xml: <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/NCT06012162</url>
    </required_header>
    <id_info>
      <org_study_id>Genomics in HTx</org_study_id>
      <nct_id>NCT06012162</nct_id>
    </id_info>
    <brief_title>Genomics in Heart Transplants</brief_title>
    <official_title>Long-read Genome Sequencing and Risk Stratification of Myocardial Ischemia in Patients With Heart Transplantation</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Heinrich-Heine University, Duesseldorf</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Heinrich-Heine University, Duesseldorf</source>
    <oversight_info>
      <has_dmc>No</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 cross-sectional analysis of 200 heart transplant recipients, combining in-depth phenotyping&#xD;
        and risk factor assessment (cardiac MRI, coronary angiogram with OCT, cardiorespiratory&#xD;
        exercise tests, exogenic factors like nutrition, smoking, lipid profile) with short-read&#xD;
        whole-genome sequencing to elucidate the interplay of established PRS from the literature and&#xD;
        exogenic risk factors with respect to HTx outcomes will be carried out.&#xD;
  &#xD;
        Besides that, a long-read whole-genome sequencing of 100 newly transplanted recipients and&#xD;
        their corresponding donors and extend latest bioinformatics methods developed by the study to&#xD;
        analyze long-read data will be performed. This will enable a comprehensive and integrated&#xD;
        analysis of structural variants, polygenic risk, high-penetrance variant genotypes,&#xD;
        immunogenetic (major and minor histocompatibility), and individual lifestyle risk factors in&#xD;
        a unique donor-recipient cohort, elucidating the extent of within-cohort variability and&#xD;
        cross-correlations between the considered potential risk factors and an exploratory analysis&#xD;
        of the utility of genetic risk scores in light of the study results will be carried out.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Background: Heart transplantation (HTx) is the treatment of choice for patients with&#xD;
        end-stage heart failure who remain symptomatic despite optimal medical therapy. Even with&#xD;
        best-practice follow-up care, one out of eight HTx patients eventually die of ischemic&#xD;
        cardiomyopathy and recurrent acute myocardial infarction (AMI). Classical risk factors like&#xD;
        the recipient indication for heart transplantation explain a fraction of adverse outcomes,&#xD;
        but no conventional risk factor alone satisfactorily predicts the probability of cardiac&#xD;
        allograft vasculopathy (CAV) or recurrent AMI in HTx patients; in addition, the underlying&#xD;
        pathomechanisms are poorly understood.&#xD;
  &#xD;
        Therefore, there is an urgent need for an improved understanding of the factors contributing&#xD;
        to recurrent myocardial ischemia in HTx patients. Recent large-scale studies of the genetic&#xD;
        architecture of coronary artery disease in the general population indicate that polygenic&#xD;
        risk scores (PRS) explain more disease risk than any single non-genetic risk factor, but, due&#xD;
        to a lack of longitudinal follow-up studies with deep phenotyping, PRS have not yet been&#xD;
        widely adopted in clinical practice. Furthermore, current genetic studies are based on&#xD;
        microarrays or short-read sequencing, severely limiting their ability to characterize the&#xD;
        effect of complex or structural genetic variation, in the whole human genome as well as in&#xD;
        key loci of potential importance for HTx outcomes, affecting, e.g., lipid metabolism (e.g.&#xD;
        LPA) and immunogenetic compatibility (e.g. the major histocompatibility complex).&#xD;
  &#xD;
        In summary, there is presently no study leveraging the improved ability to resolve human&#xD;
        genomes with long-read sequencing technologies in a deeply phenotyped cohort for an improved&#xD;
        understanding of recurring myocardial ischemia.&#xD;
  &#xD;
        Study design and aims: In an innovative three-component study design, comprehensive&#xD;
        phenotyping with the latest long-read sequencing technology and algorithmic advances in&#xD;
        computational genomics to elucidate the interplay of genetic and non-genetic risk factors of&#xD;
        myocardial ischemia in HTx patients at unprecedented resolution and pave the way towards&#xD;
        detailed risk stratification and tailored treatment, will be combined&#xD;
  &#xD;
        Significance and translational potential: By enabling the integrated analysis of structural&#xD;
        variants, high-penetrance complex variants, and high-resolution immunogenetics, long-read&#xD;
        sequencing will enable improved genetic models of the development of ischemia in HTx patients&#xD;
        and contribute to an improved understanding of underlying pathomechanisms. Based on this, the&#xD;
        investigators will be able to propose schemes to incorporate integrated risk scores in future&#xD;
