly Kreinin, MD, PHD</investigator_full_name>
    <investigator_title>Director of Psychiatric Department</investigator_title>
  </responsible_party>
  <keyword>Clozapine</keyword>
  <keyword>Schizophrenia</keyword>
  <keyword>Remissia</keyword>
  <keyword>polymorphism</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Schizophrenia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clozapine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01663077
org study id: KBK2012
secondary id: 03/11
nct id: NCT01663077
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Clozapine steady state plasma level
time frame: 3 month
measure: Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in clinically stable schizophrenic adult patients
time frame: Once
arm group label: Clozapine
arm group type: Experimental
description: Clozapine tablet 150 mg at the day and 150 mg in the evening by mouth per day for 3 month
intervention type: Drug
intervention name: Clozapine
description: A fixed dose of Clozapine 300 mg/day (150 mg x 2)for 3 month
arm group label: Clozapine
other name: Leponex
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Anatoly Kreinin, MD, Phd
role: Study Director
affiliation: Tirat Carmel Mental Health Center
last name: Yedidia Bentur, MD
role: Principal Investigator
affiliation: Rambam Health Care Campus, Haifa
last name: Norberto Krivoy, MD
role: Principal Investigator
affiliation: Rambam Health Care Campus, Haifa
last name: David Rabinowitz, MD
role: Principal Investigator
affiliation: Rambam Health Care Campus, Haifa
last name: Kamal Farhat, MD
role: Principal Investigator
affiliation: The Nazareth Hospital-EMM
last name: Vladimir Lerner, MD, Phd
role: Principal Investigator
affiliation: Beersheva Mental Health Center
last name: Boaz Bloch, MD
role: Principal Investigator
affiliation: Haemek Hospital, Afula
last name: Alexander Grinshpoon, MD, MHA, PhD
role: Principal Investigator
affiliation: Shaar Menashe MHC
facility: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Tirat Carmel Mental Health Center
investigator full name: Anatoly Kreinin, MD, PHD
investigator title: Director of Psychiatric Department
mesh term: Schizophrenia
mesh term: Clozapine