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Phenomics and Genomics of Clozapine Pharmacotherapy (CLOZIN)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03253367
Recruitment Status : Recruiting
First Posted : August 17, 2017
Last Update Posted : July 20, 2018
Information provided by (Responsible Party):
Rene Kahn, UMC Utrecht

Brief Summary:
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.

Condition or disease Intervention/treatment
Schizophrenia Spectrum and Other Psychotic Disorders Other: Blood is obtained, mostly during routine venipuncture

  Show Detailed Description

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Study Type : Observational
Estimated Enrollment : 2500 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: Phenomics and Genomics in Clozapine Pharmacotherapy: Current, Former and New Clozapine Users
Actual Study Start Date : January 19, 2016
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Clozapine

Group/Cohort Intervention/treatment
Current/former clozapine users
This group has only one visit.
Other: Blood is obtained, mostly during routine venipuncture
New clozapine users
This group will be followed for 6 months prospectively.
Other: Blood is obtained, mostly during routine venipuncture

Primary Outcome Measures :
  1. Predict clozapine response. [ Time Frame: 2016-2021 ]
    To predict clozapine response based on phenotypic information from our questionnaire (CGI + ALDA) and genetic information from GWAS

  2. Predict side effects from clozapine use [ Time Frame: 2016-2021 ]
    To predict clozapine response based on phenotypic information from our questionnaire (LUNSERS) and genetic information from GWAS

  3. Assess differences in genetic architecture (GWAS) [ Time Frame: 2016-2021 ]
    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.

Secondary Outcome Measures :
  1. Detect genetic associations (GWAS) Detect genetic associations current severe SCZ phenotype [ Time Frame: 2016-2021 ]
    To detect genetic associations with the current severe SCZ phenotype by performing a case-control comparison with healthy participants (GWAS).

  2. Increase or decrease cardiovascular disease? [ Time Frame: 2016-2031 ]
    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

Biospecimen Retention:   Samples With DNA
For current and former users we obtain DNA and for new users we also obtain RNA

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
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 13,000 healthy control subjects for whom genotype data are available in-house.

Inclusion Criteria:

  • he/she currently uses CLZ or he/she has used CLZ in the past/will use CLZ
  • he/she has received a diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder or psychotic disorder NOS.
  • his/her age must be ≥18 years old
  • he/she must be able to speak and read the language of the Informed Consent (differs per country)
  • he/she must be mentally competent and have decisional capacity with regard to a decision to participate in the current study

Exclusion Criteria:

  • admission to a psychiatric unit involuntarily (not all countries)
  • a history of Parkinson's disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03253367

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Contact: Cynthia Pfeifer, MSc. 0652385871 ext +31
Contact: Jurjen Luykx, PhD 0887568638 ext +31

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Medical University Innsbruck Recruiting
Innsbruck, Austria, 6020
Contact: Monika Edlinger, MD   
Niuvanniemen hospital Recruiting
Kuopio, Finland, 70240
Contact: Jari Tiihonen, Prof.         
LMU Munich Recruiting
München, Munich, Germany, 80336
Contact: Alkomiet Hasan, MD, PhD         
Charité Universitätsmedizin Berlin Recruiting
Berlin, Germany, 10117
Contact: Stefanie Schreiter, MD    004930450517009   
Contact: Stefan Gutwinski, MD    004930450517009   
Vincent van Gogh Institute Withdrawn
Venray, Limburg, Netherlands, 5803 AC
Reinier van Arkel Recruiting
's-Hertogenbosch, Noord-Brabant, Netherlands, 5211 LJ
Contact: Koen Grootens, MD         
GGZ-NHN Enrolling by invitation
Heerhugowaard, Noord-Holland, Netherlands, 1703 WC
GGZ Rivierduinen Enrolling by invitation
Leiden, Oegstgeest, Netherlands, 2342 EJ
Yulius Terminated
Barendrecht, Zuid Holland, Netherlands, 2994 GC
UMC Utrecht Recruiting
Utrecht, Netherlands, 3508 GA
Contact: Cynthia Pfeifer, MSc.    0652385871 ext +31   
Altrecht Enrolling by invitation
Utrecht, Netherlands, 3512 PK
Sponsors and Collaborators
Rene Kahn

Additional Information:
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Responsible Party: Rene Kahn, Sponsor, UMC Utrecht Identifier: NCT03253367     History of Changes
Other Study ID Numbers: ABR: 52726 & 52728
First Posted: August 17, 2017    Key Record Dates
Last Update Posted: July 20, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymous data can be shared with other investigators when the sponsor agreed on the workpackage of that investigator.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rene Kahn, UMC Utrecht:
Schizophrenia Spectrum and Other Psychotic Disorders

Additional relevant MeSH terms:
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Mental Disorders
Psychotic Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
GABA Antagonists
GABA Agents