Abstract
Importance:
Extremely preterm infants are at high risk for bronchopulmonary dysplasia (BPD) and death. Multiple small randomized controlled trials (RCT) showed that a combination of budesonide with surfactant compared to surfactant alone reduced BPD or death.
Objective:
To determine if early intratracheal administration of a combination of 0.25 mg/kg budesonide mixed with surfactant, as compared to surfactant alone, reduces physiologic BPD or death by 36 weeks’ post-menstrual age (PMA) in extremely preterm infants.
Design, Setting, and Participants:
This double-masked RCT was conducted from April 2021 to June 2024 in the 17 centers of the United States Neonatal Research Network. Infants 22 – 28 weeks gestation or 401–1000 grams birthweight were enrolled after clinical decision to give surfactant, with the first dose of surfactant being study drug (prior surfactant was an exclusion criterion).
Interventions:
Infants were randomly allocated 1:1 to receive 1–2 doses of budesonide with surfactant (poractant alfa) or surfactant alone via endotracheal tube within 50 hours of birth.
Main Outcomes and Measures:
The primary outcome was physiologic BPD or death by 36 weeks’ PMA. There were five pre-specified secondary outcomes and multiple prespecified exploratory and safety outcomes.
Results:
The trial was stopped with 641 infants enrolled (55.3% of planned n=1160; mean [±SD] birth weight, 810 ±256 g; gestational age, 25.9 ±1.9 weeks), because interim analysis at 50% enrollment reached the pre-specified futility threshold. The incidence of BPD or death was 68.5% in the budesonide with surfactant group and 67.9% in the surfactant-only group [adjusted relative risk (aRR) 1.00; 95% confidence interval (CI): 0.90,1.11]. No differences were noted in mortality (15.3% vs. 13.2%, aRR 1.13; 95% CI: 0.78, 1.64) or BPD among survivors to 36 weeks’ PMA (62.9% vs. 63.0%, aRR 0.99; 95% CI: 0.87, 1.12). More infants who received budesonide with surfactant compared to surfactant alone had hyperglycemia (66.7% vs. 49.8%, aRR 1.33; 95% CI: 1.17, 1.51).
Conclusions and Relevance:
In this large multicenter trial, the combination of budesonide with surfactant did not reduce the risk of BPD/death at 36 weeks’ PMA in extremely preterm infants.
Trial Registration:
ClinicalTrials.gov NCT04545866; submitted 2020–09-04
Introduction
Infants born extremely preterm (<29 weeks’ gestation) or with birth weight ≤1000 g are at high risk of mortality and morbidity.1,2 Bronchopulmonary dysplasia (BPD), the most common serious morbidity in such extremely preterm infants,2 is associated with long-term adverse respiratory3 and neurodevelopmental outcomes.4,5 BPD is defined by the magnitude of respiratory support and supplemental oxygen postnatally at 36 weeks’ postmenstrual age (PMA)6–9 and characterized pathologically by impairment of lung development.10 While survival of extremely preterm infants has improved in recent decades, the incidence of BPD has stayed constant or increased.2,11,12
Inflammation due to hyperoxia, oxidative stress, ventilation-associated lung injury, and chorioamnionitis likely contributes to BPD.13 Systemic corticosteroids soon after birth (<7 days age) reduce the combined outcome of BPD or death (BPD/death) before 36 weeks’ PMA, but also increase gastrointestinal perforation and cerebral palsy.14 Direct intra-tracheal instillation of the corticosteroid budesonide mixed with surfactant reduces lung injury in preterm animal models.15–17 In preterm infants, intra-tracheal instillation of budesonide mixed with surfactant reduced BPD/death in small randomized controlled trials (RCT)18,19 and in meta-analyses including these trials.20–22 This evidence led to the design and implementation of two large multicenter trials conducted nearly simultaneously to evaluate the benefits and risks of combining budesonide with surfactant in extremely preterm infants – the Preventing Lung Disease Using Surfactant + Steroid (PLUSS)23 and the Budesonide in Babies (BiB) trials. The PLUSS trial (conducted in Australia, New Zealand, Canada, and Singapore) found no difference in survival free of BPD.23 The BiB trial reported here was conducted in the United States testing the hypothesis that intra-tracheal administration of budesonide with surfactant, versus surfactant alone, would reduce the frequency of physiologic BPD/death by 36 weeks’ PMA in extremely preterm infants.
Methods
Trial design and oversight
The BiB trial was a multicenter, double-masked RCT (ClinicalTrials.gov NCT04545866) with 1:1 parallel allocation to budesonide with surfactant (poractant alfa) or surfactant alone (protocol available as Supplement 1; Manual of Operations as Supplement 2). BiB was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) under an Investigational New Drug (IND) application (142279) approved by the Food and Drug Administration (FDA). The trial was approved by institutional review boards at each center. RTI International was the Data Coordinating Center (DCC). The independent NRN Data and Safety Monitoring Board (DSMB), in collaboration with the DCC, conducted interim analyses after the first 40 infants reached the primary outcome and after 25% and 50% of patients reached this milestone to assess safety, efficacy, and/or futility (statistical analysis plan; Supplement 3). This report follows the Consolidated Standards of Reporting Trials (CONSORT) guideline.24
Participants
Infants 22 weeks 0 days −28 weeks 6 days gestational age (GA) or 401–1000 g birth weight were eligible after a clinical decision was made at ≤48 hours postnatal age to administer surfactant. Infants were excluded if they were judged unlikely to survive or had a decision to redirect or limit support, or there was:
use of surfactant or systemic steroids before enrollment,
maternal exposure to indomethacin within 24 hours of delivery or by the infant before enrollment,
intent to use indomethacin within 7 days of the last dose of study drug,
serious chromosomal abnormality or major malformation, known congenital infection, permanent neuromuscular condition affecting respiration, or
enrollment in a conflicting clinical trial.
Randomization
Written parental informed consent was obtained before or after birth. Study drug was administered within 50 hours after birth. Infants were stratified by study site and by gestational age (<26 or ≥26 weeks). Multiple births were randomized independently. Step-forward randomization was implemented to enable expeditious delivery room randomization, adopting ‘use next’ drug kits with a block urn design.25,26 Based on a DCC-generated randomization schedule, drug kits of budesonide respules or sham (empty respules) were randomized, assembled, masked, and labeled by the investigational drug/research pharmacy at each site, then stored in a location that permitted rapid access by the respiratory therapist or designee. Drug kits were added to the queue such that there were three or more sets of kits available for each gestational stratum at any given time. Two drug kits were prepared for each randomization number in case a second dose was needed. Infants were considered randomized when the masked drug kit was opened immediately before treatment administration. Infants of multiple gestations were randomized separately. Infants were randomized 1:1 to either surfactant (poractant alfa) 2.5 ml/kg mixed with 0.25 mg/kg (1 ml/kg) budesonide (intervention) or surfactant 2.5 ml/kg alone (active comparator).
Interventions
The study drug was administered through an endotracheal tube. Minimally invasive or less invasive surfactant administration was not used for the trial because it is not an FDA-approved method of surfactant administration. A maximum of two doses of study drug could be administered before 50 hours postnatal age, with the second dose containing 1 ml/kg budesonide and surfactant 1.25 ml/kg. The study drug was administered by an unmasked (due to need for mixing of study drug) respiratory therapist or qualified designee out of sight of other staff, so other caregivers and researchers remained masked to treatment allocation. Infants receiving more than two surfactant doses within 50h after birth could receive additional doses of open label surfactant at clinician discretion.
Administration of systemic steroids < 7 days of last dose of study drug was discouraged and reserved at clinician discretion for infants with fluid-resistant/vasopressor-resistant hypotension or evidence of hyponatremia with low serum cortisol concentration (per local definitions). Other clinical practices were per usual clinical protocol and clinician preference.
Outcomes
The primary outcome was the composite of physiologic BPD6,27,28 or death by 36 weeks’ PMA. Physiologic BPD was defined as receiving mechanical ventilation or continuous positive airway pressure (CPAP), oxygen by hood at fraction of inspired oxygen (FiO2) >0.3, oxygen by nasal cannula at an effective FiO2 >0.3 (calculated using conversion tables), or failing oxygen reduction challenge from FiO2 <0.3 by hood or effective FiO2 <0.3 by cannula (Appendix in Supplement 2: Manual of Operations and Generic Database Manual; adjudication was not necessary for this validated definition). Infants discharged home or transferred out of network before 36 weeks’ PMA were assessed for physiologic BPD based on the level of respiratory support at discharge/transfer.
Secondary outcomes assessed at 36 weeks’ PMA included: death; physiologic BPD; BPD severity (ordinal)7; Grade 3 BPD7; and postnatal steroid use from 7 days after last dose of study drug through 36w PMA.
Multiple exploratory outcomes were also evaluated (Protocol in Supplement 1): BPD severity by the NIH Workshop definition9; days on mechanical ventilation by 28 postnatal days; days on invasive mechanical ventilation by 36 weeks’ PMA; intubation after 50 postnatal hours and within the first 28 days; intubation after 50 hours and before 36 weeks’ PMA; and repeat administration of surfactant doses after 50 hours and within 7 days of last dose of study drug. Additional outcomes analyzed include common clinical outcomes assessed through 120 postnatal days, and standardized growth metrics at 36 weeks’ PMA. We conducted analyses of survival without physiologic BPD at 36 weeks’ PMA within subgroups defined by baseline characteristics.
Pre-specified adverse events (AEs; defined in Protocol in Supplement 1 and Manual of Operations in Supplement 2) considered likely to be associated with study intervention were monitored within 7 days of last dose of study drug. These included hyperglycemia, hypertension, prolonged hypoxemia with bradycardia, endotracheal tube blockage, and any other AE deemed moderate or worse in severity. Moderate hyperglycemia was defined as blood glucose 120–180 mg/dL on 2 consecutive determinations at least 6 hours apart or more than 2 determinations within a 24-hour period with no in-between normal range values. Severe hyperglycemia was defined as >180 mg/dL. Spontaneous intestinal perforation and periventricular leukomalacia within 30 days of final drug administration were also monitored as pre-specified AEs. Several risks of prematurity were monitored within 7 days of last study drug (hypotension, pulmonary air leak, culture-positive sepsis, and intracranial hemorrhage).
Sample size estimation and statistical analysis
A detailed statistical analysis plan for the BiB trial is available (Supplement 3). Sample size calculations were based on the primary outcome. Based on the ≥20% absolute risk reduction observed by prior RCTs18,19 and the observed incidence of BPD or death of 58% at participating sites, BiB was designed to detect an absolute risk reduction of 10% (from 58% to 48%) corresponding to a relative risk (RR) of 0.83. Simulation studies for the primary analysis method indicated that a sample size of 550 per arm (1100 total) would attain 90% power for an overall type I error of 0.05. Accounting for 5% attrition for the primary outcome, the planned sample size was 1160 infants.
The primary analysis compared the proportion of infants who died or developed BPD at 36 weeks’ PMA using a robust Poisson regression model.29,30 Randomization stratification factors of center and GA (<26 or ≥26 weeks) were included as fixed explanatory variables in the model. The primary outcome analysis was performed at α = 0.049 to adjust for multiplicity of interim efficacy analyses and preserve an overall type I error rate of α = 0.05. Analyses of the primary, secondary and exploratory efficacy outcomes were based on intention-to-treat (ITT), unless otherwise specified. In contrast, safety, clinical, and growth outcomes were analyzed based on actual treatment received (“as-treated” population). Secondary and exploratory dichotomous outcomes were analyzed with the robust Poisson methods described for the primary outcome. For models with convergence or fit issues, the RR was estimated by the Mantel-Haenszel common odds ratio, stratified by the cross-classification of center and GA strata, or by the crude odds ratio (unadjusted) and Fisher’s exact test. Continuous outcomes estimated adjusted mean difference via linear regression; count outcomes were analyzed as continuous outcomes using robust variance estimation. Comparisons of secondary outcomes between study arms should be considered exploratory.
Results
Trial population
Patients were randomized from April 2021 to June 2024. When 641 infants (55.3% of planned 1160) had been enrolled from 17 centers, the DSMB in June 2024 recommended study termination at 50% enrollment based on having met the prespecified futility criterion (80% confidence interval for conditional power falling below 0.50)31–33 (Statistical Analysis Plan in Supplement). A total of 5353 antenatally screened mothers (n=4042) and postnatally screened infants (n=1311) were assessed for eligibility (Figure 1). Consent was not obtained due to lack of eligibility (n=1784), consent declined (n=1417), or other reasons (n=841). Of 1311 mothers/infants with consent, 670 were subsequently eligible (Figure 1). In total, 641 infants were randomized (637 of the 670 eligible and consented, 1 non-consented, and 3 ineligible), with 323 randomized to budesonide + surfactant and 318 to surfactant alone. The primary endpoint at 36 weeks’ PMA was available for all but two infants in the intervention arm. Additional information about participant study experience is tabulated in Supplement 4.
Figure 1:
BiB Trial Flow Diagram
ITT = intention-to-treat; ITT excluding untreated participants = all randomized patients who received at least one dose of study drug; PP = per protocol.
a Assessments of eligibility include antenatal screenings of mothers and postnatal screenings of infants. Families who declined consent antenatally or who consent antenatally but delivered out of gestational age window were each captured once, regardless of single or multiple gestation.
b Reasons for ineligibility include prior use of surfactant (1356), no clinical decision to give surfactant (811), gestational age and/or birthweight out of eligibility window (387), prior indomethacin use (224), terminally ill or a decision to redirect support (193), serious chromosomal abnormality or neuromuscular condition (138), > 48 hours postnatal age at time of randomization (59), enrolled in a conflicting trial (58), stillbirth (47), prior use of systemic steroids (20), and known congenital infection (15). Multiple reasons for ineligibility may be provided.
c 815 parents declined consent antenatally and prior to assessment of infant eligibility; 453 parents declined consent postnatally of which 399 infants were eligible and 54 had not been assessed for eligibility.
d Other reasons not enrolled include passive non-consent (e.g., parent/guardian no decision, not approached, or unavailable), physician decision not to consent and/or enroll, or logistic barriers to the consent and/or enrollment process (e.g., staff availability, drug kit availability, urgent delivery, parent/guardian did not speak English, early study closure).
e One infant was randomized and treated in error after the parent/guardian declined consent. The infant was withdrawn from the trial upon discovery of the protocol violation. At the parent’s request, the infant’s data have been fully redacted. No data are available for reporting or analysis (including treatment allocation), and this participant is excluded from the intention to treat (ITT) population.
f Participants who received budesonide with surfactant for either or both doses of study drug are considered to be treated under the Budesonide + Surfactant arm.
g Two infants improved and did not require surfactant; one was ineligible and randomized in error.
h One infant died prior to treatment; one became too medically unstable to participate; one was ineligible and randomized in error.
i In addition to the withdrawn infant (see footnote e), two randomized infants withdrew prior to primary endpoint assessment. One infant was randomized and treated without consent; parent/guardian declined consent to continue. The other infant was ineligible and randomized in error (not treated); effectively withdrawn since they were also ineligible for the Generic Data Base data collection.
j The primary analysis was performed for the ITT analysis population, and the model excluded participants missing the primary endpoint (2). This model was repeated for two analysis subpopulations as a planned sensitivity analysis. The ITT excluding untreated participants analysis also excluded participants who were not treated (5). The PP analysis also excluded participants who either were not treated (5) or had a major treatment protocol violation (5 ineligible enrollments; 4 treated under the wrong group or both groups; 3 received over 2.4 times the intended dose; 2 received less than half of the intended dose; 1 treated after the dosing window; and 2 other dosing administration violation).
The maternal and neonatal baseline clinical characteristics were similar between the two arms (Table 1). Overall, the mean GA was 25.9 weeks (SD 1.9) and the mean birth weight was 810 g (SD 256), with 41.8% in the <26 weeks stratum, 50.1% male, and 23.0% born following multiple gestation pregnancies. Nearly all (99.1%) infants were exposed to antenatal steroids, with 89.8% exposed to a full course. 96.1% were exposed to magnesium sulfate and 71.2% to antibiotics within 72 hours of birth. At delivery, 85.1% of infants received positive pressure ventilation and 64.5% received CPAP. 58.5% of infants were intubated at birth, and about half those infants (27.6% overall) received their first dose of study drug in the delivery room.
Table 1.
Maternal, Labor and Delivery, and Neonatal Baseline Characteristics, Intention-to-treat Population
| Characteristic | Budesonide + Surfactant (n=323) | Surfactant Alone (n=318) |
|---|---|---|
| Maternal | ||
| Age (years) Mean (SD) | 29.1 (6.1) | 29.7 (5.8) |
| Race, self-reported, n (%) | 305 | 307 |
| Black or African American | 101 (33.1) | 122 (39.7) |
| White | 183 (60.0) | 168 (54.7) |
| American Indian or Alaska Native | 5 (1.6) | 4 (1.3) |
| Asian, Native Hawaiian, or Other Pacific Islander | 12 (3.9) | 8 (2.6) |
| More than One Race | 4 (1.3) | 5 (1.6) |
| Ethnicity, self-reported, n (%) | 304 | 308 |
| Hispanic or Latino | 50 (16.4) | 54 (17.5) |
| Not Hispanic or Latino | 254 (83.6) | 254 (82.5) |
| Education, n (%) | 259 | 269 |
| Less than high school diploma | 31 (12.0) | 27 (10.0) |
| High school diploma | 87 (33.6) | 77 (28.6) |
| Partial college | 56 (21.6) | 81 (30.1) |
| College degree or more | 85 (32.8) | 84 (31.2) |
| Health insurance, n (%) | 321 | 318 |
| Private | 160 (49.8) | 160 (50.3) |
| Public | 149 (46.4) | 143 (45.0) |
| Self-pay/uninsured | 12 (3.7) | 15 (4.7) |
| Body mass index, pre-pregnancy, Mean (SD) | 30.8 (8.9) | 31.4 (8.8) |
| Hypertensive disorder of pregnancy, n/N (%) | 142/321 (44.2) | 164/318 (51.6) |
| Diabetes, pre-pregnancy, n/N (%) | 16/321 (5.0) | 29/318 (9.1) |
| Diabetes, gestational, n/N (%) | 22/298 (7.4) | 16/296 (5.4) |
| Chorioamnionitis, clinical, n/N (%) | 39/321 (12.1) | 38/318 (11.9) |
| Chorioamnionitis, histologic, n/N (%) | 118/300 (39.3) | 112/302 (37.1) |
| Multiple birth, n/N (%) | 78/321 (24.3) | 69/318 (21.7) |
| Labor and Delivery | ||
| Antenatal steroids, any, n/N (%) | 318/321 (99.1) | 314/317 (99.1) |
| Antenatal steroids, full course, n/N (%) | 282/319 (88.4) | 288/316 (91.1) |
| Magnesium sulfate, n/N (%) | 307/321 (95.6) | 306/317 (96.5) |
| Antibiotics given <72 hours prior to delivery, n/N (%) | 236/321 (73.5) | 219/318 (68.9) |
| Prolonged rupture of membrane (>18 hours), n/N (%) | 98/319 (30.7) | 89/315 (28.3) |
| Cesarean section delivery, n/N (%) | 243/321 (75.7) | 236/318 (74.2) |
| Delayed cord clamping, n/N (%) | 146/321 (45.5) | 156/317 (49.2) |
| Infant | ||
| Birth weight (grams), Mean (SD) | 808.1 (268.8) | 812.3 (242.6) |
| Gestational age (weeks), Mean (SD) | 25.8 (1.9) | 25.9 (2.0) |
| Gestational age stratum, n/N (%) | ||
| < 26 0/7 weeks | 138/323 (42.7) | 130/318 (40.9) |
| ≥ 26 0/7 weeks | 185/323 (57.3) | 188/318 (59.1) |
| Sex, n/N (%) | ||
| Male | 158/321 (49.2) | 162/318 (50.9) |
| Female | 163/321 (50.8) | 156/318 (49.1) |
| Small for gestational age (<10th percentile for gestational age and sex), n/N (%) | 62/321 (19.3) | 50/318 (15.7) |
| 1 minute Apgar score, Median (Q1-Q3) | 3 (2 – 5) | 4 (2 – 6) |
| 5 minute Apgar score, Median (Q1-Q3) | 7 (5 – 8) | 7 (6 – 8) |
| Delivery room positive pressure ventilation (PPV), n/N (%) | 278/320 (86.9) | 265/318 (83.3) |
| Delivery room continuous positive airway pressure (CPAP), n/N (%) | 202/319 (63.3) | 208/317 (65.6) |
| Delivery room chest compression, n/N (%) | 4/321 (1.2) | 4/318 (1.3) |
| Delivery room epinephrine, n/N (%) | 3/321 (0.9) | 4/318 (1.3) |
| Delivery room intubationa, n/N (%) | 191/321 (59.5) | 183/318 (57.5) |
| Type of Respiratory Support at Baselineb, n (%) | 232 | 235 |
| CPAP | 115 (49.6) | 119 (50.6) |
| Conventional Mechanical Ventilation | 67 (28.9) | 62 (26.4) |
| High Frequency Ventilation | 45 (19.4) | 47 (20.0) |
| Hood | 1 (0.4) | 2 (0.9) |
| None | 4 (1.7) | 5 (2.1) |
| IMV Respiratory Support at Baselineb, n/N (%) | 112/232 (48.3) | 109/235 (46.4) |
| FiO2 at Baselineb | (n=228) | (n=230) |
| Median (Q1-Q3) | 0.40 (0.30 – 0.60) | 0.40 (0.30 – 0.56) |
| High FiO2 (≥0.5) at Baselineb, n/N (%) | 86/228 (37.7) | 81/230 (35.2) |
| Partial pressure of carbon dioxide (pCO2) at Baselineb | (n=164) | (n=156) |
| Mean (SD) | 52.0 (14.2) | 50.8 (14.6) |
| Blood Gas pH at Baselineb | (n=164) | (n=156) |
| Mean (SD) | 7.3 (0.1) | 7.3 (0.1) |
| Study Drug Exposures | ||
| Number of Doses, n (%) | ||
| One Dose | 221 (69.1) | 194 (61.6) |
| Two Doses | 99 (30.9) | 121 (38.4) |
| Administered in delivery roomc, n/N (%) | 90/318 (28.3) | 83/308 (26.9) |
| Postnatal age (h) of Dose 1 | (n=320) | (n=315) |
| Mean (SD) | 4.07 (7.49) | 3.68 (6.78) |
| Postnatal age (h) of Dose 2 | (n=99) | (n=121) |
| Mean (SD) | 23.38 (11.85) | 21.76 (10.10) |
FiO2 = fraction of inspired oxygen; h = hour; Q1 = first quartile (25th percentile); Q3 = third quartile (75th percentile); SD = standard deviation.
Resuscitation/stabilization at birth with intubation excludes intubations that were performed for suctioning or surfactant administration and then immediately removed.
