The Budesonide in Babies (BiB) Trial (BiB)

• ClinicalTrials.gov Identifier: NCT04545866
• Recruitment Status: Recruiting
• First Posted: September 11, 2020
• Last Update Posted: May 9, 2023
• Sponsor: NICHD Neonatal Research Network
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): NICHD Neonatal Research Network

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Bronchopulmonary Dysplasia (BPD); Respiratory Distress Syndrome; Prematurity; Extreme; Neonatal	Drug: budesonide (Pulmicort nebulizing suspension).; Drug: surfactant (poractant alfa;Curosurf)	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, 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.
• Primary Purpose: Treatment
• Official Title: Randomized Controlled Trial of Budesonide + Surfactant Versus Surfactant Alone in Extremely Preterm Infants ("The Budesonide in Babies (BiB) Trial")
• Actual Study Start Date: March 15, 2021
• Estimated Primary Completion Date: September 30, 2025
• Estimated Study Completion Date: September 30, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: budesonide with surfactant; 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).; 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.; Other Name: Pulmicort nebulizing suspension.
Active Comparator: surfactant alone; Infants randomized to the active control arm receive a dose of surfactant (poractant alfa; Curosurf).	Drug: surfactant (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.; Other Name: poractant alfa;Curosurf

Outcome Measures

Primary Outcome Measures :

1. Number of Participants with Physiologic BPD or death [ Time Frame: Randomization to 36 weeks' post-menstrual age ]
   Physiologic BPD or death by 36 weeks' PMA. Physiologic BPD is determined using existing NRN GDB criteria at 36 weeks' PMA.

Secondary Outcome Measures :

1. Number of Participants with Death by 36 weeks' post-menstrual age [ Time Frame: Randomization to 36 weeks' post-menstrual age ]
   Death by 36 weeks' PMA
2. Number of Participants with Physiologic BPD [ Time Frame: 36 weeks' post-menstrual age ]
   Physiologic BPD as determined by existing NRN GDB criteria at 36 weeks' PMA.
3. Grade of BPD Severity [ Time Frame: 36 weeks' post-menstrual age ]

   BPD severity is defined as in Jensen et al. (2019; PMID: 30995069) at 36 weeks' PMA according to treatment with the following respiratory support:

   1. No BPD: room air;
   2. Grade 1: nasal cannula at flow rates ≤ 2 L/min;
   3. Grade 2: nasal cannula at flow rates > 2 L/min or noninvasive positive airway pressure;
   4. Grade 3: invasive mechanical ventilation.
4. Number of Participants with Grade 3 BPD [ Time Frame: 36 weeks' post-menstrual age ]
   Grade 3 BPD at 36 weeks' PMA according to the Jensen et al. (2019 PMID: 30995069) definition.
5. Number of Participants with Use of Additional Postnatal Steroids [ Time Frame: 7 days post final dose of study drug through 36 weeks' post-menstrual age ]
   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.
6. Number of Participants with Severe Neurodevelopmental Impairment (NDI) [ Time Frame: 22-26 months corrected age ]

   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:

   1. Cognitive composite score on the BSID IV < 70,
   2. GMFCS level 3-5,
   3. Severe hearing impairment (no functional hearing despite amplification), or
   4. Bilateral severe visual impairment (bilateral blindness despite correction).
7. Number of Participants with Death by 2 years [ Time Frame: Randomization to 22-26 months corrected age ]
   Death by 2-year follow-up (22-26 months corrected age)
8. Number of Participants with Severe NDI or death [ Time Frame: Randomization to 22-26 months corrected age ]
   Severe NDI or death as assessed at 2-year follow-up (22-26 months corrected age)

Eligibility Criteria

• Ages Eligible for Study: up to 48 Hours (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Namasivayam Ambalavanan, MD; (205) 934 4680; ambal@uab.edu

