Mesenchymal stromal cells for periventricular hemorrhagic infarction in extremely preterm infants: a double-blinded randomized controlled phase IIa clinical trial

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Abstract Background Periventricular hemorrhagic infarction in extremely preterm infants (PVHI; the most severe form of intraventricular hemorrhage) are associated with a high risk of mortality and neurodevelopmental disability with no effective treatments. We aimed to assess the safety and potential efficacy of mesenchymal stromal cells (MSCs) for PVHI in preterm infants. Methods We conducted a single-center, phase 2a double-blind randomized controlled trial at the Samsung Medical Center. Twenty-two preterm infants (23–31 weeks gestation) with PVHI were double-blindly randomized (1:1) to receive intraventricular MSCs (1 × 107 cells/kg) or normal saline within 7 days post-diagnosis. Primary outcome was combined rate of ventriculo-peritoneal shunt or death. Secondary outcomes included safety, mortality, cerebral palsy (CP), epilepsy, developmental delays. Results The primary endpoint of shunt or death by 36 weeks’ postmenstrual age did not differ between groups (relative risk 1.14, 95% CI 0.64 to 2.03). Among survivors assessed through 2 years’ corrected age, the MSC group had lower observed rates of cerebral palsy, epilepsy, and microcephaly than the placebo group, although confidence intervals were wide; lower incidence of CP (relative risk 0.56, 95% CI 0.27 to 1.17), epilepsy (relative risk 0.38, 95% CI 0.10 to 1.36) and microcephaly (relative risk 0.30, 95% CI 0.08 to 1.07). No serious treatment-related adverse events occurred. Conclusions Intraventricular MSC therapy did not reduce the mortality or VP shunting dependence in premature infants with PVHI. However, 2-year exploratory long-term neurodevelopmental outcomes suggested potential benefits, which warranting confirmation in larger trials. Trial registration The study protocol was registered at Clinical Trials.gov (NCT02890953) on September 6, 2016.