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Non Invasive Prenatal Diagnosis of Trisomy 21 by Genetic Analysis of Circulating Fetal Cells (ISETTRI21)

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ClinicalTrials.gov Identifier: NCT01725438
Recruitment Status : Active, not recruiting
First Posted : November 12, 2012
Last Update Posted : December 8, 2017
Sponsor:
Collaborators:
Institut National de la Santé Et de la Recherche Médicale, France
Rarecells
University of Paris 5 - Rene Descartes
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE November 8, 2012
First Posted Date  ICMJE November 12, 2012
Last Update Posted Date December 8, 2017
Study Start Date  ICMJE June 19, 2012
Actual Primary Completion Date March 31, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 9, 2012)
non-invasive method of PND of Trisomy 21. [ Time Frame: 9 months ]
Clinical validation of a non-invasive method of PND of Trisomy 21.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01725438 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Non Invasive Prenatal Diagnosis of Trisomy 21 by Genetic Analysis of Circulating Fetal Cells
Official Title  ICMJE Clinical Validation of the ISET Method for the Non Invasive Prenatal Diagnosis of Trisomy 21 by Genetic Analysis of Circulating Trophoblastic Cells
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Trisomy 21
Intervention  ICMJE Other: sample blood
Other Names:
  • Non Invasive
  • Prenatal Diagnosis
  • Trisomy 21
Study Arms  ICMJE Experimental: Pregnant women accepting an invasive prenatal diagnosis
Pregnant women accepting an invasive prenatal diagnosis and a sample blood (non invasive diagnosis)
Intervention: Other: sample blood
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 27, 2015)
150
Original Estimated Enrollment  ICMJE
 (submitted: November 9, 2012)
500
Estimated Study Completion Date  ICMJE December 31, 2017
Actual Primary Completion Date March 31, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pregnant women older than 18 years old
  • Pregnant women followed at a prenatal diagnostic centre
  • Pregnant woman having a risk (> 1/250) of trisomy 21 based on the combined screening "serological tests/nuchal ultrasonography "
  • Sample of blood and cervical smear obtained between the 8th and the 10th WG
  • Pregnant women accepting an invasive prenatal diagnosis
  • Father of the child agreeing to participate in the clinical study (accepting to give a saliva sample)
  • Pregnant women beneficiary of a national insurance program
  • Pregnant women and fathers signing an informed consent

Exclusion Criteria:

  • Pregnant women with combined risk of trisomy 21 < 1/250
  • Pregnant women non accepting the invasive prenatal diagnosis
  • Pregnant women participating another clinical study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01725438
Other Study ID Numbers  ICMJE AOM10123
P100118 ( Other Identifier: AP-HP )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE
  • Institut National de la Santé Et de la Recherche Médicale, France
  • Rarecells
  • University of Paris 5 - Rene Descartes
Investigators  ICMJE
Principal Investigator: Patrizia Paterlini-Bréchot, MD, PhD Necker Enfants Malades Hospital
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date December 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP