Clinical trial NCT00877292: A New Prenatal Blood Test for Down Syndrome
Official title: The RNA (RNA-Based Noninvasive Aneuploidy) Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Down Syndrome
Trisomy 21
Keywords: Down Syndrome
trisomy 21
prenatal testing
pregnant women
Lead sponsor: Women and Infants Hospital of Rhode Island
Sponsor class: OTHER
Collaborators: name: Sequenom, Inc.
First posted: 2009-04-07
Enrollment: 4664
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Pregnant women between about 10 weeks and 21 weeks 6 days gestation who are undergoing a diagnostic procedure (i.e., chorionic villus sampling or amniocentesis) for karyotype analysis.

Brief summary: The study will examine the sensitivity and specificity of a circulating cell-free nucleic acid test (DNA/RNA) to identify Down syndrome between about 10 weeks and 21 weeks 6 days gestation. In addition, the new test may be used to identify trisomy 13 and 18 as part of a more complete laboratory developed test. We hypothesize that the new circulating cell-free fetal NA-based test will accurately and precisely measure specific fetal markers in maternal circulation and that measurement will lead to the ability to noninvasively identify with high sensitivity and specificity, fetal chromosome abnormalities, such as Down syndrome.

Detailed description: The RNA study is an observational trial whose primary aim is to document the performance (sensitivity and specificity) of one or more laboratory developed test (LDT) using circulating cell-free fetal nucleic acids from maternal plasma to identify Down syndrome. Multiple test modalities are being pursued, including massively parallel sequencing and those utilizing differential methylation. The population being studied is women already having a diagnostic test (e.g., amniocentesis, CVS) between 10 weeks and 21 weeks 6 days gestation, and whose pregnancy is at high risk for having Down syndrome. The women provide informed consent. The karyotype will provide the gold standard against which the LDT test is judged. Samples and karyotypes will be collected from up to 25 prenatal diagnostic centers around the world and tested in several laboratories in the United States. The secondary aim is to develop a nucleic acid sample bank to allow documentation of subsequent improvements or new methodologies to identify fetal aneuploidy using circulating cell-free fetal nucleic acids.

Eligibility criteria: Inclusion Criteria:

* Pregnant women between about 10 weeks and 21 weeks 6 days gestation who are undergoing a diagnostic procedure (i.e., chorionic villus sampling or amniocentesis) for karyotype analysis who have, on average, a high prevalence of Down syndrome (about 1:30 to 1:50).
* Three main sources are pregnancies screen positive for:

  1. the combined test at 10 to 13 weeks (NT, PAPP-A and hCG)
  2. the second trimester quadruple test at 15 to 18 weeks gestation
  3. integrated screening (PAPP-A and the quadruple test, with or without NT).
* Variations of the integrated test such as sequential testing will also be acceptable.
* Other, less common high risk groups would be women having diagnostic testing because of maternal age of 38 years or older at delivery, pregnancies with an abnormal ultrasound highly suggestive of a chromosome abnormality (e.g., major heart defect, clenched fist), and women with an inherited form of Down syndrome (Robertsonian translocation).

Exclusion Criteria:

* Nonpregnant women and women at relatively low risk for a Down syndrome baby.

