Clinical trial NCT05490173: The Pilot Experimental Study of the Neuroprotective Effects of Exosomes in Extremely Low Birth Weight Infants
Official title: The Pilot Experimental Study of the Neuroprotective Effects of Exosomes in Extremely Low Birth Weight Infants
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Premature Birth
Extreme Prematurity
Preterm Intraventricular Hemorrhage
Hypoxia-Ischemia, Cerebral
Neurodevelopmental Disorders
Keywords: Extremely low birth weight, neuroprotection
Lead sponsor: Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare
Sponsor class: OTHER_GOV
First posted: 2022-08-05
Enrollment: 10
Sex: ALL
Minimum age (years): 1
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Occurrence and rate of dose limiting toxicity
timeFrame: Up to 1 week following after intranasal administration of EVs
Secondary outcomes:
measure: Rate of death
timeFrame: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)
measure: Occurrence of Other Severe Complications of Prematurity
timeFrame: From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)
measure: Need for Ventilatory Support
timeFrame: From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)
measure: Changes in Hemodynamics
timeFrame: Time Frame: At enrollment, 48 hours following intranasal administration of EVs, 28 days of life, and 36 weeks corrected gestational age
measure: Feasibility: Administration
timeFrame: Day of life 1-10
measure: Feasibility: Recruitment Efficiency
timeFrame: Day of life 1-10
measure: Feasibility: Recruitment Timing
timeFrame: Day of life 1-10
measure: Feasibility: Participant Retainment
timeFrame: From enrollment until follow-up at 18-36 months-of-age
measure: Griffiths-II and Bayley Scales of Infant Development (2nd edition)
timeFrame: 18-36 months-of-age
measure: Long-term Safety Follow-Up
timeFrame: 3 years following follow-up visit
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare
Study officials:
affiliation: NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
name: Oleg Ionov, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
name: Ekaterina Balashova, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
name: Denis Silachev, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
name: Anna Kirtbaya, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
name: Victor Zubkov, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
name: Dmitriy Degtyarev, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ophelders DR, Wolfs TG, Jellema RK, Zwanenburg A, Andriessen P, Delhaas T, Ludwig AK, Radtke S, Peters V, Janssen L, Giebel B, Kramer BW. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia. Stem Cells Transl Med. 2016 Jun;5(6):754-63. doi: 10.5966/sctm.2015-0197. Epub 2016 May 9.
citation: Drommelschmidt K, Serdar M, Bendix I, Herz J, Bertling F, Prager S, Keller M, Ludwig AK, Duhan V, Radtke S, de Miroschedji K, Horn PA, van de Looij Y, Giebel B, Felderhoff-Muser U. Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury. Brain Behav Immun. 2017 Feb;60:220-232. doi: 10.1016/j.bbi.2016.11.011. Epub 2016 Nov 12.
citation: Gamage TKJB, Fraser M. The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury. Front Neurosci. 2021 Sep 24;15:744840. doi: 10.3389/fnins.2021.744840. eCollection 2021.