Inhaled Budesonide for Non-ventilated Infants at High Risk of Bronchopulmonary Dysplasia: the i-BUD Pilot Study

Study Overview
=================
Brief Summary
-----------------
Bronchopulmonary dysplasia (BPD) is one of the most important morbidities of preterm infants with a high incidence and significant impact on resource utilization and long-term outcome. Systemic corticosteroids have been shown to be effective in the prevention of BPD through their potent anti-inflammatory effects but there are serious concerns on their potential detrimental effects on neurodevelopment of infants. In contrast, inhaled corticosteroids administered to ventilated infants are thought to be safer due to their topical effect but have not been shown to improve outcomes including BPD. To date, there have been few studies evaluating the effect of inhaled corticosteroids administered to non-ventilated infants for the prevention of BPD. Hence, we are conducting a double-blind randomized controlled pilot trial to examine the impact of inhaled budesonide on non-ventilated infants. The study objectives, in a cohort of very preterm infants with signs of early BPD are: 1) to evaluate the effect of aerosolized budesonide on 'days on supplemental oxygen', and 2) to gain an estimate of the impact on BPD and 3) to assess the safety of the intervention in a small cohort of preterm infants. This will be a single-center randomized double-blind controlled pilot trial. We will recruit a total of 50 infants born at less than 30 weeks gestation who are on continuous positive airway pressure (CPAP) with fraction of inspired oxygen ≥25% on day 14 of life or later. Inhaled budesonide 1mg (intervention group) or normal saline (placebo) will be administered three times a day until the infants do not need CPAP or supplemental oxygen or reach 36+0/7 weeks corrected gestational age. We will evaluate 'days on supplemental oxygen', BPD, re-intubation rates, days on mechanical ventilation and days on CPAP as well as adverse outcomes. The prevention of BPD would have a significant positive impact on patient quality of life and medical resource utilization and costs. The study hypothesis is that inhaled budesonide on non-ventilated infants with early signs of BPD will reduce the 'days on supplemental oxygen' indicating a positive effect for the prevention of BPD. The result of this pilot study might also justify and support to proceed to a large confirmatory study to evaluate an effect of the intervention on BPD, in which the estimate of the impact on BPD gained in this pilot trial may be used to calculate a sample size.

Official Title
-----------------
Evaluation of the Effectiveness of Inhaled Budesonide for Non-ventilated Infants at High Risk of Bronchopulmonary Dysplasia: the i-BUD Pilot Study

Conditions
-----------------
Bronchopulmonary Dysplasia

Intervention / Treatment
-----------------
* Drug: Inhaled budesonide
* Drug: Normal saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Spontaneous breathing preterm Infants on day 14 to day 42 of age Born at < 30 0/7 weeks gestational age Requiring FiO2 ≥ 25% on CPAP including biphasic CPAP or high flow nasal canula Exclusion Criteria: Presence of chromosomal defects or major congenital anomalies Presence of severe infections including sepsis, meningitis, pneumonia, systemic fungal infections History of administration of systemic corticosteroids for pulmonary problems, not including that for hypotension

Ages Eligible for Study
-----------------
Minimum Age: 14 Days
Maximum Age: 42 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled budesonide<br>Inhaled budesonide 1mg/dose (2ml) three tid | Drug: Inhaled budesonide<br>* Inhaled budesonide 1 mg tid until 36 weeks' corrected gestational age or fully weaned from supplemental oxygen and respiratory support (CPAP or high flow nasal canula)<br>* Other names: PULMICORT® NEBUAMP®;|
| Placebo Comparator: Normal saline<br>Normal saline inhalation 2ml tid | Drug: Normal saline<br>* 2 ml normal saline by inhalation<br>* Other names: Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total days on supplemental oxygen from birth to discharge |  | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bronchopulmonary dysplasia | Bronchopulmonary dysplasia is defined as supplemental oxygen use at 36+0/7 weeks corrected gestational age | At 36+0/7 weeks corrected gestational age | 
| Mortality (all causes) |  | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Death or bronchopulmonary dysplasia |  | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Days on supplement oxygen after the study enrollment |  | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Days on continuous positive airway pressure (CPAP) | Support with continuous positive airway pressure, including use of biphasic CPAP and high flow nasal canula (>= 1L/minutes). | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Days with significant apneas | Significant apneas with more than 12 episodes requiring stimulation or more than one episode requiring mask-bagging in a six hour period | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Culture proven sepsis |  | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Gastrointestinal bleeding |  | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Persistent hyperglycemia | blood glucose > 10mmol/L more than twice in one day | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Hypertension | blood pressure ≥ 95th percentile for infant's gestational and postnatal ages | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 
| Salivary cortisol level |  | 2 weeks after the study entry and at the first follow up visit at 6 week's corrected age | 
| Postnatal growth | Weight, Head Circumference and Length | at 36 weeks corrected gestational age and at first follow-up visit at 6 weeks' corrected age | 
| Patent ductus arteriosus | PDA diagnosed clinically or by echocardiography | Participants will be followed for the duration of hospital stay, an expected average of 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Budesonide, Inhalation, Premature infants