A Randomized, Double-Blind, Placebo-Controlled Trial on Intravenous Ibuprofen L-Lysine for the Early Closure of Nonsymptomatic Patent Ductus Arteriosus within 72 Hours of Birth in Extremely Low-Birth-Weight Infants

ABSTRACT

A multicenter, double-blind, randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of intravenous (IV) ibuprofen (L-lysine) for the early closure of nonsymptomatic patent ductus arteriosus (PDA) within 72 hours of birth in extremely low-birth-weight (ELBW) infants with evidence of ductal shunting by echocardiogram. Eleven sites enrolled 136 infants with nonsymptomatic early PDA (gestational age < 30 weeks; body weight 500 to 1000 g) to receive a 3-day course (10 mg/kg, 5 mg/kg, and 5 mg/kg) of IV ibuprofen (n = 68) or placebo (n = 68). Cardiac echocardiogram was performed on study days 1 and 14, and with rescue. Infants were followed to 36 weeks postconceptional age. Patient demographics, mean (standard deviation), were similar between ibuprofen and placebo: birth weight: 798.5 g (128.7) versus 797.3 g (132.8); gestational age: 26.1 weeks (1.3) versus 26.2 weeks (1.4); and age at first dose: 1.5 days (0.7). The intent-to-treat analysis of the primary endpoint, subjects rescued, died, or dropped through study day 14, was 21/68 (30.9%) with ibuprofen and 36/68 (52.9%) for placebo (p = 0.005). Death, intraventricular hemorrhage, necrotizing enterocolitis, daily fluid intake/output, liver function, bronchopulmonary dysplasia, and retinopathy of prematurity did not differ. A trend toward decreased periventricular leukomalacia by ibuprofen was noted. IV ibuprofen was effective and safe in the early closure of PDA in preterm neonates.

KEYWORDS

Ibuprofen - patent ductus arteriosus - premature newborn - cyclooxygenase inhibitors - randomized clinical trial

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APPENDIX 1

List of participating institutions and site investigators (The IV Ibuprofen Clinical Trials Group):

• University of Texas Southwestern Medical Center, Dallas, TX: Blaire Cox, M.D. (deceased), Charles Rosenfeld, M.D.

• Univ Hosp Antwerp, Belgium: Bart Van Overmeire, M.D., Ph.D., Pat Van Reempts, M.D., Ph.D.

• Sharp Mary Birch Hospital, University of California PPRU, San Diego, CA: Paul Wozniak, M.D.

• University of Miami, Jackson Memorial Hospital, Miami, FL: Ilene Sosenko, M.D.

• University of Alabama, Birmingham, AL: Waldemar Carlo, M.D., Robert Schelonka, M.D.

• Children's Hospital of Michigan, Wayne State University, Detroit, MI: Virginia Delaney-Black, M.D., Ron Thomas, Ph.D., J. Parker, G. Steinhilber

• Children's Hospital of New York City, New York, NY: Richard Polin, M.D.

• University of Utah Medical Center, Salt Lake City, UT: Robert Ward, M.D.

• Dornbecher Children's Hospital/OHSU, Portland, OR: Linda Wallen, M.D.

• New York Medical College Westchester Medical Center, Westchester, NY: Lance Parton, M.D.

• Winthrop University Hospital, Mineola, NY: Jonathan Davis, M.D., Linda Genen, M.D., Carolyn Levine, M.D., Donna Better, M.D., Carlos Montoya, M.D.

• Ross Abbott IV Ibuprofen Trial Team, Columbus, OH: Kevin Mahan, Ph.D., Alan Ryan, Ph.D., Robert Shalwitz, M.D., Gregory Gomez, Anand Seth, Ph.D., Geraldine Baggs, Ph.D., Jeffery Oliver, M.S., Susan Toth, M.P.H., Linna Liu, M.S., Sue Zhang, M.S., Nel VanLommel, Mark Poulson, Kelly Samaie, Veronica Knox, Mary Ann Cockram, Jerry Young, M.P.H., Charles Paule, M.S., Kristen Deluca, R.D., L.D., M.S., and Bobbie Swearengin, R.N.

• Data Safety Monitoring Committee: Ronald Clyman, M.D. (UCSF), Yvette Johnson, M.D., M.P.H. (Baylor) (Chair), Leonard Weissman, M.D. (Baylor); Stanley Lemeshow, Ph.D. (OSU)

The NICHD Pediatric Pharmacology Research Unit Network (NICHD PPRU), Children's Hospital of Michigan and Wayne State University, Detroit, MI, and the Intravenous Ibuprofen Clinical Trial Group.

0 Deceased.