Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus

Phase 2CompletedNCT01958320

University of California, San Francisco202 enrolled

Overview

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".

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

202

Conditions

Patent Ductus Arteriosus

Interventions

pharmacologic treatment of the PDAOTHER

Following randomization, infants will be treated with medications used to produce PDA closure.

no pharmacologic treatment of the PDAOTHER

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).

NSAIDDRUG

Indomethacin, ibuprofen or acetaminophen will be used as standard of care treatment

Eligibility

Sex: ALLMin age: 5 DaysMax age: 14 Days

Medical Language ↔ Plain English

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. \- 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. \-

Locations (18)

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

Mednax Neonatology of San Jose/Pediatrix Medical Group

San Jose, California, United States

Kaiser Permanente Santa Clara

Santa Clara, 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

...and 8 more locations

Outcomes

Primary Outcomes

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)

Time frame: through hospital discharge (approximately 6 months unless death occurs first)

Secondary Outcomes

Duration of Gavage Feeding Assistance

duration of gavage feeding assistance

Time frame: up to 20 weeks of age

Incidence of Necrotizing Enterocolitis or Spontaneous Perforation

incidence of necrotizing enterocolitis or spontaneous perforation

Time frame: through hospital discharge (approximately 6 months unless death occurs first)

the Average Daily Weight Gain

the average daily weight gain

Time frame: up to 20 weeks of age

Incidence of Bronchopulmonary Dysplasia or Death

incidence of bronchopulmonary dysplasia or death

Time frame: determined between 36-37 weeks corrected age

Incidence of Death

incidence of death

Time frame: 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.

Time frame: 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).

Time frame: 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

Time frame: through hospital discharge (approximately 6 months unless death occurs first)