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/NCT06026592</url>
    </required_header>
    <id_info>
      <org_study_id>APHP230298</org_study_id>
      <nct_id>NCT06026592</nct_id>
    </id_info>
    <brief_title>Detection of Plasma DNA of Renal Origin in Kidney Transplant Patients</brief_title>
    <acronym>DART-REIN</acronym>
    <official_title>Detection of Plasma DNA of Renal Origin in Kidney Transplant Patients</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Assistance Publique - Hôpitaux de Paris</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Assistance Publique - Hôpitaux de Paris</source>
    <oversight_info>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential diagnostic tool to&#xD;
        monitor the rejection status of the kidney transplant. It has been suggested that dd-cfDNA is&#xD;
        increasing in the blood of kidney transplant patient presenting a graft rejection. In this&#xD;
        project, investigators proposed a different approach to predict and characterize kidney&#xD;
        transplant rejection/dysfunction based on the quantification of epigenetic signatures present&#xD;
        on the donor-cell-free DNA. In 2018, Moss et al. develops a deconvolution model capable of&#xD;
        identifying the tissue origin of circulating DNA by taking advantage of its epigenetic&#xD;
        properties. The study confirmed that the cell-free DNA circulating in healthy subjects comes&#xD;
        mainly from blood cells and endothelial cells, but not from kidney cells.&#xD;
  &#xD;
        In this study, researchers investigate the evolution of blood renal-specific cell-free DNA&#xD;
        amount in patient with chronic kidney disease before and after the transplantation surgery by&#xD;
        testing a set of renal-specific epigenetic markers. The purpose of this study is to identify&#xD;
        the biological noise of &quot;native kidney&quot; on renal-specific cell-free DNA and to compare it&#xD;
        with signal coming from &quot;transplanted kidney&quot;.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        At the diagnostic level, routine monitoring of graft functionality after kidney&#xD;
        transplantation relies on the use of non-specific markers, such as serum creatinine (allowing&#xD;
        estimation of glomerular filtration rate or GFR) and proteinuria. Definitive diagnosis of&#xD;
        renal allograft dysfunction still requires invasive allograft biopsy, which remains the gold&#xD;
        standard for assessing graft status. The histopathological diagnosis of renal graft&#xD;
        dysfunction is based on the Banff classification and makes it possible to examine the immune&#xD;
        infiltrate and the cellular lesions of the graft to make a precise diagnosis. However, Renal&#xD;
        biopsy has certain limitations: 1/ It is invasive for the patient, with associated&#xD;
        complications, mainly hemorrhagic in 1 to 3.5% of cases; 2/ Its effectiveness in predicting&#xD;
        early rejection (3 months) post-transplant remains controversial. A lack of patient benefit&#xD;
        has been proven by several studies for screening biopsy; 3/ Histological analysis is subject&#xD;
        to intra- and inter-observer variations; and 4/ it is an expensive examination due to the&#xD;
        medical time required to perform and interpret the biopsy.&#xD;
  &#xD;
        The &quot;donor-cell-free DNA (dd-cfDNA)&quot; has been suggested as a diagnostic tool at the service&#xD;
        of the graft. Analyzes based on molecular signatures on the circulating DNA of the donor&#xD;
        (Single Polymorphism Nucleotide (SNP)) have made it possible to discriminate the circulating&#xD;
        cell-free DNA from the transplanted kidney (from the donor) from the circulating cell-free&#xD;
        DNA specific to the recipient. Data from several studies suggest that blood dd-cfDNA levels&#xD;
        can detect rejection in heart, lung, liver and kidney allografts. First studied by multiplex&#xD;
        qPCR and then NGS technologies, the SNPs present on the dd-cfDNA were then quantified by&#xD;
        digital PCR techniques.&#xD;
  &#xD;
        In this study, investigators proposed a different approach to predict and characterize kidney&#xD;
        transplant rejection/dysfunction based on the quantification of epigenetic signatures present&#xD;
        on the donor-cell-free DNA. In 2018, Moss et al. develops a deconvolution model capable of&#xD;
        identifying the tissue origin of circulating DNA by taking advantage of its epigenetic&#xD;
        properties. The study confirmed that the cell-free DNA circulating in healthy subjects comes&#xD;
        mainly from blood cells and endothelial cells, but not from kidney cells. In 2023, Loyfer et&#xD;
        al. proposed a methylation atlas of more than 200 cells type and suggested that each cell has&#xD;
        its own epigenetic signature that can be study in cell-free DNA.&#xD;
  &#xD;
        In this study, researchers investigate the evolution of blood renal-specific cell-free DNA&#xD;
