This is a randomized, parallel-group, double-blind, placebo-controlled multicenter phase 2b/3 study with an adaptive seamless design.
The goal fo this study is to determine if an investigational drug, Zelpultide Alfa, can reduce the occurrence of Bronchopulmonary Dysplasia (BPD) in extremely premature babies.
The study comprises 2 parts:
* Part 1: Phase 2b, dose selection and exploratory efficacy and safety. * Part 2: Phase 3, confirmatory efficacy and safety.
In Part 1, the study subjects will be randomized with a 1:1:1 allocation ratio to either :
1. Standard of care + zelpultide alfa 4 mg/kg or, 2. Standard of care + zelpultide alfa 6 mg/kg or, 3. Standard of care + placebo (air-sham).
In Part 1, all three arms will be evaluated descriptively to support dose selection based on safety, tolerability, and exploratory efficacy signals. Upon completion of Part 1, the DSMC will recommend which Phase 2b dose ("selected dose") to progress into Part 2 to the Study Steering Committee, which will decide the dose for Part 2 (Phase 3). A sample size reassessment will be performed after Part 1 completion.
In Part 2, the selected dose of zelpultide alfa will be compared against placebo (air-sham) in a confirmatory analysis on the primary and key secondary endpoints. The study subjects will be randomized with a 1:1 allocation ratio to either:
1. Standard of care + zelpultide alfa (selected dose from Part 1), or 2. Standard of care + placebo (air-sham). The main objective in part 2 is to compare the efficacy of zelpultide alfa added to standard of care versus standard of care plus placebo (air-sham) in terms of incidence of grade 2 and grade 3 bronchopulmonary dysplasia (BPD) and death in neonates at high risk for developing BPD.
In both parts, treatment will be administered intratracheally. Participants will receive up to 7 administrations of zelpultide alfa at (4mg/kg or 6 mg/kg) or air-sham in 24 h intervals while the subjects are still intubated per standard of care.
Born between gestational age (GA) 22 0/7 to 27 6/7 weeks, inclusive.
Received at least 1 dose of SOC-indicated animal-derived pulmonary surfactant treatment after birth.
Intubated and on invasive mechanical ventilation per SOC.
Able to receive the first dose of zelpultide alfa or air-sham at least 15 min after the surfactant administration but within 96 h of birth and within 48 h from the start of invasive mechanical ventilation. Subjects extubated and re-intubated after their pulmonary surfactant dose(s) are eligible as long as the inclusion criteria are met.
Birth weight < 400 g or > 1,500 g.
Clinically relevant Potter-like syndrome and any pulmonary congenital anomalies,
Clinically relevant congenital diaphragmatic hernia,
Omphalocele or gastroschisis, esophageal atresia,
Parallel
Air-sham
Other interventionRoom air for intratracheal administration
Zelpultide alfa
DrugReconstituted Zelpultide alfa for intratracheal administration
Incidence of grade 2 or grade 3 Bronchopulmonary Dysplasia (BPD) or death
BPD is defined and graded based on the classification according to Jensen et al., 2019 (2019 PMID: 30995069)
Ventilator-free days
A ventilator-free day is defined as a natural calendar day without being on invasive mechanical ventilation (ie, invasive ventilation via ETT or tracheostomy); tracheostomy will be treated as all invasive ventilation.
Incidence of grade 2 or grade 3 Bronchopulmonary Dysplasia (BPD)
Incidence of death
Incidence of grade 2 or grade 3 Bronchopulmonary Dysplasia (BPD) or death assessed on 3 consecutive days at week 36 PMA
BPD is defined and graded based on the classification according to Jensen et al., 2019 (2019 PMID: 30995069)
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