Clinical trial NCT03782610: Early Prediction of Spontaneous Patent Ductus Arteriosus (PDA) Closure and PDA-Associated Outcomes
Official title: Early Prediction of Spontaneous Patent Ductus Arteriosus (PDA) Closure and PDA-Associated Outcomes
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Patent Ductus Arteriosus
Preterm Infant
Bronchopulmonary Dysplasia
Neurodevelopmental Abnormality
Keywords: Patent Ductus Arteriosus
Preterm Infant
Echocardiogram
Prospective Cohort
Prediction Modeling
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Ohio State University
name: OhioHealth
name: Mount Carmel Health System
First posted: 2018-12-20
Enrollment: 675
Sex: ALL
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: A cohort of consecutively enrolled preterm infants born between 23- and 30-weeks gestation with patent ductus arteriosus (PDA) documented on echocardiogram within 72-hours postnatal.

Brief summary: Patent ductus arteriosus (PDA), very common in preterm infants, is the delayed closure of a fetal blood vessel that limits blood flow through the lungs. PDA is associated with mortality and harmful long term outcomes including chronic lung disease and neurodevelopmental delay. Although, treatments to close PDA likely benefit some infants, widespread routine treatment of all preterm infants with PDA may not improve important outcomes. Left untreated, most PDAs close spontaneously. Thus, PDA treatment is increasingly controversial and varies markedly between hospitals and individual providers. The relevant and still unanswered clinical question is not whether to treat all preterm infants with PDA, but whom to treat and when. Treatment detriments may outweigh benefits, since all forms of deliberate PDA closure have potential adverse effects, especially in infants destined for early, spontaneous PDA closure. Unfortunately, clinicians cannot currently predict in the 1st month which infants are at highest risk for persistent PDA, and which combination of clinical risk factors, echocardiographic (echo) measurements, and serum biomarkers may best predict PDA-associated harm. The American Academy of Pediatrics has acknowledged early identification of infants at high-risk from PDA as a key research goal for informing future PDA-treatment effectiveness trials.

Our objective is to use a prospective cohort of untreated infants with PDA to predict spontaneous ductal closure timing and identify echo measurements and biomarkers that are present in the 1st postnatal month and associated with long-term impairment. Our central hypothesis is that these risk factors can be determined to inform appropriate clinical treatments when necessary. Clinical, serum and urine biomarkers (BNP, NTpBNP, NGAL, H-FABP), and echo variables sequentially collected during each of the first 4 postnatal weeks will be examined. In addition myocardial deformation imaging (MDI) and tissue Doppler imaging (TDI), innovative echo methods, will facilitate the quantitative evaluation of myocardial performance. Aim 1 will estimate the probability of spontaneous PDA closure and predict the timing of ductal closure using echo, biomarker, and clinical predictors. Aim 2 will specify which echo predictors and biomarkers are associated with mortality and severity of respiratory illness at 36-weeks PMA. Aim 3 will identify which echo predictors and biomarkers are associated with 22- to 26-month neurodevelopment. All models will be validated in a separate cohort. This project will significantly contribute to clinical outcomes and PDA management by reducing unnecessary and harmful overtreatment of infants with a high probability of early spontaneous PDA closure, and will permit the development of outcomes-focused trials to examine the effectiveness of PDA closure in those "high-risk" infants most likely to receive benefit.


Eligibility criteria: Inclusion Criteria:

* Born between 23-weeks + 0 days (23_0/7 wks) and 29-weeks + 6 days (29_6/7 wks) gestation, inclusive
* Admitted to a study neonatal intensive care unit (NICU) within 72-hours of birth
* PDA noted on initial screening echo at \<72 postnatal hours

Exclusion Criteria:

* Life-threatening congenital abnormalities, including congenital heart disease (other than PDA or small atrial septal defects/patent foramen ovale/muscular VSD)
* Parents have chosen to allow natural death (placed a do not resuscitate order)

