Timing of PDA Closure and Respiratory Outcome in Premature Infants

The investigators propose the present study with the following aims:

• to determine whether early patent ductus arteriosus (PDA) treatment with ibuprofen treatment at the onset of clinical symptoms is superior to late ibuprofen treatment only when symptoms of a hemodynamically significant PDA are present in the evolution of bronchopulmonary dysplasia (BPD) defined as duration of supplemental oxygen exposure during the first 28 days
• to determine whether early PDA treatment with ibuprofen will be superior to late treatment with ibuprofen in efficacy of PDA closure, need for rescue therapy, need for PDA ligation and incidence of major complications of prematurity.

Hypothesis: Early pharmacologic closure of PDA with ibuprofen will improve respiratory course and reduce BPD as reflected by a reduction in duration of supplemental oxygen during the first 28 days of age vs. late pharmacologic treatment with ibuprofen.

Outcome variables: The primary outcome of this study is the number of days spent on supplemental oxygen by each infant during the first 28 days.

Other outcomes to be determined between groups include:

• Mortality
• Other respiratory variables: total days on supplemental oxygen, days on mechanical ventilation, oxygen dependence at 36 weeks post menstrual age, age at final extubation.
• Other respiratory complications: pneumothorax, pulmonary interstitial emphysema, need for high frequency ventilation, pulmonary hypertension
• Efficacy of PDA closure: number of courses of medication required, need for ligation
• Other neonatal complications: intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intestinal perforation, sepsis, renal dysfunction (oliguria, elevated creatinine)
• Time to achieving full enteral feedings, time to regain birth weight, weight at discharge.
• Length of hospital stay

Study Overview

• Status: Terminated
• Conditions: Patent Ductus Arteriosus
• Intervention / Treatment: Drug: Early ibuprofen; Other: Late ibuprofen expectant group (placebo)

Detailed Description

Study terminated when intravenous (IV) ibuprofen withdrawn for both clinical and research use.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital/Holtz Children's Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Inborn patients at JHS hospitals (admitted to the NICU at JMH within the first 72 hrs of age
• BW 500-1250 grams
• 23-32 wks gestational age
• > 1d but < 14d of age.

Exclusion Criteria:

• Major congenital malformations
• Proven sepsis (positive blood culture)
• Contraindications to the use of Ibuprofen or Indomethacin
• Terminal condition, not expected to survive beyond 48 h
• Infants born excessively SGA(3 S.D. below the mean for GA)
• Infants with initial PDA presentation that is hemodynamically significant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: early ibuprofen; Drug: Early ibuprofen IBUPROFEN DOSING SCHEDULE: At the diagnosis of PDA, infants randomized to "early treatment" will receive blinded ibuprofen initial dose 10 mg/kg, then two doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Initial therapy will be blinded. This group will then be eligible to receive unblinded, open label ibuprofen for a hemodynamically significant PDA include: SIGNS OF PDA + Presence of significant pulmonary hemorrhage ALONE OR SIGNS OF PDA +: Pulmonary edema, plus a large heart on CXR + one of the following: Hypotension, Respiratory failure (not due to something other than PDA) defined as at least two of the following respirator settings: Need for supplemental O2 > 50%; need IMV >40; need for PIP > 20; or need for HFOV.	Drug: Early ibuprofen; IBUPROFEN SCHEDULE: initial dose 10 mg/kg, then 2 doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Initial therapy is blinded. At PDA diagnosis, infants randomized to "early treatment" receive blinded ibuprofen. Infants randomized to "late treatment" receive blinded placebo. Hemodynamically significant PDA criteria: SIGNS OF PDA + pulmonary hemorrhage OR SIGNS OF PDA +: Pulmonary edema, plus a large heart on CXR + one of the following: Hypotension, Respiratory failure (due to PDA) defined as at least two of the following: Need for supplemental O2 > 50%; need IMV >40; need for PIP > 20; or need for HFOV. Once hemodynamically significant PDA criteria met, if echo is positive, infants from both groups can receive open label ibuprofen.
Other: Late Ibuprofen expectant group (placebo); Late ibuprofen expectant group (placebo): Ibuprofen schedule: At PDA diagnosis, infants randomized to "late expectant group" will receive blinded placebo. If hemo-dynamically significant PDA develops, infants now receive open label ibuprofen, initial dose of 10 mg/kg, then 2 doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Signs of a hemodynamically significant PDA: Signs of PDA + pulmonary hemorrhage alone or Signs of PDA + Pulmonary edema, plus a large heart on CXR + one of the following: Hypotension, Respiratory failure (due to PDA) defined as at least two of the following respirator settings: Need for supplemental O2 > 50%; need IMV >40; need for PIP > 20; or need for HFOV. Infants who had received placebo will ibuprofen for the first time (thus, "late" ibuprofen or expectant).	Other: Late ibuprofen expectant group (placebo); Drug: Late ibuprofen expectant group (placebo): DOSING SCHEDULE: At PDA diagnosis infants randomized to "late ibuprofen expectant group" will receive blinded placebo. If hemodynamically significant PDA develops, infants now receive open label ibuprofen at an initial dose of 10 mg/kg, then two doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Signs of a hemodynamically significant PDA include: SIGNS OF PDA + pulmonary hemorrhage ALONE OR SIGNS OF PDA +: Pulmonary edema, plus a large heart on CXR + one of the following: Hypotension, Respiratory failure (due PDA) defined as at least 2 of the following settings: Need for supplemental O2 > 50%; need IMV >40; need for PIP > 20; or need for HFOV.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Days Spent on Supplemental Oxygen During the First 28 Days.	28 days of life

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Participants on Oxygen at 36 Weeks Postmenstrual Age	at 36 weeks postmenstrual age

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: H. Lundbeck A/S
• Investigators: Principal Investigator: Ilene RS Sosenko, MD, University of Miami

Publications and helpful links

General Publications

• Sosenko IR, Fajardo MF, Claure N, Bancalari E. Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial. J Pediatr. 2012 Jun;160(6):929-35.e1. doi: 10.1016/j.jpeds.2011.12.031. Epub 2012 Jan 28.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: December 4, 2008
• First Submitted That Met QC Criteria: December 4, 2008
• First Posted (Estimate): December 5, 2008

Study Record Updates

• Last Update Posted (Estimate): February 5, 2014
• Last Update Submitted That Met QC Criteria: January 3, 2014
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Patent ductus arteriosus; Respiratory outcome
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Ductus Arteriosus, Patent; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ibuprofen
• Other Study ID Numbers: 20070871