A Dose Ranging Pilot Study for Intracerebroventricular (ICV) Delivery of Valproate in Subjects With Temporal Seizures

Epilepsy patients that are refractory to oral anti-epileptic drug (AED) treatment have significantly higher mortality, higher morbidity, higher economic costs and diminished quality of life compared to those who suffer from epilepsy that can be adequately controlled with medical management. Current options for refractory patients include neurosurgical brain resection, responsive neurostimulation, and vagal nerve stimulation. None of these options is satisfactory due to the low applicability of surgery for patients with poorly localized or multifocal seizures and the limited success of currently available alternative treatment options. In this study, patients with medically refractory focal epilepsy will be treated with intracerebroventricular (ICV) administration of valproate using an implantable drug pump system. This is a dose ranging study, with a randomized, double-blind dose escalation component, to establish the dose range of ICV valproate delivery. Clinical assessments, adverse events (AEs), seizure diaries, concomitant medications, blood samples and cerebrospinal fluid (CSF) will be collected and reviewed at designated time points. Magnetic resonance imaging (MRI) and electroencephalography (EEG) will also be performed. Subjects will have their surgery, dose changes and pharmacokinetics performed in an inpatient setting. The ICV Valproate dose will be escalated stepwise from 3 mg/day to 60 mg/day through Day 64 if tolerated, or stopped earlier upon establishment of a subject's maximum tolerated dose (MTD). The MTD for each subject will be determined based on the highest dose tolerated without experiencing a dose-limiting adverse event (AE). After establishing a subject's MTD, delivery of ICV Valproate will continue at the MTD through Day 64 of the blinded evaluation period. Subjects and assessing physicians will remain blinded to the treatment dose during the blinded evaluation period. Subjects can continue in the open-label evaluation period (non-blinded) for 52 weeks following the blinded evaluation period.