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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
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment
Trisomy 21 Other: sample blood

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 Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 150 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Clinical Validation of the ISET Method for the Non Invasive Prenatal Diagnosis of Trisomy 21 by Genetic Analysis of Circulating Trophoblastic Cells
Study Start Date : June 19, 2012
Primary Completion Date : March 31, 2017
Estimated Study Completion Date : December 31, 2017

Arms and Interventions

Arm Intervention/treatment
Experimental: Pregnant women accepting an invasive prenatal diagnosis
Pregnant women accepting an invasive prenatal diagnosis and a sample blood (non invasive diagnosis)
Other: sample blood
Other Names:
  • Non Invasive
  • Prenatal Diagnosis
  • Trisomy 21

Outcome Measures

Primary Outcome Measures :
  1. non-invasive method of PND of Trisomy 21. [ Time Frame: 9 months ]
    Clinical validation of a non-invasive method of PND of Trisomy 21.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01725438

Hopital de Béclère
Clamart, France, 75014
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
University of Paris 5 - Rene Descartes
Principal Investigator: Patrizia Paterlini-Bréchot, MD, PhD Necker Enfants Malades Hospital
More Information

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01725438     History of Changes
Other Study ID Numbers: AOM10123
P100118 ( Other Identifier: AP-HP )
First Posted: November 12, 2012    Key Record Dates
Last Update Posted: December 8, 2017
Last Verified: December 2017

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Circulating Trophoblastic Cells
Non-Invasive Prenatal Diagnosis
Genetic analysis
Trisomy 21
Down's Syndrome

Additional relevant MeSH terms:
Down Syndrome
Chromosome Aberrations
Pathologic Processes
Chromosome Duplication
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Abnormalities, Multiple
Congenital Abnormalities
Chromosome Disorders
Genetic Diseases, Inborn