Kim Annink

265 General discussion / Conclusions & clinical implications / Future directions FUTURE DIRECTIONS The future of neuroprotective trials in HIE Different trial design Optimal neuroprotection and reduction of brain injury after perinatal asphyxia will ultimately be a combination of therapeutic hypothermia and inhibition of the different destructive pathways with intervening drugs each at their specific optimal points of time and with optimal dosing. Current studies investigate these various pharmaceutical interventions separately as add-on to therapeutic hypothermia. Setting up and conducting such randomized controlled trials is not very effective, because it takes years and requires many resources. Alternatively, a combination of (pharmacological) add-on therapies might be more effective, since this integrated approach targets the destructive pathways all together leading to optimal protection of the threatened brain (4). A Master Protocol allows to investigate different therapies in parallel within one study protocol, this design is also commonly used in pediatric oncology (62–64). Drugs that are proven to be effective, as therapeutic hypothermia, will be standard of care and patients can be randomized for the other drugs that are investigated. This approach has several advantages (63,64). First of all, neuroprotective drugs can be investigated more efficient and in parallel, which will save time. Also, the infrastructure, resources and costs can be shared by all research groups that participate in the trial. The sample size will be met sooner with (international) collaboration. Finally, if there is only one research protocol for all infants with HIE in the Netherlands, clinicians will be more likely to remember to ask patients for informed consent, even in the emergency setting. The Master Protocol also allows to randomize patients within the protocol based on specific (genetic or molecular) biomarkers for individualized target therapies (63). At present, there are no such biomarkers for HIE. In the future genetic or molecular biomarkers might become available that stratify infants with HIE in different groups. For example, some patients with HIE might benefit more from reducing superoxide formation and others from improving regeneration or preventing inflammation. 12