Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

Study Overview
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Brief Summary
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The primary goal of the trial is to compare two different Patent Ductus Arteriosus (PDA) treatment approaches: 1) an early treatment approach or 2) a conservative approach. For the purposes of the study infants will be enrolled if they are delivered before 28 weeks gestation and have a moderate/large PDA present at 5-7 days after birth. The hypothesis is: treatment of a moderate size patent ductus arteriosus (PDA) will decrease the time needed for assisted respiratory support, diuretic therapy, and gavage feeding assistance, in addition to decreasing the incidence of ductus ligations or need for future outpatient cardiology follow-up appointments. The investigators hypothesize that one or more of these benefits will occur without an increase in the time taken to achieve full enteral feedings or in the incidence of necrotizing enterocolitis (NEC) or spontaneous intestinal perforations (SIP).The investigators will be comparing the effectiveness of early pharmacologic treatment with a control group of conservatively managed infants who will only receive treatment if they meet specific criteria for rescue treatment.

Detailed Description
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Prior studies showed that, if a moderate/large Patent Ductus Arteriosus (PDA) is still present at 5 days after birth (among infants delivered at 23 and 0/7 to 25 and 6/7 weeks gestation) or at 7 days after birth (among infants delivered at 26 and 0/7 to 27 and 6/7 weeks gestation), it will persist for at least another 4-12 weeks if it is left untreated.

Official Title
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Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus in Preterm infants-a Multicenter Trial

Conditions
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Patent Ductus Arteriosus, Surgery, Necrotizing Enterocolitis, Intestinal Perforation

Intervention / Treatment
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* Other: pharmacologic treatment of the PDA
* Other: no pharmacologic treatment of the PDA
* Drug: NSAID


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: This will be a prospective randomized, multi-center, controlled trial that will enroll infants delivered between 23 & 0/7 - 27 & 6/7 weeks gestation: infants must be between 5-14 days old (if delivered between 23 and 0/7 - 25 and 6/7 weeks) or 7-14 days old (if delivered between 26 & 0/7 - 27 & 6/7 weeks) and have a moderate size PDA (defined as a PDA on echocardiogram that has at least one of the following criteria: internal ductus diameter ≥1.5 mm/kg (or PDA:LPA ratio ≥0.5), ductus flow velocity ≤2.5 m/s or mean pressure gradient across the ductus <8 mm, LA/Ao ratio ≥1.5, left pulmonary artery diastolic (or mean) flow velocity >0.2 (or >0.42) m/sec, respectively, and/or reversed diastolic flow in the descending aorta)(13, 68, 69) and are receiving respiratory support consisting of either mechanical ventilation, nasal CPAP, SiPAP, or nasal cannula flow ≥2 L/min. - Exclusion Criteria: prior treatment with indomethacin, ibuprofen, or acetaminophen, contraindications for the use of indomethacin, ibuprofen, or acetaminophen (these include: hydrocortisone administration within 24 hrs, urine output < 1 ml/kg/h during the preceding 8 h, serum creatinine level >1.6 mg/dl, platelet count <50, 000/mm3, abnormal coagulation studies, or total bilirubin concentration (in mg/dL) > 8 x weight (in kg)), chromosomal anomalies, congenital or acquired gastrointestinal anomalies, prior episode of necrotizing enterocolitis or intestinal perforation. -

