VAlidation of a Lower Cost aneUploidy scrEen

NCT03087357 | Completed

• 1 other identifier: 940244
• Study Type: observational
• Target: 2,443
• Locations: 3 countries
• Sites: 16

Brief Summary

This study will document the detection rate and false positive rate as well as failure rate of a new prenatal screening approach ('Smart NIPT') as described at www.vanadisdx.com and implemented in an academic laboratory with limited molecular testing experience. Testing will be performed on samples from a general risk pregnancy population, with additional high-risk cases added to improve confidence in the detection rate. Additional characteristics of this non-NGS test such as turn-around time, costs (equipment, training, per test), results reporting, fetal sex, fetal fraction, and quality measures will also be examined.

Conditions

Down Syndrome; Trisomy 18; Trisomy 13

Outcome Measures

Primary Outcomes (3)

• Down syndrome detection rate

  The cfDNA test detection rate for Down syndrome will utilize both the general population (low risk) enrollment (2,400 pregnancies) as well as the high risk enrollment (250 pregnancies, all confirmed trisomy 21/18/13) and be defined as TP/(TP+FN). All low risk women with a cfDNA test positive for trisomy 21 will have comprehensive diagnostic follow-up as will all high risk women, assuring that all affected pregnancies in these two groups will have karyotype confirmation. The true positive (TP) SmartNIPT cfDNA test results will be positive and agree with the abnormal karyotype finding. The false negative (FN) SmartNIPT cfDNA test results will be negative for the abnormal karyotype finding.

  Karyotype at chorionic villous sampling (CVS)/amniocentesis within 48 hours of enrollment OR at examination of products of conception if fetal loss up to 30 weeks post enrollment OR at newborn examination 24-48 hours after birth

• Down syndrome false positive rate

  The false positive rate for Down syndrome will be computed using data from the general population (low risk) enrollment only (2,400 pregnancies) and be defined as FP/(FP+TN) x 100. The false positive (FP) results are from pregnancies with a SmartNIPT cfDNA test result positive for Down syndrome that are determined to be euploid after diagnostic testing or birth follow-up. True negatives (TN) will be defined as those pregnancies with a cfDNA test result negative for Down syndrome.

  Karyotype at chorionic villous sampling (CVS)/amniocentesis within 48 hours of enrollment OR at examination of products of conception if fetal loss up to 30 weeks post enrollment. OR negative newborn examination 24-48 hours after birth

• Down syndrome failure rate

  The cfDNA test failure rate will be computed using data from the general population (low) enrollment only (2,400 pregnancies) and be defined as TF/Total. The cfDNA initial test will be classified as an initial test failure (iTF), if the first sample tested fails to produce a complete set of interpretable results. All test failures will be followed by testing a second available sample, and if that is also unsuccessful in producing a complete set of interpretable results, it will be characterized as a test failure (TF).

  Documentation of the failed result for Down syndrome will be considered confirmed when no results are returned for the second tested sample, typically within 14 days after enrollment.

Secondary Outcomes (10)

• Trisomy 18 detection rate

  Karyotype at chorionic villous sampling (CVS)/amniocentesis within 48 hours of enrollment OR at examination of products of conception if fetal loss up to 30 weeks post enrollment OR at newborn examination 24-48 hours after birth

• Trisomy 13 detection rate

  Karyotype at chorionic villous sampling (CVS)/amniocentesis within 48 hours of enrollment OR at examination of products of conception if fetal loss up to 30 weeks post enrollment OR at newborn examination 24-48 hours after birth

• Trisomy 18 false positive rate

  Karyotype at chorionic villous sampling (CVS)/amniocentesis within 48 hours of enrollment OR at examination of products of conception if fetal loss up to 30 weeks post enrollment. OR negative newborn examination 24-48 hours after birth

• Trisomy 13 false positive rate

  Karyotype at chorionic villous sampling (CVS)/amniocentesis within 48 hours of enrollment OR at examination of products of conception if fetal loss up to 30 weeks post enrollment. OR negative newborn examination 24-48 hours after birth

• Trisomy 18 failure rate

  Documentation of the failed result for Down syndrome will be considered confirmed when no results are returned for the second tested sample, typically within 14 days after enrollment.

Other Outcomes (1)

• Develop a post-hoc statistical algorithm suitable for expanded use of SmartNIPT

  2 months after confirmation of birth outcome of outstanding cases

Study Arms (2)

Low Risk

The Low Risk group will consist of 2,400 pregnancies with no high risk findings (e.g., abnormal ultrasound, positive serum screen) who are undergoing initial clinical cfDNA screening. To simulate a general pregnancy population, approximately 20% of these women will be age 35 and older. An estimated 2% (48) of these LR women will have a failed/no call cfDNA test. Consenting women will provide samples for SmartNIPT testing.

Other: SmartNIPT

High Risk

The High Risk group will consist of 250 women with a positive cfDNA screen reported by a Clinical Laboratory Improvement Amendments (CLIA)-approved commercial laboratory, and who present for consideration of a confirmatory diagnostic test, (i.e., CVS or amniocentesis). Consenting women will provide samples for SmartNIPT testing.

