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Budesonide With Intratracheal Surfactants in Extremely Preterm Infants (BITS)

Primary Purpose

Bronchopulmonary Dysplasia, Respiratory Distress Syndrome in Premature Infant

Status

Unknown status

Phase

Phase 1

Locations

Canada

Study Type

Interventional

Intervention

Budesonide in bovine lipid extract surfactant (BLES)

About this trial

This is an interventional prevention trial for Bronchopulmonary Dysplasia focused on measuring Surfactant, Budesonide, Steroid, Intratracheal, Preterm, Bronchopulmonary Dysplasia, Respiratory Distress Syndrome, Bovine Lipid Extract Surfactant

Eligibility Criteria

1 Hour - 5 Days (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Children's Hospital-Health Science Centre
St. Boniface General Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Dosing Level 1

Dosing Level 2

Dosing Level 3

Arm Description

0.0625 mg/kg Budesonide in bovine lipid extract surfactant (BLES)

0.125 mg/kg Budesonide in bovine lipid extract surfactant (BLES)

0.25 mg/kg Budesonide in bovine lipid extract surfactant (BLES)

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Bronchopulmonary Dysplasia free survival

NICHD criteria will be used to diagnose and grade the infants for presence of BPD.

Neonatal Mortality

Survival of the infants

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)

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.

Duration of Hospital Stay

VentilationStrategy

Duration and modality of ventilation used in the preterm infants

Respiratory Severity Score

The product of Fraction of inspired oxygen and mean airway pressure will be used to estimate the respiratory severity score

Duration of Supplemental Oxygen

Level of Supplemental Oxygen Administered

the concentration of supplemental oxygen given at discharge or 36 weeks PMA compared to baseline.

Presence of Respiratory Support

the presence or absence of any method of respiratory support at discharge or 36 weeks PMA compared to baseline.

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.

Percentage of Participants with Hypothalamic pituitary axis (HPA) suppression

Cortisol levels will be measured

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

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.

Percentage of Participants with Intra-ventricular Hemorrhage

presence or absence of will be compared across the 3 dosing groups and within the dosing groups.

Percentage of Participants with Sepsis

As per the third international consensus definitions for sepsis and septic shock (Sepsis-3)

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.

Percentage of Participants with Severe Retinopathy at Prematurity

retinopathy of ≥grade III will be recorded

Full Information

NCT ID

NCT04019106

First Posted

August 15, 2018

Last Updated

July 16, 2019

Sponsor

University of Manitoba

Collaborators

Health Sciences Centre, Winnipeg, Manitoba, St. Boniface Hospital, Manitoba Institute of Child Health, University of Utah, Winnipeg Rh Institute Foundation Inc., BLES Biochemicals Inc.

1. Study Identification

Unique Protocol Identification Number

NCT04019106

Brief Title

Budesonide With Intratracheal Surfactants in Extremely Preterm Infants

Acronym

BITS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Unknown status

Study Start Date

October 15, 2019 (Anticipated)

Primary Completion Date

October 15, 2020 (Anticipated)

Study Completion Date

January 15, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Manitoba

Collaborators

Health Sciences Centre, Winnipeg, Manitoba, St. Boniface Hospital, Manitoba Institute of Child Health, University of Utah, Winnipeg Rh Institute Foundation Inc., BLES Biochemicals Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Bronchopulmonary Dysplasia, Respiratory Distress Syndrome in Premature Infant

Keywords

Surfactant, Budesonide, Steroid, Intratracheal, Preterm, Bronchopulmonary Dysplasia, Respiratory Distress Syndrome, Bovine Lipid Extract Surfactant

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Dosing Level 1

Arm Type

Experimental

Arm Description

0.0625 mg/kg Budesonide in bovine lipid extract surfactant (BLES)

Arm Title

Dosing Level 2

Arm Type

Experimental

Arm Description

0.125 mg/kg Budesonide in bovine lipid extract surfactant (BLES)

Arm Title

Dosing Level 3

Arm Type

Experimental

Arm Description

0.25 mg/kg Budesonide in bovine lipid extract surfactant (BLES)

Intervention Type

Drug

Intervention Name(s)

Budesonide in bovine lipid extract surfactant (BLES)

Other Intervention Name(s)

Pulmicort respule, BLES

Intervention Description

Budesonide in bovine lipid extract surfactant

Primary Outcome Measure Information:

Title

Area under the curve from serial budesonide levels

Description

Blood samples will be drawn from patients to determine the serum budesonide levels to determine the area under the curve

Time Frame

At 24 hour time point following dosing

Secondary Outcome Measure Information:

Title

Bronchopulmonary Dysplasia free survival

Description

NICHD criteria will be used to diagnose and grade the infants for presence of BPD.

