Non-invasive Chromosomal Examination of Trisomy Study (NEXT)

Non-invasive Chromosomal Examination of Trisomy

The purpose of this blinded, multi-center, prospective, case-controlled study is to compare the Ariosa Harmony™ Prenatal Test for trisomy 21 detection with a standard first-trimester prenatal screening test consisting of serum screening (PAPP-A,free beta-hCG [β-hCG] or total hCG) and a nuchal translucency (NT) measurement (i.e. combined first trimester screening) in a general screened population.

The performance characteristics of these two test modalities will be assessed relative to the clinical reference standard of genetic analysis of the fetus or phenotypic characterization and genetic analysis of the newborn.

Study Overview

• Status: Completed
• Conditions: Trisomy 21

• Study Type: Observational
• Enrollment (Actual): 18955

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • University Hospitals Leuven
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Early Risk Assessment Program - University of Alberta
  • Ontario
    • Ottawa, Ontario, Canada, ON1Kh8L6
      • Ottawa Hospital and Research Institute
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai University
    • Toronto, Ontario, Canada, M5G1X8
      • University of Toronto
• Italy
  • Perugia, Italy, 06132
    • University Of Perugia
• Netherlands
  • Leiden, Netherlands, 2333
    • Leiden University Medical Center
  • Maastricht, Netherlands, 6202
    • Maastricht University Medical Center
• Sweden
  • Gothenburg, Sweden, SE-41685
    • Sahlgrenska University Medical Center
  • Stockholm, Sweden, 14186
    • Karolinska University Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85712
      • Tucson Medical Center
  • California
    • Oakland, California, United States, 94609
      • East Bay Perinatal Associates
    • Palo Alto, California, United States, 94305-5317
      • Stanford University
    • Riverside, California, United States, 92501
      • Perinatal Diagnostic Center
    • San Diego, California, United States, 92037-1300
      • University of California San Diego
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • San Francisco, California, United States, 94118
      • California Pacific Medical Center
    • San Gabriel, California, United States, 91776
      • The Institute of Prenatal Diagnosis and Reproductive Medicine
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System
  • Florida
    • Lake Worth, Florida, United States, 33461
      • Altus Research
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • Fetal Diagnostic Institute of the Pacific
  • Illinois
    • Evanston, Illinois, United States, 60201
      • Northshore University Health System
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Norton Healthcare
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital - Center for Fetal Medicine and Prenatal Genetics
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minnesota Perinatal Associates
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson School of Medicine
    • New Brunswick, New Jersey, United States, 08901
      • St. Peters University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
    • Portland, Oregon, United States, 97225
      • Northwest Perinatal Center
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson Univeristy Hospital
    • Wynnewood, Pennsylvania, United States, 19096
      • Women's Health Care Group of Pennsylvania
  • Rhode Island
    • Pawtucket, Rhode Island, United States, 02860
      • Partners in Obstetrics and Gynecology
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pregnant women presenting for combined first trimester screening as part of routine prenatal care

Description

Inclusion Criteria:

1. Subject is at least 18 years old and can provide informed consent.
2. Subject is planning a hospital delivery.
3. Subject has a singleton pregnancy with a documented gestational age between 10 weeks, 0 days, and 14 weeks, 2 days, inclusive, at the time of the study blood sample collection.
4. Subject is planning to undergo combined first trimester prenatal screening that includes NT measurement, and when indicated, serum screening with total or free β-hCG and PAPP-A.

Exclusion Criteria:

1. Subject has known aneuploidy.
2. Subject has active or history of malignancy requiring major surgery and/or systemic chemotherapy.
3. Subject has a twin demise at any gestational age. Twin demise includes any reductions, spontaneous or elective, after sonographic identification of a second (or more) gestational sac. Any clinical, sonographic, or other testing that suggests twin demise would serve as an exclusion criterion.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Case; Patient with a trisomy 21 pregnancy confirmed by genetic testing.
Control; Patients without a trisomy 21 pregnancy confirmed by either genetic testing or a normal newborn phenotype.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Difference in sensitivity and specificity of Ariosa Harmony™ Prenatal Test (AUCt) and combined first-trimester screening for detection of T21.	Enrollment to delivery

Collaborators and Investigators

• Sponsor: Roche Sequencing Solutions
• Collaborators: Perinatal Quality Foundation: Nuchal Translucency Quality Review
• Investigators: Principal Investigator: Mary E. Norton, MD, Stanford University

