Premature infants with bronchopulmonary dysplasia (BPD) often die and survivors have life-long morbidities. BPD is the most common morbidity of prematurity, and affects ~17,000 infants per year in the US. Because the consequences of BPD are catastrophic, neonatologists frequently use drugs, including diuretics, in an attempt to prevent BPD. Furosemide is a loop diuretic approved by the US Food and Drug Administration (FDA) for treatment of pulmonary edema in adults. In small trials in premature infants, furosemide improved short-term lung compliance reducing the need for exogenous oxygen and increased ventilator support, both implicated in the development of BPD. These findings suggest that furosemide may be an effective therapy to prevent BPD. We will perform a randomized, controlled, masked, tiered, safety, phase II trial of 4 weeks of furosemide in up to 120 premature infants at high risk for BPD at 25 clinical sites randomized 3:1 to 1 mg/kg furosemide every 24 hours intravenously: placebo. We will increase dose after a safety review of each 40 participants. The long-term goal is to advance public health by developing therapeutics to prevent BPD in premature infants. The short-term goals are to 1) Determine the safety of furosemide in premature infants at risk for BPD; 2) Determine the change in risk of BPD in premature infants exposed to furosemide; and 3) Determine the PK of furosemide in premature infants at risk for BPD. The proposal will be led by Dr. Laughon, a neonatologist with strong training in epidemiology and clinical pharmacology. Dr. Laughon has led multicenter clinical pharmacology trials in premature infants. The team assembled is uniquely qualified, and strengths include extensive clinical research experience; internationally recognized thought leadership in neonatal and pediatric cardiology quantitative methods; and a successful history of productive on time and on budget NIH projects. The research environment including the Translational and Clinical Sciences Institute at UNC and the DCRI at Duke provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals. At the conclusion of this proposal, the research team will submit these data to the FDA and provide critical safety, change in risk of BPD, and PK data for the pivotal phase III efficacy trial which, if successful, will provide evidence for the only therapeutic conducted under federal regulatory oversight to prevent BPD in premature infants.

Public Health Relevance

This proposal will determine the safety, change in risk of bronchopulmonary dysplasia, and pharmacokinetics of furosemide in premature infants. This information is critical for optimizing the dose of furosemide for phase III trials to prevent bronchopulmonary dysplasia in premature infants.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
5R01FD005101-03
Application #
9483207
Study Section
Special Emphasis Panel (ZFD1)
Project Start
2016-06-01
Project End
2020-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Jackson, W; Hornik, C P; Messina, J A et al. (2017) In-hospital outcomes of premature infants with severe bronchopulmonary dysplasia. J Perinatol 37:853-856