Primary outcomes:
measure: Patent ductus arteriosus (PDA) closure documented via echocardiogram by 36-weeks postmenstrual age (PMA) (binary)
timeFrame: Outcome will be documented between <72-hour screening echo and 36-weeks PMA.
measure: Mortality or supplemental oxygen or positive-pressure respiratory support at 36-weeks PMA (binary)
timeFrame: Outcome will be documented between <72-hour screening echo and 36-weeks PMA
measure: Composite Bayley III Motor Score at 22-26 months corrected age (continuous)
timeFrame: Bayley III Score Testing will occur at 22 to 26 months corrected age (CA) (age since birth - number of weeks born before 40-weeks gestation)
Secondary outcomes:
measure: Mortality by 36-weeks PMA (binary)
timeFrame: Death occuring between 72-hours postnatal and 36-weeks PMA
measure: Bayley III Gross Motor Development Scaled Standard Score at 22-26 months corrected age (continuous)
timeFrame: Recorded at 22-26 months corrected age
measure: Bayley III Fine Motor Development Scaled Standard Score postnatal age at 22-26 months corrected age (continuous)
timeFrame: Recorded at 22-26 months corrected age
measure: Bayley III Cognitive Composite Score at 22-26 months corrected age (continuous)
timeFrame: Recorded at 22-26 months corrected age
measure: Bayley III Language Composite Score at 22-26 months corrected age (continuous)
timeFrame: Recorded at 22-26 months corrected age
Other outcomes:
measure: Normal cardiac function at 36-weeks PMA (binary)
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Quantitative myocardial deformation imaging (MDI) at 36-weeks PMA (continuous)
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Quantitative tissue Doppler imaging (TDI) at 36-weeks PMA (continuous)
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Pulmonary Hypertension at 36-weeks PMA (binary)
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Normal left atrial size at 36-weeks PMA (binary)
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Normal left ventricular size at 36-weeks PMA (binary)
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Normal right ventricular size at 36-weeks PMA (binary)
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Oxygen Dependency (Moderate BPD) (binary)
timeFrame: Recorded at 36-weeks PMA
measure: Positive-Pressure Dependency (Severe BPD) (binary)
timeFrame: Recorded at 36-weeks PMA
measure: Length at 36-weeks PMA
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: General Movements Assessment (GMA) at 36-weeks corrected age
timeFrame: Recorded at 36-weeks PMA
measure: Time to enteral feed initiation
timeFrame: 72 hours postnatal to 36-weeks PMA
measure: Time to a full enteral feed diet
timeFrame: 72 hours postnatal to 36-weeks PMA
measure: Oral feeding status (binary)
timeFrame: Recorded at 36-weeks PMA
measure: Weight at 36-weeks PMA
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Occipitofrontal circumference (OFC) at 36-weeks PMA
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Body Mass Index (BMI) at 36-weeks PMA
timeFrame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks
measure: Supplemental oxygen or positive-pressure respiratory support at 40-weeks PMA (binary)
timeFrame: Recorded at 40-weeks PMA
measure: Mortality by 22-26 months corrected age
timeFrame: Death occuring between 72-hours postnatal and 22-26 months corrected age
measure: Duration of ductal patency from 72-hours postnatal until 22 to 26-months corrected age follow-up
timeFrame: 72 hours postnatal until 22-26 months follow-up visit
measure: Supplemental oxygen support (binary) at 22-26 months corrected age
timeFrame: Recorded at 22-26 months study follow-up visit
measure: Supplemental positive-pressure ventilation support (binary) at 22-26 months corrected age
timeFrame: Recorded at 22-26 months study follow-up visit
measure: Weight at 22-26 months corrected age
timeFrame: Recorded at 22-26 months study follow-up visit
measure: Length at 22-26 months corrected age
timeFrame: Recorded at 22-26 months study follow-up visit
measure: Body Mass Index (BMI) at 22-26 months corrected age
timeFrame: Recorded at 22-26 months study follow-up visit
measure: Feeding status via full oral feeding or gastric-tube (binary) at 22-26 months corrected age
timeFrame: Recorded at 22-26 months study follow-up visit
Locations:
city: Columbus
country: United States
facility: Nationwide Children's Hospital Main Campus Neonatal Intensive Care Unit
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Neonatal Intensive Care Unit at The Ohio State University Wexner Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Neonatal Intensive Care Unit at OhioHealth Riverside Methodist Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital Neonatal Intensive Care Unit at OhioHealth Grant Medical Center
state: Ohio
Study officials:
affiliation: Nationwide Children's Hospital/The Ohio State University
name: Jonathan L Slaughter, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Nationwide Children's Hospital/The Ohio State University
name: Carl H Backes, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Benitz WE; Committee on Fetus and Newborn, American Academy of Pediatrics. Patent Ductus Arteriosus in Preterm Infants. Pediatrics. 2016 Jan;137(1). doi: 10.1542/peds.2015-3730. Epub 2015 Dec 15.
citation: Slaughter JL, Reagan PB, Newman TB, Klebanoff MA. Comparative Effectiveness of Nonsteroidal Anti-inflammatory Drug Treatment vs No Treatment for Patent Ductus Arteriosus in Preterm Infants. JAMA Pediatr. 2017 Mar 6;171(3):e164354. doi: 10.1001/jamapediatrics.2016.4354. Epub 2017 Mar 6.
citation: Pavlek LR, Slaughter JL, Berman DP, Backes CH. Catheter-based closure of the patent ductus arteriosus in lower weight infants. Semin Perinatol. 2018 Jun;42(4):262-268. doi: 10.1053/j.semperi.2018.05.009. Epub 2018 Jun 13.
citation: Runte KE, Flyer JN, Edwards EM, Soll RF, Horbar JD, Yeager SB. Variation of Patent Ductus Arteriosus Treatment in Very Low Birth Weight Infants. Pediatrics. 2021 Nov;148(5):e2021052874. doi: 10.1542/peds.2021-052874. Epub 2021 Oct 21.
citation: Slaughter JL, Cua CL, Notestine JL, Rivera BK, Marzec L, Hade EM, Maitre NL, Klebanoff MA, Ilgenfritz M, Le VT, Lewandowski DJ, Backes CH. Early prediction of spontaneous Patent Ductus Arteriosus (PDA) closure and PDA-associated outcomes: a prospective cohort investigation. BMC Pediatr. 2019 Sep 13;19(1):333. doi: 10.1186/s12887-019-1708-z.