        clinical trials for personalized treatment stratification.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">January 2024</start_date>
    <completion_date type="Anticipated">January 2028</completion_date>
    <primary_completion_date type="Anticipated">January 2028</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>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>rate of Clinically significant ischemia</measure>
      <time_frame>5 years</time_frame>
      <description>defined by cardiac allograft vasculopathy (CAV) grade &gt;1 &amp; cardiac magnetic resonance imaging (cMRI)</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>cardiovascular death</measure>
      <time_frame>5 years</time_frame>
      <description>cardiovascular event as primary cause of death</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>myocardial infarction</measure>
      <time_frame>5 years</time_frame>
      <description>Incidence of Type I or II myocardial infarction (assessed by CMR, electrocardiogram, laboratory parameters according to the 4th universal definition of myocardial infarction)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Hospitalisation (w/o allograft rejection)</measure>
      <time_frame>5 years</time_frame>
      <description>All-cause hospitalisation with exception of acute allograft rejection</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cardiac allograft vasculopathy (macrocirculatory)</measure>
      <time_frame>5 years</time_frame>
      <description>Incidence: Coronary angiogram (+/- optic coherence tomography (OCT))</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>number of coronary microvascular dysfunction</measure>
      <time_frame>5 years</time_frame>
      <description>measured by fractional flow reserve</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>number of coronary microvascular dysfunction</measure>
      <time_frame>5 years</time_frame>
      <description>measured by cardiac magnetic resonance imaging</description>
    </secondary_outcome>
    <enrollment type="Anticipated">200</enrollment>
    <condition>Heart Transplantation</condition>
    <biospec_retention>Samples With DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        Collection of blood samples through clinical routine&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          Patients undergoing heart transplantation&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients &gt; 18 years old undergoing heart transplantation in our centre&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  &lt; 18 years&#xD;
  &#xD;
            -  incapable of giving consent&#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_official>
      <last_name>Malte Kelm, Prof.</last_name>
      <role>Study Chair</role>
      <affiliation>Clinic for Cardiology, Pneumology and Angiology at University Hospital Düsseldorf</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Daniel Oehler, MD</last_name>
      <phone>+492118118800</phone>
      <email>Daniel.oehler@med.uni-duesseldorf.de</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Lisa Dannenberg, MD</last_name>
      <phone>+49211811800</phone>
      <email>lisa.dannenberg@med.uni-duesseldorf.de</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>University-Hospital Düsseldorf Division of Cardiology, Pulmonary Disease and Vascular Medicine</name>
        <address>
          <city>Düsseldorf</city>
          <zip>40225</zip>
          <country>Germany</country>
        </address>
      </facility>
      <contact>
        <last_name>Clinical Trial Unit</last_name>
        <phone>+492118105315</phone>
        <email>ctu@med.uni-duesseldorf.de</email>
      </contact>
      <investigator>
        <last_name>Daniel Oehler, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Germany</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>April 4, 2023</study_first_submitted>
    <study_first_submitted_qc>August 21, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 25, 2023</study_first_posted>
    <last_update_submitted>August 21, 2023</last_update_submitted>
    <last_update_submitted_qc>August 21, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 25, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>heart transplantation</keyword>
    <keyword>long-read genomics</keyword>
    <keyword>risk stratification</keyword>
    <keyword>myocardial ischemia</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Myocardial Ischemia</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06012162
  org study id: Genomics in HTx
  nct id: NCT06012162
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  A cross-sectional analysis of 200 heart transplant recipients, combining in-depth phenotyping
        and risk factor assessment (cardiac MRI, coronary angiogram with OCT, cardiorespiratory
        exercise tests, exogenic factors like nutrition, smoking, lipid profile) with short-read
        whole-genome sequencing to elucidate the interplay of established PRS from the literature and
        exogenic risk factors with respect to HTx outcomes will be carried out.
  
