Budesonide With Intratracheal Surfactants in Extremely Preterm Infants (BITS)

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

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.

Study Overview

• Status: Unknown
• Conditions: Bronchopulmonary Dysplasia; Respiratory Distress Syndrome in Premature Infant
• Intervention / Treatment: Drug: Budesonide in bovine lipid extract surfactant (BLES)

Detailed Description

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:

1. Children's Hospital-Health Sciences Centre (HSC), Winnipeg
2. 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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Geert W 't Jong, MD, Ph.D; Phone Number: (204)789-3206; Email: gtjong@chrim.ca
• Study Contact Backup: Name: Abin Chandrakumar, Pharm.D, M.Sc.; Phone Number: (204)594-5359; Email: achandrakumar@chrim.ca

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • Children's Hospital-Health Science Centre
      • Contact: Geert 't Jong, MD, PhD; Phone Number: 2047893206; Email: gtjong@chrim.ca
      • Contact: Abin Chandrakumar, PharmD, MSc; Phone Number: 2045945359; Email: achandrakumar@chrim.ca
      • Sub-Investigator: Mary Seshia, MB,BCh,FRCP
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • St. Boniface General Hospital
      • Sub-Investigator: Ruben Alvaro, MD, FAAP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 5 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female infant born between 23 and 28+6 weeks of GA
2. Infant diagnosed with RDS according to clinical protocol criteria
3. Able to adhere to surfactant administration protocol
4. The patient is born in the study centre.
5. 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.
6. 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:

1. Older than five days at inclusion.
2. Presence of known clinically significant congenital heart disease or other major congenital malformation
3. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dosing Level 1; 0.0625 mg/kg Budesonide in bovine lipid extract surfactant (BLES)	Drug: Budesonide in bovine lipid extract surfactant (BLES); Budesonide in bovine lipid extract surfactant; Other Names: Pulmicort respule; BLES
Experimental: Dosing Level 2; 0.125 mg/kg Budesonide in bovine lipid extract surfactant (BLES)	Drug: Budesonide in bovine lipid extract surfactant (BLES); Budesonide in bovine lipid extract surfactant; Other Names: Pulmicort respule; BLES
Experimental: Dosing Level 3; 0.25 mg/kg Budesonide in bovine lipid extract surfactant (BLES)	Drug: Budesonide in bovine lipid extract surfactant (BLES); Budesonide in bovine lipid extract surfactant; Other Names: Pulmicort respule; BLES

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Manitoba
• Collaborators: Health Sciences Centre, Winnipeg, Manitoba; University of Utah; St. Boniface Hospital; Manitoba Institute of Child Health; Winnipeg Rh Institute Foundation Inc.; BLES Biochemicals Inc.
• Investigators: Principal Investigator: Geert W 't Jong, MD, Ph.D, Children's Hospital Research Institute of Manitoba

Study record dates

Study Major Dates

• Study Start (Anticipated): October 15, 2019
• Primary Completion (Anticipated): October 15, 2020
• Study Completion (Anticipated): January 15, 2021

Study Registration Dates

• First Submitted: August 15, 2018
• First Submitted That Met QC Criteria: July 11, 2019
• First Posted (Actual): July 15, 2019

Study Record Updates

• Last Update Posted (Actual): July 17, 2019
• Last Update Submitted That Met QC Criteria: July 16, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Steroid; Surfactant; Preterm; Budesonide; Intratracheal; Bronchopulmonary Dysplasia; Respiratory Distress Syndrome; Bovine Lipid Extract Surfactant
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Budesonide; Pulmonary Surfactants
• Other Study ID Numbers: BITS-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No