Hypoxic-ischemic brain injury (HIBI) is a leading cause of death and lifelong disability in near-term and term infants, most often caused by perinatal arterial ischemic stroke (PAIS, incidence approximately 1:5000 live births) or perinatal asphyxia (PA, incidence 1-2:1000 live births). No treatment currently exists to repair or limit HIBI, and many affected infants go on to develop cerebral palsy, cognitive impairment, epilepsy, or visual or hearing deficits. Intranasally administered bone marrow-derived mesenchymal stromal cells (IN-MSC) are a candidate regenerative therapy for HIBI. Preclinical studies show that IN-MSC migrate to injured brain regions, dampen neuroinflammation, and stimulate endogenous neural repair, improving both structural and functional outcomes in animal models of HIBI. A first-in-human phase I trial (PASSIoN) in 10 neonates with PAIS showed that intranasal MSC administration was feasible and well tolerated, with no serious adverse events and promising early efficacy signals at 2-year follow-up. iSTOP-CP is a phase II, single-center (UMC Utrecht, the Netherlands), double-blind, randomized, placebo-controlled trial evaluating whether IN-MSC therapy can prevent or reduce motor and other disabilities in infants with MRI-confirmed HIBI due to PAIS or PA. Eligible infants are born at 35.0 weeks of gestation or later, have HIBI confirmed on brain MRI or MRS in predefined brain regions predictive of poor outcome, and are diagnosed with PAIS or PA, with or without prior therapeutic hypothermia. A total of 162 infants will be randomized 1:1 to IN-MSC or matching placebo, stratified by the cause of HIBI and, within the PAIS group, by stroke territory. Infants with suspected chromosomal, metabolic, or congenital central nervous system anomalies, intracranial hemorrhage as the main injury, or contraindications to intranasal administration are excluded, as are infants for whom the clinical team has decided to withdraw intensive care. Participants receive a single intranasal dose of bone marrow-derived MSC or a visually indistinguishable placebo within 7 days after birth. Participants are followed for 24 months, with neurodevelopmental follow-up visits at 3-4, 6, 9-12, and 24 months of age and a brain MRI at 52 weeks postmenstrual age. The primary endpoint is the motor composite score of the Dutch version of the Bayley Scales of Infant and Toddler Development, 4th edition (Bayley-IV-NL), assessed at 24 months corrected age. Key secondary endpoints include cognitive development, the incidence of sensorineural disability, neuroregenerative imaging biomarkers, safety, health-related quality of life for infants and their parents, and the cost-effectiveness of IN-MSC treatment, evaluated through a health technology assessment.
Neonates with a gestational age ≥35.0 weeks at birth
Diagnosed with HIBI on MRI, caused either by PAIS (ORPHA 439175) or PA (ORPHA 137577) diagnosis (will be randomized separately)
Resuscitation
Mechanical ventilation following resuscitation ≥ 10 minutes after birth
Suspicion of chromosomal anomaly, metabolic disorder, genetic syndrome, congenital central nervous system (CNS) malformation, congenital CNS infection and main injury intracranial haemorrhage.
Once a clinical team decides on withdrawal of Neonatal Intensive Care Unit (NICU) care, the patient is not eligible for inclusion: infants with very severe brain injury on MRI and need for ventilation support (not breathing independently), who have a prognosis of severe multiple handicaps and/or no realistic prospect of survival at the discretion of the infant's clinical care team in the NICU, will not be eligible for iSTOP-CP, to avoid unnecessary suffering and an unacceptable quality of life.
Contraindications for intranasal administration of medication, nasal obstruction caused by e.g. choanal atresia, nasal septal abnormalities, nasal trauma, epistaxis, excessive nasal mucus or blood, and intranasal obstructive damage.
Parallel
MSC, marrow
DrugAllogeneic BM-MSCs
Placebo
DrugPlacebo is intranasally administered within 7 days.
Bayley Scales of Infant and Toddler Development 4th Edition (Bayley-IV-NL)
The motor composite score of the Bayley Scales of Infant and Toddler Development, Fourth Edition, Dutch version (Bayley-IV-NL), assessed at 24 months of age. The motor composite combines the Fine Motor and Gross Motor subdomains into a standard score with a mean of 100 and standard deviation of 15, with higher scores indicating better motor development (a score below 70 indicates substantial developmental delay).
The cognitive composite score of the Bayley-IV-NL.
he cognitive composite score of the Bayley Scales of Infant and Toddler Development, Fourth Edition, Dutch version (Bayley-IV-NL), assessed at 24 months of age, used to evaluate neurodevelopmental outcome beyond motor outcome. The cognitive composite is a standard score with a mean of 100 and standard deviation of 15, with higher scores indicating better cognitive development (a score below 70 indicates substantial developmental delay).
Sensorineural disability at 2 years
The incidence of one or more of the following components: development of cerebral palsy (CP) with a Gross Motor Function Classification System (GMFCS) of at least 1, neuromotor delay, cognitive neurodevelopmental delay, epilepsy, moderate-severe visual impairment, moderate-severe hearing impairment.
Incidence of Treatment-Related Adverse Events Following Intranasal MSC Administration
Patients will be regularly monitored until 24 months of age for adverse events related to intranasal MSC treatment in (near-)term infants with HIBI.
Neuroregenerative effects seen on MRI
Volumetric analyses, white matter integrity of the major white matter tracts, metabolic profile of central gray and white matter, network-level function connectivity using resting-state functional MRI
Pharmacodynamic biomarker assessments
Blood plasma will be used to quantify circulating markers reflecting mechanistic pathways identified in preclinical studies. In addition, plasma samples may be used for exploratory high-sensitivity analyses to further characterize neuroregenerative activity.
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