Clobazam Adjunctive Treatment of Adults With Refractory Focal Epilepsy

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.

Inclusion Criteria:

1. Age 18-65

2. Stable focal epilepsy, with partial complex seizures including partial complex
seizures with or without secondary generalization, partial simple seizures with a
clear motor component with or without secondary generalization, and partial simple
seizures with secondary generalization.

3. Stable AED doses for at least 30 days

4. Epilepsy duration for > 2 years

5. Past/current treatment with > 4 AEDs. Vagal nerve stimulator treatment will be
allowed and will not count as an AED. VNS setting must be stable for 3 months prior
to enrollment.

6. Seizure frequency of ≥1/month

Exclusion Criteria:

1. Primary generalized epilepsy

2. Simple partial seizures without motor components or secondary generalization

3. Non-epileptic seizures

4. Progressive neurological disease including neoplasm, CNS degenerative disorders
including Alzheimer's disease, other forms of dementia

5. Any systemic illness or unstable medical condition that might pose additional risk,
including renal or liver disease, clinically uncontrolled cardiac disease, other
unstable metabolic or endocrine disturbances, and active systemic cancer

6. Change in the dose of any Antiepileptic Drug within 30 days prior to enrollment

7. Psychosis within six months of enrollment.

8. Active drug or alcohol dependence or any other factors that, in the opinion of the
site investigators would interfere with adherence to study requirements;

9. Pregnancy

10. Use of any CNS-active investigational drugs within 3 months of enrollment.

11. Inability or unwillingness of subject or legal guardian/representative to give
written informed consent.