Pharmacokinetics, safety and preliminary efficacy study of montelukast in critically ill infants with developing bronchopulmonary dysplasia (PRISM)

Bronchopulmonary dysplasia (BPD) is an inflammatory disease stemming from premature birth and iatrogenic lung injury. BPD is relatively common and frequently fatal; despite this, there are no FDA-approved therapies. Montelukast is increasingly used to treat developing BPD despite scant safety and efficacy data. Infants with developing BPD have high levels of inflammatory leukotrienes; montelukast blocks the cysteinyl leukotriene receptor. Montelukast shows promise due to results from several small BPD studies. For this <i>Pharmacokinetic and pharmacodynamic study of montelukast in infants with developing BPD (PRISM)</i> trial, we chose the smallest dose and shortest treatment duration that maintained a prospect for direct benefit. PRISM is a randomized, double-blind, placebo-controlled trial (5 sites, n = 28) of 0.75 mg/kg enteral montelukast dosed every 24 h for up to 7 days. Eligible infants (<28 weeks' gestation, birthweight <1000 g) require mechanical ventilation and supplemental oxygen (FiO2 ≥30%) at age 7 to 28 days of life. The primary outcome will be apparent clearance of montelukast from a population pharmacokinetic analysis; we will also estimate the apparent volume of distribution, half-life, and exposure metrics. Safety will be assessed by comparing all-cause and neuropsychiatric adverse events and laboratory evaluations between treatment and placebo groups. Comprehensive neurodevelopmental evaluations will occur periodically to 24 months of age. Preliminary efficacy will be measured by oxygen saturation index and time on respiratory supports. These data are intended to demonstrate a reassuring initial risk-benefit profile to justify a dose-escalating PRISM2 trial involving a larger cohort of infants with developing BPD.