The Budesonide in Babies (BiB) Trial

Study Overview
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Brief Summary
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This is a Phase 3, randomized, masked, active-controlled, multicenter trial designed to determine whether early intratracheal administration of a combination of budesonide with surfactant, as compared to surfactant alone, will reduce the incidence of physiologic bronchopulmonary dysplasia (BPD) or death by 36 weeks' post-menstrual age in extremely preterm infants.

Detailed Description
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From a study of 9575 extremely preterm (22-28 weeks gestational age and 401-1500g birth weight) infants born between 2003 and 2007 and enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), it is anticipated that 93% of extremely preterm infants will develop respiratory distress syndrome, 68% will develop bronchopulmonary dysplasia (BPD), 16% will develop severe intraventricular hemorrhage, and 36% will develop late-onset sepsis (PMID: 20732945). Furthermore, in 2014 20% of the infants enrolled in the NRN Generic Database (GDB) died (8% by less than 12 hours, 12% between 12 hours and 120 days, and 1% after 120 days) and 47% of infants who survived to 36 weeks' post-menstrual age (PMA) developed physiologic BPD (NRN GDB data). BPD is therefore one of the most common morbidities in extremely preterm infants. Death is a competing outcome for BPD, as infants who die before ascertainment of BPD at 36 weeks' PMA cannot be diagnosed with BPD even though they may have been at the highest risk. As children get older, BPD has been shown to be associated with worse cognitive outcomes in school age and with abnormal pulmonary function in adolescence and adulthood (PMID: 14595077; 15499947; 2247118). Recent randomized trials have indicated a lower incidence of BPD/death with the use of a combination of budesonide with surfactant (budesonide + surfactant) compared to surfactant alone when administered soon after birth. Therefore, after obtaining informed consent and confirming eligibility for the trial, infants are randomized in a 1:1 allocation ratio to either the budesonide + surfactant arm or the surfactant alone arm within 48 hours of birth.

Official Title
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Randomized Controlled Trial of Budesonide + Surfactant Versus Surfactant Alone in Extremely Preterm Infants (The Budesonide in Babies (BiB) Trial)

Conditions
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Bronchopulmonary Dysplasia (BPD), Neonatal, Respiratory Distress Syndrome, Prematurity; Extreme

Intervention / Treatment
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* Drug: budesonide (Pulmicort nebulizing suspension).
* Drug: surfactant (poractant alfa;Curosurf)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liveborn infants 22 0/7 - 28 6/7 weeks gestation or 401 - 1000 grams (inclusive) birth weight Clinical decision to give surfactant Less than or equal to 48 hours postnatal age Exclusion Criteria: Terminal illness (heart rate < 100 beats per minute, unresponsiveness to resuscitation) or unlikely to survive as judged by the clinician Decision to redirect or limit support Use of surfactant before enrollment (first dose of surfactant must be study drug) Infant received systemic steroids prior to enrollment Use of indomethacin, either received by the mother within 24 hours prior to delivery,received by the infant prior to enrollment, or intent to administer to the infant for IVH prophylaxis or PDA management from enrollment up to 7 days of final dose of study drug Serious chromosomal abnormalities or major malformations Known congenital infections including, but not limited to, confirmed sepsis, congenital CMV, etc. Infants with a permanent neuromuscular condition that affects respiration Enrollment in a conflicting clinical trial

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: budesonide with surfactant<br>Infants randomized to the intervention arm receive a dose of surfactant (poractant alfa; Curosurf) mixed with budesonide (Pulmicort nebulizing suspension) within 50 hours of birth and administered via endotracheal tube. | Drug: budesonide (Pulmicort nebulizing suspension).<br>* The first dose of budesonide is 0.25 mg/kg in a volume of 1 ml/kg, for a total volume of 2.5 ml/kg of Curosurf + 1 ml/kg of budesonide. If the infant is to receive a second dose of study drug within 50 hours of birth, the dosage of Curosurf is 1.25 ml/kg for the second dose and 1 ml/kg of budesonide.<br>* Other names: Pulmicort nebulizing suspension.;|
| Active Comparator: surfactant alone<br>Infants randomized to the active control arm receive a dose of surfactant (poractant alfa; Curosurf). | Drug: surfactant (poractant alfa;Curosurf)<br>* The first dose of surfactant (poractant alfa; Curosurf) is 2.5 ml/kg. If the infant is to receive a second dose of study drug within 50 hours of birth, the dosage of Curosurf is 1.25 ml/kg for the second dose.<br>* Other names: poractant alfa;Curosurf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Physiologic BPD or death | Physiologic BPD or death by 36 weeks' PMA. Physiologic BPD is determined using existing NRN GDB criteria at 36 weeks' PMA. | Randomization to 36 weeks' post-menstrual age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Death by 36 weeks' post-menstrual age | Death by 36 weeks' PMA | Randomization to 36 weeks' post-menstrual age | 
| Number of Participants with Physiologic BPD | Physiologic BPD as determined by existing NRN GDB criteria at 36 weeks' PMA. | 36 weeks' post-menstrual age | 
| Grade of BPD Severity | BPD severity is defined as in Jensen et al. (2019; PMID: 30995069) at 36 weeks' PMA according to treatment with the following respiratory support: No BPD: room air; Grade 1: nasal cannula at flow rates ≤ 2 L/min; Grade 2: nasal cannula at flow rates > 2 L/min or noninvasive positive airway pressure; Grade 3: invasive mechanical ventilation. | 36 weeks' post-menstrual age | 
| Number of Participants with Grade 3 BPD | Grade 3 BPD at 36 weeks' PMA according to the Jensen et al. (2019 PMID: 30995069) definition. | 36 weeks' post-menstrual age | 
| Number of Participants with Use of Additional Postnatal Steroids | Use of postnatal steroids for treatment of evolving chronic lung disease (separate from study drug) from 7 days after the final dose of study drug through 36 weeks' PMA. | 7 days post final dose of study drug through 36 weeks' post-menstrual age | 
| Number of Participants with Severe Neurodevelopmental Impairment (NDI) | Severe NDI is assessed at the 2-year follow-up (22-26 months corrected age). In light of the upcoming transition to BSID IV, severe NDI assessment will be based on the agreed upon definition at the time of the first participant's follow-up assessment. An example of such a definition could be presence of any of the following: Cognitive composite score on the BSID IV < 70, GMFCS level 3-5, Severe hearing impairment (no functional hearing despite amplification), or Bilateral severe visual impairment (bilateral blindness despite correction). | 22-26 months corrected age | 
| Number of Participants with Death by 2 years | Death by 2-year follow-up (22-26 months corrected age) | Randomization to 22-26 months corrected age | 
| Number of Participants with Severe NDI or death | Severe NDI or death as assessed at 2-year follow-up (22-26 months corrected age) | Randomization to 22-26 months corrected age |