Ignite Creation Date:
2024-05-06 @ 10:25 AM
Last Modification Date:
2024-10-26 @ 12:29 PM
Study NCT ID:
NCT03253367
Status:
UNKNOWN
Last Update Posted:
2020-03-05
First Post:
2017-05-29
Brief Title:
Phenomics and Genomics of Clozapine Pharmacotherapy
Sponsor:
Jurjen Luykx
Organization:
UMC Utrecht
Study Overview
Official Title:
Phenomics and Genomics in Clozapine Pharmacotherapy Current Former and New Clozapine Users
Status:
UNKNOWN
Status Verified Date:
2020-03
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CLOZIN
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 epigenetic 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 levelspatterns 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 2500 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 N59 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 eg next-generation sequencing focused on both CLZ and SCZ disease genetics eg 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 eg 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 illnessThe 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 UsersThe 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
Detailed Description:
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 andor 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 UsersThe 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 levelspatterns 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 andor side effects
Study population The investigators will include 2500 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 2500 subjects who use or have used CLZ will be age and sex-matched to 30000 healthy control subjects for whom genotype data are available in-house
Intervention No intervention will be applied
Main study parametersendpoints
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 andor 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
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 levelspatterns 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 andor side effects
Study population The investigators will include 2500 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 2500 subjects who use or have used CLZ will be age and sex-matched to 30000 healthy control subjects for whom genotype data are available in-house
Intervention No intervention will be applied
Main study parametersendpoints
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 andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None