Abstracts

Rationale: Epilepsy is a major neurological manifestation of Tuberous Sclerosis Complex (TSC), occurring in 80-90% of patients. Previous studies with everolimus to treat subependymal giant cell astrocytoma (SEGA) yielded differing results, possibly due to uncontrolled variables with potential influence on the secondary endpoint measures related to epilepsy in these studies. The current study is an open-label, multi-center combined phase I/II clinical trial where these same variables were identified and controlled to better determine the benefit of everolimus on seizure control. Methods: Patients ≥ 2 years of age with confirmed diagnosis of TSC and medically refractory epilepsy (defined as failure of two or more approved antiepileptic drug therapies and currently experiencing two or more seizures/week) were treated with everolimus 5 mg/m2/day and titrated to serum trough level between 5-15 ng/ml over a four week period. Patients then continued treatment for an additional eight weeks. Changes in concomitant antiepileptic medications were not permitted during observation, titration, and maintenance study phases. The primary efficacy endpoint was percentage of patients demonstrating a 50% or greater reduction in seizure frequency at the end of the maintenance period compared to baseline. Patients with 25% or greater reduction were considered partial responders. Secondary endpoints evaluated effect of treatment on 23-hour continuous video EEG recordings, quality of life assessments, and behavioral rating scales. Patients demonstrating beneficial effect after completing the maintenance study phase were eligible for optional extension. Results: Between May 2010 and August 2011, 20 patients were enrolled. Mean age was 9.0 years (range 2-21 years). Mean number of seizures/week was 14 (range 4-17) at baseline. All 20 patients completed the main study phase. We found that everolimus significantly decreases seizure frequency and shortens seizure duration in TSC patients with severe epilepsy overall (p-value=0.0004, 0.0258, respectively). Post-hoc analysis by ILAE classification suggests that the decreased seizure counts and shortened seizure duration was mainly driven by significant changes in complex partial seizures (p-value=0.0007, 0.0049). Individually, 19 of the 20 patients demonstrated a reduction in seizure frequency. 14 were considered responders, including 4 becoming seizure-free. Another 4 were partial-responders and the remaining 2 were non-responders. All responders and near-responders continued treatment in the extension phase. As of data cut-off (December 31, 2011), 17 patients in extension demonstrate continued efficacy and remain on treatment. Overall medication was well tolerated, with most common AE encountered being mouth ulcers and upper respiratory symptoms, consistent with previously published results. Conclusions: Patients with TSC and medically refractory epilepsy demonstrated a clinically and statistically significant reduction in seizure frequency and duration following treatment with everolimus.