Intratracheal Budesonide With Surfactant to Prevent Bronchopulmmonary Dysplasia.

Study Overview
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Brief Summary
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This study is designed to determine whether intratracheal administration of budesonide combined with surfactant, as compared to surfactant alone, will modify ecographic (lung ultrasound score) and biological markers (IL-6 concentration in respiratory secretions) at 7 days of life in preterm infants ≤32 weeks of gestational age (GA).

Detailed Description
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Bronchopulmonary dysplasia (BPD) is one of the main morbidities associated with extreme prematurity and, despite the improvement of respiratory care in the latest years, overall incidence is not decreasing. Etiology of BPD is multifactorial and local inflammation plays an important role in it, therfore, local anti-inflammatory drugs could be effective in preventing BPD. Recent randomised trials have shown a lower incidence of BPD/death with the use of a combination of budesonide with surfactat compared to surfactant alone, and further clinical trials are currently ongoing. This is a controlled phase IV, randomised, unicenter clinical trial designed to evaluate the effect of intratracheal administration of budesonide combined with surfactant, as compared to surfactant alone, in BPD in preterm infants ≤32 weeks of GA. Investigators will compare ecographic and biological markers, as well as respiratory outcomes.

Official Title
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Efficacy and Safety of the Intratracheal Administration of Budesonide With Porcine Pulmonary Surfactant in Very Preterm Infants to Prevent Bronchopulmonary Dysplasia: Randomized Clinical Trial (BuS Trial)

Conditions
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Bronchopulmonary Dysplasia, Respiratory Distress Syndrome in Premature Infant, Prematurity

Intervention / Treatment
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* Drug: Poractant Alfa Intratracheal Suspension [Curosurf]
* Drug: Budesonide 0.5 MG/ML


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants born equal or earlier than 32 weeks of gestational age admitted in the Neonatal Intensive Care Unit. Parental consent signed. Less than or equal to 48 hours postnatal age. Exclusion Criteria: Infants with known major congenital anomalies (eg. congenital upper airwayobstruction, congenital lung anomaly, severe pulmonary hypoplasia, hydrops,neuromuscular diseases, chromosomopaties) Infants with poor prognosis and risk of imminent death Infants who have received the first dose of surfactant before of the enrolment to the study.

Ages Eligible for Study
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Maximum Age: 48 Hours

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomised trial. Infants who fit criteria for surfactante administration will be randomly assigned into 2 groups: Standard treatment group receiving only intratracheal surfactant, and Interventional treatment group receiving intratracheal surfactant combined with budesoinde. It will be a third group of patients ≤32 weeks (Control group) who won´t fit criteria for surfactant administration.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard treatment group<br>Infants randomised to the standard treatment arm will receive intratracheal surfactant as per usual clinical indications of respiratory distress syndrome in these preterm infants. In that sense, and based in those clinical indications, we have developed a risk calculator for surfactant administration in preterm infants ≤32 weeks GA. We will use it to decide what patients will receive surfactant (calculator available on: https://1drv.ms/x/s!Arjkl83HIXSngP8TWh8O6oi6Ztdw3w?e=gNCMxP). | Drug: Poractant Alfa Intratracheal Suspension [Curosurf]<br>* Poractant alfa (Curosurf®): First dose of treatment: 200mg/Kg. Further doses (up to a total maximum of 3 within first 48 hours of life): 100mg/Kg.<br>* Other names: Curosurf®;|
| Experimental: Interventional treatment group<br>Infants randomised to the interventional treatment arm will receive intratracheal surfactant mixed with budesonide. Indication of surfactant, as equal as for the standard treatment arm, will be decided using the calculator. | Drug: Poractant Alfa Intratracheal Suspension [Curosurf]<br>* Poractant alfa (Curosurf®): First dose of treatment: 200mg/Kg. Further doses (up to a total maximum of 3 within first 48 hours of life): 100mg/Kg.<br>* Other names: Curosurf®;Drug: Budesonide 0.5 MG/ML<br>* Poractant alfa (Curosurf®) + Budesonide nebulizer solution (Budesonida Aldo-Unión 0.5mg/mL suspensión para inhalación por nebulizador®): First dose: 200mg/Kg of surfactant + 0.25mg/Kg of budesonide. Further doses (up to a total maximum of 3 within first 48 hours of life): 100mg/Kg of surfactant + 0.25mg/Kg of budesonide.<br>* Other names: Budesonida Aldo-Unión 0.5mg/mL suspensión para inhalación por nebulizador®;|
| No Intervention: Control group<br>Infants ≤32 weeks with no indications for surfactant administration. Their clinical management will be the usual in our neonatal unit. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung ultrasound score at 7 days of life. | LUS will be performed with the patients in supine position and slightly lying on the side of the taken view. Each lung will be divided in five areas through longitudinal orientation and images will be taken using the linear probe (VF 13-5MHz). | 7 days of life | 
| IL-6 concentration in respiratory secretions at 7 days of life. | Nasopharyngeal aspirate (NPA) will be collected by standard procedure. IL-6 concentration will be determined by Human IL-6 Quantikine ELISA (R&D Systems Inc., Minneapolis, MN, USA). | 7 days of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung ultrasound score at 28 days of life. | LUS will be performed with the patients in supine position and slightly lying on the side of the taken view. Each lung will be divided in five areas through longitudinal orientation and images will be taken using the linear probe (VF 13-5MHz). | 28 days of life | 
| IL-6 concentration in respiratory secretions at 28 days of life. | Nasopharyngeal aspirate (NPA) will be collected by standard procedure. IL-6 concentration will be determined by Human IL-6 Quantikine ELISA (R&D Systems Inc., Minneapolis, MN, USA). | 28 days of life | 
| Number of days of oxygen | Number of days on FiO2 >21% supplied by any respiratory support | 7 and 28 days of age, 36 weeks of post-menstrual age. | 
| Number of days of respiratory support | Number of days on each level of respiratory support: No respiratory support Nasal cannula at flow rates ≤ 2L/min Nasal cannula at flow rates > 2L/min CPAP/BIPAP Invasive mechanical ventilation | 7 and 28 days of age, 36 weeks of post-menstrual age. | 
| Mean airway pressure (MAP) | Maximum MAP mesured in cmH2O at 7 and 28 days of age, 36 weeks of postmenstrual age. | 7 and 28 days of age, 36 weeks of post-menstrual age. | 
| Incidence of bronchopulmonary dysplasia | BPD will be defined according to the 2001 workshop definition (Jobe AH, Bancalari E. Bronchopulmonary dysplasia. American Journal of Respiratory and Critical Care Medicine. American Lung Association; 2001; pp 1723-9). | 36 weeks of post-menstrual age. | 
| Respiratory status and neurodevelopment | Neurodevelopment will be assessed using Bayley-III test. | 24 months of age. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bronchopulmonary dysplasia, Respiratory Distress Syndrome in premature infant, Prematurity, Lung injury, Poractant alfa, Pulmonary surfactant, Budesonide, Anti-inflammatory agents, Glucocorticoids, Lung ultrasound, IL-6