Phase II Randomized, Placebo‑Controlled Trial of Intranasal Bone‑Marrow Derived Mesenchymal Stromal Cells (Remestemcel) in Neonates with Hypoxic‑Ischemic Brain Injury

The primary objective is to evaluate whether intranasal stem cell therapy (IN-MSC) reduces cerebral injury and improves motor function in neonates with hypoxic‑ischemic brain injury confirmed by MRI, establishing therapeutic efficacy and safety for potential integration into clinical practice. Secondary objectives include:

• Assessment of the treatment’s effect on neurodevelopmental outcomes at 24 months of age.
• Evaluation of safety parameters in the treated infant population.
• Investigation of neuroregenerative changes on cranial MRI at 52 weeks post‑menstrual age.
• Comparison of health‑related quality of life between the IN-MSC group and standard supportive care.
• Analysis of the economic impact and cost‑effectiveness of the intervention relative to standard care.

The trial enrolled neonates of both sexes with a gestational age of ≥ 35 weeks who were diagnosed with hypoxic-ischemic brain injury due to perinatal asphyxia or perinatal arterial ischemic stroke, confirmed by MRI criteria; the sponsor did not provide the total number of participants. Eligible infants displayed clinical signs such as seizures or respiratory difficulty and met predefined biochemical thresholds (e.g., 5‑minute Apgar ≤ 5, pH < 7.0, lactate > 10 mmol/L). Selection required written informed consent from custodial parents, and participants were otherwise typical newborns receiving standard neonatal care, with no specific lifestyle restrictions beyond routine feeding and activity. The population comprised vulnerable patients, and inclusion was limited to those with documented injury in specified brain regions (e.g., posterior limb of the internal capsule, basal ganglia, thalami, corticospinal tract).

The iSTOP‑CP trial is a randomized, double‑blind, placebo‑controlled phase II study evaluating intranasal bone‑marrow‑derived mesenchymal stromal cells (0.6 ml nasal drops) versus a placebo consisting of potassium chloride and 10 % human serum albumin administered in the same volume. Eligible neonates (≥35 weeks gestation) with MRI‑confirmed hypoxic‑ischemic brain injury due to perinatal asphyxia or arterial ischemic stroke are enrolled after a screening visit that confirms eligibility criteria and obtains parental consent. Participants receive a single intranasal dose on Day 0, followed by scheduled assessments: a safety MRI at 52 weeks post‑menstrual age (approximately 3–4 months), developmental and neurological evaluations at 3, 9–12, and 24 months, and health‑related quality‑of‑life questionnaires at the same intervals. The primary efficacy endpoint is the Bayley‑IV‑NL motor score measured at 24 months, with secondary endpoints including cognitive scores, sensorineural disability, MRI biomarkers, and health‑economic outcomes. Each infant remains in the study for approximately 24 months from enrollment, with the final visit constituting the end‑of‑study assessment.

The investigational product, identified as remestemcel, is a bone‑marrow derived mesenchymal stromal cell preparation supplied as nasal drops. Each dose consists of 0.6 ml of the formulation and is administered by the intranasal route in accordance with the study dosing schedule.

The placebo comparator comprises two components: potassium chloride (RVG051680; SUB12559MIG) and a 10 % human serum albumin solution (RVG 103594; SUB20344). The human serum albumin is delivered intranasally as 0.6 ml of nasal drops; the potassium chloride component is included without a specified dose or route, serving solely as an inert element of the placebo mixture.

All administrations are performed under controlled conditions, with dosing recorded in the study case report form. Compliance is monitored through documented administration logs and verification of the administered volume for each intranasal application. Any deviations from the prescribed dosing schedule are reported and evaluated according to the protocol’s safety monitoring procedures.

Efficacy will be assessed using a set of predefined clinical and neuroimaging endpoints. The primary efficacy endpoint is the Bayley-IV-NL motor score measured at 24 months of age. Secondary efficacy assessments include cognitive development at 2 years, evaluated with the cognitive composite score of the Bayley-IV-NL, and a composite sensorineural disability outcome at 2 years defined by the presence of any of the following: cerebral palsy (GMFCS ≥ 1), neuromotor delay (Bayley-IV-NL motor score < ‑1 SD), cognitive delay (Bayley-IV-NL cognitive score < ‑1 SD), epilepsy per ILAE criteria, or moderate to severe visual or hearing impairment attributable to the perinatal injury.

Neuroimaging efficacy parameters are scheduled at specific post‑menstrual ages. For infants with hypoxic‑ischemic brain injury due to perinatal asphyxia, white‑matter integrity will be examined at 52 weeks post‑menstrual age using diffusion‑tensor MRI with tract‑based fractional anisotropy analysis. For infants with perinatal arterial ischemic stroke, changes in brain tissue volume will be compared between an early neonatal MRI performed before 8 days of life and a follow‑up MRI at 52 weeks post‑menstrual age.

Additional efficacy‑related outcomes include health‑related quality of life for patients and families, collected at 3, 9–12, and 24 months using standardized questionnaires (EQ‑5D‑5L, PCL‑5, LTO, KLIK Pain, CIS‑4, WEMWBS for caregivers; EQ‑TIPS and PedsQL‑Infant for infants). The economic impact at 24 months will be evaluated through a health‑technology assessment comprising cost‑of‑illness, cost‑effectiveness, and budget‑impact analyses.