Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

Phase 2

Completed

• Conditions: Patent Ductus Arteriosus; Necrotizing Enterocolitis; Surgery; Intestinal Perforation
• Interventions: Other: pharmacologic treatment of the PDA; Other: no pharmacologic treatment of the PDA; Drug: NSAID

• Registration Number: NCT01958320
• Lead Sponsor: University of California, San Francisco

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2013-10-04
• Study First Submitted QC: 2013-10-08
• Study First Posted: 2013-10-09
• Study Start: 2013-12
• Primary Completion: 2017-06
• Study Completion: 2017-06
• Results First Submitted: 2018-10-09
• Status Verified: 2018-11
• Results First Submitted QC: 2018-11-28
• Last Update Submitted: 2018-11-28
• Results First Posted: 2018-11-30
• Last Update Posted: 2018-11-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 202

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:

1. 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

2. 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

3. are receiving respiratory support consisting of either mechanical ventilation, nasal CPAP, SiPAP, or nasal cannula flow ≥2 L/min.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Early treatment	pharmacologic treatment of the PDA	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.
Early treatment	NSAID	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.
Conservative Treatment	no pharmacologic treatment of the PDA	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.
Conservative Treatment	NSAID	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.

Primary Outcome Measures

Name	Time	Method
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)	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)

Secondary Outcome Measures

Name	Time	Method
Incidence of Death	through hospital discharge (approximately 6 months unless death occurs first)	incidence of death
Incidence of Necrotizing Enterocolitis or Spontaneous Perforation	through hospital discharge (approximately 6 months unless death occurs first)	incidence of necrotizing enterocolitis or spontaneous perforation
Number of Infants Receiving ≥ 14 Days of Diuretic Treatment	through hospital discharge (approximately 6 months unless death occurs first)	number of infants receiving ≥ 14 days of diuretic treatment
Duration of Gavage Feeding Assistance	up to 20 weeks of age	duration of gavage feeding assistance
the Average Daily Weight Gain	up to 20 weeks of age	the average daily weight gain
the Incidence of Persistent Moderate-to-large PDA Shunt 10 Days After Enrollment	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.
the Incidence of Rescue Treatment Eligibility Criteria Met	through hospital discharge (approximately 6 months unless death occurs first)	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).
Incidence of Bronchopulmonary Dysplasia or Death	determined between 36-37 weeks corrected age	incidence of bronchopulmonary dysplasia or death

Trial Locations

Locations (18)

Columbia University; 🇺🇸 New York, New York, United States

University Hospital, Umea, Sweden; 🇸🇪 Umea, Sweden

Sisli Hamidiye Etfal Training and Research Hospital; 🇹🇷 Istanbul, Turkey

Mednax Neonatology of San Jose/Pediatrix Medical Group; 🇺🇸 San Jose, California, United States

Ankara University School of Medicine Children's Hospital; 🇹🇷 Ankara, Turkey

Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

Inonu University School of Medicine Turgut Ozal Medical Center; 🇹🇷 Malatya, Turkey

Kaiser Permanente Santa Clara; 🇺🇸 Santa Clara, California, United States

University of Glasgow, Royal Hospital for Sick Children; 🇬🇧 Glasgow, Scotland, United Kingdom

University of California San Diego; 🇺🇸 San Diego, California, United States

Sharp Mary Birch Hospital for Women and Newborns; 🇺🇸 San Diego, California, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States

South Miami Hospital; 🇺🇸 Miami, Florida, United States

University of Chicago Medicine; 🇺🇸 Chicago, Illinois, United States

Northshore University Health System; 🇺🇸 Evanston, Illinois, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Providence St Vincent Medical Center; 🇺🇸 Portland, Oregon, United States