The Budesonide in Babies (BiB) Trial

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.

• budesonide (Pulmicort nebulizing suspension). (Drug), also known as 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.
• surfactant (poractant alfa;Curosurf) (Drug), also known as 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.

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: any to 48 Hours

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

Participant flow

Outcome results

• Physiologic BPD or Death by 36 Weeks PMA (Primary), Count of participants, Participants: BUDE 101; SURF 102
• Death by 36 Weeks PMA (Secondary), Count of participants, Participants: BUDE 272; SURF 276
• Physiologic BPD (Secondary), Count of participants, Participants: BUDE 101; SURF 102
• Grade of BPD Severity (Secondary), Count of participants, Participants: BUDE 70; SURF 66
• Severe BPD (Secondary), Count of participants, Participants: BUDE 241; SURF 244
• Use of Additional Postnatal Steroids (Secondary), Count of participants, Participants: BUDE 216; SURF 202

Adverse events

Time frame: Adverse events were monitored from treatment through 7 days (168 hours) post-treatment, or treatment through 30 days (720 hours) post-treatment for SIP and PVL. All-cause mortality was monitored from randomization through 36 weeks PMA.

Serious adverse events by term

Other adverse events by term

• Results publication: Ambalavanan N, Carlo WA, Nowak KJ, Wiener LE, Cosby SS, Bhatt AJ, Watterberg KL, Poindexter BB, Keszler M, D'Angio CT, Brion LP, Narendran V, Rau CA, Cotten CM, Laughon MM, Das A, Rysavy MA, Hibbs AM, Fuller J, Puopolo KM, Katheria A, Patel RM, Bermick JR, Laptook AR, Prelipcean I, Wyckoff MH, Moore R, Merhar SL, Ohls RK, Yoder BA, Perez M, Ghavam S, Meyer LR, Chock VY, DeMauro SB, Jackson WM, Handa D, Walsh MC; National Institute of Child Health and Human Development Neonatal Research Network. Early Intratracheal Budesonide to Reduce Bronchopulmonary Dysplasia in Extremely Preterm Infants: The Budesonide in Babies (BiB) Randomized Clinical Trial. JAMA. 2025 Oct 28;334(16):1452-1462. doi: 10.1001/jama.2025.16450. PMID 41026481

• Study Protocol (PDF, 2023-09-08)
• Statistical Analysis Plan (PDF, 2024-09-10)
• Informed Consent Form (PDF, 2020-05-15)

• Namasivayam Ambalavanan, MD, Principal investigator, University of Alabama at Birmingham

NIH grants: UG1HD034216, UG1HD027904, UG1HD021364, UG1HD027853, UG1HD040689, UG1HD040492, UG1HD027851, UG1HD087229, UG1HD053109, UG1HD068278, UG1HD068244, UG1HD068263, UG1HD027880, UG1HD053089, UG1HD087226, UG1HD112079, UG1HD112097, UG1HD112100, U24HD095254