Kim Annink

198 Chapter 9 respiratory support for ≥ 10 min postpartum, 4) abnormal primitive reflexes/ abnormal movements i.e. seizures. The most important exclusion criteria were gestational age <36 weeks, estimated birth weight <2500 gram or severe congenital abnormalities. Infants who met the inclusion criteria for the ALBINO, but did not meet the therapeutic hypothermia criteria because of a quick and spontaneous recovery, received the initial dose of allopurinol or placebo but did not receive the second dose. Further details of the study protocol are previously published (26). The trial is registered at www.clinicaltrials.gov (NCT03162653). Therapeutic hypothermia was conducted according to the national treatment protocols (29,30). Therapeutic hypothermia was started within 6 hours after birth to a core temperature of 33.5˚C for 72 hours. Thereafter, patients were slowly rewarmed to normothermia and after rewarming, body temperature was stabilized at 36.5˚C for 24 hours (29,30). Short oral consent was obtained from at least one parent before administering the study medication. After the first dose, but before the (potential) second dose, full written consent was obtained from both parents. In case parents did not sign informed consent, blood samples collected shortly after birth were destroyed. The medical ethics committee of the University Medical Center Utrecht and the Central Committee on Human Research approved the study for the Netherlands (NL57237.041.16) and the German Federal Authority (EudraCT 2016-000222-19) as well as the leading Ethics Committee Tuebingen approved the study for Germany. Target exposure The pre-defined minimum target AUC of 43.5mg/L*h for allopurinol and 26.5mg/L*h for oxypurinol between 0-12 hours were expected to be reached in more than two thirds (>66%) of the analyzed patients. This minimum target AUC was calculated based on the lowest individual values observed in previous clinical studies of postnatal allopurinol in neonates (18,27). Timing of this preliminary assessment of pharmacokinetics According to the ALBINO study protocol the pharmacokinetic study should include 48-52 patients corresponding to about 20-25 infants receiving allopurinol. This sample size was intended to be reached within 12 months after the first included