Primary outcomes:
measure: The RNA study is an observational trial whose primary aim is to document the performance (sensitivity and specificity) of a laboratory developed test (LDT), using fetal nucleic acid in maternal plasma to identify Down syndrome in early pregnancy.
timeFrame: Within 1st and 2nd trimesters
Secondary outcomes:
measure: The secondary aim is to develop a sample bank to allow documentation of subsequent improvements in the existing LDT or documenting performance of new methodologies.
timeFrame: Late1st and early 2nd trimesters
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Chicago
country: United States
facility: Northwestern University, FSM
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Providence
country: United States
facility: New Beginnings Perinatal Consultants
state: Rhode Island
city: Providence
country: United States
facility: Women and Infants Hospital
state: Rhode Island
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Murray
country: United States
facility: Intermountain Health Care
state: Utah
city: Charlottesville
country: United States
facility: UVA Medical Center
state: Virginia
city: Buenos Aires
country: Argentina
facility: Center for Medical Education and Clinical Investiagtion
city: Buenos Aires
country: Argentina
facility: Sociedad Italiana de Beneficencia en Buenos Aires - Hospital Italiano
city: St. Leonards
country: Australia
facility: University of Sydney
state: New South Wales
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Vancouver
country: Canada
facility: Children's and Women's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Zlin
country: Czech Republic
facility: Imalab
state: Zlinsky kraj
city: Ceske Budejovice
country: Czech Republic
facility: Centrum lekarske genetiky s.r.o.
city: Budapest
country: Hungary
facility: Semmelweis University
city: Pecs
country: Hungary
facility: Pecs University
city: Dublin
country: Ireland
facility: Rotunda Hospital
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Genova
country: Italy
facility: U.O. Ostetricia e Ginecologia Laboratorio Sperimentale di Tecniche
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona - Maternitat Campus
state: Catalonia
Study officials:
affiliation: Women and Infants Hospital
name: Barbara O'Brien, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Grody WW, Nelson SF, Canick JA. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet Med. 2012 Mar;14(3):296-305. doi: 10.1038/gim.2011.73. Epub 2012 Feb 2.
citation: Canick JA, Kloza EM, Lambert-Messerlian GM, Haddow JE, Ehrich M, van den Boom D, Bombard AT, Deciu C, Palomaki GE. DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations. Prenat Diagn. 2012 Aug;32(8):730-4. doi: 10.1002/pd.3892. Epub 2012 May 14.
citation: Palomaki GE, Kloza EM, Lambert-Messerlian GM, van den Boom D, Ehrich M, Deciu C, Bombard AT, Haddow JE. Circulating cell free DNA testing: are some test failures informative? Prenat Diagn. 2015 Mar;35(3):289-93. doi: 10.1002/pd.4541. Epub 2015 Jan 8.
citation: Lambert-Messerlian G, Kloza EM, Williams J 3rd, Loucky J, O'Brien B, Wilkins-Haug L, Mahoney MJ, De Biasio P, Borrell A, Ehrich M, van den Boom D, Bombard AT, Deciu C, Palomaki GE. Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies. Genet Med. 2014 May;16(5):419-22. doi: 10.1038/gim.2013.149. Epub 2013 Oct 3.
citation: Mazloom AR, Dzakula Z, Oeth P, Wang H, Jensen T, Tynan J, McCullough R, Saldivar JS, Ehrich M, van den Boom D, Bombard AT, Maeder M, McLennan G, Meschino W, Palomaki GE, Canick JA, Deciu C. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn. 2013 Jun;33(6):591-7. doi: 10.1002/pd.4127.
citation: Canick JA, Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE. The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies. Prenat Diagn. 2013 Jul;33(7):667-74. doi: 10.1002/pd.4126. Epub 2013 May 31.
citation: Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Deciu C, Grody WW, Nelson SF, Canick JA. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med. 2011 Nov;13(11):913-20. doi: 10.1097/GIM.0b013e3182368a0e.
citation: Palomaki GE, Ashwood ER, Best RG, Lambert-Messerlian G, Knight GJ. Is maternal plasma DNA testing impacting serum-based screening for aneuploidy in the United States? Genet Med. 2015 Nov;17(11):897-900. doi: 10.1038/gim.2015.39. Epub 2015 Apr 2.
citation: Kloza EM, Haddow PK, Halliday JV, O'Brien BM, Lambert-Messerlian GM, Palomaki GE. Evaluation of patient education materials: the example of circulating cell free DNA testing for aneuploidy. J Genet Couns. 2015 Apr;24(2):259-66. doi: 10.1007/s10897-014-9758-8. Epub 2014 Sep 10.