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出境医 / 临床实验 / Budesonide With Intratracheal Surfactants in Extremely Preterm Infants (BITS)

Budesonide With Intratracheal Surfactants in Extremely Preterm Infants (BITS)

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.

Condition or disease Intervention/treatment Phase
Bronchopulmonary Dysplasia Respiratory Distress Syndrome in Premature Infant Drug: Budesonide in bovine lipid extract surfactant (BLES) Phase 1 Phase 2

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 Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Pharmacokinetics and Pharmacodynamics of Budesonide With Intratracheal Surfactant (BITS) Administration in Preterm Infants < 29 Weeks Gestational Age
Estimated Study Start Date : October 15, 2019
Estimated Primary Completion Date : October 15, 2020
Estimated Study Completion Date : January 15, 2021
Arms and Interventions
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

Outcome Measures
Primary Outcome Measures :
  1. Area under the curve from serial budesonide levels [ Time Frame: At 24 hour time point following dosing ]
    Blood samples will be drawn from patients to determine the serum budesonide levels to determine the area under the curve


Secondary Outcome Measures :
  1. Bronchopulmonary Dysplasia free survival [ Time Frame: at 36 weeks PMA or discharge, whichever comes first ]
    NICHD criteria will be used to diagnose and grade the infants for presence of BPD.

  2. Neonatal Mortality [ Time Frame: up to 40 weeks PMA or discharge, whichever comes first ]
    Survival of the infants

  3. Concentration of Inflammatory Biomarkers in Tracheal Aspirates [ Time Frame: Baseline, 24 hours, 48 hours,1 week, 4 weeks and 36 weeks Gestational Age ]
    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)

  4. Concentration of Inflammatory Biomarkers in Serum [ Time Frame: Baseline, 24 hours, 48 hours and 1 week. ]
    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.

  5. Duration of Hospital Stay [ Time Frame: from day 0 (birth date) to 40 weeks ]
  6. VentilationStrategy [ Time Frame: till 36 weeks PMA or discharge, whichever comes first ]
    Duration and modality of ventilation used in the preterm infants

  7. Respiratory Severity Score [ Time Frame: at baseline and till 36 weeks PMA or discharge, whichever comes first ]
    The product of Fraction of inspired oxygen and mean airway pressure will be used to estimate the respiratory severity score

  8. Duration of Supplemental Oxygen [ Time Frame: till 36 weeks PMA or discharge, whichever comes first ]
  9. Level of Supplemental Oxygen Administered [ Time Frame: at baseline and at 36 week Post menstrual age or discharge, whichever comes first ]
    the concentration of supplemental oxygen given at discharge or 36 weeks PMA compared to baseline.

  10. Presence of Respiratory Support [ Time Frame: at 36 week Post menstrual age or discharge, whichever comes first ]
    the presence or absence of any method of respiratory support at discharge or 36 weeks PMA compared to baseline.

  11. Percentage of Participants with Pulmonary Hemorrhage [ Time Frame: at baseline and 48 hours after budesonide with surfactant administration ]
    Clinical signs of pallor, cyanosis, bradycardia, apnoea and blood gas changes. Radiographic evidences of patchy infiltrates to complete opacification of lung fields.

  12. Percentage of Participants with Hypothalamic pituitary axis (HPA) suppression [ Time Frame: at 0 and 24 hours after dosing ]
    Cortisol levels will be measured

  13. Percentage of Participants with Pneumothorax on Chest X-ray [ Time Frame: at baseline and 48 hours after budesonide with surfactant administration ]
    Identified in X-ray as hyperlucent shadow outside the lungs without pulmonary vascular markings, with or without mediastinal shift

  14. Percentage of Participants with Spontaneous Intestinal Perforation (SIP) on abdominal X-ray [ Time Frame: at baseline and 48 hours after budesonide with surfactant administration ]
    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.

  15. Percentage of Participants with Intra-ventricular Hemorrhage [ Time Frame: at baseline and 48 hours after budesonide with surfactant administration ]
    presence or absence of will be compared across the 3 dosing groups and within the dosing groups.

  16. Percentage of Participants with Sepsis [ Time Frame: at baseline and till 36 weeks PMA or discharge, whichever comes first ]
    As per the third international consensus definitions for sepsis and septic shock (Sepsis-3)

  17. Percentage of Participants with Necrotising Enterocolitis (NEC) [ Time Frame: 48 hours after budesonide with surfactant administration ]
    presence or absence of NEC will be compared across the 3 dosing groups and within the dosing groups.

  18. Percentage of Participants with Severe Retinopathy at Prematurity [ Time Frame: baseline and 48 hours after budesonide with surfactant administration ]
    retinopathy of ≥grade III will be recorded


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   up to 5 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Geert W 't Jong, MD, Ph.D (204)789-3206 gtjong@chrim.ca
Contact: Abin Chandrakumar, Pharm.D, M.Sc. (204)594-5359 achandrakumar@chrim.ca