Baseline respiratory and clinical blood gas metrics report the last available data collected prior to study drug initiation. These data collections were optional and have high levels of missingness not at random. Most infants who received study drug within 1 hour of birth do not have baseline collections, and some infants may have no baseline data or baseline data that was captured several hours before treatment initiation.
By study design, all surfactant administrations in delivery room were the first study drug intervention.
Primary outcome:
Physiologic BPD or death by 36 weeks’ PMA occurred in 68.5% of infants in the budesonide + surfactant arm and 67.9% in the surfactant alone arm [adjusted RR (aRR) 1.00; 95% CI: 0.90, 1.11] (Table 2).
Table 2.
Primary Efficacy Outcome and its Components
| Efficacy Outcomes | Budesonide + Surfactant (n=323) | Surfactant Alone (n=318) | Risk Difference (95% CI) | Relative Risk (95% CI) |
|---|---|---|---|---|
| Primary Outcome a | ||||
| Physiologic BPD or Death before 36 weeks PMA | ||||
| Intention-to-treat, n/N (%) | 220/321 (68.5) | 216/318 (67.9) | 0.02 (−6.81, 6.85) | 1.00 (0.90, 1.11) |
| Intention-to-treat excluding untreated participants, n/N (%) | 218/319 (68.3) | 215/315 (68.3) | −0.31 (−7.18, 6.56) | 1.00 (0.90, 1.10) |
| Per protocol, n/N (%) | 212/309 (68.6) | 210/308 (68.2) | −0.14 (−7.11, 6.83) | 1.00 (0.90, 1.11) |
| Primary Components, intention-to-treat | ||||
| Death before 36 weeks PMA, n/N (%) | 49/321 (15.3) | 42/318 (13.2) | 1.73 (−3.56, 7.01) | 1.13 (0.78, 1.64) |
| Physiologic BPD at 36 weeks PMAb, n/N (%) | 171/272 (62.9) | 174/276 (63.0) | −0.73 (−8.38, 6.93) | 0.99 (0.87, 1.12) |
BPD = bronchopulmonary dysplasia; CI = confidence interval; PMA = postmenstrual age.
Treatment group represents randomized treatment assignment for all analysis populations in this table.
Modeled estimates compare the Budesonide + Surfactant group to the Surfactant Alone group, adjusting for gestational age strata and pooled center (7-level). Risk differences and confidence intervals (reported as percents) were estimated with robust generalized linear regression (normal distribution with identity link); relative risks and confidence intervals were estimated by robust Poisson regression.
Primary outcome models were each adjusted for multiplicity from sequential testing (performed at alpha = 0.049). Multiplicity adjustment was not applied for multiple testing of sensitivity analyses. All other models were performed at alpha = 0.05 for descriptive purposes only.
- Effective oxygen <27% and majority of saturations ≥90% in prior 24 hours
- Effective oxygen 27–30% AND majority of saturations ≥96%
- Room air by nasal cannula
Secondary outcomes:
There were no differences between treatment arms in death (15.3% budesonide + surfactant vs. 13.2% surfactant alone, aRR 1.13; 95% CI: 0.78, 1.64) or physiologic BPD (62.9% budesonide + surfactant vs. 63.0% surfactant alone, aRR 0.99; 95% CI: 0.87, 1.12). Other outcomes including BPD severity7 at 36 weeks’ PMA; Grade 3 BPD7 at 36 weeks’ PMA; and postnatal steroid use from 7 days post-study drug administration through 36 weeks’ PMA also did not differ between the arms (Table 3).
Table 3.
Secondary and Exploratory Efficacy Outcomes, Intention-to-treat Population
| Outcomes | Budesonide + Surfactant (n=323) | Surfactant Alone (n=318) | Risk difference (RD) or mean difference (MD) (95% CI) | Relative Risk (RR) or Odds Ratio (OR) (95% CI) |
|---|---|---|---|---|
| Secondary Outcomes | ||||
| BPD Severity at 36 weeks’ PMA, Pragmatic a, n (%) | 269 | 270 | ||
| No BPD | 70 (26.0) | 66 (24.4) | (reference) | |
| Grade 1 (Mild) | 72 (26.8) | 78 (28.9) | -- | OR: 0.87 (0.54, 1.41) |
| Grade 2 (Moderate) | 99 (36.8) | 100 (37.0) | -- | OR: 0.88 (0.55, 1.42) |
| Grade 3 (Severe) | 28 (10.4) | 26 (9.6) | -- | OR: 0.99 (0.51, 1.89) |
| Grade 3 (Severe) BPD at 36 weeks’ PMA, Pragmatic a, n/N (%) | 28/269 (10.4) | 26/270 (9.6) | RD: 0.69 (−4.34, 5.71) | RR: 1.07 (0.65, 1.77) |
| Use of additional postnatal steroids between 7 days PLD and 36 weeks’ PMA b, n/N (%) | 102/318 (32.1) | 109/311 (35.0) | RD: −3.84 (−10.45, 2.77) | RR: 0.89 (0.73, 1.09) |
| Exploratory Outcomes | ||||
| BPD Severity at 36 weeks’ PMA, NIH consensus definition c, n (%) | 270 | 270 | ||
| No BPD | 29 (10.7) | 27 (10.0) | (reference) | |
| Grade 1 (Mild) | 70 (25.9) | 57 (21.1) | -- | OR: 1.13 (0.59, 2.17) |
| Grade 2 (Moderate) | 32 (11.9) | 45 (16.7) | -- | OR: 0.63 (0.30, 1.34) |
| Grade 3 (Severe) | 139 (51.5) | 141 (52.2) | -- | OR: 0.87 (0.47, 1.63) |
| Number of days on IMV before 28 days postnatal age d | (n=283) | (n=278) | ||
| Median (Q1-Q3) | 7 (1 – 26) | 10 (2 – 28) | MD: −1.49 (−2.97, −0.01) | NA |
| Number of days on IMV before 36 weeks’ PMA d | (n=262) | (n=265) | ||
| Median (Q1-Q3) | 10 (1 – 36) | 13 (2 – 37) | MD: −2.04 (−5.32, 1.23) | NA |
| Intubated after treatment window and before 28 days postnatal age e, n/N (%) | 192/312 (61.5) | 206/302 (68.2) | RD: −9.09 (−15.48, −2.69) | RR: 0.87 (0.78, 0.96) |
| Intubated after treatment window and before 36 weeks’ PMA e, n/N (%) | 195/301 (64.8) | 211/295 (71.5) | RD: −9.12 (−15.50, −2.73) | RR: 0.87 (0.79, 0.96) |
| Additional open-label surfactant after treatment window and by 7 days after last dose of study drug f, g, n/N (%) | 13/312 (4.2) | 18/299 (6.0) | RD: −1.87 (−5.29, 1.55) | RR: 0.69 (0.33, 1.46) |
BPD = bronchopulmonary dysplasia; CI = confidence interval; d = day(s); IMV = invasive mechanical ventilation; MD = mean difference; NA = not applicable; NIH = National Institutes of Health; OR = odds ratio; Q1 = first quartile (25th percentile); Q3 = third quartile (75th percentile); RD = risk difference; RR = relative risk; PMA = postmenstrual age; w = week.
n/N (%) reported for each outcome is the number of participants experiencing the outcome over the number of participants with a non-missing value for the outcome.
Binary outcomes report risk difference (RD; as percents) and relative risks (RR); ordinal outcomes report odds ratio (OR); count outcomes report least squares mean difference (MD). Risk differences and least square means differences were estimated by robust generalized linear models (normal distribution with identity link); relative risks were estimated by robust Poisson regression; and odds ratios were estimated by logistic regression (generalized logit). RD are not shown for BPD severity as reduced sample sizes lead to very wide confidence intervals for pairwise comparisons. All models compared the Budesonide + Surfactant group to the Surfactant Alone group, adjusting for gestational age strata and pooled center. All analyses were performed at the alpha = 0.05 significance level for descriptive purposes only.
