Efficacy and Safety of Zelpultide Alfa in Preterm Neonates at High Risk of Developing Bronchopulmonary Dysplasia (BPD)

Official title

Randomized, Double-Blind Parallel-Group, Adaptive, Three-Arm, Phase 2b/3 Multicenter Study to Evaluate the Efficacy and Safety of Zelpultide Alfa in Preventing Bronchopulmonary Dysplasia (BPD) in High-Risk Preterm Neonates Compared to Standard of Care (SOC)

Overview

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.

Interventions

• Other Air-sham
  Room air for intratracheal administration
• Drug Zelpultide alfa
  Reconstituted Zelpultide alfa for intratracheal administration

Primary outcome measures

• Incidence of grade 2 or grade 3 Bronchopulmonary Dysplasia (BPD) or death [Time frame: Week 36 Post Menstrual Age (PMA)]

Secondary outcome measures (12)

• Ventilator-free days [Time frame: From birth to 36 weeks Post Menstrual Age (PMA)]
• Incidence of grade 2 or grade 3 Bronchopulmonary Dysplasia (BPD) [Time frame: Week 36 Post Menstrual Age (PMA)]
• Incidence of death [Time frame: Week 36 Post Menstrual Age (PMA)]
• Incidence of grade 2 or grade 3 Bronchopulmonary Dysplasia (BPD) or death assessed on 3 consecutive days at week 36 PMA [Time frame: Week 36 Post Menstrual Age (PMA)]
• The proportion of subjects with no Bronchopulmonary Dysplasia (BPD), grade 1, grade 2, or grade 3 BPD [Time frame: Week 36 Post Menstrual Age (PMA)]
• The proportion of subjects with no Bronchopulmonary Dysplasia (BPD), grade 1, grade 2, or grade 3 BPD assessed on 3 consecutive days at week 36 PMA [Time frame: Week 36 Post Menstrual Age (PMA)]
• Ventilator-free days [Time frame: From birth to day 28 of life]
• Total average days on supplemental oxygen [Time frame: From birth to 36 Weeks Post Menstrual Age (PMA)]
• Total average days on continuous positive airway pressure (CPAP) or high flow nasal cannula (HFNC) [Time frame: From birth to week 36 Post Menstrual Age (PMA)]
• Extubation rate [Time frame: Study Day 7]
• Average preductal oxygen saturation measured by oxygen saturation to fraction of inspired oxygen ratio (SF) [Time frame: From Study Days 1 to 7]
• Average preductal oxygen saturation measured by oxygen saturation index (OSI) [Time frame: From Study Days 1 to 7]

Eligibility criteria

Inclusion criteria

• 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.
• Informed consent and personal information authorization form signed by the subject's parent(s) or legal guardian(s).

Exclusion criteria

• Birth weight < 400 g or > 1,500 g.
• Major apparent congenital abnormalities impacting cardio and pulmonary function identified before randomization, such as, but not limited to:

• Clinically relevant Potter-like syndrome and any pulmonary congenital anomalies,
• Clinically relevant congenital diaphragmatic hernia,
• Omphalocele or gastroschisis, esophageal atresia,
• Known or suspected cyanotic congenital heart disease (ie, tetralogy of fallot, transposition of the great arteries, etc).
• Active do no resuscitate (DNR) order in place.
• History of allergy or sensitivity to any surfactant or any component of zelpultide alfa.
• Concurrent enrollment in any clinical study that utilizes treatments (investigational medical products or devices) outside of SOC or participation in studies within the last 30 days (or 5 half-lives of an IMP) prior to birth (for the mother) or up to week 36 PMA.
• Any condition or situation that, in the Investigator's judgement, puts the neonate at significant risk, could confound the study results, or may interfere significantly with the neonate's participation in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

Spain · 13 centers

• Hospital General Universitario de Alicante Dr. Balmis — Alicante
• Hospital Clínic de Barcelona — Barcelona
• Hospital de la Santa Creu i Sant Pau — Barcelona
• Hospital Sant Joan de Déu — Barcelona
• Hospital Universitario Cruces - OSI Ezkerraldea-Enkarterri-Cruces — Bilbao
• Hospital Universitario Puerta del Mar — Cadiz
• Hospital Universitari Arnau de Vilanova de Lleida — Lleida
• Hospital General Universitario Gregorio Marañón — Madrid
• … and 5 more centers

France · 8 centers

• CHU Lille - Hôpital Jeanne de Flandre — Lille
• CHRU Nancy — Nancy
• CHU Nice — Nice
• AP-HP CHU Robert-Debré - Hôpitaux de Paris — Paris
• AP-HP Paris Saclay University - Hôpitaux Antoine-Béclère — Paris
• AP-HP Paris Saclay University Bicêtre Hospital — Paris
• AP-HP University Hospital Cochin - Port Royal — Paris
• Hôpital de Poissy Saint-Germain-en-Laye — Poissy

Italy · 6 centers

• IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant'Orsola — Bologna
• Istituto Giannina Gaslini — Genova
• Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico — Milan
• Ospedale dei Bambini "V. Buzzi" — Milan
• Università degli Studi di Napoli Federico II — Naples
• Azienda Ospedale Università di Padova — Padova

Poland · 6 centers

• Uniwersyteckie Centrum Kliniczne — Gdansk
• University Hospital in Krakow — Krakow
• Polish Mother's Memorial Hospital - Research Institute in Lodz — Lodz
• Gynecological Obstetric Clinical Hospital of Poznan University of Medical Sciences — Poznan
• University Clinical Hospital No. 2 PUM — Szczecin
• University Hospital Wroclaw — Wroclaw

Belgium · 5 centers

• ZAS Middelheim — Antwerp
• Cliniques Universitaires Saint-Luc — Brussels
• UZ Leuven — Leuven
• CHU de Liege - Hospital de la Citadelle — Liège
• Clinique CHC MontLégia — Liège

Israel · 5 centers

• Bnai Zion Medical Center — Haifa
• Rambam Medical Center — Haifa
• Haddasah medical center — Jerusalem
• Shaare-Zedek Medical Center — Jerusalem
• Ziv Medical Center — Safed

Argentina · 4 centers

• Clínica y Maternidad Suizo Argentina — Buenos Aires
• Hospital Italiano de Buenos Aires — Buenos Aires
• Hospital Sanatorio de la Trinidad San Isidro — Buenos Aires
• Hospital Universitario Austral — Buenos Aires

Germany · 3 centers

• Medical Faculty of TU Dresden — Dresden
• Universitätsklinikum Freiburg — Freiburg im Breisgau
• University Children's Hospital Regensburg (KUNO) — Regensburg

Identifiers

NCT: NCT06897839 · ZEL-003 · 2024-513420-41-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