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| Name | Class |
|---|---|
| ZonMw: The Netherlands Organisation for Health Research and Development | OTHER |
| M.D. Anderson Cancer Center | OTHER |
| The University of Texas Health Science Center at San Antonio | OTHER |
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This study will assess safety and feasibility of bone marrow-derived allogeneic MSCs, administered by the nasal route, in neonates who suffered from PAIS.
Perinatal arterial ischemic stroke (PAIS) is an important perinatal cause of long-lasting neurodevelopmental problems. Recent studies report an incidence of PAIS of 1 per 2300 full-term infants born alive. Adverse consequences of PAIS include hemiplegia, cognitive dysfunction, epilepsy and speech problems. In 50-75% of infants, neonatal stroke leads to abnormal neuromotor and -developmental outcome or epilepsy. The estimated annual mortality rate of neonatal stroke is 3.49/100,000 annually. Current treatment options for PAIS mainly focus on controlling convulsions and associated infections. There is no treatment available that leads to reduction of neonatal brain damage in this severely affected group of infants. This leads to life-long consequences of PAIS and forms a large burden for patients and society. The overall aim of this project is to meet this need by developing a cell based treatment strategy. Animal models of neonatal brain injury provide evidence for the feasibility and efficacy of intranasal mesenchymal stromal cell (MSC) application in the treatment of PAIS. Additionally, results from human trials with MSCs in the treatment of adult stroke or other pathologic conditions provide evidence that MSC treatment is safe. This project aims at making the first step towards clinical application of MSCs to treat PAIS. Successful completion of this project will provide the first evidence of the safety and feasibility of MSCs to treat brain damage in newborn infants. This study will assess safety and feasibility of bone marrow-derived allogeneic MSCs, administered by the nasal route, in neonates who suffered from PAIS.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Mesenchymal Stem Cells | Experimental | All (near-)term newborns ≥36 weeks of gestation with or without clinical symptoms of PAIS but with a magnetic resonance imaging (MRI) confirmed PAIS (in the Middle Cerebral Artery region) will be eligible for this study. Following written parental consent, 10 patients will be included in our study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Mesenchymal Stem Cells | Biological | One dose of 50x10^6 bone marrow-derived allogeneic MSCs via the nasal route as soon as possible after confirmation of the stroke (in the middle cerebral artery), but within the first week of onset of presenting clinical symptoms. Within 30 minutes after cleaning the nose with saline, using standard procedures operative at the Neonatal Intensive Care Unit, the MSC will be delivered. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Acute Setting. | The primary objective is to determine if MSC treatment in neonates with PAIS is safe and tolerable in the acute setting. This will be measured by the number of Participants with treatment-related adverse events after MSC treatment. | 24 hours after treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Subacute/Long-term Setting | The secondary objective is to determine subacute and long-term safety of MSC treatment at 3 months. This will be measured by the occurence of treatment-related adverse events after the initial hospital stay, such as infections or cerebral tumorigenicity on MRI. Follow-up assessment at 3 months is part of regular care for neonates with PAIS. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Manon Benders, MD, PhD | UMC Utrecht | Principal Investigator |
| Floris Groenendaal, MD, PhD | UMC Utrecht | Principal Investigator |
| Frank van Bel, MD, PhD | UMC Utrecht | Principal Investigator |
| Cora Nijboer, PhD | UMC Utrecht | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Wilhelmina Childrens Hostpital/University Medical Center Utrecht | Utrecht | 3584 EA | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23403379 | Background | Donega V, van Velthoven CT, Nijboer CH, Kavelaars A, Heijnen CJ. The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment. J Cereb Blood Flow Metab. 2013 May;33(5):625-34. doi: 10.1038/jcbfm.2013.3. Epub 2013 Feb 13. | |
| 23300948 | Background |
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Between Feb 11, 2020, and April 29, 2021,10 infants were included in the PASSIoN trial. Neonates were eligible for the study if they had been born at one of the ten neonatal intensive care units (NICU) in the Netherlands and had signs of suspected PAIS. All eligible patients were transferred to the NICU of the Wilhelmina Children's Hospital (part of the University Medical Center, Utrecht, Netherlands) for confirmation of PAIS by MRI, then MSC treatment, within 7 days after presentation.
