Project Details

E.W. "Al" Thrasher

Status: Funded - Closed

Steroids and Surfactant in Extremely Low Gestational Age Infants (SASSIE), Pilot Dose Escalation Trial

Cynthia McEvoy, MD

Summary

BACKGROUND: Extremely low gestational age newborns (ELGANS) are at high risk for bronchopulmonary dysplasia (BPD), a chronic lung disease that is associated with death or continuing pulmonary disease, including asthma, as well as neurodevelopmental disability; currently there no highly effect preventative treatments. Pilot studies in which lungs of infants with respiratory distress syndrome were treated with budesonide, a synthetic glucocorticoid

with strong anti-inflammatory action, suspended in surfactant found reduced BPD without apparent adverse effects. GAP: Information is needed to determine the optimal dose and frequency of treatment with budesonide administered in surfactant for both benefit and safety before performing a large clinical study among critically ill infants.

HYPOTHESIS: We hypothesized that an appropriate dose of budesonide delivered directly to the lung in surfactant will be effective and safe in decreasing the short term clinical respiratory needs and the inflammatory response that contributes to BPD in ventilated preterm infants. METHODS: We treated 8 infants at each of the following 3 dosing levels of budesonide in surfactant, starting with the lowest dose, then evaluating benefit and safety parameters before treating the next group of infants (total of 32 infants). ELGANS who required intubation and mechanical ventilation between 3 and 10 days after birth were enrolled; clinical data, safety data, lung fluid, and blood samples were collected to measure drug efficacy. Case matched infants from the TOLSURF (Trial of Late Surfactant) for the prevention of BPD served as the reference group.

RESULTS: Only 25 of 272 (9%) ELGAN screened were enrolled at the 3 dosing levels over 12 months. 1 infants was withdrawn by parents. There was one clinical responder as per predefined clinical criteria at the lowest dosing level of budesonide (0.025 mg/kg of budesonide given in surfactant), and no clinical responders at dosing level 2 (0.05 mg/kg) or dosing level 3 (0.10 mg/kg). All 21 surviving infants required respiratory support at 28d. 17% survived without BPD at 36 weeks and 29% at 40 weeks. None of the 4 deaths or serious AEs were judged to be treatment related. Blood levels of budesonide peaked at ≤ 15 min, with a mean value of 23 ng/ml for the 0.1 mg/kg budesonide dose, and decreased with a t½ of ~3 h for all doses. Budesonide levels for doses of 0.025 and 0.05 mg/kg were both approximately half of those for the highest dose. The blood levels of budesonide with 0.1 mg/kg dosing was similar to that previously reported by Yeh et al. (Pediatrics, 2008; Am J Resp Crit Care Med, 2016) for infants receiving 0.25 mg/kg budesonide. Metabolomic studies identified a number of categories of metabolites with significant changes in response to budesonide.

IMPACT: Clinical and laboratory results from this dose escalation study will be important considerations when designing dosing regimes used in future trials of budesonide given in surfactant to extremely low gestational age newborns.

Keywords:

Bronchopulmonary Displasia, Human, Neonatal, Pharmacokinetics, Respiratory

Publications:

Development and validation of an assay for quantifying budesonide in dried blood spots collected from extremely low gestational age neonates