Time Frame

at 36 weeks PMA or discharge, whichever comes first

Title

Neonatal Mortality

Description

Survival of the infants

Time Frame

up to 40 weeks PMA or discharge, whichever comes first

Title

Concentration of Inflammatory Biomarkers in Tracheal Aspirates

Description

Time Frame

Baseline, 24 hours, 48 hours,1 week, 4 weeks and 36 weeks Gestational Age

Title

Concentration of Inflammatory Biomarkers in Serum

Description

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.

Time Frame

Baseline, 24 hours, 48 hours and 1 week.

Title

Duration of Hospital Stay

Time Frame

from day 0 (birth date) to 40 weeks

Title

VentilationStrategy

Description

Duration and modality of ventilation used in the preterm infants

Time Frame

till 36 weeks PMA or discharge, whichever comes first

Title

Respiratory Severity Score

Description

The product of Fraction of inspired oxygen and mean airway pressure will be used to estimate the respiratory severity score

Time Frame

at baseline and till 36 weeks PMA or discharge, whichever comes first

Title

Duration of Supplemental Oxygen

Time Frame

till 36 weeks PMA or discharge, whichever comes first

Title

Level of Supplemental Oxygen Administered

Description

the concentration of supplemental oxygen given at discharge or 36 weeks PMA compared to baseline.

Time Frame

at baseline and at 36 week Post menstrual age or discharge, whichever comes first

Title

Presence of Respiratory Support

Description

the presence or absence of any method of respiratory support at discharge or 36 weeks PMA compared to baseline.

Time Frame

at 36 week Post menstrual age or discharge, whichever comes first

Title

Percentage of Participants with Pulmonary Hemorrhage

Description

Clinical signs of pallor, cyanosis, bradycardia, apnoea and blood gas changes. Radiographic evidences of patchy infiltrates to complete opacification of lung fields.

Time Frame

at baseline and 48 hours after budesonide with surfactant administration

Title

Percentage of Participants with Hypothalamic pituitary axis (HPA) suppression

Description

Cortisol levels will be measured

Time Frame

at 0 and 24 hours after dosing

Title

Percentage of Participants with Pneumothorax on Chest X-ray

Description

Identified in X-ray as hyperlucent shadow outside the lungs without pulmonary vascular markings, with or without mediastinal shift

Time Frame

at baseline and 48 hours after budesonide with surfactant administration

Title

Percentage of Participants with Spontaneous Intestinal Perforation (SIP) on abdominal X-ray

Description

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.

Time Frame

at baseline and 48 hours after budesonide with surfactant administration

Title

Percentage of Participants with Intra-ventricular Hemorrhage

Description

presence or absence of will be compared across the 3 dosing groups and within the dosing groups.

Time Frame

at baseline and 48 hours after budesonide with surfactant administration

Title

Percentage of Participants with Sepsis

Description

As per the third international consensus definitions for sepsis and septic shock (Sepsis-3)

Time Frame

at baseline and till 36 weeks PMA or discharge, whichever comes first

Title

Percentage of Participants with Necrotising Enterocolitis (NEC)

Description

presence or absence of NEC will be compared across the 3 dosing groups and within the dosing groups.

Time Frame

48 hours after budesonide with surfactant administration

Title

Percentage of Participants with Severe Retinopathy at Prematurity

Description

retinopathy of ≥grade III will be recorded

Time Frame

baseline and 48 hours after budesonide with surfactant administration

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Hour

Maximum Age & Unit of Time

5 Days

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Geert W 't Jong, MD, Ph.D

Phone

(204)789-3206

gtjong@chrim.ca

First Name & Middle Initial & Last Name or Official Title & Degree

Abin Chandrakumar, Pharm.D, M.Sc.

Phone

(204)594-5359

achandrakumar@chrim.ca

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Geert W 't Jong, MD, Ph.D

Organizational Affiliation

Children's Hospital Research Institute of Manitoba

Official's Role

Principal Investigator

Facility Information:

Facility Name

Children's Hospital-Health Science Centre

City

Winnipeg

State/Province

Manitoba

ZIP/Postal Code

R3E 3P4

Country

Canada

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Geert 't Jong, MD, PhD

Phone

2047893206

gtjong@chrim.ca

First Name & Middle Initial & Last Name & Degree

Abin Chandrakumar, PharmD, MSc

Phone

2045945359

achandrakumar@chrim.ca

First Name & Middle Initial & Last Name & Degree

Mary Seshia, MB,BCh,FRCP

Facility Name

St. Boniface General Hospital

City

Winnipeg

State/Province

Manitoba

ZIP/Postal Code

R3E 3P4

Country

Canada

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ruben Alvaro, MD, FAAP

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Budesonide With Intratracheal Surfactants in Extremely Preterm Infants

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