Budesonide With Intratracheal Surfactants in Extremely Preterm Infants

Study Overview
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Brief Summary
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This is a phase I/II trial in preterm infants aimed at identifying the optimal dose of budesonide with bovine lipid extract surfactant as vehicle for intratracheal administration.

Detailed Description
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Premature infants of gestational age less than 29 weeks with respiratory distress syndrome and clinical indication for surfactant administration will be recruited for this Phase I/II open-label study. A total of 30 subjects will be recruited from 2 neonatal intensive care units: Children's Hospital-Health Sciences Centre (HSC), Winnipeg St. Boniface General Hospital, Winnipeg, MB 3 groups of 10 infants each will receive single dose of intratracheal budesonide (0.0625 mg/kg, 0.125 mg/kg, and 0.25 mg/kg) with BLES surfactant (5 ml/kg). PK/PD analysis will be done using clinical parameters, serum biomarkers, tracheal aspirate biomarkers and plasma budesonide levels obtained at fixed intervals. The duration of subject participation will involve 12-17 weeks for the clinical intervention, depending on gestational age at birth and discharge date. Participants will be followed until 40 weeks or discharge, whichever comes first.

Official Title
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Pharmacokinetics and Pharmacodynamics of Budesonide With Intratracheal Surfactant (BITS) Administration in Preterm Infants < 29 Weeks Gestational Age

Conditions
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Bronchopulmonary Dysplasia, Respiratory Distress Syndrome in Premature Infant

Intervention / Treatment
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* Drug: Budesonide in bovine lipid extract surfactant (BLES)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female infant born between 23 and 28+6 weeks of GA Infant diagnosed with RDS according to clinical protocol criteria Able to adhere to surfactant administration protocol The patient is born in the study centre. Subject's parent(s)/legal guardian(s) has provided signed and dated informed consent and authorization to use protected health information, as required by national and local regulations. In the investigator's opinion, the subject's parent(s)/legal guardian(s) understand(s) and can comply with protocol requirements, instructions, and protocol-stated restrictions, and is likely to complete the study as planned. Exclusion Criteria: Older than five days at inclusion. Presence of known clinically significant congenital heart disease or other major congenital malformation Subjects with clinically significant laboratory abnormalities which are deemed by the investigator to represent a safety risk to participation in this study. Other laboratory parameters outside the reference range for the subject's age may be included if the investigator considers the abnormalities unlikely to introduce additional risk factors and will not interfere with data interpretation.

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 5 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dosing Level 1<br>0.0625 mg/kg Budesonide in bovine lipid extract surfactant (BLES) | Drug: Budesonide in bovine lipid extract surfactant (BLES)<br>* Budesonide in bovine lipid extract surfactant<br>* Other names: BLES;|
| Experimental: Dosing Level 2<br>0.125 mg/kg Budesonide in bovine lipid extract surfactant (BLES) | Drug: Budesonide in bovine lipid extract surfactant (BLES)<br>* Budesonide in bovine lipid extract surfactant<br>* Other names: BLES;|
| Experimental: Dosing Level 3<br>0.25 mg/kg Budesonide in bovine lipid extract surfactant (BLES) | Drug: Budesonide in bovine lipid extract surfactant (BLES)<br>* Budesonide in bovine lipid extract surfactant<br>* Other names: BLES;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve from serial budesonide levels | Blood samples will be drawn from patients to determine the serum budesonide levels to determine the area under the curve | At 24 hour time point following dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bronchopulmonary Dysplasia free survival | NICHD criteria will be used to diagnose and grade the infants for presence of BPD. | at 36 weeks PMA or discharge, whichever comes first | 
| Neonatal Mortality | Survival of the infants | up to 40 weeks PMA or discharge, whichever comes first | 
| Concentration of Inflammatory Biomarkers in Tracheal Aspirates | Tracheal aspirates will be centrifuged to isolate a large aggregate surfactant fraction that will be assayed for both phospholipid (surfactant recovery) and total protein concentration. The supernatant fraction after surfactant isolation will be assayed for total protein, and selected cytokines (IL-1 β, IL-6, IL-8, IL-10, CCL2 and TNF-ɑ) | Baseline, 24 hours, 48 hours,1 week, 4 weeks and 36 weeks Gestational Age | 
| Concentration of Inflammatory Biomarkers in Serum | Cytokines IL-1 β, IL-6, IL-8, IL-10, CCL2 and TNF-ɑ will be analyzed in serum samples obtained from the infants following BITS administration using commercially available ELISA kits. | Baseline, 24 hours, 48 hours and 1 week. | 
| Duration of Hospital Stay |  | from day 0 (birth date) to 40 weeks | 
| VentilationStrategy | Duration and modality of ventilation used in the preterm infants | till 36 weeks PMA or discharge, whichever comes first | 
| Respiratory Severity Score | The product of Fraction of inspired oxygen and mean airway pressure will be used to estimate the respiratory severity score | at baseline and till 36 weeks PMA or discharge, whichever comes first | 
| Duration of Supplemental Oxygen |  | till 36 weeks PMA or discharge, whichever comes first | 
| Level of Supplemental Oxygen Administered | the concentration of supplemental oxygen given at discharge or 36 weeks PMA compared to baseline. | at baseline and at 36 week Post menstrual age or discharge, whichever comes first | 
| Presence of Respiratory Support | the presence or absence of any method of respiratory support at discharge or 36 weeks PMA compared to baseline. | at 36 week Post menstrual age or discharge, whichever comes first | 
| Percentage of Participants with Pulmonary Hemorrhage | Clinical signs of pallor, cyanosis, bradycardia, apnoea and blood gas changes. Radiographic evidences of patchy infiltrates to complete opacification of lung fields. | at baseline and 48 hours after budesonide with surfactant administration | 
| Percentage of Participants with Hypothalamic pituitary axis (HPA) suppression | Cortisol levels will be measured | at 0 and 24 hours after dosing | 
| Percentage of Participants with Pneumothorax on Chest X-ray | Identified in X-ray as hyperlucent shadow outside the lungs without pulmonary vascular markings, with or without mediastinal shift | at baseline and 48 hours after budesonide with surfactant administration | 
| Percentage of Participants with Spontaneous Intestinal Perforation (SIP) on abdominal X-ray | Abdominal X-ray showing presence of free air. Presence or absence of SIP will be compared across the 3 dosing groups and within the dosing groups. | at baseline and 48 hours after budesonide with surfactant administration | 
| Percentage of Participants with Intra-ventricular Hemorrhage | presence or absence of will be compared across the 3 dosing groups and within the dosing groups. | at baseline and 48 hours after budesonide with surfactant administration | 
| Percentage of Participants with Sepsis | As per the third international consensus definitions for sepsis and septic shock (Sepsis-3) | at baseline and till 36 weeks PMA or discharge, whichever comes first | 
| Percentage of Participants with Necrotising Enterocolitis (NEC) | presence or absence of NEC will be compared across the 3 dosing groups and within the dosing groups. | 48 hours after budesonide with surfactant administration | 
| Percentage of Participants with Severe Retinopathy at Prematurity | retinopathy of ≥grade III will be recorded | baseline and 48 hours after budesonide with surfactant administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Surfactant, Budesonide, Steroid, Intratracheal, Preterm, Bronchopulmonary Dysplasia, Respiratory Distress Syndrome, Bovine Lipid Extract Surfactant