<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/NCT03253367</url>
  </required_header>
  <id_info>
    <org_study_id>ABR: 52726 &amp; 52728</org_study_id>
    <nct_id>NCT03253367</nct_id>
  </id_info>
  <brief_title>Phenomics and Genomics of Clozapine Pharmacotherapy</brief_title>
  <acronym>CLOZIN</acronym>
  <official_title>Phenomics and Genomics in Clozapine Pharmacotherapy: Current, Former and New Clozapine Users</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jurjen Luykx</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A burgeoning body of research has pointed to increased efficacy of clozapine (CLZ) over other&#xD;
      antipsychotics in schizophrenia (SCZ). On the other hand, safety concerns likely cause&#xD;
      underutilization across a range of European and other nations. The lack of data available to&#xD;
      predict efficacy and adverse drug reactions (ADRs) of CLZ further contributes to&#xD;
      underprescription rates in these countries. Here, we hypothesize that (epi)genetic and&#xD;
      non-genetic factors aid to help predict treatment outcome (efficacy + ADRs) to CLZ. We&#xD;
      furthermore posit that such prediction will result in enhanced quality of life of both&#xD;
      patients and family members. Our primary objective is to predict CLZ treatment outcome based&#xD;
      on phenotypic and genetic data obtained through the current design. The first secondary&#xD;
      objective is to investigate which methylation levels/patterns are correlated with CLZ&#xD;
      treatment outcome. The second secondary objective is to aid in the further elucidation of the&#xD;
      genetic architecture of SCZ and any possible differences between 'regular' SCZ patients and&#xD;
      those on CLZ, who are generally more severely ill. We thus intend to cover two currently&#xD;
      unmet needs using a precision medicine approach: the lack of knowledge about determinants of&#xD;
      treatment response to CLZ and the lack of insight into neurobiological differences between&#xD;
      'regular' SCZ and relatively treatment resistant subjects (CLZ users). The prime analysis&#xD;
      will be a common variant hypothesis-generating genotyping endeavor investigating treatment&#xD;
      response to CLZ. Additional analyses include whole-genome methylation and gene expression&#xD;
      analyses and analyses of non-genetic determinants of response. We will include 2,500 CLZ&#xD;
      treated patients for our discovery cohort, which is in line with previous whole-genome&#xD;
      pharmacogenomics studies and our power calculations. We will replicate any genome-wide loci&#xD;
      using our prospectively collected cohort of new users (N=59). Potential yields include a&#xD;
      publicly available prediction tool to help identify patients responsive to CLZ in early&#xD;
      disease stages and prevent harmful effects. In addition, common variant analyses compounded&#xD;
      by pathway analyses may help elucidate the mechanisms of action of CLZ. We ask for broad&#xD;
      informed consent from participants ensuring rich, longitudinal phenotypic and genotypic data&#xD;
      resources for both currently planned and future analyses, allowing e.g. next-generation&#xD;
      sequencing focused on both CLZ and SCZ disease genetics (e.g. in large consortia). We plan to&#xD;
      also generate polygenic risk scores (PRS) of CLZ efficacy and use those to identify other&#xD;
      diseases or patients for which CLZ may be helpful, e.g. schizoaffective disorder patients who&#xD;
      are sometimes first treated with mood stabilizers. Last, evidence hints that disparaging&#xD;
      genetic loci influence efficacy to different antipsychotics. Adding genetic data from our&#xD;
      cohort to existing datasets of response to other antipsychotics may help identify such loci.&#xD;
      Finally, comparison studies with non-CLZ using patients suffering from SCZ may deepen the&#xD;
      understanding of biological mechanisms underlying treatment resistance (or: a relatively&#xD;
      severe course of illness).The results of this genetic part of the study will be combined with&#xD;
      the results from our other research protocol 'Phenomics and genomic of clozapine&#xD;
      pharmacotherapy - New Users'.The overarching goal of both projects is to create a prediction&#xD;
      model for clozapine outcome (response (and side effects). This model includes genetic,&#xD;
      epigenetic and clinical data.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale Clozapine (CLZ) is generally prescribed if at least two trials of antipsychotic&#xD;
      agents have not led to satisfactory clinical improvement, thereby implying that patients on&#xD;
      CLZ generally suffer from more severe and/or persistent symptoms than patients suffering from&#xD;