Locations
Layout table for location information
Canada, Manitoba
Children's Hospital-Health Science Centre
Winnipeg, Manitoba, Canada, R3E 3P4
Contact: Geert 't Jong, MD, PhD    2047893206    gtjong@chrim.ca   
Contact: Abin Chandrakumar, PharmD, MSc    2045945359    achandrakumar@chrim.ca   
Sub-Investigator: Mary Seshia, MB,BCh,FRCP         
St. Boniface General Hospital
Winnipeg, Manitoba, Canada, R3E 3P4
Sub-Investigator: Ruben Alvaro, MD, FAAP         
Sponsors and Collaborators
University of Manitoba
Health Sciences Centre, Winnipeg, Manitoba
St. Boniface Hospital
Manitoba Institute of Child Health
University of Utah
Winnipeg Rh Institute Foundation Inc.
BLES Biochemicals Inc.
Investigators
Layout table for investigator information
Principal Investigator: Geert W 't Jong, MD, Ph.D Children's Hospital Research Institute of Manitoba
Tracking Information
First Submitted Date  ICMJE August 15, 2018
First Posted Date  ICMJE July 15, 2019
Last Update Posted Date July 17, 2019
Estimated Study Start Date  ICMJE October 15, 2019
Estimated Primary Completion Date October 15, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2019)
Area under the curve from serial budesonide levels [ Time Frame: At 24 hour time point following dosing ]
Blood samples will be drawn from patients to determine the serum budesonide levels to determine the area under the curve
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 11, 2019)
  • Bronchopulmonary Dysplasia free survival [ Time Frame: at 36 weeks PMA or discharge, whichever comes first ]
    NICHD criteria will be used to diagnose and grade the infants for presence of BPD.
  • Neonatal Mortality [ Time Frame: up to 40 weeks PMA or discharge, whichever comes first ]
    Survival of the infants
  • Concentration of Inflammatory Biomarkers in Tracheal Aspirates [ Time Frame: Baseline, 24 hours, 48 hours,1 week, 4 weeks and 36 weeks Gestational Age ]
    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 [ Time Frame: Baseline, 24 hours, 48 hours and 1 week. ]
    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 [ Time Frame: from day 0 (birth date) to 40 weeks ]
  • VentilationStrategy [ Time Frame: till 36 weeks PMA or discharge, whichever comes first ]
    Duration and modality of ventilation used in the preterm infants
  • Respiratory Severity Score [ Time Frame: at baseline and till 36 weeks PMA or discharge, whichever comes first ]
    The product of Fraction of inspired oxygen and mean airway pressure will be used to estimate the respiratory severity score
  • Duration of Supplemental Oxygen [ Time Frame: till 36 weeks PMA or discharge, whichever comes first ]
  • Level of Supplemental Oxygen Administered [ Time Frame: at baseline and at 36 week Post menstrual age or discharge, whichever comes first ]
    the concentration of supplemental oxygen given at discharge or 36 weeks PMA compared to baseline.
  • Presence of Respiratory Support [ Time Frame: at 36 week Post menstrual age or discharge, whichever comes first ]
    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 [ Time Frame: at baseline and 48 hours after budesonide with surfactant administration ]
    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 [ Time Frame: at 0 and 24 hours after dosing ]
    Cortisol levels will be measured
  • Percentage of Participants with Pneumothorax on Chest X-ray [ Time Frame: at baseline and 48 hours after budesonide with surfactant administration ]
    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 [ Time Frame: at baseline and 48 hours after budesonide with surfactant administration ]
    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 [ Time Frame: at baseline and 48 hours after budesonide with surfactant administration ]
    presence or absence of will be compared across the 3 dosing groups and within the dosing groups.
  • Percentage of Participants with Sepsis [ Time Frame: at baseline and till 36 weeks PMA or discharge, whichever comes first ]
    As per the third international consensus definitions for sepsis and septic shock (Sepsis-3)
  • Percentage of Participants with Necrotising Enterocolitis (NEC) [ Time Frame: 48 hours after budesonide with surfactant administration ]
    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 [ Time Frame: baseline and 48 hours after budesonide with surfactant administration ]
    retinopathy of ≥grade III will be recorded
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Budesonide With Intratracheal Surfactants in Extremely Preterm Infants
Official Title  ICMJE Pharmacokinetics and Pharmacodynamics of Budesonide With Intratracheal Surfactant (BITS) Administration in Preterm Infants < 29 Weeks Gestational Age
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:

  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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Bronchopulmonary Dysplasia
  • Respiratory Distress Syndrome in Premature Infant
Intervention  ICMJE Drug: Budesonide in bovine lipid extract surfactant (BLES)
Budesonide in bovine lipid extract surfactant
Other Names:
  • Pulmicort respule
  • BLES
Study Arms  ICMJE
  • Experimental: Dosing Level 1
    0.0625 mg/kg Budesonide in bovine lipid extract surfactant (BLES)
    Intervention: Drug: Budesonide in bovine lipid extract surfactant (BLES)
  • Experimental: Dosing Level 2
    0.125 mg/kg Budesonide in bovine lipid extract surfactant (BLES)
    Intervention: Drug: Budesonide in bovine lipid extract surfactant (BLES)
  • Experimental: Dosing Level 3
    0.25 mg/kg Budesonide in bovine lipid extract surfactant (BLES)
    Intervention: Drug: Budesonide in bovine lipid extract surfactant (BLES)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: July 11, 2019)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 15, 2021
Estimated Primary Completion Date October 15, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 5 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04019106
Other Study ID Numbers  ICMJE BITS-03
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party University of Manitoba
Study Sponsor  ICMJE University of Manitoba
Collaborators  ICMJE
  • Health Sciences Centre, Winnipeg, Manitoba
  • St. Boniface Hospital
  • Manitoba Institute of Child Health
  • University of Utah
  • Winnipeg Rh Institute Foundation Inc.
  • BLES Biochemicals Inc.
Investigators  ICMJE
Principal Investigator: Geert W 't Jong, MD, Ph.D Children's Hospital Research Institute of Manitoba
PRS Account University of Manitoba
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP