Kim Annink

185 ALBINO trial: study protocol A significant beneficial effect of allopurinol in moderately asphyxiated neonates has been found on long-term (4-5 years) neurodevelopmental outcome by Kaandorp et al. (2012), which was a meta-analyses of the study from van Bel et al. (1998) and Benders et al. (2006) (12,13). These latter trials administered 2 times 20mg/kg birth weight allopurinol with 12 hours interval. The doses of the ALBINO trial are based on these three studies. However, pharmacokinetics of allopurinol during hypothermia have not yet been determined before in neonates with HIE. The second dose in the ALBINO trial (only during hypothermia) is adjusted for the hypothermia treatment which may possibly slow-down allopurinol and oxypurinol metabolism and elimination. In the latter case this would lead to higher circulating concentrations of allopurinol respectively oxypurinol. In previous studies the plasma concentrations of allopurinol were often supra- therapeutic without any side effect (19,29). These supra-therapeutic levels seem to be important for the direct scavenging of hydroxyl and free iron by allopurinol. However, to ensure that in addition to therapeutic hypothermia plasma concentrations are not lower than in the earlier clinical trials indicating efficacy, blood sampling for pharmacokinetic analyses will be performed in 48 to 52 infants (in selected centers) recruited during the first year of the study and may lead to adaptation of doses. Mannitol is used as placebo, since its freeze-dried white powder and the reconstituted solution, have the same visual aspects and volume as the freeze-dried sodium salt of allopurinol and its reconstitution solution (10 ml of a colorless, clear solution in a 20 ml vial). The dosage of mannitol is 50 times lower than the dose of mannitol used for neuroprotection (30), and a normal daily dose of intravenous paracetamol will include more mannitol as supporting agent than the dose administered in ALBINO (i.e. 100 ml solution for injection contains 1000 mg acetaminophen and 3670-3850 mg mannitol (31,32). For each single dose of 12.5 mg/kg paracetamol i.v. (33), 45.9-48.1 mg/kg of Mannitol are concomitantly administered). Inclusion and exclusion criteria were selected to recruit a patient population similar to the TOBY trial of whole body cooling (3), but took into account that the assessment for eligibility has to be done much earlier, i.e. within 30 min after birth. 8