Perinatal Arterial Stroke Treated With Stromal Cells Intranasally

Neonatal Stroke Clinical Trial

— PASSIoN  

Official title:

Adult Mesenchymal Stromal Cells to Regenerate the Neonatal Brain: the PASSIoN Trial (Perinatal Arterial Stroke Treated With Stromal Cells IntraNasally)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03356821
• Other study ID #: NL59265.000.16
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: February 11, 2020
• Est. completion date: July 27, 2021

Study information

• Verified date: December 2023
• Source: UMC Utrecht
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will assess safety and feasibility of bone marrow-derived allogeneic MSCs, administered by the nasal route, in neonates who suffered from PAIS.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: July 27, 2021
• Est. primary completion date: July 27, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 10 Days

Eligibility

Inclusion Criteria:

• (Near-)Term infants, =36+0 weeks of gestation, admitted to one of the Dutch Neonatal Intensive Care Units, diagnosed with PAIS, confirmed by MRI within 3 days after presentation with clinical symptoms.

• PAIS as characterized by a predominantly unilateral ischemic lesion within the territory of the middle cerebral artery, with involvement of the corticospinal tracts, cortex, white matter and basal ganglia.

• Written informed consent from custodial parent(s).

Exclusion Criteria:

• Any proven or suspected congenital anomaly, chromosomal disorder, metabolic disorder.

• Presence of an infection of the central nervous system.

• No realistic prospect of survival, (e.g. severe brain injury), at the discretion of the attending physician.

Related Conditions & MeSH terms

• Ischemic Stroke
• Neonatal Stroke
• Perinatal Arterial Ischemic Stroke
• Stroke

Intervention

Biological:
• 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.

Locations

Country	Name	City	State
Netherlands	Wilhelmina Childrens Hostpital/University Medical Center Utrecht	Utrecht

Sponsors (4)

Lead Sponsor	Collaborator
UMC Utrecht	M.D. Anderson Cancer Center, The University of Texas Health Science Center at San Antonio, ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	24 hours after treatment
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.	3 months postnatal age