Phase I Single Arm, Dose Escalating and Phase II Double Blind, Randomized, Placebo-controlled, Dose Finding Clinical Trial Assessing Safety and Efficacy of Intratracheal Administration of Allogeneic Umbilical Cord Mesenchymal Cells-derived Extracellular Vesicles in Preventing Bronchopulmonary Dysplasia in Extremely Preterm Newborns
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 265
- 试验地点
- 8
- 主要终点
- Number of subjects with BPD grade II-III incidence rate per groups (phase 2).
研究概览
简要总结
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).
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
盲法说明
Phase 1 is an open-label, dose-escalation and single-arm study. In phase 2, Investigators will remain blinded to each subject's assigned treatment throughout the study. The Sponsor will put in place procedures to maintain this blind. Indeed, to ensure the blinding of the groups, the preparation and administration of the test product will be organized by different teams. In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded study treatment records at the site(s) to verify that randomisation/dispensing has been done accurately. Blinding will be broken by the Investigator for emergency purposes only, where knowledge of the blinded treatment could influence further subject care. In addition, subjects will be unblinded for safety reports, as per regulatory requirements. Study blind will be broken after the database lock.
入排标准
- 年龄范围
- — 至 10 Days（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
EXOB-001 (Phase 1)
EXOB-001 will be administered via the endotracheal route in an already intubated newborn. EXOB-001 will be administered in three dose levels (low dose, medium dose and high dose) with one or three administrations.
干预措施: Endotracheopulmonary Instillation, Suspension (Biological)
Active group 1 EXOB-001 (Phase 2)
In phase 2, active group 1 consists of administering the first (out of two) of the safest selected dose/regimen of EXOB-001 based on phase 1 interim results.
干预措施: Endotracheopulmonary Instillation, Suspension (Biological)
Active group 2 EXOB-001 (Phase 2)
In phase 2, active group 2 consists of administering the second (out of two) of the safest selected dose/regimen of EXOB-001 based on phase 1 interim results.
干预措施: Endotracheopulmonary Instillation, Suspension (Biological)
Placebo (Phase 2)
In phase 2, the saline solution for infusion is used as a placebo.
干预措施: Endotracheopulmonary Instillation, Suspension (Biological)
结局指标
主要结局
Number of subjects with BPD grade II-III incidence rate per groups (phase 2).
时间窗: 36 weeks PMA
BPD grade II-III incidence rate per group assessed at 36 weeks PMA. The severity of BPD is assessed according to the modified NICHD severity grading (Grade I to IIIA) definition.
Number of subjects with treatment-emergent adverse events (phase 1)
时间窗: From EXOB-001 administration up to 36 weeks post-menstrual age (PMA)
The proportion of subjects exhibiting acute and short-term safety of the intratracheal administration of EXOB-001 (single dose or multiple doses at different dose levels).
次要结局
- Number of subjects with dose-limiting toxicity (DLT) (phase 1)(6 hours and 24 hours after EXOB-001 administration)
- Assessment of BPD incidence and severity (phase 1/2)(28 days of chronological age, 36 weeks PMA and 40 weeks PMA)
- Number of subjects needing for oxygen and ventilation for BPD incidence (phase 1/2)(28 days chronological age, 36 weeks PMA, 40 weeks PMA)
- Assessment of medium-term safety of EXOB-001 (phase 1/2)(From EXOB-001 administration to hospital discharge (between 36 and 40 weeks PMA))
- Safety evaluation (phase 1/2)(From enrolment to 2 years of corrected age (end of study))
- Assessment of immune markers (phase 2)(Baseline (before EXOB-001 administration), baseline + 24 hours before EXOB-001 administration, baseline + 72 hours if the the subject is still intubated)
- Number of subjects with complications of prematurity (phase 1/2)(From baseline to 2 years of corrected age (end of study))
- Assessment of the respiratory morbidity (phase 1/2)(From hospital discharge to 2 years of corrected age (end of study))
- Assessment of neurodevelopment (phase 1/2)(From hospital discharge to 2 years of corrected age (end of study))
- Assessment of lung ultrasound score (phase 1/2)(From baseline to 2 years of corrected age (end of study))