Prematurity Risk Assessment Combined With Clinical Interventions for Improving Neonatal outcoMEs

Study Overview
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Brief Summary
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This prospective, randomized, controlled study evaluates the safety and efficacy of a preterm birth (PTB) prevention strategy versus standard of care pregnancy management to reduce the incidence of adverse pregnancy outcomes.

Detailed Description
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Prospective subjects will be randomized to the PTB prevention strategy (PTB Prevention arm) or to standard of care management (Control arm). Subjects randomized to the preterm birth prevention strategy will receive either routine standard of care pregnancy management or a multimodal intervention protocol reserved for higher risk pregnancies based on the results of a commercially-available laboratory developed test, PreTRM® (Sera Prognostics, Inc). The intervention protocol utilizes well-established high-risk pregnancy interventions to improve maternal and neonatal health outcomes. After enrollment, all subjects will have a blood sample collected once between 18 0/7 weeks and 20 6/7 weeks (126-146 days) of pregnancy. Subjects will be randomized 1:1 to participate in the preterm birth prevention strategy arm or standard of care for pregnancy (Control) arm. Subjects randomized to the Control arm will not receive PreTRM® test results. Subjects randomized to the PTB Prevention arm will receive the results of the PreTRM® test. Results will be reported to the subject, the study Investigator, and the subject's primary pregnancy care provider as higher risk of prematurity (≥15%) or not higher risk. Subjects with results less than 15% risk (Not Higher Risk Group) by the PreTRM® test will receive standard of care for the duration of pregnancy through hospital discharge. Subjects with results at 15% risk of preterm delivery or greater (Higher Risk Group, equivalent to 2.0-fold the general population risk) by the PreTRM® test will complete a second consenting process to receive a prespecified intervention protocol directed toward reducing risk of adverse pregnancy outcomes inclusive of neonatal morbidity and mortality. All subjects will be followed through the duration of the pregnancy and delivery, and their neonates until initial hospital discharge to assess the course of pregnancy, labor, and any related maternal or fetal complications. Birth outcomes will be obtained, and liveborn neonates followed through hospital discharge. Readmission of infants will be assessed at 180 days, 1 year and 3 years of life using the HealthCore Integrated Research Database to evaluate longer-term outcomes and costs associated with preterm delivery.

Official Title
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Prematurity Risk Assessment Combined With Clinical Interventions for Improving Neonatal outcoMEs

Conditions
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Preterm Labor, Preterm Birth

