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

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

Detailed Description
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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.

Official Title
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Steroids and Surfactant in Extremely Low Gestation Age Infants Pilot Dose Escalation Trial

Conditions
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Bronchopulmonary Dysplasia (BPD)

Intervention / Treatment
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* Drug: Budesonide in Calfactant


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Days
Maximum Age: 14 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.025 mg/kg Budesonide<br>0.025 mg/kg Budesonide in Calfactant | Drug: Budesonide in Calfactant<br>* Budesonide in Calfactant<br>* Other names: infasurf;|
| Experimental: 0.050 mg/kg Budesonide<br>0.050 mg/kg Budesonide in Calfactant | Drug: Budesonide in Calfactant<br>* Budesonide in Calfactant<br>* Other names: infasurf;|
| Experimental: 0.10 mg/kg Budesonide<br>0.10 mg/kg Budesonide in Calfactant | Drug: Budesonide in Calfactant<br>* Budesonide in Calfactant<br>* Other names: infasurf;|
| Experimental: 0.15 mg/kg Budesonide<br>0.15 mg/kg Budesonide in Calfactant | Drug: Budesonide in Calfactant<br>* Budesonide in Calfactant<br>* Other names: infasurf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 28 days of life for each dosing group | 
| 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 | 28 days of life for each dosing group | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events/Subject Safety | 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. | Through 28 days of life | 
| Serial Budesonide Levels | 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. | At 15 minutes, 1 and 4 hours after first dose and prior to each additional dose | 
| Mean Airway Pressure and Oxygen Requirement at 28 Days of Age | 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. | 28 days of life for each dosing group | 
| Mean Airway Pressure and Oxygen Requirement Correlated to Budesonide levels | The individual patient's decrease in RSS will be correlated with their budesonide exposure measures by the area under the concentration time curve (AUC). | 28 days of life for each dosing group | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bronchopulmonary dysplasia, Pulmonary, Surfactant, Steroids, Extremely low gestational age