The pragmatic definition of BPD severity grades was defined by Jensen, et al7. No BPD is defined as no support at 36 weeks PMA, Grade 1 is defined as nasal cannula <= 2 liters per minute, Grade 2 is defined as nasal cannula > 2 liters per minute or noninvasive positive airway pressure, Grade 3 is defined as invasive mechanical ventilation.
“Additional postnatal steroids” specifically refer to steroids used to treat evolving BPD or chronic lung disease. This outcome is limited to those who were alive and in hospital at the end of the 7d after last dose safety monitoring window.
The NIH consensus definition of BPD severity grades was defined by Jobe and Bancalari9. The scoring algorithm considers an infant’s gestational age, duration of respiratory support through 28 days postnatal age, and the level of respiratory support at 36 weeks postmenstrual age.
IMV includes high-frequency ventilation and conventional ventilation; nasal cannula respiratory support is not considered invasive per this protocol. IMV outcomes are limited to infants who were alive and in hospital at the specified analysis endpoint (28 days postnatal age or 36 weeks’ PMA).
Intubations after the treatment window include new or continued intubations after 50 hours postnatal age. Intubation outcomes are limited to infants who were alive and in hospital at 50 hours postnatal age.
Relative risk was estimated by Mantel-Haenszel methods, approximated by the common odds ratio, due to convergence issues with the robust Poisson model. The analysis was stratified by the cross-classifications of gestational age strata and pooled center.
Additional surfactant administrations do not include any open label administrations within the treatment window (50h postnatal age). This outcome is limited to infants who were alive and in hospital at 50 hours postnatal age.
Exploratory outcomes
Several pre-defined exploratory efficacy outcomes were also evaluated. BPD severity by the NIH Workshop definition9 did not differ between the arms, but there were fewer days on mechanical ventilation before 28 days in the budesonide + surfactant arm (median (interquartile range [IQR]) 7 (1–26) d vs 10 (2–28) d; mean difference (95% CI): −1.49 (−2.97, −0.01)). There were fewer infants exposed to invasive ventilation after the treatment window (continued on, or new intubation) in the budesonide + surfactant arm compared to the surfactant-alone arm before 28 days (61.5% vs 68.2%, aRR 0.87; 95% CI: 0.78, 0.96) and before 36 weeks’ PMA (64.8% vs 71.5%, aRR 0.87; 95% CI: 0.79, 0.96). Open-label surfactant doses after the treatment window and within 7 days after the last dose of the study drug did not differ between the arms (Table 3).
Safety Outcomes:
The probability of experiencing at least one adverse event (AE) differed between the groups (75.4% budesonide + surfactant vs. 64.5% surfactant alone; aRR 1.16; 95% CI: 1.05, 1.28) (Supplement 4), primarily due to an increase in moderate hyperglycemia without a difference in any serious AEs.
Clinical and growth outcomes:
Clinically diagnosed patent ductus arteriosus (PDA) was less common in the budesonide + surfactant compared to the surfactant alone arm (49.8% vs. 56.8%; aRR 0.86; 95% CI 0.75, 0.99), but no differences were observed for PDA managed with medical therapy, PDA managed with surgery or cardiac catheterization, or the composites of death and PDA outcome (Supplement 4). No other clinical or growth differences were observed between treatment arms.
Sensitivity and subgroup analyses:
The primary efficacy outcome was reassessed for the ITT population excluding untreated participants (all randomized patients who received at least one dose of study drug) (N=635) and the per-protocol population (N=617). Both ITT excluding untreated participants and per-protocol excluded 6 randomized infants who never initiated treatment; Per-protocol also excluded 18 infants with a major protocol violation (Supplement 4). No differences were detected between arms for these sensitivity analyses (Table 2).
No significant differences in survival without physiologic BPD at 36 weeks’ PMA by treatment arm were observed for any subgroups defined by baseline characteristics (Figure 2).
Figure 2:
Survival without physiologic BPD at 36 weeks PMA by Subgroup, Intention-to-treat Population
BPD = bronchopulmonary dysplasia; CI = confidence interval; GA = gestational age; FiO2 = fraction of inspired oxygen; NA = not applicable; PMA = postmenstrual age.
Subgroup analyses considered relative risk of a favorable outcome (alive and without physiologic BPD) at 36 weeks’ PMA, comparing the Budesonide + Surfactant group to the Surfactant alone group. Relative risks and 95% confidence intervals were estimated using robust Poisson regression. The gestational age subgroup models adjusted for pooled center; all other models adjusted for gestational age strata and pooled center. All analyses were performed at the alpha = 0.05 significance level for descriptive purposes only.
n/N (%) reported for each subgroup is the number of participants alive and without physiologic BPD over the number of participants in the subgroup with a non-missing value for the outcome.
a Gestational age group reflects actual gestational age (best clinical estimate), regardless of randomization strata.
b Baseline FiO2 refers to the last known level of respiratory support prior to treatment initiation. The FiO2 subgroups exclude 182 participants from the intention-to-treat population who do not have baseline respiratory data. Most of the excluded participants (138, 76%) initiated treatment within 30 minutes of birth.
c “Other” race includes self-reports of American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or more than one race.
| Subgroup: | Surfactant Alone, n/N (%) | Budesonide + Surfactant, n/N (%) | Relative Risk (95% CI) | P-value for interaction | |
|---|---|---|---|---|---|
| Overall Model: | NA | 102/318 (32.1) | 101/321 (31.5) | 1.00 (0.81, 1.24) | NA |
| Gestational Age a: | < 26 weeks | 22/130 (16.9) | 22/140 (15.7) | 0.92 (0.54, 1.58) | 0.72 |
| ≥ 26 weeks | 80/188 (42.6) | 79/181 (43.6) | 1.03 (0.82, 1.30) | ||
| Chorioamnionitis (either histological or clinical): | No | 61/177 (34.5) | 51/174 (29.3) | 0.91 (0.68, 1.21) | 0.35 |
| Yes | 38/127 (29.9) | 45/129 (34.9) | 1.12 (0.81, 1.55) | ||
| Baseline FiO2 b: | < 0.5 | 64/150 (42.7) | 62/142 (43.7) | 1.04 (0.81, 1.33) | 0.45 |
| ≥ 0.5 | 13/81 (16.0) | 19/86 (22.1) | 1.35 (0.72, 2.51) | ||
| Sex: | Male | 50/162 (30.9) | 44/158 (27.8) | 0.88 (0.64, 1.22) | 0.28 |
| Female | 52/156 (33.3) | 57/163 (35.0) | 1.12 (0.84, 1.48) | ||
| Race: | Black | 43/122 (35.2) | 40/101 (39.6) | 1.18 (0.86, 1.63) | 0.33 |
| White | 53/168 (31.5) | 47/183 (25.7) | 0.84 (0.61, 1.15) | ||
| Other c | 4/17 (23.5) | 7/21 (33.3) | 0.93 (0.33, 2.66) |
Discussion
In this multicenter RCT, administration of intratracheal budesonide mixed with surfactant did not reduce BPD or death in extremely preterm infants as compared to surfactant alone. The intervention was associated with fewer days on mechanical ventilation by postnatal day 28 as well as an increased incidence of hyperglycemia. This study’s results are consistent with the findings from the PLUSS trial23, which also found that the combination of budesonide and surfactant did not significantly improve survival free of BPD in extremely preterm infants.
This trial provides a rigorous evaluation of the intervention in a large and diverse high-risk population of extremely preterm infants, using strict inclusion and exclusion criteria, double-masking, well-defined pre-specified outcomes, and detailed analyses. These extremely preterm infants received high-risk obstetric care (99% exposed to antenatal steroids; 96% to magnesium sulfate; 75% to cesarean delivery) and had high survival (86% survival to 36 weeks’ PMA). Infants also received the study drug through an endotracheal tube, ensuring that study drug was administered into the lungs. Study drug was given as the first dose of surfactant, thereby ensuring early use of the intervention. Infants who had already received surfactant were excluded, avoiding prior exposure that could blur potential efficacy or harm signals.
Neither this trial nor a prior multinational trial23 identified a benefit of budesonide combined with surfactant on survival free of BPD among extremely preterm infants. The populations in both trials were diverse- in the current trial, 36% of infants were born to Black mothers, and 17% to Hispanic mothers, while the multinational trial included infants born to mothers of primarily Caucasian, Asian, Maori, and Pacific Islander origins.
The key novel contribution of the current trial is that administration of the study intervention with the first dose of surfactant more closely parallels the way budesonide would be used in real-world practice, in contrast to the multinational trial, where 57% of infants had received prior surfactant. Another difference is that about 14% of the infants in the prior trial received surfactant via a thin catheter which may be safe and associated with reductions in BPD.34 However, this was not permitted in the current trial as surfactant administration via endotracheal tube is the only method currently approved by the FDA. Despite such differences, the similar results of these two multicenter trials indicate these differences are unlikely to influence the utility of the intervention.
Benefits of budesonide with surfactant were noted in trials by Yeh et al.18,19 which enrolled infants who were generally more mature at birth, less likely to be exposed to chorioamnionitis or antenatal steroids, met specific FiO2 threshold requirements, and had lower incidence of BPD/death in controls as compared to the two multicenter trials. This study did not observe a difference in the post hoc subgroup analysis to assess the influence of baseline FiO2 on intervention effect. It is possible that differences in GA, exposure to antenatal steroids, clinical practices,35 genetic predispositions,36 and other factors led to differences in effects of interventions and frequency of BPD. It is unlikely that higher doses of budesonide are necessary, as even one-tenth the dose of budesonide (0.025 mg/kg) appears effective for lung-targeted anti-inflammatory action.37
Limitations
This study’s limitations include, first, that early termination of the trial resulted in a smaller sample size than planned, reducing power for secondary outcomes and subgroup analyses.
Second, the results from BiB may be generalizable to extremely preterm infants with similar characteristics (high exposure to antenatal steroids, cesarean delivery, and maternal hypertension) such as seen in the NICHD Neonatal Research Network2 and the Vermont Oxford Network38,39.
Conclusions
In extremely preterm infants, intratracheal budesonide mixed with surfactant did not reduce BPD or death by 36 weeks’ PMA, or the components of this outcome.
Supplementary Material
Supplement 1: Protocol
Supplement 2: Manual of Operations for BiB and Generic Database
Supplement 3: Statistical Analysis Plan
Supplement 4: Supplemental Tables
Key Points:
Question:
Does intratracheal administration of budesonide mixed with surfactant, as compared to surfactant alone, reduce bronchopulmonary dysplasia or death by 36 weeks’ post-menstrual age in preterm infants <29 weeks’ gestation?
Findings:
In this multicenter randomized trial, after recruiting 641 infants, recruitment was stopped early when prespecified futility criteria were satisfied. There was no difference in bronchopulmonary dysplasia or death between infants receiving budesonide with surfactant (68.5%) versus those receiving surfactant alone (67.9%; adjusted relative risk 1.00, 95% CI 0.90, 1.11)
Meaning:
In extremely preterm infants, mixing budesonide with surfactant did not reduce bronchopulmonary dysplasia or death.
Acknowledgements
The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources (NCRR), and the National Center for Advancing Translational Sciences (NCATS) provided grant support for the Neonatal Research Network’s Budesonide in Babies (BiB) trial through cooperative agreements. While NICHD staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government.
The clinical sites as well as the Data Coordinating Center (DCC) participating in this trial were all part of the NICHD Neonatal Research Network (NRN), a cooperative agreement grant established by NICHD, NIH, to improve healthcare and outcomes for newborns by conducting rigorous multicenter clinical trials in neonates. NRN centers and the DCC are chosen competitively every 5–7 years through open competition as per usual NIH peer review processes. Patient or public involvement in the design, conduct and reporting of the trial are not applicable as the Community Engagement Board was not in operation at the time BiB was designed and started.
Participating NRN sites collected data and transmitted it to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, RTI International had full access to all the data in the study, and with the NRN Center Principal Investigators, takes responsibility for the integrity of the data and accuracy of the data analysis. Individual patient data from this trial, suitably deidentified, along with associated documentation will be available on the NICHD Data and Specimen Hub (N-DASH).
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chair: Christine A. Gleason, MD, University of Washington – Seattle, (2023-present); Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University, (2011–2023).
Data and Safety Monitoring Board: Robin H. Steinhorn, MD, Chair, University of California – San Diego, Rady Children’s Specialists of San Diego; Robert J. Boyle, MD, Vice Chair, University of Virginia Health System; Traci Clemons, PhD, The EMMES Corporation; Cornelia R. Graves, MD FACOG, Vanderbilt University; Dorothea D. Jenkins, MD, Medical University of South Carolina; Jeannette Lee, PhD, University of Arkansas for Medical Sciences; Yvonne W. Wu, MD MPH, University of California, San Francisco; Steven Weiner, PhD; The Biostatistics Coordinating Center, The George Washington University.
Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904) – Angelita M. Hensman, PhD RNC-NIC; Kim Porras, BS; Elisa Vieira, RN BSN; Lucille St. Pierre, BS.
Ann & Robert H. Lurie Children’s Hospital of Chicago, Prentice Women’s Hospital/Northwestern University (UG1 HD112079) – Aaron Hamvas, MD; Daniel T. Robinson, MD MSc; Raye-Ann deRegnier, MD; Cassandra Montoya, MD; Rachael (Meckley) Henry, MS; Steven M. Ward, BS RRT.
Case Western Reserve University, Rainbow Babies & Children’s Hospital (UG1 HD21364) – Nancy S. Newman, RN; Deanne E. Wilson-Costello, MD; Sarah Smucny, BSN RNC-NIC; Bonnie S. Siner, RN.
Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital (UG1 HD27853, UL1 TR77) – Kurt Schibler, MD; Jae Kim, MD PhD; Cathy Grisby, BSN CCRC; Kristin Kirker, CRCIII; Julia Thompson, RN BSN; Traci Beiersdorfer, RN BSN; Haley Kramer, RN BSN; Lisa Radcliff, RN BSN; Carla King, RN BSN; Katherine McKeown, RN BSN; Megan Hess, RN BSN; Cynthia Reid, RN BSN; Amy Graber-Pels, RN BSN; David Russell, JD; Greg Muthig, BA.
Duke University School of Medicine, University of North Carolina, and Maynard Children’s Hospital at East Carolina University Health (UG1 HD40492, UL1 TR1117) – Ronald N. Goldberg, MD; Samia Aleem, MD; Joanne Finkle, RN JD; Kimberley A. Fisher, PhD FNP-BC IBCLC; Caitlin Stone, MA; Jennifer Talbert, MS RN; Melissa Babilonia-Rosa, PhD; Cindy Clark, RN; Sneha Makhijani, BS; Sherry Moseley, RN; Vickie Bergstedt, RN; Kelly Bear, MD.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (UG1 HD27851, UL1 TR454) – David P. Carlton, MD; Yvonne Loggins, RN; Diane Bottcher, RN; Judith Laursen, RN; Colleen Mackie, RRT; Shelly Connor, RN MScA; Jayontra Thompson, RN.
Eunice Kennedy Shriver National Institute of Child Health and Human Development – Rosemary D. Higgins, MD; Andrew A. Bremer, MD PhD; Stephanie Wilson Archer, MA.
McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital (U10 HD21373, UG1 HD87229) – Amir M. Khan, MD; Gabriela Dominguez, BSN RN; Ronald Pucio, RRT; Emily Stephens, BSN RNC-NIC; Jaleesa Wade, BSN CCRN.
RTI International (U10 HD036790) – Jennifer Talbert, MS BSN RDH RN CCRP; Jeanette O’Donnell Auman, BS; Kristin M. Zaterka-Baxter, RN BSN CCRP; Anna Mazur, BA; James W. Pickett, BS; Amanda Lewis.
Sharp Mary Birch Hospital for Women & Newborns (UG1 HD112100) – Rebecca Dorner, MD MHS FAAP; Jenny Koo, MD; Kathy Arnell, RNC-NIC; Felix Ines, RCP-RRT; April Peirson, BSN RNC-NIC C-NNIC IBCLC; Catherine Peterson, BS; Gabi Aliyev, DNP MSN Ed RNC-MNN; Jason Sauberan, PharmD.
Stanford University and Lucile Packard Children’s Hospital (UG1 HD27880, UL1 TR93) – Krisa P. Van Meurs, MD; Alexis S. Davis, MD MS Epi; M. Bethany Ball, BS CCRC; Dona Bahmani, CRC; Karen K. Morris, MPVM PhD CCRP; Barbara P. Recine, MA; Jennifer E. Chuck, MS; Lilia Rutkowska, MA; Gabrielle Green, MB BChir DPhil.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (UG1 HD34216) – Colm P. Travers, MD; Samuel Gentle, MD; Ariel A. Salas, MD; Vivek S. Shukla, MD; Cindie L. Buie, RN BSN; Sharon E. Owen, RN ADN; Sandra M. Turner, RN BSN; Rachel L. Benz, RN MSN; Kathryn M. Foshee, RN MSN.
University of Iowa and Sanford Health (UG1 HD53109, UL1 TR442) –Edward F. Bell, MD; Patrick J. McNamara, MB BCH BAO DCH MSc (Paeds) MRCP MRCPCH; Karen J. Johnson, RN BSN; Mendi L. Schmelzel, RN MSN; Jacky R. Walker, RN; Claire A. Goeke, RN; Laurie A. Hogden, MD; Megan M. Henning, RN; Chelsey Elenkiwich, BSN RN; Megan Broadbent, RN BSN; Sarah Van Muyden, RN BSN.
University of Mississippi, University of Mississippi Medical Center (UG1 HD112097) - Mobolaji Famuyide, MD; Chelsea A. Giachelli, MHA; Nathan J. Taylor, BS; Sara Hodges, RRT-NPS; Christopher McKenzie, PharmD; Samantha Jackson, PharmD.
University of New Mexico Health Sciences Center (UG1 HD53089, UL1 TR41) –Sandra Sundquist Beauman, MSN RNC-NIC; Elizabeth Kuan, RN BSN; Nicole J. Salazar, RN BSN; Jennifer Montoya, RN BSN.
University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, Children’s Hospital of Philadelphia, and Virtua Voorhees Hospital (UG1 HD68244) – Eric C. Eichenwald, MD; Toni Mancini, RN BSN CCRC; Jonathan Snyder, RN BSN; Lauren Booth, APN BSN NNP-BC; Megan A. Dhawan, MSN CRNP; Christine Catts, CRNP; Melanie Crisafulli BSN RNC-NIC; Kimberly Zola, RN BSN; Mary Catherine Gambacorta, RN BSN.
University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (UG1 HD68263, UL1 TR42) –Ann Marie Reynolds, MD Ronnie Guillet, MD PhD; Satyan Lakshminrusimha, MD; Ann Marie Scorsone, MS CCRC; Constance Orme; Premini Sabaratnam, MPH; Alison Kent, BMBS FRACP MD; Rachel Jones; Elizabeth Boylin, BA; Daisy Rochez, BS MHA; Emily Li, BA; Rosemary Jensen; Kelsey Voelker, BS; Ashley Williams, MSEd; Deanna Maffett, RN; Diane Prinzing; Julianne Hunn, BS; Stephanie Guilford, BS; Mary Rowan, RN; Michael Sacilowski, MAT CCRC; Holly I.M. Wadkins, MA; Kyle Binion, BS; Melissa Bowman, RN NP; Jennifer Donato, BS; Melissa Moreland, MEd.
University of Texas Southwestern Medical Center, Parkland Health & Hospital System, and Children’s Medical Center Dallas (UG1 HD40689) –Vishal Kapadia, MD; Shalini Ramachandran, MD; Venkat Kakkilaya, MD; Michelle Harrod Webbon, MSN RN; Joanne Duran, RN BSN; Melissa Kawamura, RN; Lindsay Roblyer, RN; Pollieanna Sepulveda, RN; Christina Cha, PharmD RPh; Rosa Hernandez, PharmD RPh; Azadeh Mozaffari, PharmD RPh; Reshma Wright, PharmD RPh; Natalie DellaValle, PharmD BCOP BCPS; Sonia Gonzales, PharmD BCOP; Mina Pak, PharmD BCPS; Kerri Perry, RRT; Franci Crockett, BSRC RRT-NPS; Linda Fields, RRT.
University of Utah Medical Center, Intermountain Medical Center, McKay-Dee Hospital, Utah Valley Hospital, and Primary Children’s Medical Center (UG1 HD87226, UL1 TR105) –
Mariana Baserga, MD MSCI; Timothy M. Bahr, MD; Stephen D. Minton, MD; Mark J. Sheffield, MD; Erick B. Gerday, MD; Lisa M. Bell, RN BSN; Kathleen Coleman, RN; Rachyl M. Davis, RN BSN; Susan Christensen, RN BSN; Brandy Davis, RN BSN; Jennifer O. Elmont, RN BSN; Manndi C. Loertscher, BS CCRP; Trisha Marchant, RNC BSN; Kandace M. McGrath, BS; Hena G. Mickelsen, BA; D. Melody Parry, RN BSN; Kimberlee Weaver-Lewis, RN MS; Kathryn D. Woodbury, RN BSN; Susie Solosth Moody, RN; Susan E. Johnson, RN BSN; Diana K. Magana, RN BSN; Rebecka Masih, RN BSN; Brandy J. Petersen RN BSN; Blake Scullin, BS BSN RN; Luaiva Floyd.
Funding Sources
The National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (U10 HD27871, U10 HD53119, UG1 HD21364, UG1 HD21373, UG1 HD21385, UG1 HD27851, UG1 HD27853, UG1 HD27856, UG1 HD27880,UG1 HD27904, UG1 HD34216, UG1 HD36790, UG1 HD40492, UG1 HD40689, UG1 HD53089, UG1 HD53109, UG1 HD68244, UG1 HD68270, UG1 HD68278, UG1 HD68263, UG1 HD68284, UG1 HD87226, UG1 HD87229) and the National Center for Advancing Translational Sciences (NCATS) (UL1 TR6, UL1 TR41, UL1 TR42, UL1 TR77, UL1 TR93, UL1 TR442, UL1 TR454, UL1 TR1117) provided grant support through cooperative agreements for the Neonatal Research Network. NICHD staff provided input into the study design, conduct, analysis, and manuscript drafting; NCRR and NCATS cooperative agreements provided infrastructure support to the NRN.
Conflicts of interest (Financial and other):
Dr. Ambalavanan has other NIH grant funding related to BPD (R01 HL156275; R01HL157256), is on the Data Safety Monitoring Board for Oak Hill Bio LLC, and is a medical advisor for ResBiotic and AlveolusBio, but there is no conflict with the contents of this manuscript. Dr. C. Michael Cotten is consulting advisory for ReAlta Life Sciences and has IP and royalties from Cyto Cell International, but there is no conflict with the contents of this manuscript. There are no other conflicts regarding other authors.
Data Sharing
Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.