        amount in patient with chronic kidney disease before and after the transplantation surgery by&#xD;
        testing a set of renal-specific epigenetic markers. The purpose of this study is to identify&#xD;
        the biological noise of &quot;native kidney&quot; on renal-specific cell-free DNA and to compare it&#xD;
        with signal coming from &quot;transplanted kidney&quot;. Researchers hypothesize that the biological&#xD;
        noise from &quot;native kidney&quot; in chronic kidney diseases is negligible compared to that of the&#xD;
        post-transplantation graft.&#xD;
  &#xD;
        To investigate this hypothesis, investigators collect blood samples before and after&#xD;
        transplant surgery to quantify kidney-specific cell-free DNA markers. They also proposed to&#xD;
        quantify cell-free DNA markers of graft perfusion fluid to validate the specificity of renal&#xD;
        markers and to study graft tissue damage during organ transport. Each renal-cell-free DNA&#xD;
        sample is quantified by a proprietary technologies using a multiplex digital-PCR assay.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 30, 2023</start_date>
    <completion_date type="Anticipated">February 6, 2024</completion_date>
    <primary_completion_date type="Anticipated">January 30, 2024</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>Amount of renal circulating cell-free DNA</measure>
      <time_frame>6 hours before kidney transplantation and 12 to 24 after transplantation surgery</time_frame>
      <description>The amount of renal-cell-free DNA (glomerular and tubular markers) will be measured 6 hours before the kidney transplant is performed and 12-24 hours after the kidney transplant by digital multiplex PCR</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Estimating the inter-individual variations of the free circulating methylome of renal origin in patients with end-stage chronic insufficiency</measure>
      <time_frame>6 hours before kidney transplantation and 12 to 24 after transplantation surgery</time_frame>
      <description>The amount of renal-cell-free DNA (glomerular and tubular markers) measured will be compared between individuals.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Identify by a method without a priori (methyl seq) specific markers of acute renal injury in terms of epigenetic signature</measure>
      <time_frame>6 hours before kidney transplantation and 12 to 24 after transplantation surgery</time_frame>
      <description>Comparison of two biomarkers quantification methods (whole genome methyl-Sequencing and multiplex digital-PCR)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Study the statistical association between the presence of free circulating methylated sequences of renal origin and the resumption of graft function</measure>
      <time_frame>7 day after the transplant</time_frame>
      <description>Comparison of circulating free methylome of renal origin between the groups of patients with immediate recovery of function and delayed recovery of function (defined on the performance of a dialysis session in the first 7 days and on the reduction ratio serum creatinine between the 1st and 2nd day after the transplant).</description>
    </secondary_outcome>
    <enrollment type="Anticipated">30</enrollment>
    <condition>Acute Kidney Injury</condition>
    <condition>Renal Transplantation</condition>
    <intervention>
      <intervention_type>Genetic</intervention_type>
      <intervention_name>determination of circulating biomarkers of renal origin circulating biomarkers of renal origin</intervention_name>
      <description>The extracted circulating DNA will be extracted and converted using the methylation kit. Finally, circulating DNA will be analyzed using the PCR mix developed by CGenetix, quantifying tubular and glomerular biomarkers (patented technology).</description>
    </intervention>
    <eligibility>
      <study_pop>
        <textblock>
          Adult subjects with end-stage renal disease about to receive a kidney transplant from a&#xD;
          deceased donor.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age ≥ 18 years old&#xD;
  &#xD;
            -  With end-stage renal failure&#xD;
  &#xD;
            -  Summoned for a kidney transplant at Pitié Salpêtrière Hospital&#xD;
  &#xD;
            -  Having been informed of the study and not objecting to the study having given free and&#xD;
               informed written consent for the genetic analysis&#xD;
  &#xD;
            -  Benefiting from a social security scheme (excluding AME)&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          Under legal protective measures (curatorship or guardianship, under judicial safeguard).&#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>Pierre Dr GALICHON, MD-PhD</last_name>
      <phone>01 42 17 72 29</phone>
      <phone_ext>+33</phone_ext>
      <email>Pierre.galichon@aphp.fr</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Geoffroy Dr POULET, PhD</last_name>
      <phone>06 67 77 23 94</phone>
