Steroids and Surfactant in Extremely Low Gestation Age Infants Dose Escalation Trial (SASSIE)

Thrasher Research Fund, University of Florida, Florida Hospital for Children, University of California, San Francisco

This is a phase I/II open-label study to determine the lowest, safe, effective dose of budesonide given with calfactant as the vehicle.

This is a phase I/II open-label study to determine the lowest safe, effective dose of budesonide given with calfactant as the vehicle; the investigators will perform an unblinded dose escalation study. The investigators will administer four dosing levels of budesonide suspended in calfactant beginning with 0.025 mg/kg of budesonide administered to 8 extremely low gestational age newborns (ELGANs) who are intubated at 3-10 days of age. Daily doses (at the same dosage) will be administered to infants who remain intubated for a potential of 5 total doses in each patient. Subsequent groups of 8 infants each will receive 0.05 mg/kg, 0.10 mg/kg, and 0.15 mg/kg of budesonide in calfactant (up to 5 total doses in each patient). A total of up to 32 infants will be enrolled in the trial. The investigators will evaluate the clinical, laboratory and safety data from each group of treated infants to 28 days of age before moving to the next dosing level of budesonide.

The clinical and anti-inflammatory efficacy of escalating doses of budesonide suspended in calfactant and given into the lungs of ELGANs by monitoring respiratory severity score (RSS).

Dose escalation will be defined as effective at the dose level in which 5 of 8 infants achieve the following: Extubation within 72 hours of first dose or after < 3 doses-without re-intubation before 28 days of age RSS on nasal continuous positive airway pressure (NCPAP) < 1.5 or on nasal cannula Fi02 <25% at < 2L/min at 28 days of age, persisting for at least 72 hours. Cumulative supplemental oxygen < 4.2 from time of enrollment to 28 days of age 4 (see calculation below) No respiratory support at 28 days, including no supplemental oxygen by nasal cannula AND a > 50% suppression of the tracheal aspirate interleukin-8 (IL-8) or CCL2 (chemokine ligand 2) at 24-72 hours (or prior to extubation if occurs at <24 hours after dosing) after the initial dose in 5 of 8 of the infants (this may be a different combination of 5 patients than those who met the above criteria).

The clinical and anti-inflammatory efficacy of escalating doses of budesonide suspended in calfactant and given into the lungs of ELGANs by monitoring tracheal aspirate cytokine levels.

B. AND a > 50% suppression of the tracheal aspirate interleukin-8 or chemokine ligand 2 at 24-72 hours (or prior to extubation if occurs at <24 hours after dosing) after the initial dose in 5 of 8 of the infants

Safety assessments will include the subject's vital signs, clinical laboratory testing, morbidities associated with prematurity, morbidities associated with administration of budesonide in calfactant, and Adverse Events (AE)s. Clinical parameters/ AEs of interest are those potentially consistent with elevated glucocorticoid levels and will be specifically evaluated. A Data and Safety Monitoring Board (DSMB) will be established to review safety data. All of the data will be reviewed to monitor subject safety.

The research team will obtain dried blood spot samples at 15 minutes, and 1 and 4 hours after the first dose of budesonide in calfactant for budesonide levels. Trough concentrations (Cmin) will be drawn before potential subsequent daily doses.

Clinical respiratory status (RSS and oxygen requirement) around dosing and at 28 days of age will be compared between dosing groups and also compared to the matched historical control patients from the "Trial of Late Surfactant:(TOLSURF) study.

The individual patient's decrease in RSS will be correlated with their budesonide exposure measures by the area under the concentration time curve (AUC).

Inclusion Criteria: > 23 0/7 and < 27 6/7 weeks of gestational age based on center's best estimate of due date (using earliest obstetrical ultrasound, last menstrual period, examination, and other pertinent available information) Day of life 3-14 from the date and time of delivery, with the date of birth being DOL 0 Intubated and mechanically ventilated and do not anticipate extubation in next 24 hours Exclusion Criteria: Serious congenital malformations or chromosomal abnormality Likely to be extubated in next 24 hours Clinically unstable Infants who have received systemic steroids prior to dosing with study medication. Infants who have received Indocin, Ibuprofen, or acetaminophen ≤ 96 hours prior to enrollment window ending

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