<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/NCT01725438</url>
  </required_header>
  <id_info>
    <org_study_id>AOM10123</org_study_id>
    <secondary_id>P100118</secondary_id>
    <nct_id>NCT01725438</nct_id>
  </id_info>
  <brief_title>Non Invasive Prenatal Diagnosis of Trisomy 21 by Genetic Analysis of Circulating Fetal Cells</brief_title>
  <acronym>ISETTRI21</acronym>
  <official_title>Clinical Validation of the ISET Method for the Non Invasive Prenatal Diagnosis of Trisomy 21 by Genetic Analysis of Circulating Trophoblastic Cells</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Institut National de la Santé Et de la Recherche Médicale, France</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Rarecells</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Paris 5 - Rene Descartes</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this project is to develop a non-invasive prenatal diagnostic test for&#xD;
      trisomy 21 which is reliable, sensitive and cost-effective, and thus, offers an alternative&#xD;
      to the currently employed invasive diagnostic tests amniocentesis and chorionic villus&#xD;
      sampling.&#xD;
&#xD;
      Current prenatal screening methods (blood markers and ultrasound) for trisomy 21 (Down&#xD;
      syndrome) detect about 90 % of cases and have a false positive rate of &gt; 90 %. The results of&#xD;
      these tests are expressed in risks for trisomy 21, the threshold being in France at 1/250.&#xD;
      Women exhibiting a higher risk are offered to undergo invasive diagnostic testing, either by&#xD;
      amniocentesis or chorionic villus sampling. However, these invasive diagnostic methods are&#xD;
      associated with a considerable risk of miscarriage (1-3 %), and thus underline the importance&#xD;
      to develop a safe and non-invasive prenatal diagnostic test for trisomy 21. The investigators&#xD;
      have planned to assess the clinical impact of a non-invasive prenatal method to detect&#xD;
      Trisomy 21 through genetic analysis of circulating trophoblastic cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators have planned and developed the following approach: fetal cells are first&#xD;
      enriched from blood of pregnant women, between 7 and 12 weeks gestation, employing the ISET&#xD;
      (isolation by size of epithelial tumor cells) technique. Cells presumed to be of fetal origin&#xD;
      are microdissected and subsequently genetically analyzed, using STR markers, to verify their&#xD;
      fetal nature. The investigators then plan to test two strategies in order to assess the&#xD;
      number of copies of chromosome 21. The first one involves the DNA of a single fetal cell to&#xD;
      be analyzed with CGH (comparative genomic hybridization) array. In fact, our team has already&#xD;
      developed an application of the metaphase CGH method to single cells isolated by ISET in&#xD;
      which we were able to demonstrate the gain of chromosome 21 DNA in single fetal cells&#xD;
      isolated from cord blood of a fetus with Down syndrome. The second strategy will be&#xD;
      accomplished with the use of quantitative fluorescent PCR analysis of short tandem repeats&#xD;
      (STRs), applied to single cells. At least 5-8 highly polymorphic STR markers specific for&#xD;
      chromosome 21 will be tested to minimize the effects of a phenomenon called allele drop out,&#xD;
      in which one allele fails to amplify, and to maximize the number of triallelic signals for an&#xD;
      accurate diagnosis of disomy or trisomy 21.&#xD;
&#xD;
      This survey is performed in collaboration with the Department of Gynaecology-Obstetrics -&#xD;
      Reproductive Medicine of Antoine Béclère Hospital in Clamart. The women included in the&#xD;
      survey will be taken a 20 ml blood sample and a cervical Pap smear before the invasive test&#xD;
      (amniocentesis). The blood sample will be treated by the ISET method within 3 hours after&#xD;
      collection and the filter will be stored at - 20°C. The cells obtained by Pap smear will be&#xD;
      kept in an appropriate liquid and then treated by the ISET method in the Biochemistry&#xD;
      Laboratory of Necker Hospital. The molecular analyses directed to the Trophoblastic cells for&#xD;
      the NI-PND of Trisomy 21 will be performed in a blind study.&#xD;
&#xD;
      The instigators have planned to use the ISET method in a blind study including 100 cases of&#xD;
      trisomy 21 and 300 control cases with normal caryotype. This study will allow to obtain&#xD;
      results with sensitivity higher than 97 % and specificity higher than 99 % (IC 95 %&#xD;
      [70-100]). The validation will be obtained by the opening of the blind study and the&#xD;
      comparison of results obtained by the invasive method (amniocentesis) and the non-invasive&#xD;
      method.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">June 19, 2012</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Actual">March 31, 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>non-invasive method of PND of Trisomy 21.</measure>
    <time_frame>9 months</time_frame>
    <description>Clinical validation of a non-invasive method of PND of Trisomy 21.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">150</enrollment>
  <condition>Trisomy 21</condition>
  <arm_group>
    <arm_group_label>Pregnant women accepting an invasive prenatal diagnosis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pregnant women accepting an invasive prenatal diagnosis and a sample blood (non invasive diagnosis)</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>sample blood</intervention_name>
    <arm_group_label>Pregnant women accepting an invasive prenatal diagnosis</arm_group_label>
    <other_name>Non Invasive</other_name>
    <other_name>Prenatal Diagnosis</other_name>
    <other_name>Trisomy 21</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pregnant women older than 18 years old&#xD;
&#xD;
          -  Pregnant women followed at a prenatal diagnostic centre&#xD;
&#xD;
          -  Pregnant woman having a risk (&gt; 1/250) of trisomy 21 based on the combined screening&#xD;
             &quot;serological tests/nuchal ultrasonography &quot;&#xD;
&#xD;
          -  Sample of blood and cervical smear obtained between the 8th and the 10th WG&#xD;
&#xD;
          -  Pregnant women accepting an invasive prenatal diagnosis&#xD;
&#xD;
          -  Father of the child agreeing to participate in the clinical study (accepting to give a&#xD;
             saliva sample)&#xD;
&#xD;
          -  Pregnant women beneficiary of a national insurance program&#xD;
&#xD;
          -  Pregnant women and fathers signing an informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant women with combined risk of trisomy 21 &lt; 1/250&#xD;
&#xD;
          -  Pregnant women non accepting the invasive prenatal diagnosis&#xD;
&#xD;
          -  Pregnant women participating another clinical study&#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>Patrizia Paterlini-Bréchot, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Necker Enfants Malades Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hopital de Béclère</name>
      <address>
        <city>Clamart</city>
        <zip>75014</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <citation>Vona G, Sabile A, Louha M, Sitruk V, Romana S, Schutze K, Capron F, Franco D, Pazzagli M, Vekemans M, Lacour B, Brechot C, Paterlini-Brechot P. Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulatingtumor cells. Am J Pathol. 2000 Jan;156(1):57-63. doi: 10.1016/S0002-9440(10)64706-2.</citation>
    <PMID>10623654</PMID>
  </reference>
  <reference>
    <citation>Vona G, Beroud C, Benachi A, Quenette A, Bonnefont JP, Romana S, Dumez Y, Lacour B, Paterlini-Brechot P. Enrichment, immunomorphological, and genetic characterization of fetal cells circulating in maternal blood. Am J Pathol. 2002 Jan;160(1):51-8. doi: 10.1016/S0002-9440(10)64348-9.</citation>
    <PMID>11786398</PMID>
  </reference>
  <reference>
    <citation>Beroud C, Karliova M, Bonnefont JP, Benachi A, Munnich A, Dumez Y, Lacour B, Paterlini-Brechot P. Prenatal diagnosis of spinal muscular atrophy by genetic analysis of circulating fetal cells. Lancet. 2003 Mar 22;361(9362):1013-4. doi: 10.1016/s0140-6736(03)12798-5.</citation>
    <PMID>12660061</PMID>
  </reference>
  <reference>
    <citation>Saker A, Benachi A, Bonnefont JP, Munnich A, Dumez Y, Lacour B, Paterlini-Brechot P. Genetic characterisation of circulating fetal cells allows non-invasive prenatal diagnosis of cystic fibrosis. Prenat Diagn. 2006 Oct;26(10):906-16. doi: 10.1002/pd.1524.</citation>
    <PMID>16832834</PMID>
  </reference>
  <reference>
    <citation>Bianchi DW, Simpson JL, Jackson LG, Elias S, Holzgreve W, Evans MI, Dukes KA, Sullivan LM, Klinger KW, Bischoff FZ, Hahn S, Johnson KL, Lewis D, Wapner RJ, de la Cruz F. Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data. National Institute of Child Health and Development Fetal Cell Isolation Study. Prenat Diagn. 2002 Jul;22(7):609-15. doi: 10.1002/pd.347.</citation>
    <PMID>12124698</PMID>
  </reference>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>November 8, 2012</study_first_submitted>
  <study_first_submitted_qc>November 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 12, 2012</study_first_posted>
  <last_update_submitted>July 5, 2021</last_update_submitted>
  <last_update_submitted_qc>July 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 7, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Circulating Trophoblastic Cells</keyword>
  <keyword>Non-Invasive Prenatal Diagnosis</keyword>
  <keyword>Genetic analysis</keyword>
  <keyword>Trisomy 21</keyword>
  <keyword>Down's Syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Down Syndrome</mesh_term>
    <mesh_term>Trisomy</mesh_term>
  </condition_browse>
  <!-- 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/NCT01725438
org study id: AOM10123
secondary id: P100118
nct id: NCT01725438
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The objective of this project is to develop a non-invasive prenatal diagnostic test for
      trisomy 21 which is reliable, sensitive and cost-effective, and thus, offers an alternative
      to the currently employed invasive diagnostic tests amniocentesis and chorionic villus
      sampling.

      Current prenatal screening methods (blood markers and ultrasound) for trisomy 21 (Down
      syndrome) detect about 90 % of cases and have a false positive rate of > 90 %. The results of
      these tests are expressed in risks for trisomy 21, the threshold being in France at 1/250.
      Women exhibiting a higher risk are offered to undergo invasive diagnostic testing, either by
      amniocentesis or chorionic villus sampling. However, these invasive diagnostic methods are
      associated with a considerable risk of miscarriage (1-3 %), and thus underline the importance
      to develop a safe and non-invasive prenatal diagnostic test for trisomy 21. The investigators
      have planned to assess the clinical impact of a non-invasive prenatal method to detect
      Trisomy 21 through genetic analysis of circulating trophoblastic cells.
The investigators have planned and developed the following approach: fetal cells are first
      enriched from blood of pregnant women, between 7 and 12 weeks gestation, employing the ISET
      (isolation by size of epithelial tumor cells) technique. Cells presumed to be of fetal origin
      are microdissected and subsequently genetically analyzed, using STR markers, to verify their
      fetal nature. The investigators then plan to test two strategies in order to assess the
      number of copies of chromosome 21. The first one involves the DNA of a single fetal cell to
      be analyzed with CGH (comparative genomic hybridization) array. In fact, our team has already
      developed an application of the metaphase CGH method to single cells isolated by ISET in
      which we were able to demonstrate the gain of chromosome 21 DNA in single fetal cells
      isolated from cord blood of a fetus with Down syndrome. The second strategy will be
      accomplished with the use of quantitative fluorescent PCR analysis of short tandem repeats
      (STRs), applied to single cells. At least 5-8 highly polymorphic STR markers specific for
      chromosome 21 will be tested to minimize the effects of a phenomenon called allele drop out,
      in which one allele fails to amplify, and to maximize the number of triallelic signals for an
      accurate diagnosis of disomy or trisomy 21.

