Intranasal Stem Cells to Treat Perinatal Brain Injury to Combat Cerebral Palsy

Phase 3Not Yet RecruitingNCT07831746

UMC Utrecht162 enrolled

Overview

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.

Study Type

Eligibility

Sex: ALLMin age: 0 DaysMax age: 8 Days

Medical Language ↔ Plain English

Inclusion Criteria: * 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) o PAIS: a neurologic condition characterized by focal cerebral ischemia and infarction following blockage of a brain artery with impairment of blood supply and oxygenation of brain tissue, clinically characterized by seizures (clinical or subclinical), respiratory difficulties, or both (unilateral or bilateral). o PA: defined as at least one out of the following: 5-min Apgar score ≤ 5 * Resuscitation * Mechanical ventilation following resuscitation ≥ 10 minutes after birth * pH \<7.0, BE \<-16 mmol/L, or lactate \> 10.0 mmol/L in umbilical cord blood sample, or in arterial, venous or capillary blood gas sample obtained within 1 hour after birth * Showing signs of hypoxic-ischemic injury in one or more of the following predefined brain areas (indicated by DWI restriction and/or abnormal ADC values and/or 1H-MRS lactate/N-acetyl aspartate (NAA) and/or NAA/Choline ratio abnormalities): * Central gray matter (basal ganglia and/or thalami), and/or * Posterior limb of the internal capsule (PLIC), and/or * Cerebral peduncles, and/or * White matter injury with corticospinal tract (CST) involvement, and/or * Rolandic cortex * Written informed consent from custodial parent(s) Exclusion Criteria: * 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.

Outcomes

Primary Outcomes

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).

Time frame: The assessment will be done when the participant is around 24 months of age.

Secondary Outcomes

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).

Time frame: The assessment will be done when the participant is around 24 months of age.

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.

Time frame: These components will be assessed when the participant is around 24 months of age.

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.

Time frame: Until the participant is 24 months of age.

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

Time frame: At approximately 3 months post-term equivalent age

Impact on Health Related Quality of Life (HRQoL)

The impact of intranasal MSC compared to standard supportive care on HRQoL by means of utility and disease specific measures. Primary at 3, 9-12 and 24 months: differences in utility between the treated and non-treated groups using the EuroQol Toddler and Infant Populations (EQ-TIPS) as a proxy measure for HRQoL in infants and the EuroQol 5D 5-level version (EQ-5D-5L) in at least one parent/caregiver. Secondary at 3, 9-12 and 24 months: Differences in disease and population specific HRQoL between the treated and non-treated groups measures via questionnaires in the infant (Pediatric Quality of Life Inventory (PedsQL)-Infant scale) and at least one parent/caregiver (depression: post-traumatic stress disorder checklist PCL-5, Burden: LTO, Pain: KLIK questionnaires Pain, fatigue: Checklist Individual Strength (CIS-4) and resilience: Warwick-Edinburgh Mental Well-being Scale (WEMWBS)).

Time frame: At 3, 9-12 and 24 months.

Health Technology Assessment

The economic impact of intranasal MSCs compared to standard supportive care at 24 months of age, assessed through Health Technology Assessment (HTA).

Time frame: When the participant is around 24 months of age.