References
- 1.Ohuma EO, Moller AB, Bradley E, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023;402(10409):1261–1271. [DOI] [PubMed] [Google Scholar]
- 2.Bell EF, Hintz SR, Hansen NI, et al. Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013–2018. JAMA. 2022;327(3):248–263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Collaco JM, Eldredge LC, McGrath-Morrow SA. Long-term pulmonary outcomes in BPD throughout the life-course. J Perinatol. 2024. doi: 10.1038/s41372-024-01957-9 [DOI] [PubMed] [Google Scholar]
- 4.Katz TA, van Kaam AH, Schuit E, et al. Comparison of New Bronchopulmonary Dysplasia Definitions on Long-Term Outcomes in Preterm Infants. J Pediatr. 2023;253:86–93 e84. [DOI] [PubMed] [Google Scholar]
- 5.DeMauro SB. Neurodevelopmental outcomes of infants with bronchopulmonary dysplasia. Pediatr Pulmonol. 2021;56(11):3509–3517. [DOI] [PubMed] [Google Scholar]
- 6.Walsh MC, Wilson-Costello D, Zadell A, Newman N, Fanaroff A. Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia. J Perinatol. 2003;23(6):451–456. [DOI] [PubMed] [Google Scholar]
- 7.Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019;200(6):751–759. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Higgins RD, Jobe AH, Koso-Thomas M, et al. Bronchopulmonary Dysplasia: Executive Summary of a Workshop. J Pediatr. 2018;197:300–308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723–1729. [DOI] [PubMed] [Google Scholar]
- 10.Thebaud B, Goss KN, Laughon M, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers. 2019;5(1):78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Stoll BJ, Hansen NI, Bell EF, et al. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993–2012. JAMA. 2015;314(10):1039–1051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Lee SM, Sie L, Liu J, Profit J, Lee HC. Evaluation of Trends in Bronchopulmonary Dysplasia and Respiratory Support Practice for Very Low Birth Weight Infants: A Population-Based Cohort Study. J Pediatr. 2022;243:47–52 e42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Surate Solaligue DE, Rodriguez-Castillo JA, Ahlbrecht K, Morty RE. Recent advances in our understanding of the mechanisms of late lung development and bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2017;313(6):L1101–L1153. [DOI] [PubMed] [Google Scholar]
- 14.Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Early (<7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021;10(10):CD001146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Gie AG, Regin Y, Salaets T, et al. Intratracheal budesonide/surfactant attenuates hyperoxia-induced lung injury in preterm rabbits. Am J Physiol Lung Cell Mol Physiol. 2020;319(6):L949–L956. [DOI] [PubMed] [Google Scholar]
- 16.Hillman NH, Kemp MW, Fee E, et al. Budesonide with surfactant decreases systemic responses in mechanically ventilated preterm lambs exposed to fetal intra-amniotic lipopolysaccharide. Pediatr Res. 2021;90(2):328–334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Ricci F, Catozzi C, Ravanetti F, et al. In vitro and in vivo characterization of poractant alfa supplemented with budesonide for safe and effective intratracheal administration. Pediatr Res. 2017;82(6):1056–1063. [DOI] [PubMed] [Google Scholar]
- 18.Yeh TF, Lin HC, Chang CH, et al. Early intratracheal instillation of budesonide using surfactant as a vehicle to prevent chronic lung disease in preterm infants: a pilot study. Pediatrics. 2008;121(5):e1310–1318. [DOI] [PubMed] [Google Scholar]
- 19.Yeh TF, Chen CM, Wu SY, et al. Intratracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016;193(1):86–95. [DOI] [PubMed] [Google Scholar]
- 20.Zhang M, Zhang W, Liao H. Efficacy and safety of different inhaled corticosteroids for bronchopulmonary dysplasia prevention in preterm infants: A systematic review and meta-analysis. Respir Med Res. 2024;85:101096. [DOI] [PubMed] [Google Scholar]
- 21.Tang W, Chen S, Shi D, et al. Effectiveness and safety of early combined utilization of budesonide and surfactant by airway for bronchopulmonary dysplasia prevention in premature infants with RDS: A meta-analysis. Pediatr Pulmonol. 2022;57(2):455–469. [DOI] [PubMed] [Google Scholar]
- 22.Phattraprayoon N, Tan B, Na Takuathung M. Efficacy of pulmonary surfactant with budesonide in premature infants: A systematic review and meta-analysis. PLoS One. 2025;20(1):e0312561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Manley BJ, Kamlin COF, Donath SM, et al. Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants: The PLUSS Randomized Clinical Trial. JAMA. 2024;332(22):1889–1899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Hopewell S, Chan AW, Collins GS, et al. CONSORT 2025 Statement: Updated Guideline for Reporting Randomized Trials. JAMA. 2025;333(22):1998–2005. [DOI] [PubMed] [Google Scholar]
- 25.Zhao W, Ciolino J, Palesch Y. Step-forward randomization in multicenter emergency treatment clinical trials. Acad Emerg Med. 2010;17(6):659–665. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Zhao W, Weng Y. Block urn design - a new randomization algorithm for sequential trials with two or more treatments and balanced or unbalanced allocation. Contemp Clin Trials. 2011;32(6):953–961. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Walsh MC, Yao Q, Gettner P, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics. 2004;114(5):1305–1311. [DOI] [PubMed] [Google Scholar]
- 28.Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116(6):1353–1360. [DOI] [PubMed] [Google Scholar]
- 29.McNutt LA, Wu C, Xue X, Hafner JP. Estimating the relative risk in cohort studies and clinical trials of common outcomes. American journal of epidemiology. 2003;157(10):940–943. [DOI] [PubMed] [Google Scholar]
- 30.Zou G A modified poisson regression approach to prospective studies with binary data. American journal of epidemiology. 2004;159(7):702–706. [DOI] [PubMed] [Google Scholar]
- 31.Wiener LE, Ivanova A, Koch GG. Methods for clarifying criteria for study continuation at interim analysis. Pharm Stat. 2020;19(5):720–732. [DOI] [PubMed] [Google Scholar]
- 32.Wendelberger B, Lewis RJ. Futility in Clinical Trials. JAMA. Jul 31 2023;doi: 10.1001/jama.2023.14111. [DOI] [PubMed] [Google Scholar]
- 33.Saville BR, Detry MA, Viele K. Conditional Power: How Likely Is Trial Success? JAMA. 2023;329(6):508–509. [DOI] [PubMed] [Google Scholar]
- 34.Yeung TY, Zhou Q, Kanmaz Kutman HG, Pandita A, Philippopoulos E, Jasani B. Surfactant delivery via thin catheter in preterm infants: A systematic review and meta-analysis. PLoS One. 2023;18(4):e0284792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ambalavanan N, Walsh M, Bobashev G, et al. Intercenter differences in bronchopulmonary dysplasia or death among very low birth weight infants. Pediatrics. 2011;127(1):e106–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Ambalavanan N, Cotten CM, Page GP, et al. Integrated genomic analyses in bronchopulmonary dysplasia. J Pediatr. 2015;166(3):531–537 e513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.McEvoy CT, Ballard PL, Ward RM, et al. Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE). Pediatr Res. 2020;88(4):629–636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Rogowski JA, Greenberg L, Edwards EM, Ehret DEY, Buzas JS, Horbar JD. Outcomes for Very Preterm Infants Across Health Systems. JAMA Netw Open. 2025;8(6):e2513274. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Edwards EM, Ehret DEY, Soll RF, Horbar JD. Survival of Infants Born at 22 to 25 Weeks’ Gestation Receiving Care in the NICU: 2020–2022. Pediatrics. 2024;154(4). [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplement 1: Protocol
Supplement 2: Manual of Operations for BiB and Generic Database
Supplement 3: Statistical Analysis Plan
Supplement 4: Supplemental Tables
Data Availability Statement
Data reported in this paper may be requested through a data use agreement. Further details are available at https://neonatal.rti.org/index.cfm?fuseaction=DataRequest.Home.