Intervention / Treatment
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* Other: Multimodal intervention strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subject is 18 years of age or older Subject is willing and able to provide informed consent and comply with intervention if applicable Subject gestational age is currently within 18 0/7 and 20 6/7 weeks using best estimated due date This is a singleton intrauterine pregnancy Subject has no signs and/or symptoms of preterm labor and has intact membranes Subject has had a 2nd trimester anatomic ultrasound, including evaluation of cervical length, completed by the date of enrollment, but no earlier than 18 In the opinion of the Investigator, the subject's delivery data will be accessible within 20 business days from delivery, and neonatal data will be available for data collection purposes within 20 business days from discharge Exclusion Criteria: Subject has had a prior spontaneous preterm delivery (gestational age at birth less than 37 0/7 weeks gestation) Subject has cervical length less than 25 millimeters (mm) on 2nd trimester transvaginal ultrasound at time of enrollment Subject has taken progesterone or progesterone-derivative medication after 13 6/7 weeks gestation Singleton gestation reduced from an original multiple gestation via embryonic reduction or vanishing twin There is a known major fetal anomaly or chromosomal/ genetic abnormality Placenta accreta spectrum disorder (accreta/ increta/ percreta) Placenta covers the internal os by more than 2.5 centimeters (cm) at time of 2nd trimester anatomic ultrasound (18 0/7 and 20 6/7 weeks gestation) The subject has experienced vaginal bleeding after 13 6/7 weeks gestation One or more of the following uterine risk factors are present: fibroids > 5.0cm, uterine malformation, history of classical cesarean section, history of prior uterine surgery with trans-myometrial penetration (excludes low transverse cesarean section) The subject has a planned cesarean section or induction of labor prior to 370/7 weeks gestation The subject had a cerclage or pessary placed prior to enrollment window in the current pregnancy The subject has received enoxaparin, heparin, heparin sodium or other low molecular weight heparin since last menstrual period Subject has current diagnosis of polyhydramnios Subject has known use of illicit drugs in the current pregnancy, including cocaine, methamphetamine, and/or opioid use disorder in the current pregnancy Subject is allergic to aspirin or has experienced gastrointestinal bleeding associated with use Subject is allergic to peanuts and/or peanut oil used in exogenous progesterone formulation Subject is participating in any other interventional research studies during the current pregnancy Subject has tested positive for COVID-19 via an FDA-authorized diagnostic test for SARS-CoV-2 within the ten days prior to PreTRM® sample collection Subject has been evaluated for COVID-19 salient symptoms per the American College of Obstetrics and Gynecology/ Society for Maternal Fetal Medicine (ACOG/SMFM) Outpatient Assessment and Management for Pregnant Women with Suspected or Confirmed Novel Coronavirus (COVID-19) in an emergency room (ER) or hospital setting since the last menstrual period (LMP) date. Subject has a chronic medical disease(s) which require intensive medical surveillance and may increase the risk of preterm delivery to include: Lupus Chronic lung diseases on oxygen replacement Cardiac disease with high risk of maternal mortality, including Marfan syndrome with dilated aortic root and significant pulmonary hypertension Neuromuscular diseases at risk for pulmonary insufficiency (e.g. myotonic dystrophy) Renal failure on dialysis Uncontrolled or poorly controlled hyperthyroidism

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: To determine the efficacy and safety of a PTB prevention strategy, this study will utilize PreTRM® to prospectively stratify pregnant women with a singleton gestation into categories of risk of PTB and adverse neonatal outcomes. Subjects randomized into the PTB Prevention arm who score at or above the predetermined threshold risk will receive protocol-specified care for the prevention of PTB throughout gestation utilizing defined interventions.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTB Prevention<br>Approximately 6500 women will be screened, consented, and have the PreTRM® test sample collected. Randomization will occur 1:1 at each site. Those randomized to the PTB Prevention arm will receive the PreTRM® test results. If high risk, women will be consented to take part in the intervention. Those not higher risk will continue on with standard of care. | Other: Multimodal intervention strategy<br>* Once weekly nurse support 200 mg/daily micronized progesterone as vaginal suppository 81 mg/daily low dose aspirin two transvaginal ultrasounds cerclage placement if cervical length is less than or equal to 10 mm prior to 24 weeks gestation<br>|
| No Intervention: Control<br>Approximately 6500 women will be screened, consented, and have the PreTRM® test sample collected. Randomization will occur 1:1 at each site. Those randomized to the Control arm will not receive the PreTRM® test results. Control arm subjects will continue on with standard of care. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neonatal morbidity/mortality | Reduction in composite neonatal morbidity and mortality in the PTB Prevention arm versus the Control arm. | Through initial neonate discharge from hospital after birth for all neonates, assessed up to 180 days. | 
| Length of neonatal hospital stay | Reduction in length of neonatal hospital stay for admissions from time of birth up to initial neonatal hospital discharge home or neonatal death, whichever occurs first, in the PTB Prevention arm versus the Control arm. | Through initial neonate discharge from hospital after birth for all neonates, assessed up to 180 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of NICU hospital stay for neonates reduction | Reduction in all days spent in the neonatal intensive care unit (NICU) for neonates from time of birth up to discharge home or neonatal death, whichever occurs first, in the PTB Prevention arm versus the Control arm. | Through initial neonate discharge from hospital after birth or until neonatal death, whichever occurs first, assessed up to 180 days. | 
| Increase gestation | Increase in duration of gestation in the PTB Prevention arm versus the Control arm. | Gestational age at delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neonate, NICU, neonatal, preterm