The Pilot Experimental Study of the Neuroprotective Effects of Exosomes in Extremely Low Birth Weight Infants
Primary Purpose
Premature Birth, Extreme Prematurity, Preterm Intraventricular Hemorrhage
Status
Not yet recruiting
Phase
Not Applicable
Locations
Russian Federation
Study Type
Interventional
Intervention
Exosomes derived from mesenchymal stromal cells (MSCs)
Sponsored by
About this trial
This is an interventional prevention trial for Premature Birth focused on measuring Extremely low birth weight, neuroprotection
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
Sites / Locations
- Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
Intranasal exosomes administration
Control
Arm Description
ELWB newborns who will receive intranasal exosomes
ELWB newborns who will not receive intranasal exosomes
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Rate of death
Rate of death until discharge or 40 weeks corrected gestational age, whichever comes 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
Need for Ventilatory Support
Time to extubation
Duration of mechanical ventilation
Duration of non-invasive positive pressure respiratory support
Duration of supplemental oxygen
Changes in Hemodynamics
Targeted neonatal echocardiography to assess
Feasibility: Administration
Successful recruitment and administration of extracellular vesicles to 10 patients in 18 months
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)
Feasibility: Recruitment Timing
Median time from screening to enrollment
Median time from screening to extracellular vesicles
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
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.
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
Full Information
NCT ID
NCT05490173
First Posted
July 4, 2022
Last Updated
September 26, 2022
Sponsor
Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare
1. Study Identification
Unique Protocol Identification Number
NCT05490173
Brief Title
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
2. Study Status
Record Verification Date
September 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 5, 2022 (Anticipated)
Primary Completion Date
May 22, 2026 (Anticipated)
Study Completion Date
December 28, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Premature Birth, Extreme Prematurity, Preterm Intraventricular Hemorrhage, Hypoxia-Ischemia, Cerebral, Neurodevelopmental Disorders
Keywords
Extremely low birth weight, neuroprotection
7. Study Design
Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
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
Participant
Allocation
Randomized
Enrollment
10 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Intranasal exosomes administration
Arm Type
Experimental
Arm Description
ELWB newborns who will receive intranasal exosomes
Arm Title
Control
Arm Type
No Intervention
Arm Description
ELWB newborns who will not receive intranasal exosomes
Intervention Type
Other
Intervention Name(s)
Exosomes derived from mesenchymal stromal cells (MSCs)
Intervention Description
Exosomes derived from mesenchymal stromal cells (MSCs) will be administered intranasal in ELBW infants
Primary Outcome Measure Information:
Title
Occurrence and rate of dose limiting toxicity
Description
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.
Time Frame
Up to 1 week following after intranasal administration of EVs
Secondary Outcome Measure Information:
Title
Rate of death
Description
Rate of death until discharge or 40 weeks corrected gestational age, whichever comes first
Time Frame
From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)
Title
Occurrence of Other Severe Complications of Prematurity
Description
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
Time Frame
From enrollment until discharge or 40 weeks corrected gestational age (whichever occurs first)
Title
Need for Ventilatory Support
Description
Time to extubation
Duration of mechanical ventilation
Duration of non-invasive positive pressure respiratory support
Duration of supplemental oxygen
Time Frame
From enrollment until discharge, 40 weeks corrected gestational age, or death (whichever occurs first)
Title
Changes in Hemodynamics
Description
Targeted neonatal echocardiography to assess
Time Frame
Time Frame: At enrollment, 48 hours following intranasal administration of EVs, 28 days of life, and 36 weeks corrected gestational age
Title
Feasibility: Administration
Description
Successful recruitment and administration of extracellular vesicles to 10 patients in 18 months
Time Frame
Day of life 1-10
Title
Feasibility: Recruitment Efficiency
Description
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)
Time Frame
Day of life 1-10
Title
Feasibility: Recruitment Timing
Description
Median time from screening to enrollment
Median time from screening to extracellular vesicles
Time Frame
Day of life 1-10
Title
Feasibility: Participant Retainment
Description
Proportion of patients that do not complete administration of extracellular vesicles
Proportion of patients enrolled that do not undergo scheduled follow-up
Time Frame
From enrollment until follow-up at 18-36 months-of-age
Title
Griffiths-II and Bayley Scales of Infant Development (2nd edition)
Description
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.
Time Frame
18-36 months-of-age
Title
Long-term Safety Follow-Up
Description
Participant's overall health will be assessed through a questionnaire administered over the phone, once a year for 3 years
Time Frame
3 years following follow-up visit
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
3 Days
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Oleg Ionov, PhD, MD
Phone
+74954382277
Email
dr.ionov@hotmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Diiana Sharafutdinova
Phone
+79859865567
Email
dikarush@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Oleg Ionov, PhD, MD
Organizational Affiliation
NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ekaterina Balashova, PhD, MD
Organizational Affiliation
NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Denis Silachev, PhD, MD
Organizational Affiliation
NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Anna Kirtbaya, PhD, MD
Organizational Affiliation
NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Victor Zubkov, PhD, MD
Organizational Affiliation
NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dmitriy Degtyarev, PhD, MD
Organizational Affiliation
NATIONAL MEDICAL RESEARCH CENTER FOR OBSTETRICS, GYNECOLOGYAND PERINATOLOGY NAMED AFTER ACADEMICIAN V.I.KULAKOV
Official's Role
Principal Investigator
Facility Information:
Facility Name
Federal State Budget Institution Research Center for Obstetrics, Gynecology and Perinatology Ministry of Healthcare
City
Moscow
ZIP/Postal Code
117997
Country
Russian Federation
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elena A Gorodnova, PhD
Phone
+7 (495) 531-44-44
Email
e_gorodnova@oparina4.ru
First Name & Middle Initial & Last Name & Degree
Diiana Sharafutdinova
Phone
+79859865567
Email
dikarush@gmail.com
First Name & Middle Initial & Last Name & Degree
Diiana RASHIDOVNA SHARAFUTDINOVA
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
27160705
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.
Results Reference
background
PubMed Identifier
27847282
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.
Results Reference
background
PubMed Identifier
34630028
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.
Results Reference
result
Links:
URL
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498217/
Description
The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury
URL
http://www.mdpi.com/1422-0067/23/2/620
Description
Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain
URL
http://pubmed.ncbi.nlm.nih.gov/34630028/
Description
The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury
URL
http://pubmed.ncbi.nlm.nih.gov/27160705/
Description
Mesenchymal Stromal Cell-Derived Extracellular Vesicles Protect the Fetal Brain After Hypoxia-Ischemia
URL
http://pubmed.ncbi.nlm.nih.gov/27847282/
Description
Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury
Learn more about this trial
The Pilot Experimental Study of the Neuroprotective Effects of Exosomes in Extremely Low Birth Weight Infants
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