Neonatal Stroke, Perinatal Arterial Ischemic Stroke
Conditions
Brief 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.
Detailed 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.
Interventions
BIOLOGICALMesenchymal 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.
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
M.D. Anderson Cancer Center
The University of Texas Health Science Center at San Antonio
UMC Utrecht
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
No minimum to 10 Days
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Acute Setting. | 24 hours after treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Subacute/Long-term Setting | 3 months postnatal age | 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. |
Countries
Netherlands
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Mesenchymal Stem Cells | — |
|---|---|---|
| Age, Continuous | 40.3 weeks of gestational age at birth | — |
| Birthweight | 3415 gram | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 6 Participants | — |
| Sex: Female, Male Male | 4 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
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.
Time frame: 24 hours after treatment
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Mesenchymal Stem Cells | Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Acute Setting. | Serious adverse event | No | 10 Participants |
| Mesenchymal Stem Cells | Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Acute Setting. | Serious adverse event | Yes | 0 Participants |
| Mesenchymal Stem Cells | Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Acute Setting. | Adverse event: fever | No | 9 Participants |
| Mesenchymal Stem Cells | Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Acute Setting. | Adverse event: fever | Yes | 1 Participants |
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.
Time frame: 3 months postnatal age
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mesenchymal Stem Cells | Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Subacute/Long-term Setting | no subacute adverse events until 3 months of age | 10 Participants |
| Mesenchymal Stem Cells | Number of Participants With Adverse Events Related to Intranasal MSC Treatment (Safety and Tolerability) in the Subacute/Long-term Setting | subacute adverse events until 3 months of age | 0 Participants |