Supplementary Material for: Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial

<b><i>Background and Objectives:</i></b> Therapeutic interventions to improve the efficacy of whole-body cooling for hypoxic-ischemic encephalopathy (HIE) are desirable. Topiramate has been effective in reducing brain damage in experimental studies. However, in the clinical setting information is limited to a small number of feasibility trials. We launched a randomized controlled double-blinded topiramate/placebo multicenter trial with the primary objective being to reduce the antiepileptic activity in cooled neonates with HIE and assess if brain damage would be reduced as a consequence. <b><i>Study Design:</i></b> Neonates were randomly assigned to topiramate or placebo at the initiation of hypothermia. Topiramate was administered via a nasogastric tube. Brain electric activity was continuously monitored. Topiramate pharmacokinetics, energy-related and Krebs’ cycle intermediates, and lipid peroxidation biomarkers were determined using liquid chromatography-mass spectrometry and MRI for assessing brain damage. <b><i>Results:</i></b> Out of 180 eligible patients 110 were randomized, 57 (51.8%) to topiramate and 53 (48.2%) to placebo. No differences in the perinatal or postnatal variables were found. The topiramate group exhibited less seizure burden in the first 24 h of hypothermia (topiramate, <i>n</i> = 14 [25.9%] vs. placebo, <i>n</i> = 22 [42%]); needed less additional medication, and had lower mortality (topiramate, <i>n</i> = 5 [9.2%] vs. placebo, <i>n</i> = 10 [19.2%]); however, these results did not achieve statistical significance. Topiramate achieved a therapeutic range in 37.5 and 75.5% of the patients at 24 and 48 h, respectively. A significant association between serum topiramate levels and seizure activity (<i>p</i> &lt; 0.016) was established. No differences for oxidative stress, energy-related metabolites, or MRI were found. <b><i>Conclusions:</i></b> Topiramate reduced seizures in patients achieving therapeutic levels in the first hours after treatment initiation; however, they represented only a part of the study population. Our results warrant further studies with higher loading and maintenance dosing of topiramate.