Clobazam Adjunctive Treatment of Adults With Refractory Focal Epilepsy

Overview

The goal of the present study is to obtain pilot data on efficacy and safety of clobazam add-on treatment on adults with drug-resistant focal epilepsy. This will be an open label study comparing seizure frequency during 12 weeks of baseline observation period with seizure frequency during 16 weeks of clobazam adjunctive treatment. 10 adults aged 18-65 with focal seizures that have failed to respond to ≥ 4 antiepileptic drugs (AEDs) +/- respective surgery will be enrolled. Following a baseline of 12 weeks patients will be started on clobazam, administered orally in b.i.d. schedule. In patients in whom seizure diaries have been kept prospectively prior to study screening visit, retrospective baseline will be accepted. Patients will be titrated up to either seizure freedom, to side effects or to 40 mg/day, whichever comes first. Titration rate will be not be forced. It is anticipated that the majority of subjects will have a 4 week-long titration period. After maximum dose is achieved, maintenance treatment will last for 12 weeks.

Approximately 35 % of patients with epilepsy do not respond to treatment with medications. There is a need for new treatment of refractory focal epilepsy. Clobazam was approved in 2011 in the US for treatment of refractory seizures in patients with Lennox Gastaut syndrome (LGS). Patients with LGS have different seizure types. While pivotal studies evaluated primary generalized seizures, LGS patients also have focal seizures. The goal of the present study is to obtain pilot data on efficacy and safety of clobazam add-on treatment on adults with drug-resistant focal epilepsy. This will be an open label study comparing seizure frequency during 12 weeks of baseline observation period with seizure frequency during 16 weeks of clobazam adjunctive treatment. 10 adults aged 18-65 with focal seizures that have failed to respond to ≥ 4 antiepileptic drugs (AEDs) +/- respective surgery will be enrolled. Following a baseline of 12 weeks, patients will be started on clobazam, administered orally in b.i.d. schedule. In patients in whom seizure diaries have been kept prospectively prior to study screening visit, retrospective baseline will be accepted. Patients will be titrated up to either seizure freedom, to side effects or to 40 mg/day, whichever comes first. Titration rate will be not be forced. It is anticipated that the majority of subjects will have a 4 week-long titration period. After maximum dose is achieved, maintenance treatment will last for 12 weeks. Primary efficacy outcome measure will be seizure freedom for 3 months of maintenance treatment with the highest tolerated clobazam dose. Secondary outcome measures will include \>75% seizure frequency reduction and median seizure frequency reduction for the whole treatment duration and for the maintenance treatment period, comparing seizure frequency per 28 day periods during treatment vs. baseline. Primary safety outcome measures will include treatment emergent adverse events, and treatment discontinuation due to treatment emergent adverse events. The number of subjects will be small, n=10. It is therefore likely that results obtained in the present study will not be statistically significant. The goal of the present study is to ascertain whether clobazam add-on treatment in adults with refractory focal epilepsy gives a signal of efficacy greater than that demonstrated with other second and third generation anticonvulsants such as levetiracetam, pregabalin, lacosamide and perampanel; specifically whether clobazam adjunctive treatment shows a trend towards 75% response and seizure freedom rate that surpasses those seen in phase 3 levetiracetam, pregabalin, lacosamide and perampanel studies. The results, if positive, will be used to design a larger controlled study would follow.