      schizophrenia spectrum disorders (SCZ) on other antipsychotic agents. Unraveling the&#xD;
      (functional) genetic variation underlying this severe SCZ phenotype therefore has the&#xD;
      potential to deepen our understanding of the biological underpinnings of SCZ beyond the&#xD;
      boundaries of DSM-based consensus criteria. Such knowledge in turn has the potential to shape&#xD;
      future pharmacotherapeutic research. The investigators here hypothesize that targeting this&#xD;
      phenotype in genome-wide association studies and next-generation sequencing studies will&#xD;
      signal genetic risk loci implicated in this severe SCZ phenotype. In the future, this may&#xD;
      lead to early detection of severe SCZ, which in turn will enable tailoring of&#xD;
      pharmacotherapeutic strategies to such SCZ subtypes. The results of this genetic part of the&#xD;
      study will be combined with the results from our other research protocol ('Phenomics and&#xD;
      genomic of clozapine pharmacotherapy - New Users').The overarching goal of both projects is&#xD;
      to create a prediction model for clozapine outcome (response (and side effects). This model&#xD;
      includes genetic, epigenetic and clinical data.&#xD;
&#xD;
      Objectives&#xD;
&#xD;
      Primary:&#xD;
&#xD;
      1) To predict CLZ efficacy and ADRs (=treatment outcome) based on phenotypic and genetic data&#xD;
      obtained in this study.&#xD;
&#xD;
      Secondary:&#xD;
&#xD;
        1. To investigate which non-genetic factors, methylation and gene expression&#xD;
           levels/patterns predict treatment outcome after initiating CLZ;&#xD;
&#xD;
        2. As the genetic architecture of SCZ has not been fully elucidated, the current project&#xD;
           will aid in the further elucidation of the genetic architecture of SCZ and any possible&#xD;
           differences between 'regular' SCZ patients (those not considered treatment resistant)&#xD;
           and those on CLZ (considered generally to be a more homogeneous and severe group).&#xD;
&#xD;
      Study design This is a mostly cross-sectional study, in which both phenotypic and genotypic&#xD;
      data are gathered from this study population that currently uses CLZ or has used CLZ in the&#xD;
      past. A genome-wide association study (GWAS) will be performed to reveal possible differences&#xD;
      in genetic architecture between patients who use or have used CLZ and the broad schizophrenia&#xD;
      phenotype on the one hand and between those who use or have used CLZ and healthy controls on&#xD;
      the other. Targeted next-generation sequencing may be used to follow-up possible positive&#xD;
      associations. The genetic data will be used to analyse which genetic variants are associated&#xD;
      with CLZ response and/or side effects.&#xD;
&#xD;
      Study population The investigators will include 2,500 patients diagnosed with schizophrenia,&#xD;
      schizophreniform disorder, schizoaffective disorder or psychotic disorder NOS (together&#xD;
      referred to as SCZ) &gt;18 years of age who are currently on CLZ treatment or have used CLZ in&#xD;
      the past. Publicly available Psychiatric Genomics Consortium (PGC) GWAS data will be used for&#xD;
      comparisons with the broad schizophrenia phenotype group. For the purpose of the case-control&#xD;
      comparison, the 2,500 subjects who use or have used CLZ will be age and sex-matched to 30,000&#xD;
      healthy control subjects for whom genotype data are available in-house.&#xD;
&#xD;
      Intervention No intervention will be applied.&#xD;
&#xD;
      Main study parameters/endpoints&#xD;
&#xD;
        1. To assess whether the genetic architecture of this severe SCZ phenotype differs from the&#xD;
           broad DSM-based SCZ phenotype.&#xD;
&#xD;
        2. To predict clozapine response and side effects based on phenotypic and genetic data&#xD;
           obtained in this study.&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness Almost all patients on CLZ regularly have their blood drawn for routine white&#xD;
      blood cell counts and/or CLZ blood level assessments. The investigators anticipate that the&#xD;
      majority of the study population will consist of such patients as white blood cell monitoring&#xD;
      is strictly enforced in clinical practice for this patient group. For these patients, no&#xD;
      additional risks will be attached to the study, as the blood necessary for DNA extraction for&#xD;
      the current study will be drawn during these routinely performed venipunctures. Time&#xD;
      investment will also be low as the patients will only undergo a 10-minute interview. A&#xD;
      minority of patients on CLZ does not have their blood routinely monitored and neither do&#xD;
      patients who have used CLZ in the past. These subjects will be asked to allow a single blood&#xD;
