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Early Prediction of Spontaneous Patent Ductus Arteriosus (PDA) Closure and PDA-Associated Outcomes

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ClinicalTrials.gov Identifier: NCT03782610
Recruitment Status : Recruiting
First Posted : December 20, 2018
Last Update Posted : May 24, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Ohio State University
OhioHealth
Mount Carmel Health System
Information provided by (Responsible Party):
Jonathan Slaughter, Nationwide Children's Hospital

Tracking Information
First Submitted Date December 17, 2018
First Posted Date December 20, 2018
Last Update Posted Date May 24, 2019
Actual Study Start Date April 1, 2019
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: December 18, 2018)
  • Patent ductus arteriosus (PDA) closure documented via echocardiogram by 36-weeks postmenstrual age (PMA) (binary) [ Time Frame: Outcome will be documented between <72-hour screening echo and 36-weeks PMA. ]
    Documented closure of PDA on echocardiogram. Echocardiograms to document the primary outcome will be conducted weekly for the first four postnatal weeks and every other week thereafter, between study entry and 36-weeks PMA until PDA-closure is documented
  • Mortality or supplemental oxygen or positive-pressure respiratory support at 36-weeks PMA (binary) [ Time Frame: Outcome will be documented between <72-hour screening echo and 36-weeks PMA ]
    Death occurring between study entry at <72-hours postnatal and 36-weeks PMA OR an oxygen or positive-pressure ventilation requirement at 36-weeks gestational age (=moderate bronchopulmonary dysplasia [BPD] or severe BPD)
  • Composite Bayley III Motor Score at 22-26 months corrected age (continuous) [ Time Frame: 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) ]
    Composite motor score at 22 to 26-months postnatal as measured by Bayley Scales of Infant and Toddler Development- 3rd Edition (Bayley III)
Original Primary Outcome Measures Same as current
Change History Complete list of historical versions of study NCT03782610 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures
 (submitted: December 18, 2018)
  • Mortality by 36-weeks PMA (binary) [ Time Frame: Death occuring between 72-hours postnatal and 36-weeks PMA ]
  • Bayley III Gross Motor Development Scaled Standard Score at 22-26 months corrected age (continuous) [ Time Frame: Recorded at 22-26 months corrected age ]
  • Bayley III Fine Motor Development Scaled Standard Score postnatal age at 22-26 months corrected age (continuous) [ Time Frame: Recorded at 22-26 months corrected age ]
  • Bayley III Cognitive Composite Score at 22-26 months corrected age (continuous) [ Time Frame: Recorded at 22-26 months corrected age ]
  • Bayley III Language Composite Score at 22-26 months corrected age (continuous) [ Time Frame: Recorded at 22-26 months corrected age ]
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 1, 2019)
  • Normal cardiac function at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    No functional abnormalities identified on the 36-week echocardiogram, as read by the study cardiologist
  • Quantitative myocardial deformation imaging (MDI) at 36-weeks PMA (continuous) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
  • Quantitative tissue Doppler imaging (TDI) at 36-weeks PMA (continuous) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
  • Pulmonary Hypertension at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    Pulmonary hypertension noted on the 36-week echocardiogram, as read by the study cardiologist
  • Normal left atrial size at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    No left atrial enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
  • Normal left ventricular size at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    No left ventricular enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
  • Normal right ventricular size at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    No right ventricular enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
  • Oxygen Dependency (Moderate BPD) (binary) [ Time Frame: Recorded at 36-weeks PMA ]
  • Positive-Pressure Dependency (Severe BPD) (binary) [ Time Frame: Recorded at 36-weeks PMA ]
  • Length at 36-weeks PMA [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    Length in centimeters
  • General Movements Assessment (GMA) at 36-weeks corrected age [ Time Frame: Recorded at 36-weeks PMA ]
    Prechtl's method for the qualitative assessment of general movements dysfunction
  • Time to enteral feed initiation [ Time Frame: 72 hours postnatal to 36-weeks PMA ]
  • Time to a full enteral feed diet [ Time Frame: 72 hours postnatal to 36-weeks PMA ]
    Infant is weaned from intravenous fluids to a full enteral feed diet (delivery of feeds may be via an enteric tube)
  • Oral feeding status (binary) [ Time Frame: Recorded at 36-weeks PMA ]
    Infant is taking all feeds by mouth (PO feeds) by 36-weeks PMA
  • Weight at 36-weeks PMA [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    Weight in grams
  • Occipitofrontal circumference (OFC) at 36-weeks PMA [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    OFC in centimeters
  • Body Mass Index (BMI) at 36-weeks PMA [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    BMI calculated by (BMI= weight in kg/length in meters squared)
  • Supplemental oxygen or positive-pressure respiratory support at 40-weeks PMA (binary) [ Time Frame: Recorded at 40-weeks PMA ]
  • Mortality by 22-26 months corrected age [ Time Frame: Death occuring between 72-hours postnatal and 22-26 months corrected age ]
  • Duration of ductal patency from 72-hours postnatal until 22 to 26-months corrected age follow-up [ Time Frame: 72 hours postnatal until 22-26 months follow-up visit ]
  • Supplemental oxygen support (binary) at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
  • Supplemental positive-pressure ventilation support (binary) at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
  • Weight at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
    Weight in kilograms
  • Length at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
    Length in centimeters
  • Body Mass Index (BMI) at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
    BMI calculated by (BMI= weight in kg/length in meters squared)
  • Feeding status via full oral feeding or gastric-tube (binary) at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
Original Other Pre-specified Outcome Measures
 (submitted: December 18, 2018)
  • Normal cardiac function at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    No functional abnormalities identified on the 36-week echocardiogram, as read by the study cardiologist
  • Quantitative myocardial deformation imaging (MDI) at 36-weeks PMA (continuous) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
  • Quantitative tissue Doppler imaging (TDI) at 36-weeks PMA (continuous) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
  • Pulmonary Hypertension at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    Pulmonary hypertension noted on the 36-week echocardiogram, as read by the study cardiologist
  • Normal left atrial size at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    No left atrial enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
  • Normal left ventricular size at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    No left ventricular enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
  • Normal right ventricular size at 36-weeks PMA (binary) [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    No right ventricular enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
  • Oxygen Dependency (Moderate BPD) (binary) [ Time Frame: Recorded at 36-weeks PMA ]
  • Positive-Pressure Dependency (Severe BPD) (binary) [ Time Frame: Recorded at 36-weeks PMA ]
  • Length at 36-weeks PMA [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    Length in centimeters
  • General Movements Assessment (GMA) at 36-weeks corrected age [ Time Frame: Recorded at 36-weeks PMA ]
    Prechtl's method for the qualitative assessment of general movements dysfunction
  • Time to enteral feed initiation [ Time Frame: 72 hours postnatal to 36-weeks PMA ]
  • Time to a full enteral feed diet [ Time Frame: 72 hours postnatal to 36-weeks PMA ]
    Infant is weaned from intravenous fluids to a full enteral feed diet (delivery of feeds may be via an enteric tube)
  • Oral feeding status (binary) [ Time Frame: Recorded at 36-weeks PMA ]
    Infant is taking all feeds by mouth (PO feeds) by 36-weeks PMA
  • Weight at 36-weeks PMA [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    Weight in grams
  • Occipitofrontal circumference (OFC) at 36-weeks PMA [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    OFC in centimeters
  • Body Mass Index (BMI) at 36-weeks PMA [ Time Frame: Recorded at 36-weeks PMA or discharge if prior to 36-weeks ]
    BMI calculated by (BMI= weight in kg/length in meters squared)
  • Mortality by 22-26 months corrected age [ Time Frame: Death occuring between 72-hours postnatal and 22-26 months corrected age ]
  • Duration of ductal patency from 72-hours postnatal until 22 to 26-months corrected age follow-up [ Time Frame: 72 hours postnatal until 22-26 months follow-up visit ]
  • Supplemental oxygen support (binary) at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
  • Supplemental positive-pressure ventilation support (binary) at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
  • Weight at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
    Weight in kilograms
  • Length at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
    Length in centimeters
  • Body Mass Index (BMI) at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
    BMI calculated by (BMI= weight in kg/length in meters squared)
  • Feeding status via full oral feeding or gastric-tube (binary) at 22-26 months corrected age [ Time Frame: Recorded at 22-26 months study follow-up visit ]
 
