Safety and Efficacy of MSC-EVs in the Prevention of BPD in Extremely Preterm Infants

The phase 1/2 trial aims to evaluate the safety and efficacy of EXOB-001 consisting of extracellular vesicles derived from umbilical cord mesenchymal stromal cells in the prevention of bronchopulmonary dysplasia (BPD) in extremely premature neonates. The study population includes babies born between 23 and 28 (27 + 6 days) weeks of gestational age and body weight between 500g and 1,500 g. Thirty-six subjects will receive one or three administrations of the three doses of EXOB-001 via the endotracheal route in phase 1. In phase 2, two dosages based on the results of phase 1 will be selected and a total of 203 subjects will be randomised to receive either EXOB-001 or placebo (saline solution).

Infants will be followed up to 2 years of corrected age (end of study).

Bronchopulmonary Dysplasia (BPD) is a chronic severe multifactorial respiratory disease that affects extremely premature infants and is the most common and severe consequence of preterm birth. BPD is associated with disrupted alveolarization and microvascular development, resulting in abnormal gas exchange and lung mechanics. BPD has a multifactorial aetiology, with pre-, peri-, and postnatal mechanisms causing inflammation and injury and resulting in the disruption of the lung's development with the insurgence of an aberrant repair mechanism.

EXOB-001 consists of a population of EVs smaller than 0.22 μm in diameter, containing proteins and nucleic acids, enclosed in a double layer of phospholipids with integral and surface-bound proteins as the main components. EVs exert anti-inflammatory and immunomodulatory activity by reducing the release of proinflammatory cytokines and reducing the recruitment of immune cells in the lung. Current evidence shows that EVs can modulate macrophage phenotype, and this is relevant for BPD, because of the role macrophages have in its pathogenesis.

Two hundred sixty-five (265), 40 in phase 1 (to reach 36 evaluable subjects) + 225 in phase 2 (to reach 203 evaluable subjects), extremely preterm infants at risk of developing BPD with 23 weeks up to 28 (27 weeks+6 days) weeks of gestational age and birth weight between 500g and 1,500g and being endotracheally intubated between postnatal day 3 and day 10 receiving mechanical ventilation with FiO2 \> 25%.

Phase 1 will start with cohorts with a single administration starting with a low dose up to a high dose and thereafter start the escalation of cohorts with 3 administrations starting with a low dose up to a high dose. In the case of 3 endotracheal administrations, there will be a window of 24 hours between the administrations (the maximal duration of the treatment with EXOB-001 will be 48 hours).

Phase 2 includes 2 groups with selected dosage levels and regimen of EXOB-001 based on phase 1 interim results. Subjects will be randomised (2:2:1) to receive either EXOB-001 or placebo (saline solution).

Eligibility Criteria:
Inclusion Criteria:

* From birth up to 10 days chronological age.
* From 23 weeks up to 28 weeks (27 week+6 days) gestational age at birth.
* Birth weight ≥ 500g but ≤1500g.
* Endotracheally intubated and receiving mechanical ventilation with FiO2 \> 25% anytime between 3 and 10 days postnatally or needing re-intubation due to respiratory complications, - Not expected to be extubated within the next 24/48 hours after enrolment.
* Written informed consent from parents/legally designated representative.

Exclusion Criteria:

* Surfactant administration less than 24 hours prior to (first) IMP administration.
* Has a congenital heart defect, except for patent ductus arteriosus (PDA), atrial septal defect or a small/moderate, restrictive ventricular septal defect.
* Has a serious malformation of the lung, such as pulmonary hypoplasia/aplasia, congenital diaphragmatic hernia, or any other congenital lung anomaly.
* Being treated with inhaled nitric oxide.
* Has a known chromosomal abnormality (e.g., Trisomy 18, Trisomy 13, or Trisomy 21) or a severe congenital malformation (e.g., hydrocephalus and encephalocele, trachea-oesophageal fistula, abdominal wall defects, and major renal anomalies).
* Has had a known severe congenital infectious disease (i.e., herpes, toxoplasmosis rubella, syphilis, human immunodeficiency virus, cytomegalovirus, etc.).
* Active systemic infection, severe sepsis, or septic shock at Screening up to baseline (phase I) or randomization (phase II).
* Underwent a surgical procedure (requiring admission to an operating room) within 72 hours before baseline (phase I)/randomization (phase II) or who is anticipated to have a surgical procedure (requiring admission to an operating room) within 72 hours before or following baseline (phase I)/randomization (phase II).
* Has had a Grade 3 or 4 intraventricular haemorrhage (IVH).
* Has active pulmonary haemorrhage.
* Has periventricular leukomalacia (PVL).
* The subject is currently participating in any other interventional clinical study.
* The subject is, in the opinion of the Investigator, so ill that death is inevitable, or is considered inappropriate for the study such as an infant that received thoracic compressions and/or adrenaline administration during stabilization in the delivery room and for any reason(s) other than those listed above.