Ages Eligible for Study
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Minimum Age: 5 Days
Maximum Age: 14 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Early routine, mandated PDA treatment versus Conservative treatment only if Rescue criteria are met
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early treatment<br>Infants randomized to the early treatment group will receive pharmacologic treatment of the PDA to produce PDA closure. Within 24-36 hr following the last treatment dose an echocardiogram will be obtained to document the degree of ductus closure or patency. Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. | Other: pharmacologic treatment of the PDA<br>* Following randomization, infants will be treated with medications used to produce PDA closure.<br>Drug: NSAID<br>* Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment<br>|
| Active Comparator: Conservative Treatment<br>Infants randomized to the Conservative Treatment approach will receive no pharmacologic treatment of the PDA but will be followed to determine if they meet criteria for later PDA rescue treatment (Infants will be eligible for rescue treatment of their persistent PDA if they meet the rescue treatment criteria.) Echocardiograms will be obtained at 1) 10-14 days after study entry (if the PDA was open and of moderate size on the last echocardiogram), and 2) at the time of hospital discharge (if the PDA was open (any size) on the last echocardiogram). The echocardiogram obtained at discharge will be used to determine the need for outpatient follow-up. | Other: no pharmacologic treatment of the PDA<br>* Following randomization, infants will NOT be treated with medications used to produce PDA closure (unless they develop rescue criteria at a later point in time).<br>Drug: NSAID<br>* Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Infants Who Undergo in Hospital PDA Ligations or Who Have an Open Ductus at the Time of Discharge (That Need Future Outpatient Cardiology Follow-up Visits) | Number of infants who undergo in hospital PDA ligations or who have an open ductus at the time of discharge (that need future outpatient cardiology follow-up visits) | through hospital discharge (approximately 6 months unless death occurs first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Gavage Feeding Assistance | duration of gavage feeding assistance | up to 20 weeks of age | 
| Incidence of Necrotizing Enterocolitis or Spontaneous Perforation | incidence of necrotizing enterocolitis or spontaneous perforation | through hospital discharge (approximately 6 months unless death occurs first) | 
| the Average Daily Weight Gain | the average daily weight gain | up to 20 weeks of age | 
| Incidence of Bronchopulmonary Dysplasia or Death | incidence of bronchopulmonary dysplasia or death | determined between 36-37 weeks corrected age | 
| Incidence of Death | incidence of death | through hospital discharge (approximately 6 months unless death occurs first) | 
| the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment | the incidence of persistent moderate-to-large PDA shunt 10 days after enrollment The echocardiographic studies included two dimensional imaging, M-mode, color flow mapping and Doppler interrogation as previously described. A moderate-to-large PDA was defined by a ductus internal diameter ≥ 1.5mm (or PDA:left pulmonary artery diameter ratio ≥0.5) and one or more of the following echocardiographic criteria: a) left atrium-to-aortic root (LA/Ao) ratio ≥1.6, b) ductus flow velocity ≤2.5m/sec or mean pressure gradient across the ductus ≤8mm, c) left pulmonary artery diastolic flow velocity > 0.2 m/sec, and/or d) reversed diastolic flow in the descending aorta. Ductus that failed to meet these criteria were considered to be constricted (small or closed) and not eligible for enrollment or treatment. | 10 days after enrollment | 
| the Incidence of Rescue Treatment Eligibility Criteria Met | Infants were eligible for rescue PDA drug treatment if they met one or more of the following prespecified Rescue criteria: 1) Inotrope-dependent hypotension for at least 3 days. 2) Oliguria that persisted for at least 2 days with no obvious cause, other than the moderate PDA, to explain the condition. 3) Requirement for gavage feedings beyond 35 weeks corrected age due to increased work of breathing. 4) Respiratory support needed after the following postnatal ages that surpassed specific minimal ventilation and FiO2 requirements: >15 days (if still required intubation and FiO2 >0.30), >20 days (if still required intubation and FiO2 ≤0.30; or still required Nasal CPAP or Nasal ventilation and FiO2 >0.30), >30 days (if still required Nasal CPAP or Nasal ventilation and FiO2 0.25-0.30), and >45 days (if still required Nasal CPAP or Nasal ventilation and FiO2 <0.25). | through hospital discharge (approximately 6 months unless death occurs first) | 
| Number of Infants Receiving ≥ 14 Days of Diuretic Treatment | number of infants receiving ≥ 14 days of diuretic treatment | through hospital discharge (approximately 6 months unless death occurs first) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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spontaneous intestinal perforation, patent ductus arteriosus, patent ductus arteriosus ligation, necrotizing enterocolitis