      draw. A venipuncture entails the risk of a hematoma (blood leaving the vessel). The&#xD;
      investigators aim to minimize this risk by only allowing experienced personnel to draw blood&#xD;
      and in the event of deeply located or thin veins request central lab personnel to perform the&#xD;
      venipuncture. Although a hematoma resulting from a traumatic puncture imposes an esthetical&#xD;
      burden on the subject, no serious health risks are involved.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 19, 2016</start_date>
  <completion_date type="Anticipated">December 2021</completion_date>
  <primary_completion_date type="Anticipated">December 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Other</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Predict clozapine response.</measure>
    <time_frame>2016-2021</time_frame>
    <description>To predict clozapine response based on phenotypic information from our questionnaire (CGI + CRES) and genetic information from GWAS</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Predict side effects from clozapine use</measure>
    <time_frame>2016-2021</time_frame>
    <description>To predict clozapine response based on phenotypic information from our questionnaire (LUNSERS) and genetic information from GWAS</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assess differences in genetic architecture (GWAS)</measure>
    <time_frame>2016-2021</time_frame>
    <description>To assess whether the genetic architecture of this severe SCZ phenotype differs from the broad DSM-based SCZ phenotype. this will be done by comparing the gentic material of clozapine users vs. non-clozapine users. Only the clozapine DNA has to be collected yet.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Detect genetic associations (GWAS) Detect genetic associations current severe SCZ phenotype</measure>
    <time_frame>2016-2021</time_frame>
    <description>To detect genetic associations with the current severe SCZ phenotype by performing a case-control comparison with healthy participants (GWAS).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Increase or decrease cardiovascular disease?</measure>
    <time_frame>2016-2031</time_frame>
    <description>To investigate whether CLZ use increases or decreases the risk of cardiovascular disease and early death. This is done by following the patients for 10 years and see whether they developed serious cardiovascular diseases</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">2500</enrollment>
  <condition>Schizophrenia Spectrum and Other Psychotic Disorders</condition>
  <arm_group>
    <arm_group_label>Current/former clozapine users</arm_group_label>
    <description>This group has only one visit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>New clozapine users</arm_group_label>
    <description>This group will be followed for 6 months prospectively.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Blood is obtained, mostly during routine venipuncture</intervention_name>
    <arm_group_label>Current/former clozapine users</arm_group_label>
    <arm_group_label>New clozapine users</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      For current and former users we obtain DNA and for new users we also obtain RNA&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The investigators will include 2,500 patients diagnosed with schizophrenia,&#xD;
        schizophreniform disorder, schizoaffective disorder or psychotic disorder NOS (together&#xD;
        referred to as SCZ) &gt;18 years of age who are currently on CLZ treatment or have used CLZ in&#xD;
        the past. Publicly available Psychiatric Genomics Consortium (PGC) GWAS data will be used&#xD;
        for comparisons with the broad schizophrenia phenotype group. For the purpose of the&#xD;
        case-control comparison, the 2,500 subjects who use or have used CLZ will be age and&#xD;
        sex-matched to 13,000 healthy control subjects for whom genotype data are available&#xD;
        in-house.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  he/she currently uses CLZ or he/she has used CLZ in the past/will use CLZ&#xD;
&#xD;
          -  he/she has received a diagnosis of schizophrenia, schizophreniform disorder,&#xD;
             schizoaffective disorder or psychotic disorder NOS.&#xD;
&#xD;
          -  his/her age must be ≥18 years old&#xD;
&#xD;
          -  he/she must be able to speak and read the language of the Informed Consent (differs&#xD;
             per country)&#xD;
&#xD;
          -  he/she must be mentally competent and have decisional capacity with regard to a&#xD;
             decision to participate in the current study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  admission to a psychiatric unit involuntarily (not all countries)&#xD;
&#xD;
          -  a history of Parkinson's disease&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Marte van der Horst, Drs.</last_name>
    <phone>0887551460</phone>
    <phone_ext>+31</phone_ext>
    <email>mzvanderhorst@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jurjen Luykx, PhD</last_name>
    <phone>0887568638</phone>
    <phone_ext>+31</phone_ext>
    <email>j.luykx@umcutrecht.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Medical University Innsbruck</name>
      <address>
        <city>Innsbruck</city>
        <zip>6020</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Monika Edlinger, MD</last_name>
      <email>monika.edlinger@i-med.ac.at</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Niuvanniemen hospital</name>
      <address>
        <city>Kuopio</city>
        <zip>70240</zip>
        <country>Finland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jari Tiihonen, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>LMU Munich</name>
      <address>
        <city>München</city>
        <state>Munich</state>
        <zip>80336</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alkomiet Hasan, MD, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Charité Universitätsmedizin Berlin</name>
      <address>
        <city>Berlin</city>
        <zip>10117</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stefanie Schreiter, MD</last_name>
      <phone>004930450517009</phone>
      <email>stefanie.schreiter@charite.de</email>
    </contact>
    <contact_backup>
      <last_name>Stefan Gutwinski, MD</last_name>
      <phone>004930450517009</phone>
      <email>stefan.gutwinski@charite.de</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Vincent van Gogh Institute</name>
      <address>
        <city>Venray</city>
        <state>Limburg</state>
        <zip>5803 AC</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Reinier van Arkel</name>
      <address>
        <city>'s-Hertogenbosch</city>
        <state>Noord-Brabant</state>
        <zip>5211 LJ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Koen Grootens, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>GGZ-NHN</name>
      <address>
        <city>Heerhugowaard</city>
        <state>Noord-Holland</state>
        <zip>1703 WC</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>GGZ Rivierduinen</name>
      <address>
        <city>Leiden</city>
        <state>Oegstgeest</state>
        <zip>2342 EJ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Enrolling by invitation</status>
  </location>
  <location>
    <facility>
      <name>Yulius</name>
      <address>
        <city>Barendrecht</city>
        <state>Zuid Holland</state>
        <zip>2994 GC</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>UMC Utrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3508 GA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marte van der Horst, Drs.</last_name>
      <phone>0887551460</phone>
      <phone_ext>+31</phone_ext>
      <email>c.pfeifer@umcutrecht.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Altrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3512 PK</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Finland</country>
    <country>Germany</country>
    <country>Netherlands</country>
  </location_countries>
  <link>
    <url>http://www.clozinstudy.com</url>
    <description>Website CLOZIN study</description>
  </link>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>May 29, 2017</study_first_submitted>
  <study_first_submitted_qc>August 14, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 17, 2017</study_first_posted>
  <last_update_submitted>March 2, 2020</last_update_submitted>
  <last_update_submitted_qc>March 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>Jurjen Luykx</investigator_full_name>
    <investigator_title>Sponsor</investigator_title>
  </responsible_party>
  <keyword>Schizophrenia Spectrum and Other Psychotic Disorders</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Schizophrenia</mesh_term>
    <mesh_term>Mental Disorders</mesh_term>
    <mesh_term>Psychotic Disorders</mesh_term>
    <mesh_term>Schizophrenia Spectrum and Other Psychotic Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Anonymous data can be shared with other investigators when the sponsor agreed on the workpackage of that investigator.</ipd_description>
  </patient_data>
  <!-- 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/NCT03253367
org study id: ABR: 52726 & 52728
nct id: NCT03253367
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
A burgeoning body of research has pointed to increased efficacy of clozapine (CLZ) over other
      antipsychotics in schizophrenia (SCZ). On the other hand, safety concerns likely cause
      underutilization across a range of European and other nations. The lack of data available to
      predict efficacy and adverse drug reactions (ADRs) of CLZ further contributes to