      <phone_ext>+33</phone_ext>
      <email>Geoffroy.poulet@cgenetix.com</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Nephrology-transplantation department Pitié-Salpétriêre hospital</name>
        <address>
          <city>Paris</city>
          <zip>75013</zip>
          <country>France</country>
        </address>
      </facility>
      <contact>
        <last_name>Pierre Dr GALICHON, MD-PhD</last_name>
        <phone>01 42 17 72 29</phone>
        <phone_ext>+33</phone_ext>
        <email>Pierre.galichon@aphp.fr</email>
      </contact>
      <contact_backup>
        <last_name>Geoffroy Dr POULET, PhD</last_name>
        <phone>06 67 77 23 94</phone>
        <phone_ext>+33</phone_ext>
        <email>Geoffroy.poulet@cgenetix.com</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 30, 2023</study_first_submitted>
    <study_first_submitted_qc>August 30, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 7, 2023</study_first_posted>
    <last_update_submitted>August 30, 2023</last_update_submitted>
    <last_update_submitted_qc>August 30, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Epigenetic</keyword>
    <keyword>Renal cell-free DNA</keyword>
    <keyword>Transplantation</keyword>
    <keyword>biomarkers</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Acute Kidney Injury</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.&#xD;
  Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_time_frame>Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor</ipd_time_frame>
      <ipd_access_criteria>Researchers who provide a methodologically sound proposal.</ipd_access_criteria>
    </patient_data>
    <!-- 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/NCT06026592
  org study id: APHP230298
  nct id: NCT06026592
  lead sponsor: 
  is fda regulated drug: No
  is fda regulated device: No
  Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential diagnostic tool to
        monitor the rejection status of the kidney transplant. It has been suggested that dd-cfDNA is
        increasing in the blood of kidney transplant patient presenting a graft rejection. In this
        project, investigators proposed a different approach to predict and characterize kidney
        transplant rejection/dysfunction based on the quantification of epigenetic signatures present
        on the donor-cell-free DNA. In 2018, Moss et al. develops a deconvolution model capable of
        identifying the tissue origin of circulating DNA by taking advantage of its epigenetic
        properties. The study confirmed that the cell-free DNA circulating in healthy subjects comes
        mainly from blood cells and endothelial cells, but not from kidney cells.
  
        In this study, researchers investigate the evolution of blood renal-specific cell-free DNA
        amount in patient with chronic kidney disease before and after the transplantation surgery by
        testing a set of renal-specific epigenetic markers. The purpose of this study is to identify
        the biological noise of "native kidney" on renal-specific cell-free DNA and to compare it
        with signal coming from "transplanted kidney".
  At the diagnostic level, routine monitoring of graft functionality after kidney
        transplantation relies on the use of non-specific markers, such as serum creatinine (allowing
        estimation of glomerular filtration rate or GFR) and proteinuria. Definitive diagnosis of
        renal allograft dysfunction still requires invasive allograft biopsy, which remains the gold
        standard for assessing graft status. The histopathological diagnosis of renal graft
        dysfunction is based on the Banff classification and makes it possible to examine the immune
        infiltrate and the cellular lesions of the graft to make a precise diagnosis. However, Renal
        biopsy has certain limitations: 1/ It is invasive for the patient, with associated
        complications, mainly hemorrhagic in 1 to 3.5% of cases; 2/ Its effectiveness in predicting
        early rejection (3 months) post-transplant remains controversial. A lack of patient benefit
        has been proven by several studies for screening biopsy; 3/ Histological analysis is subject
        to intra- and inter-observer variations; and 4/ it is an expensive examination due to the
        medical time required to perform and interpret the biopsy.
  
        The "donor-cell-free DNA (dd-cfDNA)" has been suggested as a diagnostic tool at the service
        of the graft. Analyzes based on molecular signatures on the circulating DNA of the donor
        (Single Polymorphism Nucleotide (SNP)) have made it possible to discriminate the circulating
        cell-free DNA from the transplanted kidney (from the donor) from the circulating cell-free
        DNA specific to the recipient. Data from several studies suggest that blood dd-cfDNA levels
        can detect rejection in heart, lung, liver and kidney allografts. First studied by multiplex
        qPCR and then NGS technologies, the SNPs present on the dd-cfDNA were then quantified by
        digital PCR techniques.
  
        In this study, investigators proposed a different approach to predict and characterize kidney
        transplant rejection/dysfunction based on the quantification of epigenetic signatures present
        on the donor-cell-free DNA. In 2018, Moss et al. develops a deconvolution model capable of
        identifying the tissue origin of circulating DNA by taking advantage of its epigenetic
        properties. The study confirmed that the cell-free DNA circulating in healthy subjects comes
        mainly from blood cells and endothelial cells, but not from kidney cells. In 2023, Loyfer et
        al. proposed a methylation atlas of more than 200 cells type and suggested that each cell has
        its own epigenetic signature that can be study in cell-free DNA.
  
        In this study, researchers investigate the evolution of blood renal-specific cell-free DNA
        amount in patient with chronic kidney disease before and after the transplantation surgery by
        testing a set of renal-specific epigenetic markers. The purpose of this study is to identify
        the biological noise of "native kidney" on renal-specific cell-free DNA and to compare it
        with signal coming from "transplanted kidney". Researchers hypothesize that the biological
        noise from "native kidney" in chronic kidney diseases is negligible compared to that of the
        post-transplantation graft.
  
        To investigate this hypothesis, investigators collect blood samples before and after
        transplant surgery to quantify kidney-specific cell-free DNA markers. They also proposed to
        quantify cell-free DNA markers of graft perfusion fluid to validate the specificity of renal
        markers and to study graft tissue damage during organ transport. Each renal-cell-free DNA
        sample is quantified by a proprietary technologies using a multiplex digital-PCR assay.
  observational model: Cohort
  time perspective: Prospective
  measure: Amount of renal circulating cell-free DNA
  time frame: 6 hours before kidney transplantation and 12 to 24 after transplantation surgery
  description: The amount of renal-cell-free DNA (glomerular and tubular markers) will be measured 6 hours before the kidney transplant is performed and 12-24 hours after the kidney transplant by digital multiplex PCR
  measure: Estimating the inter-individual variations of the free circulating methylome of renal origin in patients with end-stage chronic insufficiency
  time frame: 6 hours before kidney transplantation and 12 to 24 after transplantation surgery
  description: The amount of renal-cell-free DNA (glomerular and tubular markers) measured will be compared between individuals.
  measure: Identify by a method without a priori (methyl seq) specific markers of acute renal injury in terms of epigenetic signature
  time frame: 6 hours before kidney transplantation and 12 to 24 after transplantation surgery
  description: Comparison of two biomarkers quantification methods (whole genome methyl-Sequencing and multiplex digital-PCR)
  measure: Study the statistical association between the presence of free circulating methylated sequences of renal origin and the resumption of graft function
  time frame: 7 day after the transplant
  description: Comparison of circulating free methylome of renal origin between the groups of patients with immediate recovery of function and delayed recovery of function (defined on the performance of a dialysis session in the first 7 days and on the reduction ratio serum creatinine between the 1st and 2nd day after the transplant).
  intervention type: Genetic
  intervention name: determination of circulating biomarkers of renal origin circulating biomarkers of renal origin
  description: The extracted circulating DNA will be extracted and converted using the methylation kit. Finally, circulating DNA will be analyzed using the PCR mix developed by CGenetix, quantifying tubular and glomerular biomarkers (patented technology).
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Pierre Dr GALICHON, MD-PhD
  phone: 01 42 17 72 29
  phone ext: +33
  email: Pierre.galichon@aphp.fr
  last name: Geoffroy Dr POULET, PhD
  phone: 06 67 77 23 94
  phone ext: +33
  email: Geoffroy.poulet@cgenetix.com
  facility: 
  contact: 
  contact backup: 
  country: France
  responsible party type: Sponsor
  mesh term: Acute Kidney Injury
  sharing ipd: Yes
  ipd description: The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.
  Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.
  ipd info type: Study Protocol
  ipd info type: Informed Consent Form (ICF)
  ipd time frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
  ipd access criteria: Researchers who provide a methodologically sound proposal.