Down SyndromeVALUENCT03087357
VAlidation of a Lower Cost aneUploidy scrEen
An observational study of Down Syndrome and Trisomy 18, run by Women and Infants Hospital of Rhode Island at 16 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Down Syndrome, Trisomy 18, Trisomy 13
- What is being tested?
- SmartNIPT
- How many people
- 2,443 participants
- Where
- 16 sitesin 3 countries
- Study dates
- 10 Oct 2017to 1 Oct 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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
Who cannot join
- Triplet or higher order pregnancy
- Low Risk group
- positive nuchal translucency (NT) or abnormal ultrasound
- previous pregnancy with aneuploidy
Trial locations and contacts
16 sites in 3 countries.
16 sites in 3 countries
United States13 sites
University of Colorado
Aurora, Colorado, 80045
Brigham and Women's Hospital
Boston, Massachusetts, 02110
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Bridgeport Hospital
Bridgeport, Connecticut, 06610
Northwestern Memorial Medical Center
Chicago, Illinois, 60611
University of Texas
Houston, Texas, 77030
Center for Fetal Medicine
Los Angeles, California, 90048
Womens Health Care Group
Oaks, Pennsylvania, 19456
Magee Womens Hospital
Pittsburgh, Pennsylvania, 15213
Women & Infants Hospital of Rhode Island
Providence, Rhode Island, 02905
Swedish Medical Center
Seattle, Washington, 98104
South Shore Hospital
South Weymouth, Massachusetts, 02190
University of South Florida
Tampa, Florida, 33606
Canada2 sites
GenoScience Diagnostic
Québec, Quebec, G1W IS2
North York General Hospital
Toronto, Ontario, M2K 1E1
About this study
Official title: The VALUE Study - Women & Infants as the Coordinating Center
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.
Read the 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.
- Conditions
- Down Syndrome, Trisomy 18, Trisomy 13
- Being tested
- SmartNIPT
- Medical subject headings
- Down Syndrome, Trisomy 18 Syndrome, Trisomy 13 Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SmartNIPTOther
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Other: SmartNIPT |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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).
Measured: 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
The cfDNA test detection rates for trisomy 18 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 18 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.
Measured: 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
The cfDNA test detection rates for trisomy 13 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 13 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.
Measured: 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
The false positive rate for trisomy 18 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 trisomy 18 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 trisomy 18.
Measured: 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
The false positive rate for trisomy 13 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 trisomy 13 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 trisomy 13.
Measured: 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
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).
Measured: 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.
Trisomy 13 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).
Measured: 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.
Fetal sex detection rate
The cfDNA test detection rate for fetal sex will utilize only the general population (low risk) enrollment (2,400 pregnancies) and be defined as TP/(TP+FN) where the male sex is the target of testing (singleton pregnancies only). All low risk women will have the results of a clinical cfDNA test available to compare with the study's test. The fetal sex result on the clinical test will be considered the gold standard. True positive results will occur when the new test agrees with the clinical test result that the fetus is male. False negative results will occur when the clinical test reports male while the study's test reports female. In any instance where the two tests report discordant results for fetal sex, pregnancy follow-up (either via 2nd trimester ultrasound or birth examination) will resolve the discrepancy.
Measured: 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
Fetal sex detection false positive rate
The false positive rate for fetal sex 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 where the male sex is the target of testing (singleton pregnancies only). All low risk women will have the results of a clinical cfDNA test available to compare with the study's test. The fetal sex result on the clinical test will be considered the gold standard. False positive (FP) results will occur when the study's cfDNA test predicts a male fetus in a pregnancy where female fetal sex is determined by clinical cfDNA testing. In any instance where the two tests report discordant results for fetal sex, pregnancy follow-up (either via 2nd trimester ultrasound or birth examination) will resolve the discrepancy. True negatives (TN) will be defined as those pregnancies where both clinical cfDNA test results and the study's DNA test results are negative for male sex.
Measured: 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
Fetal sex detection 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 retested using a second sample and if that fails to produce a complete set of interpretable results, it will be counted as a test failure (TF).
Measured: 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.
Documentation of resources needed to implement SmartNIPT
Determination of effort needed by non-molecular lab staff to implement SmartNIPT technology, costs and effort associated with bringing this non-NGS methodology into a non-molecular laboratory, and effort required to maintain proficiency in a clinical laboratory.
Measured: Through study completion, 2 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Mar 2017
- Study start10 Oct 2017
- Primary completion19 Nov 2019
- Study completion1 Oct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Down SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 2,443 participants (actual)
Sponsor and investigators
- Lead sponsor
- Women and Infants Hospital of Rhode Island
- Sponsor type
- University, hospital or other
- Collaborators
- PerkinElmer, Inc.
- Responsible party
- Sponsor
- Investigators
- Glenn E Palomaki, PhD, Principal investigator, Women and Infants Hospital of Rhode Island
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03087357
- Sponsor's protocol ID
- 940244
- Acronym
- VALUE
- Status last verified
- Sep 2022
- First submitted
- 1 Mar 2017
- Last updated
- 22 Sep 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 29540801Ericsson 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.
PubMed 31429096Palomaki 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.
PubMed 36103259
Study at a glance
From the registry record, last updated by the sponsor on 22 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The VALUE Study - Women & Infants as the Coordinating Center
- ClinicalTrials.gov ID
- NCT03087357
- Acronym / sponsor ID
- VALUE / 940244
- Conditions
- Down Syndrome, Trisomy 18, Trisomy 13
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 2,443 participants (actual)
- Lead sponsor
- Women and Infants Hospital of Rhode IslandUniversity, hospital or other
- Collaborators
- PerkinElmer, Inc.
- Study start
- 10 Oct 2017 (actual)
- Primary completion
- 19 Nov 2019 (actual)
- Study completion
- 1 Oct 2020 (actual)
- First posted
- 22 Mar 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Low Risk | – | Other: SmartNIPTThe 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. |
| High Risk | – | Other: SmartNIPTThe 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (8 listed)
- At least 18 years old
- 10-20 weeks gestation
- no known aneuploidy risk
- scheduled for cfDNA screen as primary aneuploidy screen
- positive cfDNA screen
Key exclusion criteria (4 listed)
- Triplet or higher order pregnancy
- positive nuchal translucency (NT) or abnormal ultrasound
- previous pregnancy with aneuploidy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SmartNIPTA novel, non-next generation sequencing (NGS) test that is designed to perform as well as conventional NGS screening while being simpler and less expensive. | Other | High Risk, Low Risk |
Primary outcome
Down syndrome detection rate
Time frame: 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
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.
Down syndrome false positive rate
Time frame: 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
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.
Down syndrome failure rate
Time frame: 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.
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).
10 secondary outcomes
Trisomy 18 detection rate
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Trisomy 13 failure rate
Time frame: 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.
Fetal sex detection rate
Time frame: 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
Fetal sex detection false positive rate
Time frame: 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
Fetal sex detection failure rate
Time frame: 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.
Documentation of resources needed to implement SmartNIPT
Time frame: Through study completion, 2 years.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Sep 2022.
- Background: PubMed 29540801Dahl 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.
- Background: PubMed 31429096Ericsson 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.
- Results publication: PubMed 36103259Palomaki 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Glenn E Palomaki, PhD principal investigator
Women and Infants Hospital of Rhode Island
16 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Down Syndrome and Trisomy 18, run by Women and Infants Hospital of Rhode Island at 16 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in United States, Canada, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Down syndrome detection rate (time frame: 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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03087357, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2022.