      underprescription rates in these countries. Here, we hypothesize that (epi)genetic and
      non-genetic factors aid to help predict treatment outcome (efficacy + ADRs) to CLZ. We
      furthermore posit that such prediction will result in enhanced quality of life of both
      patients and family members. Our primary objective is to predict CLZ treatment outcome based
      on phenotypic and genetic data obtained through the current design. The first secondary
      objective is to investigate which methylation levels/patterns are correlated with CLZ
      treatment outcome. The second secondary objective is to aid in the further elucidation of the
      genetic architecture of SCZ and any possible differences between 'regular' SCZ patients and
      those on CLZ, who are generally more severely ill. We thus intend to cover two currently
      unmet needs using a precision medicine approach: the lack of knowledge about determinants of
      treatment response to CLZ and the lack of insight into neurobiological differences between
      'regular' SCZ and relatively treatment resistant subjects (CLZ users). The prime analysis
      will be a common variant hypothesis-generating genotyping endeavor investigating treatment
      response to CLZ. Additional analyses include whole-genome methylation and gene expression
      analyses and analyses of non-genetic determinants of response. We will include 2,500 CLZ
      treated patients for our discovery cohort, which is in line with previous whole-genome
      pharmacogenomics studies and our power calculations. We will replicate any genome-wide loci
      using our prospectively collected cohort of new users (N=59). Potential yields include a
      publicly available prediction tool to help identify patients responsive to CLZ in early
      disease stages and prevent harmful effects. In addition, common variant analyses compounded
      by pathway analyses may help elucidate the mechanisms of action of CLZ. We ask for broad
      informed consent from participants ensuring rich, longitudinal phenotypic and genotypic data
      resources for both currently planned and future analyses, allowing e.g. next-generation
      sequencing focused on both CLZ and SCZ disease genetics (e.g. in large consortia). We plan to
      also generate polygenic risk scores (PRS) of CLZ efficacy and use those to identify other
      diseases or patients for which CLZ may be helpful, e.g. schizoaffective disorder patients who
      are sometimes first treated with mood stabilizers. Last, evidence hints that disparaging
      genetic loci influence efficacy to different antipsychotics. Adding genetic data from our
      cohort to existing datasets of response to other antipsychotics may help identify such loci.
      Finally, comparison studies with non-CLZ using patients suffering from SCZ may deepen the
      understanding of biological mechanisms underlying treatment resistance (or: a relatively
      severe course of illness).The results of this genetic part of the study will be combined with
      the results from our other research protocol 'Phenomics and genomic of clozapine
      pharmacotherapy - New Users'.The overarching goal of both projects is to create a prediction
      model for clozapine outcome (response (and side effects). This model includes genetic,
      epigenetic and clinical data.
Rationale Clozapine (CLZ) is generally prescribed if at least two trials of antipsychotic
      agents have not led to satisfactory clinical improvement, thereby implying that patients on
      CLZ generally suffer from more severe and/or persistent symptoms than patients suffering from
      schizophrenia spectrum disorders (SCZ) on other antipsychotic agents. Unraveling the
      (functional) genetic variation underlying this severe SCZ phenotype therefore has the
      potential to deepen our understanding of the biological underpinnings of SCZ beyond the
      boundaries of DSM-based consensus criteria. Such knowledge in turn has the potential to shape
      future pharmacotherapeutic research. The investigators here hypothesize that targeting this
      phenotype in genome-wide association studies and next-generation sequencing studies will
      signal genetic risk loci implicated in this severe SCZ phenotype. In the future, this may
      lead to early detection of severe SCZ, which in turn will enable tailoring of
      pharmacotherapeutic strategies to such SCZ subtypes. The results of this genetic part of the
      study will be combined with the results from our other research protocol ('Phenomics and
      genomic of clozapine pharmacotherapy - New Users').The overarching goal of both projects is
      to create a prediction model for clozapine outcome (response (and side effects). This model
      includes genetic, epigenetic and clinical data.