Other: SmartNIPT

Interventions

SmartNIPT OTHER

A novel, non-next generation sequencing (NGS) test that is designed to perform as well as conventional NGS screening while being simpler and less expensive.

High Risk; Low Risk

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

1. Pregnant women who either have no known risk factors for fetal aneuploidy (Low Risk group) and who present for cfDNA screening as their primary screen at a qualified Enrollment Site. 2. Pregnant women who have had a positive cfDNA screen and who present for discussion of confirmatory diagnostic testing (High Risk group) at a qualified Enrollment Site.

You may qualify if:

• At least 18 years old
• weeks gestation
• Low Risk group
• no known aneuploidy risk
• scheduled for cfDNA screen as primary aneuploidy screen
• High Risk group
• positive cfDNA screen
• scheduled to discuss CVS/amniocentesis as confirmatory test

You may not qualify if:

• Triplet or higher order pregnancy
• Low Risk group
• positive nuchal translucency (NT) or abnormal ultrasound
• previous pregnancy with aneuploidy

Sponsors & Collaborators

• Women and Infants Hospital of Rhode Island: lead
• PerkinElmer, Inc.: collaborator

Study Sites (16)

Center for Fetal Medicine

Los Angeles, California, 90048, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Bridgeport Hospital

Bridgeport, Connecticut, 06610, United States

Location

University of South Florida

Tampa, Florida, 33606, United States

Location

Northwestern Memorial Medical Center

Chicago, Illinois, 60611, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02110, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

South Shore Hospital

South Weymouth, Massachusetts, 02190, United States

Location

Womens Health Care Group

Oaks, Pennsylvania, 19456, United States

Location

Magee Womens Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

Women & Infants Hospital of Rhode Island

Providence, Rhode Island, 02905, United States

Location

University of Texas

Houston, Texas, 77030, United States

Location

Swedish Medical Center

Seattle, Washington, 98104, United States

Location

North York General Hospital

Toronto, Ontario, M2K 1E1, Canada

Location

GenoScience Diagnostic

Québec, Quebec, G1W IS2, Canada

Location

University of Genoa - Hospital San Martino

Genova, Italy

Location

Related Publications (3)

• Dahl F, Ericsson O, Karlberg O, Karlsson F, Howell M, Persson F, Roos F, Stenberg J, Ahola T, Alftren I, Andersson B, Barkenas E, Brandner B, Dahlberg J, Elfman S, Eriksson M, Forsgren PO, Francois N, Gousseva A, Hakamali F, Janfalk-Carlsson A, Johansson H, Lundgren J, Mohsenchian A, Olausson L, Olofsson S, Qureshi A, Skarpas B, Savneby A, Astrom E, Ohman O, Westgren M, Kopp-Kallner H, Fianu-Jonasson A, Syngelaki A, Nicolaides K. Imaging single DNA molecules for high precision NIPT. Sci Rep. 2018 Mar 14;8(1):4549. doi: 10.1038/s41598-018-22606-0.

  PMID: 29540801 BACKGROUND

• Ericsson O, Ahola T, Dahl F, Karlsson F, Persson F, Karlberg O, Roos F, Alftren I, Andersson B, Barkenas E, Boghos A, Brandner B, Dahlberg J, Forsgren PO, Francois N, Gousseva A, Hakamali F, Janfalk-Carlsson A, Johansson H, Lundgren J, Mohsenchian A, Olausson L, Olofsson S, Qureshi A, Skarpas B, Svahn P, Savneby A, Astrom E, Sahlberg A, Fianu-Jonasson A, Gautier J, Costa JM, Jacobsson B, Nicolaides K. Clinical validation of a novel automated cell-free DNA screening assay for trisomies 21, 13, and 18 in maternal plasma. Prenat Diagn. 2019 Oct;39(11):1011-1015. doi: 10.1002/pd.5528. Epub 2019 Aug 19.

  PMID: 31429096 BACKGROUND

• Palomaki GE, Eklund EE, Kloza EM, Lambert-Messerlian GM. Assessment of a Simplified Cell-Free DNA Method for Prenatal Down Syndrome Screening. Clin Chem. 2022 Nov 3;68(11):1449-1458. doi: 10.1093/clinchem/hvac131.

  PMID: 36103259 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Residual plasma samples, only with permission of enrolled women

MeSH Terms

Conditions

Down Syndrome; Trisomy 18 Syndrome; Trisomy 13 Syndrome

Condition Hierarchy (Ancestors)

Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases

Study Officials

• Glenn E Palomaki, PhD

  Women and Infants Hospital of Rhode Island

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 1, 2017
• First Posted: March 22, 2017
• Study Start: October 10, 2017
• Primary Completion: November 19, 2019
• Study Completion: October 1, 2020
• Last Updated: September 22, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2); US (13); IT (1)