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| ID | Title | Description |
|---|---|---|
| FG000 | Mesenchymal Stem Cells | Ten (near-)term newborns ≥36 weeks of gestation with or without clinical symptoms of PAIS but with a magnetic resonance imaging (MRI) confirmed PAIS (in the Middle Cerebral Artery region), and written parental consent were included this study. Mesenchymal Stem Cells: One dose of 50x10^6 bone marrow-derived allogeneic MSCs via the nasal route as soon as possible after confirmation of the stroke (in the middle cerebral artery), but within the first week of onset of presenting clinical symptoms. Within 30 minutes after cleaning the nose with saline, using standard procedures operative at the Neonatal Intensive Care Unit, the MSC will be delivered. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Mesenchymal Stem Cells | All (near-)term newborns ≥36 weeks of gestation with or without clinical symptoms of PAIS but with a magnetic resonance imaging (MRI) confirmed PAIS (in the Middle Cerebral Artery region) will be eligible for this study. Following written parental consent, 10 patients will be included in our study. Mesenchymal Stem Cells: One dose of 50x10^6 bone marrow-derived allogeneic MSCs via the nasal route as soon as possible after confirmation of the stroke (in the middle cerebral artery), but within the first week of onset of presenting clinical symptoms. Within 30 minutes after cleaning the nose with saline, using standard procedures operative at the Neonatal Intensive Care Unit, the MSC will be delivered. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Acute Setting. | The primary objective is to determine if MSC treatment in neonates with PAIS is safe and tolerable in the acute setting. This will be measured by the number of Participants with treatment-related adverse events after MSC treatment. | Posted | Count of Participants | Participants | 24 hours after treatment |
|
Treatment-related adverse events were monitored for 4 days after MSC administration (hospital stay), and until the age of 3 months (parent report).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Mesenchymal Stem Cells | Ten (near-)term newborns ≥36 weeks of gestation with or without clinical symptoms of PAIS but with a magnetic resonance imaging (MRI) confirmed PAIS (in the Middle Cerebral Artery region), and written parental consent were included this study. Mesenchymal Stem Cells: One dose of 50x10^6 bone marrow-derived allogeneic MSCs via the nasal route as soon as possible after confirmation of the stroke (in the middle cerebral artery), but within the first week of onset of presenting clinical symptoms. Within 30 minutes after cleaning the nose with saline, using standard procedures operative at the Neonatal Intensive Care Unit, the MSC will be delivered. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fever | General disorders | Systematic Assessment | One patient developed a fever of 38˚C 1 h after MSC administration that resolved spontaneously after 2 h, without clinical signs of distress or illness, and other vital parameters stayed within normal ranges. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. M.J.N.L. Benders, MD, PhD, neonatologist | UMC Utrecht, The Netherlands | +31 88 755 5555 | m.benders@umcutrecht.nl |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 16, 2020 | Jun 3, 2022 | Prot_SAP_000.pdf |
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A phase I/II, open-label, single-arm, single-center intervention study in the NICU at the Wilhelmina children's Hospital / University Medical Centre in Utrecht of (near-)term newborns ≥36 weeks of gestation within the first week of onset of presenting clinical symptoms.