      Objectives

      Primary:

      1) To predict CLZ efficacy and ADRs (=treatment outcome) based on phenotypic and genetic data
      obtained in this study.

      Secondary:

        1. To investigate which non-genetic factors, methylation and gene expression
           levels/patterns predict treatment outcome after initiating CLZ;

        2. As the genetic architecture of SCZ has not been fully elucidated, the current project
           will aid in the further elucidation of the genetic architecture of SCZ and any possible
           differences between 'regular' SCZ patients (those not considered treatment resistant)
           and those on CLZ (considered generally to be a more homogeneous and severe group).

      Study design This is a mostly cross-sectional study, in which both phenotypic and genotypic
      data are gathered from this study population that currently uses CLZ or has used CLZ in the
      past. A genome-wide association study (GWAS) will be performed to reveal possible differences
      in genetic architecture between patients who use or have used CLZ and the broad schizophrenia
      phenotype on the one hand and between those who use or have used CLZ and healthy controls on
      the other. Targeted next-generation sequencing may be used to follow-up possible positive
      associations. The genetic data will be used to analyse which genetic variants are associated
      with CLZ response and/or side effects.

      Study population The investigators will include 2,500 patients diagnosed with schizophrenia,
      schizophreniform disorder, schizoaffective disorder or psychotic disorder NOS (together
      referred to as SCZ) >18 years of age who are currently on CLZ treatment or have used CLZ in
      the past. Publicly available Psychiatric Genomics Consortium (PGC) GWAS data will be used for
      comparisons with the broad schizophrenia phenotype group. For the purpose of the case-control
      comparison, the 2,500 subjects who use or have used CLZ will be age and sex-matched to 30,000
      healthy control subjects for whom genotype data are available in-house.

      Intervention No intervention will be applied.

      Main study parameters/endpoints

        1. To assess whether the genetic architecture of this severe SCZ phenotype differs from the
           broad DSM-based SCZ phenotype.

        2. To predict clozapine response and side effects based on phenotypic and genetic data
           obtained in this study.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness Almost all patients on CLZ regularly have their blood drawn for routine white
      blood cell counts and/or CLZ blood level assessments. The investigators anticipate that the
      majority of the study population will consist of such patients as white blood cell monitoring
      is strictly enforced in clinical practice for this patient group. For these patients, no
      additional risks will be attached to the study, as the blood necessary for DNA extraction for
      the current study will be drawn during these routinely performed venipunctures. Time
      investment will also be low as the patients will only undergo a 10-minute interview. A
      minority of patients on CLZ does not have their blood routinely monitored and neither do
      patients who have used CLZ in the past. These subjects will be asked to allow a single blood
      draw. A venipuncture entails the risk of a hematoma (blood leaving the vessel). The
      investigators aim to minimize this risk by only allowing experienced personnel to draw blood
      and in the event of deeply located or thin veins request central lab personnel to perform the
      venipuncture. Although a hematoma resulting from a traumatic puncture imposes an esthetical
      burden on the subject, no serious health risks are involved.
observational model: Cohort
time perspective: Other
measure: Predict clozapine response.
time frame: 2016-2021
description: To predict clozapine response based on phenotypic information from our questionnaire (CGI + CRES) and genetic information from GWAS
measure: Predict side effects from clozapine use
time frame: 2016-2021
description: To predict clozapine response based on phenotypic information from our questionnaire (LUNSERS) and genetic information from GWAS
measure: Assess differences in genetic architecture (GWAS)
time frame: 2016-2021
description: To assess whether the genetic architecture of this severe SCZ phenotype differs from the broad DSM-based SCZ phenotype. this will be done by comparing the gentic material of clozapine users vs. non-clozapine users. Only the clozapine DNA has to be collected yet.
measure: Detect genetic associations (GWAS) Detect genetic associations current severe SCZ phenotype
time frame: 2016-2021
description: To detect genetic associations with the current severe SCZ phenotype by performing a case-control comparison with healthy participants (GWAS).
measure: Increase or decrease cardiovascular disease?
time frame: 2016-2031
description: To investigate whether CLZ use increases or decreases the risk of cardiovascular disease and early death. This is done by following the patients for 10 years and see whether they developed serious cardiovascular diseases
arm group label: Current/former clozapine users
description: This group has only one visit.
arm group label: New clozapine users
description: This group will be followed for 6 months prospectively.
intervention type: Other
intervention name: Blood is obtained, mostly during routine venipuncture
arm group label: Current/former clozapine users
arm group label: New clozapine users
For current and former users we obtain DNA and for new users we also obtain RNA
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marte van der Horst, Drs.
phone: 0887551460
phone ext: +31
email: mzvanderhorst@gmail.com
last name: Jurjen Luykx, PhD
phone: 0887568638
phone ext: +31
email: j.luykx@umcutrecht.nl
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Withdrawn
facility: 
status: Recruiting
contact: 
facility: 
status: Terminated
facility: 
status: Enrolling by invitation
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
facility: 
status: Terminated
country: Austria
country: Finland
country: Germany
country: Netherlands
url: http://www.clozinstudy.com
description: Website CLOZIN study
responsible party type: Sponsor-Investigator
investigator affiliation: UMC Utrecht
investigator full name: Jurjen Luykx
investigator title: Sponsor
mesh term: Schizophrenia
mesh term: Mental Disorders
mesh term: Psychotic Disorders
mesh term: Schizophrenia Spectrum and Other Psychotic Disorders
sharing ipd: Yes
ipd description: Anonymous data can be shared with other investigators when the sponsor agreed on the workpackage of that investigator.