The Pilot Experimental Study of the Neuroprotective Effects of Exosomes in Extremely Low Birth Weight Infants

Study Overview
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Brief Summary
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To study the safety and efficacy of intranasal administration of exosomes derived from mesenchymal stromal cells on long-term neurodevelopmental outcome in extremely low birth weight infants born at gestational age 25/0-27/6 weeks.

Detailed Description
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Surviving extremely low birth weight (ELBW) infants are at risk of severe neurodevelopmental disability. Exosomes or extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) can mediate a variety of different effects, including synaptic plasticity, nutritional metabolic support, nerve regeneration, inflammatory response, anti-stress effect, cellular waste disposal, treating neurological injury, preventing hemorrhagic and ischemic brain lesions, playing an important role in health and neuroprotection in extremely premature newborns during neonatal intensive care. The proposed blinded randomized controlled trial was designed to compare the effect of intranasal administration of exosomes on long-term neurodevelopmental outcome in ELBW infants. ELBW infants will be randomized to receive (group 1) and not receive exosomes (control group). Group 1 - Neonates will receive exosomes (1 dose will be obtained from a daily conditioned culture medium of 120 million MSCs) suspended in 500 µl of phosphate buffer in each nostril at 50 µl with an interval of 2-3 minutes. The therapeutic course will consist of 5 instillations with an interval of 1 days. The primary outcome measure is the incidence of death, the incidence of survival with any of either severe intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL), or brain injury on cranial ultrasound and MRI or major neurodevelopmental impairment determined at 36 months of age corrected for prematurity (where major neurodevelopmental impairment is defined as any of the following: cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Cognitive delay defined as mental developmental index (MDI) score of the Griffiths-II and Bayley Scales of Infant Development (2nd edition) < 85, cerebral palsy, or severe visual or hearing impairment. To investigate this outcomes and the mechanisms by which extracellular vesicles (EVs) might effect we will analyze the biomarkers of perinatal brain injury (S-100, NSE, EPO) and mRNA. Key secondary outcomes are incidences of short term outcomes: individual components of the composite primary outcome, survival with and without major neonatal morbidity including severe retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC). Safety analyses will assess the injures or damages of the nasal mucosa, allergic reaction to EVs and any adverse events after intranasal administration of EVs. The results of this trial may help to improve the quality of life of ELBW infants and reduce long-term health care costs.

Official Title
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The Pilot Experimental Study of the Neuroprotective Effects of Exosomes in Extremely Low Birth Weight Infants

Conditions
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Neurodevelopmental Disorders, Premature Birth, Extreme Prematurity, Preterm Intraventricular Hemorrhage, Hypoxia-Ischemia, Cerebral

Intervention / Treatment
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* Other: Exosomes derived from mesenchymal stromal cells (MSCs)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Premature newborns of gestational age (GA) 25/0-27/6 weeks, Exclusion Criteria: Missing written parental consent Damages to the nasal mucosa Maxillofacial defects Major congenital anomalies (including chromosomal aberrations, cyanotic congenital heart defects, syndromes likely affecting long-term outcome, and major congenital malformations requiring surgical correction during newborn period) Infants who died before 48 hours, infants in whom the clinical decision to withhold intensive care was made, infants who were not considered viable Infants with edematous hemolytic disease of newborns, non-immune fetal dropsy, Multifetal Gestations Participation in another study with ongoing use of an unlicensed investigational product from 28 days before study enrollment until the end of the study

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 3 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants (ELBW infants GA 25/0-27/6 week) are randomized to one of two groups in parallel for the duration of the study. The first group (exosome treatment group) will receive intranasal administration of exosomes and the second (control group) will not receive exosomes. Patients in both groups will receive standard basic therapy
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intranasal exosomes administration<br>ELWB newborns who will receive intranasal exosomes | Other: Exosomes derived from mesenchymal stromal cells (MSCs)<br>* Exosomes derived from mesenchymal stromal cells (MSCs) will be administered intranasal in ELBW infants<br>|
| No Intervention: Control<br>ELWB newborns who will not receive intranasal exosomes | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence and rate of dose limiting toxicity | Dose limiting toxicity consists of the following events: Death occurring within 24 hours after intranasal administration of EVs; Hypersensitivity / anaphylactic to EVs defined as any severe systemic inflammatory response syndrome with negative blood culture not consistent with the overall clinical course of the infant occurring within 72 hours after intranasal administration of EVs; Any other serious adverse event not expected in this patient population for which there is no alternative explanation but the administration of EVs, occurring within 1 week of injection. | Up to 1 week following after intranasal administration of EVs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of death | Rate of death until discharge or 40 weeks corrected gestational age, whichever comes first | From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first) | 
| Occurrence of Other Severe Complications of Prematurity | Blood culture-proven sepsis Patent ductus arteriosus (treated medically or surgically) Necrotizing enterocolitis Isolated intestinal perforation Retinopathy of prematurity requiring treatment Severe intraventricular hemorrhage (≥ grade 3) Cystic periventricular leukomalacia Incidence and Severity of BPD, Measured as mild, moderate, or severe | From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first) | 
| Need for Ventilatory Support | Time to extubation Duration of mechanical ventilation Duration of non-invasive positive pressure respiratory support Duration of supplemental oxygen | From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first) | 
| Changes in Hemodynamics | Targeted neonatal echocardiography to assess | Time Frame: At enrollment, 48 hours following intranasal administration of EVs, 28 days of life, and 36 weeks corrected gestational age | 
| Feasibility: Administration | Successful recruitment and administration of extracellular vesicles to 10 patients in 18 months | Day of life 1-10 | 
| Feasibility: Recruitment Efficiency | Proportion of potentially eligible patients that are successfully screened Proportion of participants successfully screened who do not enroll (reason for failure to enroll will be recorded) | Day of life 1-10 | 
| Feasibility: Recruitment Timing | Median time from screening to enrollment Median time from screening to extracellular vesicles | Day of life 1-10 | 
| Feasibility: Participant Retainment | Proportion of patients that do not complete administration of extracellular vesicles Proportion of patients enrolled that do not undergo scheduled follow-up | From enrollment until follow-up at 18-36 months-of-age | 
| Griffiths-II and Bayley Scales of Infant Development (2nd edition) | Assessment of cognitive, language, and motor development. Cognitive delay defined as mental developmental index (MDI) score of the Griffiths-II and Bayley Scales of Infant Development (2nd edition) < 85, cerebral palsy, or severe visual or hearing impairment. | 18-36 months-of-age | 
| Long-term Safety Follow-Up | Participant's overall health will be assessed through a questionnaire administered over the phone, once a year for 3 years | 3 years following follow-up visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extremely low birth weight, neuroprotection