        Besides that, a long-read whole-genome sequencing of 100 newly transplanted recipients and
        their corresponding donors and extend latest bioinformatics methods developed by the study to
        analyze long-read data will be performed. This will enable a comprehensive and integrated
        analysis of structural variants, polygenic risk, high-penetrance variant genotypes,
        immunogenetic (major and minor histocompatibility), and individual lifestyle risk factors in
        a unique donor-recipient cohort, elucidating the extent of within-cohort variability and
        cross-correlations between the considered potential risk factors and an exploratory analysis
        of the utility of genetic risk scores in light of the study results will be carried out.
  Background: Heart transplantation (HTx) is the treatment of choice for patients with
        end-stage heart failure who remain symptomatic despite optimal medical therapy. Even with
        best-practice follow-up care, one out of eight HTx patients eventually die of ischemic
        cardiomyopathy and recurrent acute myocardial infarction (AMI). Classical risk factors like
        the recipient indication for heart transplantation explain a fraction of adverse outcomes,
        but no conventional risk factor alone satisfactorily predicts the probability of cardiac
        allograft vasculopathy (CAV) or recurrent AMI in HTx patients; in addition, the underlying
        pathomechanisms are poorly understood.
  
        Therefore, there is an urgent need for an improved understanding of the factors contributing
        to recurrent myocardial ischemia in HTx patients. Recent large-scale studies of the genetic
        architecture of coronary artery disease in the general population indicate that polygenic
        risk scores (PRS) explain more disease risk than any single non-genetic risk factor, but, due
        to a lack of longitudinal follow-up studies with deep phenotyping, PRS have not yet been
        widely adopted in clinical practice. Furthermore, current genetic studies are based on
        microarrays or short-read sequencing, severely limiting their ability to characterize the
        effect of complex or structural genetic variation, in the whole human genome as well as in
        key loci of potential importance for HTx outcomes, affecting, e.g., lipid metabolism (e.g.
        LPA) and immunogenetic compatibility (e.g. the major histocompatibility complex).
  
        In summary, there is presently no study leveraging the improved ability to resolve human
        genomes with long-read sequencing technologies in a deeply phenotyped cohort for an improved
        understanding of recurring myocardial ischemia.
  
        Study design and aims: In an innovative three-component study design, comprehensive
        phenotyping with the latest long-read sequencing technology and algorithmic advances in
        computational genomics to elucidate the interplay of genetic and non-genetic risk factors of
        myocardial ischemia in HTx patients at unprecedented resolution and pave the way towards
        detailed risk stratification and tailored treatment, will be combined
  
        Significance and translational potential: By enabling the integrated analysis of structural
        variants, high-penetrance complex variants, and high-resolution immunogenetics, long-read
        sequencing will enable improved genetic models of the development of ischemia in HTx patients
        and contribute to an improved understanding of underlying pathomechanisms. Based on this, the
        investigators will be able to propose schemes to incorporate integrated risk scores in future
        clinical trials for personalized treatment stratification.
  observational model: Cohort
  time perspective: Prospective
  measure: rate of Clinically significant ischemia
  time frame: 5 years
  description: defined by cardiac allograft vasculopathy (CAV) grade >1 & cardiac magnetic resonance imaging (cMRI)
  measure: cardiovascular death
  time frame: 5 years
  description: cardiovascular event as primary cause of death
  measure: myocardial infarction
  time frame: 5 years
  description: Incidence of Type I or II myocardial infarction (assessed by CMR, electrocardiogram, laboratory parameters according to the 4th universal definition of myocardial infarction)
  measure: Hospitalisation (w/o allograft rejection)
  time frame: 5 years
  description: All-cause hospitalisation with exception of acute allograft rejection
  measure: Cardiac allograft vasculopathy (macrocirculatory)
  time frame: 5 years
  description: Incidence: Coronary angiogram (+/- optic coherence tomography (OCT))
  measure: number of coronary microvascular dysfunction
  time frame: 5 years
  description: measured by fractional flow reserve
  measure: number of coronary microvascular dysfunction
  time frame: 5 years
  description: measured by cardiac magnetic resonance imaging
  Collection of blood samples through clinical routine
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Malte Kelm, Prof.
  role: Study Chair
  affiliation: Clinic for Cardiology, Pneumology and Angiology at University Hospital Düsseldorf
  last name: Daniel Oehler, MD
  phone: +492118118800
  email: Daniel.oehler@med.uni-duesseldorf.de
  last name: Lisa Dannenberg, MD
  phone: +49211811800
  email: lisa.dannenberg@med.uni-duesseldorf.de
  facility: 
  contact: 
  investigator: 
  country: Germany
  responsible party type: Sponsor
  mesh term: Myocardial Ischemia