PErsonalized Genomics for Prenatal Abnormalities Screening USing Maternal Blood

Study Overview
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Brief Summary
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This project aims to provide high- quality evidence to inform decisions by health care organisations about using first-tier non-invasive prenatal screening (NIPS) to replace traditional screening tests for trisomy 21, and potentially to screen for other fetal chromosome anomalies. We will compare the current screening approach of second-tier NIPS with the use of first-tier NIPS in a large cohort of pregnant women.

Detailed Description
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There is some data on the performance of NIPS as a first tier screening test but our systematic review has shown that no trial comparing the effectiveness (utility) of 2nd-tier NIPS with that of first-tier NIPS has been published . Further it is important for health care decision makers to have evidence produced in Canada since the geographical context of healthcare can affect uptake as well as patient decision and thus their healthcare trajectories. There is a need for a trial that is between an explanatory trial and a pragmatic trial to provide the types of answer that we aim to document in the present state of knowledge on NIPS-based screening strategies in Canada. Our Objective is to perform a pan-Canadian large-scale comparative utility (clinical outcomes) study of first-tier NIPS (expanded or not) as compared to the new standard of care (NIPS as a 2nd tier test performed much later during pregnancy and only in high risk pregnancies).

Official Title
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PErsonalized Genomics for Prenatal Abnormalities Screening USing Maternal Blood : Towards First Tier Screening and Beyond

Conditions
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Prenatal Disorder, Aneuploidy

Intervention / Treatment
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* Diagnostic Test: Traditional integrated prenatal screening
* Diagnostic Test: Second-tier Non-invasive prenatal screening (NIPS)
* Diagnostic Test: First-tier Non-invasive prenatal screening (NIPS)
* Diagnostic Test: Invasive prenatal testing for fetal aneuploidy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant women 19 years or older wanting prenatal screening 10-13+6 wks determined by dating ultrasound or last menstrual period. Not intending to pursue self pay NIPT Exclusion Criteria: Known fetal anomaly at the time of recruitment Multiple gestation Known twin demise Planned CVS or amnio for known genetic condition.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label prospective comparative-effectiveness (utility) randomised trial between first-tier NIPS and the standard of care (2nd-tier NIPS).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care (2nd tier NIPS)<br>For the standard-of-care arm (2nd tier NIPS) women will undergo Traditional integrated prenatal screening i.e. traditional biochemical (+/- NT) and those with a positive screen for T21 or T18 will be offered Second-tier Non-invasive prenatal screening (NIPS) (for T21, T18, T13) or Invasive prenatal testing for fetal aneuploidy. Ultrasound examination in first and second trimester will be done based on clinical care practice ordered by health care provider. Pregnant women with a positive NIPS test will be offered Invasive prenatal testing for fetal aneuploidy (fetal chromosome analysis). | Diagnostic Test: Traditional integrated prenatal screening<br>* biochemical prenatal screening with or without nuchal translucency by US<br>* Other names: IPS;Diagnostic Test: Second-tier Non-invasive prenatal screening (NIPS)<br>* genomics based NIPS after a positive traditional prenatal screen<br>* Other names: second tier non-invasive prenatal testing (NIPT);Diagnostic Test: Invasive prenatal testing for fetal aneuploidy<br>* amniocentesis or chorionic villi sampling (CVS)<br>|
| Experimental: First-tier NIPS<br>For the intervention arm (1st tier NIPS) women will receive First-tier Non-invasive prenatal screening (NIPS) i.e. provide a blood sample between 10-13+5 weeks gestation with NIPS results within 7 - 10 days of sample collection. Ultrasound examination in first and second trimester will be done based on clinical care practice ordered by health care provider. In case of a failed NIPS test (expected to be between 2% and 4% of samples), a new blood sample will be drawn for NIPS retest as well as for a traditional SIPS(serum integrated prenatal screening) or QUAD(quadruple marker prenatal screening) screen (depending on gestational age). Pregnant women with a positive NIPS test will be offered Invasive prenatal testing for fetal aneuploidy (fetal chromosome analysis). | Diagnostic Test: First-tier Non-invasive prenatal screening (NIPS)<br>* genomics based NIPS at first trimester<br>* Other names: first tier NIPT, Universal NIPS, Universal NIPT;Diagnostic Test: Invasive prenatal testing for fetal aneuploidy<br>* amniocentesis or chorionic villi sampling (CVS)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gestational age at diagnosis | gestational age at final result in the sub-set of participants that have received a positive NIPS result and that have been offered diagnostic testing | Up to 24 weeks of gestational age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gestational age at negative screening result | gestational age at final result in the sub-set of participants that have received a negative screening result | Up to 24 weeks of gestational age | 
| Gestational age at positive screening result | gestational age at final result in the sub-set of participants that have received a positive screening result | Up to 24 weeks of gestational age | 
| proportion of women with no results | proportion of women with no NIPS result at first and second attempt | Up to 24 weeks of gestational age | 
| numbers of days for women with false positive result of screen to wait for result of definite test | Difference between gestational age (in days) at first positive prenatal screening result and final negative screening result | Up to 24 weeks of gestational age | 
| Change in PROMIS-29 Score | The PROMIS-29 assesses seven health domains: physical function, anxiety, depression, fatigue, sleep disturbance, pain interference, and ability to participate in social roles and activities. Each of the seven domains has four questions which are scored on a five-point Likert scale. The PROMIS-29 scales will be scored using a T-score metric method available at the Assessment Center website (http://assessmentcenter.net). A score of 50 points represents the population average for each scale, and 10 points represent one standard deviation. Higher scores mean more of the specific scale's construct, which may indicate a desirable or an undesirable outcome. The assessment will be done at recruitment (10-13 weeks of gestation) and at week 16 and week 22 of gestation. | At weeks of gestation 10-13, week 16 and week 22 | 
| Change in PROMIS Emotional Distress - Anxiety - Short Form 8a Score | The PROMIS-Anxiety short form assesses anxiety with 8 questions. The form includes 8 items and uses a scale of 1-5 (1=Never, 2=Almost never, 3= Sometimes, 4=Often, 5=Almost always). The raw score is the sum of the points for each response. A higher than average raw score indicates higher than average anxiety. A higher score represents higher levels of anxiety. The assessment will be done at recruitment (10-13 weeks of gestation) and at week 16 and week 22 of gestation. | At weeks of gestation 10-13, 16 and 22 | 
| Patient-Reported Experience Measure (PREM) - Score | A 17-questions validated PREM questionnaire on pregnancy experience that measures three dimensions - type of prenatal care received and test results (seven questions), pregnancy visits (four questions (scales 1-5) and prenatal screening experience (six questions). A profile score by looking at frequencies of responses for each item will be used. | At 22 weeks of gestation | 
| gestational age at termination of pregnancy | Gestational age at termination of pregnancy for participants having volountary termination | Up to 24 weeks of gestational age | 
| percentage of women undergoing invasive diagnostic testing | see outcome title | Up to 24 weeks of gestational age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Real life comparative effectiveness, Non-invasive prenatal screening, Fetal aneuploidy, Randomized controlled trial