Kim Annink

184 Chapter 8 the Steering Committee, the relevant issues were subsequently incorporated into the study protocol. Medical ethics committees At the time of publication, the relevant ethics committees in ten European countries approved the study with either the short oral consent procedure or the deferred consent procedure. Applications for approvals are currently underway in two additional countries. National Regulatory/Competent Authorities At the time of publication, eleven European National Regulatory/Competent Authorities approved the study. Application for approval is currently underway in one additional country. DISCUSSION ALBINO is a randomized controlled trial investigating the safety and efficacy of allopurinol in (near-) term infants with HIE. A decision was made for a large phase III trial for efficacy and safety because preliminary clinical data from postnatal and prenatal allopurinol trials already suggested a reduction in brain injury by allopurinol without apparent adverse effects. Another small proof-of-principle or dose seeking study would have added little with respect to safety and clinically relevant outcomes. Survival without NDI was selected as the primary endpoint of this study, because this outcome parameter is most meaningful to the children and their families. The calculated starting dose was based on previous studies: the doses used in the first studies with allopurinol in neonates undergoing extracorporeal membrane oxygenation and in neonates diagnosed with hypoplastic left heart syndrome (10 and 30 mg/kg birth weight respectively) gave 100% xanthine-oxidase inhibition (21,23). Higher concentrations may be needed for the iron chelating and reactive oxygen scavenging effect of allopurinol. Even with higher doses (up to 40 mg/kg birth weight per day for 3 days) no adverse effects were seen, with special attention to skin rashes and leukopenia (15).