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 mesenchymal cells-derived extracellular vesicles in preventing bronchopulmonary dysplasia in extremely preterm newborns.

The primary objective of this clinical trial is to evaluate the **acute and short-term safety** of the intratracheal administration of EXOB-001 in extremely preterm newborns at 36 weeks postmenstrual age (PMA). This assessment is crucial for determining the immediate safety profile of EXOB-001, which is derived from allogeneic umbilical mesenchymal cells, and its potential role in preventing bronchopulmonary dysplasia (BPD), a serious lung condition in preterm infants. Additionally, the trial aims to assess the efficacy of EXOB-001 in reducing BPD grade II-III at 36 weeks PMA compared to a placebo group, which is clinically significant for improving respiratory outcomes in this vulnerable population.

Secondary objectives include: - Assessing medium-term safety of EXOB-001 up to hospital discharge. - Evaluating dose-limiting toxicity within 6 and 24 hours post-administration. - Assessing tolerability and the number of cases and severity of BPD. - Evaluating lung development, confirming parenchymal lung disease, and assessing pulmonary hypertension. - Assessing overall health status up to 2 years corrected age, with a focus on pulmonary morbidity. - Evaluating mortality caused by lung failure and long-term safety of EXOB-001. - Assessing the duration of mechanical ventilation, respiratory support, and hospital stay, as well as known complications and sequelae of prematurity. - Evaluating neurodevelopmental condition and respiratory morbidity up to 2 years corrected age. - Testing immune markers in tracheal aspirate fluid in a subset of subjects.

The clinical trial focuses on assessing the safety and efficacy of EXOB-001 in neonates diagnosed with **Bronchopulmonary Dysplasia**. The study population includes both male and female subjects, specifically targeting a vulnerable population of newborns. Participants are selected based on specific criteria, including a gestational age at birth ranging from 23 to 28 weeks and a birth weight between 500g and 1500g. Eligible subjects are those who are endotracheally intubated and receiving mechanical ventilation with FiO2 greater than 25% anytime between 3 and 10 days postnatally or require re-intubation due to respiratory complications. The age range for inclusion is from birth up to 10 days chronological age. The sponsor has not provided the total number of participants involved in the trial. Written informed consent from parents or legally designated representatives is required for participation. The trial does not specify any particular lifestyle considerations such as diet or physical activity, given the nature of the study population.

The clinical trial is designed to evaluate the safety and efficacy of **allogeneic umbilical cord mesenchymal cells-derived extracellular vesicles** in preventing **bronchopulmonary dysplasia** in extremely preterm newborns. This study is structured in two phases: Phase I is a single-arm, dose-escalating trial, while Phase II is a double-blind, randomized, placebo-controlled dose-finding trial. The trial is expected to run from July 2023 to June 2028, with participant involvement lasting until 36 weeks postmenstrual age (PMA).

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as gestational age, birth weight, and respiratory status. Following enrollment, participants will receive the investigational product, EXOB-001, or a placebo, administered intratracheally. The primary objective of Phase I is to assess the acute and short-term safety of EXOB-001, while Phase II aims to evaluate its efficacy in reducing the incidence of BPD grade II-III compared to a placebo group.

Study visits will include regular follow-up assessments to monitor treatment-emergent adverse events (TEAEs), clinical examinations, and various diagnostic tests such as lung ultrasounds and chest X-rays. The end-of-study visit will occur at 36 weeks PMA, where the primary and secondary endpoints will be evaluated, including the incidence and severity of BPD and any adverse events. Participants may be withdrawn from the study if they experience significant adverse reactions or if they no longer meet the study criteria.

The trial's design ensures rigorous monitoring and data collection to achieve its objectives, with a focus on safety and efficacy outcomes. The study's randomized, double-blind, placebo-controlled methodology enhances the reliability of the results, providing valuable insights into the potential benefits of EXOB-001 in this vulnerable population.

The clinical trial involves the administration of two distinct treatments. The first treatment is **EXOB-001**, a biological product formulated as an **endotracheopulmonary instillation, suspension**. This investigational medication contains **allogeneic umbilical cord mesenchymal cells-derived extracellular vesicles**. The route of administration is endotracheopulmonary, and the treatment is designed to be administered intratracheally. The primary objective of the trial is to assess the safety and efficacy of EXOB-001 in preventing bronchopulmonary dysplasia in extremely preterm newborns. The trial includes both a single-dose and multiple-dose regimen at varying dose levels, with the aim of determining the optimal dosing strategy. EXOB-001 is designated as an orphan drug, indicating its potential use in treating a rare condition.

The second treatment used in the trial is a **placebo**, specifically a **sodium chloride** solution, marketed as "NaCl 0,9 % B. Braun, solution pour perfusion." This solution is a **chemical** product provided in the form of a **solution for injection/infusion**. The placebo is administered via the same endotracheopulmonary route as the experimental treatment. The sodium chloride solution serves as the comparator in the double-blind, randomized, placebo-controlled phase of the trial, allowing for the assessment of the efficacy of EXOB-001 against a standard saline solution. The placebo is utilized to ensure the validity of the trial results by providing a baseline for comparison with the investigational treatment.

The efficacy of the clinical trial will be assessed primarily in Phase II by evaluating the reduction of **bronchopulmonary dysplasia (BPD)** grade II-III at 36 weeks postmenstrual age (PMA) in comparison to a placebo group receiving a saline solution. The primary endpoint for Phase II is the incidence rate of BPD grade II-III, assessed using the modified NICHD severity grading definition. Secondary endpoints in Phase II include the need for oxygen and ventilation support, BPD incidence and severity rate at 36 weeks PMA, and the incidence rate of BPD grade I-II-III, all assessed per group. Additional assessments will include clinical examinations, blood tests, lung ultrasound, chest X-rays, and functional and anatomic echocardiography. The trial will also monitor the occurrence of adverse events (AEs) and serious adverse events (SAEs), including all-cause deaths, and the duration of mechanical ventilation and hospitalisation. The trial will utilize validated scales such as the ASQ3 Ages and Stages questionnaire and the Liverpool Respiratory Symptom Questionnaire (LRSQ) for further assessments. Biomarkers such as IL-6, IL-8, TNFa, TGFb1, IL1b, and IL1ra will be measured in a subset of subjects across all groups. These efficacy parameters will be collected and analyzed at specified timepoints, including 36 weeks PMA and day 28 chronological age, to determine the effectiveness of the investigational product, EXOB-001, in preventing BPD in extremely preterm newborns.