Contact: Abhik Das, PhD; 301-230-4640; adas@rti.org

Locations

United States, Alabama

University of Alabama; Recruiting

Birmingham, Alabama, United States, 35249-7335

Contact: Namasivayam A. Ambalavanan, MD

Principal Investigator: Waldemar Carlo, MD

United States, California

Stanford University; Not yet recruiting

Palo Alto, California, United States, 94304

Contact: Krisa P Van Meurs, MD

Principal Investigator: Krisa P Van Meurs, MD

United States, Georgia

Emory University; Recruiting

Atlanta, Georgia, United States, 30303

Contact: Ravi Patel, MD

Sub-Investigator: Brenda Poindexter, MD

Principal Investigator: Ravi Patel, MD

United States, Iowa

University of Iowa; Recruiting

Iowa City, Iowa, United States, 52242

Contact: Edward F Bell, MD

Principal Investigator: Edward F Bell, MD

United States, New Mexico

University of New Mexico; Recruiting

Albuquerque, New Mexico, United States, 87131

Contact: Kristi L Watterberg, MD

Principal Investigator: Kristi L Watterberg, MD

United States, New York

University of Rochester; Recruiting

Rochester, New York, United States, 14642

Contact: Carl T D'Angio, MD

Principal Investigator: Carl T D'Angio, MD

United States, North Carolina

RTI International; Active, not recruiting

Durham, North Carolina, United States, 27705

Duke University; Recruiting

Durham, North Carolina, United States, 27710

Contact: C. Michael Cotten, MD

Principal Investigator: C. Michael Cotten, MD MHS

United States, Ohio

Cincinnati Children's Medical Center; Recruiting

Cincinnati, Ohio, United States, 45267

Contact: Stephanie Merhar, MD MS

Sub-Investigator: Vivek Narendran, MD, MBA

Principal Investigator: Stephanie Merhar, MD MS

Case Western Reserve University, Rainbow Babies and Children's Hospital; Recruiting

Cleveland, Ohio, United States, 44106

Contact: Anna Maria C. Hibbs, MD, MSCE

Sub-Investigator: Deanne C. Wilson, MD

Principal Investigator: Anna Maria C. Hibbs, MD, MSCE

Research Institute at Nationwide Children's Hospital; Not yet recruiting

Columbus, Ohio, United States, 43205

Contact: Pablo Sanchez, MD

Principal Investigator: Pablo Sanchez, MD

United States, Pennsylvania

University of Pennsylvania; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Eric Eichenwald, MD

Principal Investigator: Eric Eichenwald, MD

United States, Rhode Island

Brown University - Women and Infants Hospital of Rhode Island; Recruiting

Providence, Rhode Island, United States, 02905

Contact: Abbot R. Laptook, MD

Principal Investigator: Abbot R Laptook, MD

United States, Texas

University of Texas Southwestern Medical Center at Dallas; Recruiting

Dallas, Texas, United States, 75235

Contact: Myra Wyckoff, MD

Principal Investigator: Myra Wyckoff, MD

University of Texas Health Science Center at Houston; Recruiting

Houston, Texas, United States, 77030

Contact: Jon E Tyson, MD MPH

Principal Investigator: Jon E. Tyson, MD MPH

United States, Utah

University of Utah; Recruiting

Salt Lake City, Utah, United States, 84108

Contact: Robin Ohls, MD

Principal Investigator: Robin Ohls, MD

Sponsors and Collaborators

NICHD Neonatal Research Network

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Namasivayam Ambalavanan, MD; University of Alabama at Birmingham

More Information

• Responsible Party: NICHD Neonatal Research Network
• ClinicalTrials.gov Identifier: NCT04545866
• Other Study ID Numbers: NICHD-NRN-0064; UG1HD034216 ( U.S. NIH Grant/Contract ); UG1HD027904 ( U.S. NIH Grant/Contract ); UG1HD021364 ( U.S. NIH Grant/Contract ); UG1HD027853 ( U.S. NIH Grant/Contract ); UG1HD040689 ( U.S. NIH Grant/Contract ); UG1HD040492 ( U.S. NIH Grant/Contract ); UG1HD027851 ( U.S. NIH Grant/Contract ); UG1HD087229 ( U.S. NIH Grant/Contract ); UG1HD053109 ( U.S. NIH Grant/Contract ); UG1HD068278 ( U.S. NIH Grant/Contract ); UG1HD068244 ( U.S. NIH Grant/Contract ); UG1HD068263 ( U.S. NIH Grant/Contract ); UG1HD027880 ( U.S. NIH Grant/Contract ); UG1HD053089 ( U.S. NIH Grant/Contract ); UG1HD087226 ( U.S. NIH Grant/Contract ); U10HD036790 ( U.S. NIH Grant/Contract )
• First Posted: September 11, 2020
• Last Update Posted: May 9, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov).

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Ventilator-Induced Lung Injury; Lung Injury; Budesonide; Poractant alfa; Pulmonary Surfactants; Anti-Inflammatory Agents; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists