The Budesonide in Babies (BiB) Trial

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

Status

Active, not recruiting

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04545866

Acronym

BiB

Enrollment

642

Registered

2020-09-11

Start date

2021-04-01

Completion date

2026-12-17

Last updated

2026-04-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Brief summary

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

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.

Interventions

DRUGbudesonide (Pulmicort nebulizing suspension).

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.

DRUGsurfactant (poractant alfa;Curosurf)

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

The investigator, primary providers, primary data collectors, and participants will be masked to randomization arm assignment. Only research pharmacists and a designated respiratory therapist (or other qualified person) will be unmasked at the enrolling sites. The designated respiratory therapist (or other qualified person) must be unmasked to allow drug mixing at bedside for expeditious study drug administration; however, this person will not be the primary medical provider nor the primary data collector for that infant, and will not be otherwise involved in the research.

Eligibility

Sex/Gender

ALL

Age

No minimum to 48 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Physiologic BPD or Death by 36 Weeks PMA	Randomization to 36 weeks PMA	A composite outcome for infants who were diagnosed with physiologic BPD or died by 36 weeks PMA. Physiologic BPD is determined using existing NRN GDB criteria at 36 weeks' PMA. Infants alive an in hospital are classified based on respiratory status at 36 week's PMA or by a room air weaning challenge performed between 36 and 37 weeks' PMA. Infants who are transferred or discharged before 36 weeks are classified based on the support they are receiving at that time. Infants who died before 36 weeks' PMA are not assessed for BPD. Deaths include all-cause deaths between randomization and 36 weeks' PMA.

Secondary

Measure	Time frame	Description
Death by 36 Weeks PMA	Randomization to 36 weeks PMA	Died (all-cause) after randomization and by 36 weeks PMA
Physiologic BPD	At 36 weeks PMA	Diagnosed with physiologic BPD at 36 weeks PMA. Physiologic BPD is determined using existing NRN GDB criteria at 36 weeks' PMA. Infants alive an in hospital are classified based on respiratory status at 36 week's PMA or by a room air weaning challenge performed between 36 and 37 weeks' PMA. Infants who are transferred or discharged before 36 weeks are classified based on the support they are receiving at that time. Infants who died before 36 weeks' PMA are not assessed for BPD.
Grade of BPD Severity	At 36 weeks PMA	BPD Severity Grade at 36 weeks PMA according to the Jensen et al. (2019; PMID: 30995069) definition, also known as pragmatic BPD. Infants are assess based on the mode of support at 36 weeks' postmenstrual age regardless of prior duration or current level of oxygen therapy.
Severe BPD	At 36 weeks PMA	Diagnosed with Severe (Grade 3) BPD at 36 weeks PMA according to the Jensen et al. (2019; PMID: 30995069) definition. This outcome is a dichotomy of the pragmatic BPD severity grades (Grade 3 vs. Grade 2, 1, or 0).
Use of Additional Postnatal Steroids	7 days post last dose of study drug through 36 weeks PMA	Use of any postnatal steroids for treatment of evolving chronic lung disease (separate from study drug) between 7 days after the final dose of study drug and 36 weeks PMA. Note: Infants were permitted up to two doses of study drug within 50 hours postnatal age, so this outcome spans 7-10 days postnatal age through 36 weeks postmenstrual age.

Countries

United States

Contacts

PRINCIPAL_INVESTIGATORNamasivayam Ambalavanan, MD

University of Alabama at Birmingham

Participant flow

Pre-assignment details

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.

Participants by arm

Arm	Count
BUDE Budesonide (Pulmicort nebulizing suspension) 1 ml/kg + Surfactant (poractant alfa; Curosurf) 2.5 ml/kg	323
SURF Surfactant (poractant alfa; Curosurf) 2.5 ml/kg	318
Total	641

Baseline characteristics

Characteristic	BUDE	SURF	Total
Age, Continuous	25.8 weeks STANDARD_DEVIATION 1.9	25.9 weeks STANDARD_DEVIATION 2	25.9 weeks STANDARD_DEVIATION 1.9
Age, Customized Greater Than or Equal to 26 0/7 weeks	185 Participants	188 Participants	373 Participants
Age, Customized Less Than 26 0/7 weeks	138 Participants	130 Participants	268 Participants
Race/Ethnicity, Customized Black or African America	101 Participants	122 Participants	223 Participants
Race/Ethnicity, Customized Hispanic or Latino	50 Participants	54 Participants	104 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	254 Participants	254 Participants	508 Participants
Race/Ethnicity, Customized Other	21 Participants	17 Participants	38 Participants
Race/Ethnicity, Customized Unknown or Not Reported	18 Participants	11 Participants	29 Participants
Race/Ethnicity, Customized White	183 Participants	168 Participants	351 Participants
Sex/Gender, Customized Female	163 Participants	156 Participants	319 Participants
Sex/Gender, Customized Male	158 Participants	162 Participants	320 Participants
Sex/Gender, Customized Missing	2 Participants	0 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	49 / 323	42 / 318
other Total, other adverse events	232 / 323	187 / 318
serious Total, serious adverse events	63 / 323	55 / 318

Outcome results

Primary

Physiologic BPD or Death by 36 Weeks PMA

A composite outcome for infants who were diagnosed with physiologic BPD or died by 36 weeks PMA. Physiologic BPD is determined using existing NRN GDB criteria at 36 weeks' PMA. Infants alive an in hospital are classified based on respiratory status at 36 week's PMA or by a room air weaning challenge performed between 36 and 37 weeks' PMA. Infants who are transferred or discharged before 36 weeks are classified based on the support they are receiving at that time. Infants who died before 36 weeks' PMA are not assessed for BPD. Deaths include all-cause deaths between randomization and 36 weeks' PMA.

Time frame: Randomization to 36 weeks PMA