Publications and helpful links

General Publications

• American College of Obstetricians and Gynecologists. Guidelines for Perinatal Care, Sixth Edition, October 2007.
• Nicolaides KH. A model for a new pyramid of prenatal care based on the 11 to 13 weeks' assessment. Prenat Diagn. 2011 Jan;31(1):3-6. doi: 10.1002/pd.2685. No abstract available.
• Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE, Carr SR, Wolfe HM, Dukes K, Bianchi DW, Rudnicka AR, Hackshaw AK, Lambert-Messerlian G, Wald NJ, D'Alton ME; First- and Second-Trimester Evaluation of Risk (FASTER) Research Consortium. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med. 2005 Nov 10;353(19):2001-11. doi: 10.1056/NEJMoa043693.
• Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol. 2005 Mar;25(3):221-6. doi: 10.1002/uog.1860.
• Cicero S, Rembouskos G, Vandecruys H, Hogg M, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with absent nasal bone at the 11-14-week scan. Ultrasound Obstet Gynecol. 2004 Mar;23(3):218-23. doi: 10.1002/uog.992.
• Borrell A. The ductus venosus in early pregnancy and congenital anomalies. Prenat Diagn. 2004 Sep;24(9):688-92. doi: 10.1002/pd.958.
• Faiola S, Tsoi E, Huggon IC, Allan LD, Nicolaides KH. Likelihood ratio for trisomy 21 in fetuses with tricuspid regurgitation at the 11 to 13 + 6-week scan. Ultrasound Obstet Gynecol. 2005 Jul;26(1):22-7. doi: 10.1002/uog.1922.
• Sonek J, Borenstein M, Dagklis T, Persico N, Nicolaides KH. Frontomaxillary facial angle in fetuses with trisomy 21 at 11-13(6) weeks. Am J Obstet Gynecol. 2007 Mar;196(3):271.e1-4. doi: 10.1016/j.ajog.2006.10.891.
• ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007 Jan;109(1):217-27. doi: 10.1097/00006250-200701000-00054.
• American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 88, December 2007. Invasive prenatal testing for aneuploidy. Obstet Gynecol. 2007 Dec;110(6):1459-67. doi: 10.1097/01.AOG.0000291570.63450.44.
• Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, Tim R, Lu V, McCullough R, McCarthy E, Nygren AO, Dean J, Tang L, Hutchison D, Lu T, Wang H, Angkachatchai V, Oeth P, Cantor CR, Bombard A, van den Boom D. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol. 2011 Mar;204(3):205.e1-11. doi: 10.1016/j.ajog.2010.12.060. Epub 2011 Feb 18.
• Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997 Aug 16;350(9076):485-7. doi: 10.1016/S0140-6736(97)02174-0.
• Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16266-71. doi: 10.1073/pnas.0808319105. Epub 2008 Oct 6.
• Chiu RW, Chan KC, Gao Y, Lau VY, Zheng W, Leung TY, Foo CH, Xie B, Tsui NB, Lun FM, Zee BC, Lau TK, Cantor CR, Lo YM. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20458-63. doi: 10.1073/pnas.0810641105. Epub 2008 Dec 10.
• Chiu RW, Sun H, Akolekar R, Clouser C, Lee C, McKernan K, Zhou D, Nicolaides KH, Lo YM. Maternal plasma DNA analysis with massively parallel sequencing by ligation for noninvasive prenatal diagnosis of trisomy 21. Clin Chem. 2010 Mar;56(3):459-63. doi: 10.1373/clinchem.2009.136507. Epub 2009 Dec 21.
• 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.
• Dhallan R, Guo X, Emche S, Damewood M, Bayliss P, Cronin M, Barry J, Betz J, Franz K, Gold K, Vallecillo B, Varney J. A non-invasive test for prenatal diagnosis based on fetal DNA present in maternal blood: a preliminary study. Lancet. 2007 Feb 10;369(9560):474-81. doi: 10.1016/S0140-6736(07)60115-9.
• Tong YK, Jin S, Chiu RW, Ding C, Chan KC, Leung TY, Yu L, Lau TK, Lo YM. Noninvasive prenatal detection of trisomy 21 by an epigenetic-genetic chromosome-dosage approach. Clin Chem. 2010 Jan;56(1):90-8. doi: 10.1373/clinchem.2009.134114. Epub 2009 Oct 22.
• Ghanta S, Mitchell ME, Ames M, Hidestrand M, Simpson P, Goetsch M, Thilly WG, Struble CA, Tomita-Mitchell A. Non-invasive prenatal detection of trisomy 21 using tandem single nucleotide polymorphisms. PLoS One. 2010 Oct 8;5(10):e13184. doi: 10.1371/journal.pone.0013184.
• Norton ME, Jacobsson B, Swamy GK, Laurent LC, Ranzini AC, Brar H, Tomlinson MW, Pereira L, Spitz JL, Hollemon D, Cuckle H, Musci TJ, Wapner RJ. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015 Apr 23;372(17):1589-97. doi: 10.1056/NEJMoa1407349. Epub 2015 Apr 1.

Helpful Links

• Click here for more information about Ariosa Diagnostics
• Click here to find more information about the Perinatal Quality Foundation

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (ACTUAL): November 1, 2013
• Study Completion (ACTUAL): May 1, 2014

Study Registration Dates

• First Submitted: January 13, 2012
• First Submitted That Met QC Criteria: January 17, 2012
• First Posted (ESTIMATE): January 18, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): July 14, 2014
• Last Update Submitted That Met QC Criteria: July 11, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: DNA; Pregnancy; cell free DNA; Down Syndrome; hCG; First trimester; PAPP-A; Trisomy 21; Fetal aneuploidy; Prenatal screening; Non-invasive prenatal testing; Combined screening; Nuchal translucency; cf DNA; Performance characteristics of non-invasive first trimester screening; Harmony Prenatal Test
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Intellectual Disability; Abnormalities, Multiple; Chromosome Disorders; Chromosome Aberrations; Aneuploidy; Chromosome Duplication; Down Syndrome; Trisomy
• Other Study ID Numbers: TD007