      This survey is performed in collaboration with the Department of Gynaecology-Obstetrics -
      Reproductive Medicine of Antoine Béclère Hospital in Clamart. The women included in the
      survey will be taken a 20 ml blood sample and a cervical Pap smear before the invasive test
      (amniocentesis). The blood sample will be treated by the ISET method within 3 hours after
      collection and the filter will be stored at - 20°C. The cells obtained by Pap smear will be
      kept in an appropriate liquid and then treated by the ISET method in the Biochemistry
      Laboratory of Necker Hospital. The molecular analyses directed to the Trophoblastic cells for
      the NI-PND of Trisomy 21 will be performed in a blind study.

      The instigators have planned to use the ISET method in a blind study including 100 cases of
      trisomy 21 and 300 control cases with normal caryotype. This study will allow to obtain
      results with sensitivity higher than 97 % and specificity higher than 99 % (IC 95 %
      [70-100]). The validation will be obtained by the opening of the blind study and the
      comparison of results obtained by the invasive method (amniocentesis) and the non-invasive
      method.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: non-invasive method of PND of Trisomy 21.
time frame: 9 months
description: Clinical validation of a non-invasive method of PND of Trisomy 21.
arm group label: Pregnant women accepting an invasive prenatal diagnosis
arm group type: Experimental
description: Pregnant women accepting an invasive prenatal diagnosis and a sample blood (non invasive diagnosis)
intervention type: Other
intervention name: sample blood
arm group label: Pregnant women accepting an invasive prenatal diagnosis
other name: Non Invasive
other name: Prenatal Diagnosis
other name: Trisomy 21
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Patrizia Paterlini-Bréchot, MD, PhD
role: Principal Investigator
affiliation: Necker Enfants Malades Hospital
facility: 
country: France
citation: Vona G, Sabile A, Louha M, Sitruk V, Romana S, Schutze K, Capron F, Franco D, Pazzagli M, Vekemans M, Lacour B, Brechot C, Paterlini-Brechot P. Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulatingtumor cells. Am J Pathol. 2000 Jan;156(1):57-63. doi: 10.1016/S0002-9440(10)64706-2.
PMID: 10623654
citation: Vona G, Beroud C, Benachi A, Quenette A, Bonnefont JP, Romana S, Dumez Y, Lacour B, Paterlini-Brechot P. Enrichment, immunomorphological, and genetic characterization of fetal cells circulating in maternal blood. Am J Pathol. 2002 Jan;160(1):51-8. doi: 10.1016/S0002-9440(10)64348-9.
PMID: 11786398
citation: Beroud C, Karliova M, Bonnefont JP, Benachi A, Munnich A, Dumez Y, Lacour B, Paterlini-Brechot P. Prenatal diagnosis of spinal muscular atrophy by genetic analysis of circulating fetal cells. Lancet. 2003 Mar 22;361(9362):1013-4. doi: 10.1016/s0140-6736(03)12798-5.
PMID: 12660061
citation: Saker A, Benachi A, Bonnefont JP, Munnich A, Dumez Y, Lacour B, Paterlini-Brechot P. Genetic characterisation of circulating fetal cells allows non-invasive prenatal diagnosis of cystic fibrosis. Prenat Diagn. 2006 Oct;26(10):906-16. doi: 10.1002/pd.1524.
PMID: 16832834
citation: Bianchi DW, Simpson JL, Jackson LG, Elias S, Holzgreve W, Evans MI, Dukes KA, Sullivan LM, Klinger KW, Bischoff FZ, Hahn S, Johnson KL, Lewis D, Wapner RJ, de la Cruz F. Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data. National Institute of Child Health and Development Fetal Cell Isolation Study. Prenat Diagn. 2002 Jul;22(7):609-15. doi: 10.1002/pd.347.
PMID: 12124698
responsible party type: Sponsor
mesh term: Down Syndrome
mesh term: Trisomy