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| 3 months postnatal age |
| Donega V, van Velthoven CT, Nijboer CH, van Bel F, Kas MJ, Kavelaars A, Heijnen CJ. Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PLoS One. 2013;8(1):e51253. doi: 10.1371/journal.pone.0051253. Epub 2013 Jan 3. |
| 24945601 | Background | Donega V, Nijboer CH, van Tilborg G, Dijkhuizen RM, Kavelaars A, Heijnen CJ. Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury. Exp Neurol. 2014 Nov;261:53-64. doi: 10.1016/j.expneurol.2014.06.009. Epub 2014 Jun 16. |
| 25396420 | Background | Donega V, Nijboer CH, Braccioli L, Slaper-Cortenbach I, Kavelaars A, van Bel F, Heijnen CJ. Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions. PLoS One. 2014 Nov 14;9(11):e112339. doi: 10.1371/journal.pone.0112339. eCollection 2014. |
| 22430383 | Background | van Velthoven CT, Kavelaars A, Heijnen CJ. Mesenchymal stem cells as a treatment for neonatal ischemic brain damage. Pediatr Res. 2012 Apr;71(4 Pt 2):474-81. doi: 10.1038/pr.2011.64. Epub 2012 Feb 8. |
| 21473911 | Background | van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell transplantation changes the gene expression profile of the neonatal ischemic brain. Brain Behav Immun. 2011 Oct;25(7):1342-8. doi: 10.1016/j.bbi.2011.03.021. Epub 2011 Apr 5. |
| 20639794 | Background | van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage. Pediatr Res. 2010 Nov;68(5):419-22. doi: 10.1203/PDR.0b013e3181f1c289. |
| 20631189 | Background | van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function. J Neurosci. 2010 Jul 14;30(28):9603-11. doi: 10.1523/JNEUROSCI.1835-10.2010. |
| 19883750 | Background | van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010 Mar;24(3):387-93. doi: 10.1016/j.bbi.2009.10.017. Epub 2009 Oct 31. |
| 19348860 | Background | van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes. Brain Res Rev. 2009 Jun;61(1):1-13. doi: 10.1016/j.brainresrev.2009.03.003. Epub 2009 Apr 5. |
| 28786482 | Background | Wagenaar N, Nijboer CH, van Bel F. Repair of neonatal brain injury: bringing stem cell-based therapy into clinical practice. Dev Med Child Neurol. 2017 Oct;59(10):997-1003. doi: 10.1111/dmcn.13528. Epub 2017 Aug 8. |
| 28949952 | Background | Wagenaar N, de Theije CGM, de Vries LS, Groenendaal F, Benders MJNL, Nijboer CHA. Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells. Pediatr Res. 2018 Jan;83(1-2):372-384. doi: 10.1038/pr.2017.243. Epub 2017 Nov 1. |
| 40654084 | Derived | Wagenaar N, Baak LM, van der Aa NE, Groenendaal F, Dudink J, Tataranno ML, Koopman C, Verhage CH, Eijsermans RMJC, van Teeseling HC, Smit LS, Jellema RK, de Haan TR, Ter Horst HJ, de Boode WP, Steggerda SJ, Mulder-de Tollenaer SM, Dijkman KP, de Haar CG, de Vries LS, van Bel F, Heijnen CJ, Nijboer CH, Benders MJNL. Perinatal Arterial Stroke Treated With Stromal Cells Intranasally: 2-Year Safety and Neurodevelopment. Stroke. 2025 Sep;56(9):2410-2418. doi: 10.1161/STROKEAHA.125.050786. Epub 2025 Jul 14. |
| 35568047 | Derived | Baak LM, Wagenaar N, van der Aa NE, Groenendaal F, Dudink J, Tataranno ML, Mahamuud U, Verhage CH, Eijsermans RMJC, Smit LS, Jellema RK, de Haan TR, Ter Horst HJ, de Boode WP, Steggerda SJ, Prins HJ, de Haar CG, de Vries LS, van Bel F, Heijnen CJ, Nijboer CH, Benders MJNL. Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study. Lancet Neurol. 2022 Jun;21(6):528-536. doi: 10.1016/S1474-4422(22)00117-X. |
| weeks of gestational age at birth |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Birthweight | Median | Inter-Quartile Range | gram |
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| Secondary | Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Subacute/Long-term Setting | The secondary objective is to determine subacute and long-term safety of MSC treatment at 3 months. This will be measured by the occurence of treatment-related adverse events after the initial hospital stay, such as infections or cerebral tumorigenicity on MRI. Follow-up assessment at 3 months is part of regular care for neonates with PAIS. | Posted | Count of Participants | Participants | 3 months postnatal age |
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| 0 |
| 10 |
| 0 |
| 10 |
| 1 |
| 10 |
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