Clinical trial NCT03087357: VAlidation of a Lower Cost aneUploidy scrEen
Official title: The VALUE Study - Women & Infants as the Coordinating Center
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Down Syndrome
Trisomy 18
Trisomy 13
Lead sponsor: Women and Infants Hospital of Rhode Island
Sponsor class: OTHER
Collaborators: name: PerkinElmer, Inc.
First posted: 2017-03-22
Enrollment: 2443
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed description: Women \& Infants Hospital of Rhode Island (WIH) will serve as the Study Center and the Laboratory Site. Enrollment Sites will secure local IRB approval, identify, consent and enroll pregnant women, ship plasma samples to WIH and collect outcome information. Eligible patients will be from one of two groups:

* The 'high risk' (HR) group - 250 women considering diagnostic testing, nearly all following a positive cell free (cf)DNA screening test. At least one case of Down syndrome should be detected for every three women enrolled, in addition to an occasional case of T18 or T13.
* The 'low risk' (LR) group - 2,400 women having conventional cfDNA screening as their primary screening test (i.e., no serum/ultrasound testing), representing the general pregnancy population. Their group risk of Down syndrome should be about 1:500. This group should have no more than 20% women age 35 and older. (Women whose conventional cfDNA screen is positive would then be eligible for a second enrollment in the 'high risk' group).

Both groups of women will be asked to provide three full 10mL Streck tubes of blood (two tubes minimum), agree to release limited clinical information, provide signed consent (including for FDA personnel to review records) and consent to have Enrollment Site staff review and report needed information from newborn/infant examination records, if requested. Identifiable patient information will be held at Enrollment Sites and not released to the Laboratory or Study Center. Sample and outcome information will be identified only by a unique study code. Individual cfDNA test results will not be returned to the Enrollment Sites, providers, or enrolled women. Enrollment Sites will receive a summary of results once the study ends.

Enrollment Sites are likely to enroll either HR or LR women, although a few sites may be able to enroll both. Both settings will have genetic counselors, physicians, research assistants or other medical staff available to identify, inform, consent and enroll women, as well as to collect and ship samples and obtain pregnancy outcome information. Staff designated as participating in the VALUE Study will be qualified to inform eligible women of the study's benefits and harms, and collect/document informed consent (which will remain at that site). The Study Center may request confirmation of consent, should it become necessary. Outcomes for HR women choosing diagnostic testing will be the results of the karyotype; those declining diagnostic testing will have newborn/infant information collected( often a newborn karyotype). In the LR population, a negative cfDNA test result will be accepted as ruling out a common autosomal trisomy, as the residual risk would be very low (\<1:20,000 to \< 1:50,000). For LR women with a positive cfDNA test, results of diagnostic testing would be requested. If diagnostic test results are unavailable, a review of the newborn examination/karyotype will be required for confirmation. Any conflicting results between the clinical tests and the VALUE Study results(false positive / false negative) would also require resolution that may involve review of newborn/infant records.

The VALUE Study intends to enroll approximately 2,400 LR women through as many as 8 LR Enrollment Sites associated with general risk obstetrical care practices. The 2,400 target is set to: 1) provide a reasonably confident estimate of an expected low false positive rate (e.g., 0.2%) and 2) provide sufficient numbers to exercise the testing platform over a 12 month time period. The target of 2,400 is large enough to meet both objectives and is slightly more than the largest number of euploid samples tested in any of the original NGS HR cfDNA validation studies (2011-2012). The number of trisomies detected in this LR group should be fewer than 10.An estimated 2% (48) of these LR women will have a failed/no call cfDNA test..

Sample handling:

Plasma samples could be tested fresh or stored and tested once the assay system has been validated. Outcome information will not be collected from Enrollment Sites until samples have been tested, ensuring blinding of laboratory to outcomes.

Timeframe:

Identification of Enrollment Sites and securing Investigational Review Board (IRB) approval will take three months. Efforts related to set-up and qualification of the testing laboratory is expected to take four to six months as will study-specific software development. Active enrollment is scheduled for 12 months. The intent is to run the majority of samples fresh, allowing for long-term assay variability to be studied. Follow-up will be completed, for the most part, within two months of the final testing (except for the small proportion of women who tested positive but did not have diagnostic testing). These will have outcomes confirmed at the time of delivery.

Eligibility criteria: Inclusion Criteria:

* At least 18 years old
* 10-20 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

Exclusion Criteria:

* Triplet or higher order pregnancy

  * Low Risk group
* positive nuchal translucency (NT) or abnormal ultrasound
* previous pregnancy with aneuploidy

Primary outcomes:
measure: Down syndrome detection rate
timeFrame: 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
measure: Down syndrome false positive rate
timeFrame: 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
measure: Down syndrome failure rate
timeFrame: 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:
measure: Trisomy 18 detection rate
timeFrame: 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
measure: Trisomy 13 detection rate
timeFrame: 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
measure: Trisomy 18 false positive rate
timeFrame: 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
measure: Trisomy 13 false positive rate
timeFrame: 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
measure: Trisomy 18 failure rate
timeFrame: 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.
measure: Trisomy 13 failure rate
timeFrame: 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.
measure: Fetal sex detection rate
timeFrame: 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
measure: Fetal sex detection false positive rate
timeFrame: 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 newborn examination 24-48 hours after birth reveal female sex
measure: Fetal sex detection failure rate
timeFrame: 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.
measure: Documentation of resources needed to implement SmartNIPT
timeFrame: Through study completion, 2 years.
Other outcomes:
measure: Develop a post-hoc statistical algorithm suitable for expanded use of SmartNIPT
timeFrame: 2 months after confirmation of birth outcome of outstanding cases
Locations:
city: Los Angeles
country: United States
facility: Center for Fetal Medicine
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Bridgeport
country: United States
facility: Bridgeport Hospital
state: Connecticut
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Medical Center
state: Illinois
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: South Weymouth
country: United States
facility: South Shore Hospital
state: Massachusetts
city: Oaks
country: United States
facility: Womens Health Care Group
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee Womens Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Houston
country: United States
facility: University of Texas
state: Texas
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Québec
country: Canada
facility: GenoScience Diagnostic
state: Quebec
city: Genova
country: Italy
facility: University of Genoa - Hospital San Martino
Study officials:
affiliation: Women and Infants Hospital of Rhode Island
name: Glenn E Palomaki, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.