Paediatric drugs · 2020
A Phase IIa Clinical Trial of 2-Iminobiotin for the Treatment of Birth Asphyxia in DR Congo, a Low-Income Country.
Клиническое исследование II фазыСтатьяНазвание и аннотация: Перевод в очереди
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Biselele Thérèse, Bambi Jephté, Betukumesu Dieu M, Ndiyo Yoly, Tabu Gabriel, Kapinga Josée, Bola Valérie, Makaya Pascal, Tjabbes Huibert, Vis Peter, Peeters-Scholte Cacha
Аннотация
AIM: The main burden of hypoxic-ischemic encephalopathy falls in low-income countries. 2-Iminobiotin, a selective inhibitor of neuronal and inducible nitric oxide synthase, has been shown to be safe and effective in preclinical studies of birth asphyxia. Recently, safety and pharmacokinetics of 2-iminobiotin treatment on top of hypothermia has been described. Since logistics and the standard of medical care are very different in low-resource settings, the aim of this study was to investigate safety and pharmacokinetics of Two-IminoBiotin in the Democratic Republic of Congo (TIBC).
METHODS: Near-term neonates, born in Kinshasa, Democratic Republic of Congo, with a Thompson score ≥ 7 were eligible for inclusion. Excluded were patients with (1) inability to insert an umbilical venous catheter for administration of the study drug; (2) major congenital or chromosomal abnormalities; (3) birth weight < 1800 g; (4) clear signs of infection; and (5) moribund patients. Neonates received six infusions of 2-iminobiotin 0.16 mg/kg started within 6 h after birth, with 4-h intervals, targeting an AUC0-4h of 365 ng*h/mL. Safety, defined as vital signs, the need for clinical intervention after administration of study drug, occurrence of (serious) adverse events, and pharmacokinetics were assessed.
RESULTS: After parental consent, seven patients were included with a median Thompson score of 10 (range 8-16). No relevant changes in vital signs were observed over time. There was no need for clinical intervention due to administration of study drug. Three patients died, two after completing the study protocol, one was moribund at inclusion and should not have been included. Pharmacokinetic data of 2-iminobiotin were best described using a two-compartment model. Median AUC0-4h was 664 ng*h/mL (range 414-917). No safety issues attributed to the administration of 2-iminobiotin were found.
CONCLUSION: The present dosing regimen resulted in higher AUCs than targeted, necessitating a change in the dose regimen in future efficacy trials. No adverse effects that could be attributed to the use of 2-iminobiotin were observed. EudraCT number 2015-003063-12.
METHODS: Near-term neonates, born in Kinshasa, Democratic Republic of Congo, with a Thompson score ≥ 7 were eligible for inclusion. Excluded were patients with (1) inability to insert an umbilical venous catheter for administration of the study drug; (2) major congenital or chromosomal abnormalities; (3) birth weight < 1800 g; (4) clear signs of infection; and (5) moribund patients. Neonates received six infusions of 2-iminobiotin 0.16 mg/kg started within 6 h after birth, with 4-h intervals, targeting an AUC0-4h of 365 ng*h/mL. Safety, defined as vital signs, the need for clinical intervention after administration of study drug, occurrence of (serious) adverse events, and pharmacokinetics were assessed.
RESULTS: After parental consent, seven patients were included with a median Thompson score of 10 (range 8-16). No relevant changes in vital signs were observed over time. There was no need for clinical intervention due to administration of study drug. Three patients died, two after completing the study protocol, one was moribund at inclusion and should not have been included. Pharmacokinetic data of 2-iminobiotin were best described using a two-compartment model. Median AUC0-4h was 664 ng*h/mL (range 414-917). No safety issues attributed to the administration of 2-iminobiotin were found.
CONCLUSION: The present dosing regimen resulted in higher AUCs than targeted, necessitating a change in the dose regimen in future efficacy trials. No adverse effects that could be attributed to the use of 2-iminobiotin were observed. EudraCT number 2015-003063-12.