Descriptive Information
Brief Title 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
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.

Detailed Description Not Provided
Study Type Observational [Patient Registry]
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration 22 Months
Biospecimen Retention:   Samples Without DNA
Description:

Serum biomarkers: beta-natriuretic peptide (BNP); N-terminal pro-B-type natriuretic peptide (NTpBNP)

Urine biomarkers: neutrophil gelatinase-associated lipocalin (NGAL); heart-fatty acid-binding protein (H-FABP)

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.
Condition
  • Patent Ductus Arteriosus
  • Preterm Infant
  • Bronchopulmonary Dysplasia
  • Neurodevelopmental Abnormality
Intervention Not Provided
Study Groups/Cohorts
  • Primary Study Cohort
    450 Infants
  • Validation Cohort
    225 Infants. Will allow subsequent validation of models derived from the Primary Study Cohort.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: December 18, 2018)
675
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 2024
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
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)
Sex/Gender
Sexes Eligible for Study: All
Ages up to 72 Hours   (Child)
Accepts Healthy Volunteers No
Contacts
Contact: Jonathan L Slaughter, MD, MPH 1-614-355-6643 Jonathan.Slaughter@nationwidechildrens.org
Contact: Carl H Backes, MD 1-614-355-6729 Carl.Backes@nationwidechildrens.org
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03782610
Other Study ID Numbers 1800684
1R01HL145032 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Yes
Plan Description: We welcome the opportunity to share data from our investigation. All patient identifiers will be removed from the final dataset. Following the completion and publication of our investigation, we will make the data available to other users under a data sharing agreement. We will ask under the agreement that other users will commit to using the data only for research purposes, that they will not identify individual study subjects, that they will securely store the data electronically using password protection or encryption, that they will delete or destroy the data after the completion of their investigation, and that they will acknowledge the contribution of the funding agency (NIH NHLBI) and our investigative team in collecting the original data.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data will become available after the completion of our planned investigation and publication of the results. We anticipate the completion of the investigation and publication will occur by December 2025
Access Criteria: Email study co-PIs Jonathan Slaughter (Jonathan.Slaughter@nationwidechildrens.org) and Carl Backes (Carl.Backes@nationwidechildrens.org)
Responsible Party Jonathan Slaughter, Nationwide Children's Hospital
Study Sponsor Nationwide Children's Hospital
Collaborators
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Ohio State University
  • OhioHealth
  • Mount Carmel Health System
Investigators
Principal Investigator: Jonathan L Slaughter, MD, MPH Nationwide Children's Hospital/The Ohio State University
Principal Investigator: Carl H Backes, MD Nationwide Children's Hospital/The Ohio State University
PRS Account Nationwide Children's Hospital
Verification Date May 2019