Background: Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of... Show moreBackground: Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of intranasally delivered bone marrow-derived allogeneic mesenchymal stromal cells (MSCs) to treat PAIS in neonates. Methods: In this open-label intervention study in collaboration with all neonatal intensive care units in the Netherlands, we included neonates born at full term (>= 36 weeks of gestation) with MRI-confirmed PAIS in the middle cerebral artery region. All eligible patients were transferred to the neonatal intensive care unit of the Wilhelmina Children's Hospital. Neonates received one dose of 45-50 x 10(6) bone-marrow derived MSCs intranasally within 7 days of presenting signs of PAIS. The primary endpoints were acute and subacute safety outcomes, including vital signs, blood markers, and the occurrence of toxicity, adverse events, and serious adverse events. The occurrence of unexpected cerebral abnormalities by a repeat MRI at 3 months of age was a secondary endpoint. As part of standard clinical follow-up at Wilhelmina Children's Hospital, we assessed corticospinal tract development on MRI and performed motor assessments at 4 months of age. This study is registered with ClinicalTrials.gov, NCT03356821. Findings: Between Feb 11, 2020, and April 29, 2021, ten neonates were enrolled in the study. Intranasal administration of MSCs was well tolerated in all ten neonates. No serious adverse events were observed. One adverse event was seen: a mild transient fever of 38 degrees C without the need for clinical intervention. Blood inflammation markers (C-reactive protein, procalcitonin, and leukocyte count) were not significantly different pre-administration versus postadministration and, although thrombocyte levels increased (p=0.011), all were within the physiological range. Followup MRI scans did not show unexpected structural cerebral abnormalities. All ten patients had initial pre-Wallerian changes in the corticospinal tracts, but only four (40%) patients showed asymmetrical corticospinal tracts at follow-up MRI. Abnormal early motor assessment was found in three (30%) infants. Interpretation: This first-in-human study demonstrates that intranasal bone marrow-derived MSC administration in neonates after PAIS is feasible and no serious adverse events were observed in patients followed up until 3 months of age. Future large-scale placebo-controlled studies are needed to determine the therapeutic effect of intranasal MSCs for PAIS. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved. Show less
Favie, L.M.A.; Peeters-Scholte, C.M.P.C.D.; Bakker, A.; Tjabbes, H.; Egberts, T.C.G.; Bel, F. van; ... ; Groenendaal, F. 2020
BACKGROUND: Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising... Show moreBACKGROUND: Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising neuroprotective agent additional to therapeutic hypothermia to improve the outcome of these neonates.METHODS: In an open-label study, pharmacokinetics and short-term safety of 2-iminobiotin were investigated in neonates treated with therapeutic hypothermia. Group A (n = 6) received four doses of 0.16 mg/kg intravenously q6h. Blood sampling for pharmacokinetic analysis and monitoring of vital signs for short-term safety analysis were performed. Data from group A was used to determine the dose for group B, aiming at an AUC(0-48 h) of 4800 ng*h/mL.RESULTS: Exposure in group A was higher than targeted (median AUC(0-48 h) 9522 ng*h/mL); subsequently, group B (n = 6) received eight doses of 0.08 mg/kg q6h (median AUC(0-48 h) 4465 ng*h/mL). No changes in vital signs were observed and no adverse events related to 2-iminobiotin occurred.CONCLUSION: This study indicates that 2-iminobiotin is well tolerated and not associated with any adverse events in neonates treated with therapeutic hypothermia after perinatal asphyxia. Target exposure was achieved with eight doses of 0.08 mg/kg q6h. Optimal duration of therapy for clinical efficacy needs to be determined in future clinical trials. Show less
Favie, L.M.A.; Peeters-Scholte, C.M.P.C.D.; Bakker, A.; Tjabbes, H.; Egberts, T.C.G.; Bel, F. van; ... ; Groenendaal, F. 2020
Objective To assess whether high and low levels of cerebral oxygenation (regional cerebral oxygenation [rScO(2)]) in infants born at <32 weeks of gestation were associated with adverse long-term... Show moreObjective To assess whether high and low levels of cerebral oxygenation (regional cerebral oxygenation [rScO(2)]) in infants born at <32 weeks of gestation were associated with adverse long-term outcome.Study design Observational cohort study including preterm infants born at <32 weeks of gestation at the Wilhelmina Children's Hospital, The Netherlands, between April 2006 and April 2013. The rScO(2) was continuously monitored for 72 hours after birth using near-infrared spectroscopy. Outcome was assessed at 15 and 24 months of corrected age by certified investigators. An unfavorable composite outcome was defined as an outcome score below -1 SD or death. Various rScO(2) thresholds were explored.Results In total, 734 infants were eligible for analysis, 60 of whom died. Associations with an unfavorable cognitive outcome in multivariable analysis were comparable for time spent with a rScO(2) below 55% and -1.5 SD (according to published reference values), with an OR of 1.4 (CI 1.1-1.7) for 20% of time below either threshold. Results at 15 months were comparable with results at 24 months. Results were not statistically significant for thresholds defining high values of rScO(2). The composite motor outcome was not significantly related to either low or high values or rScO(2).Conclusions Low, but not high, rScO(2) was associated with an unfavorable cognitive outcome. This suggests the use of a threshold of rScO(2) <55% for future clinical studies when using adult near-infrared sensors (rScO(2) <65% for neonatal sensors, approximately). Show less
