A Study of the Efficacy and Safety of Topiramate as add-on Therapy in the Treatment of Epilepsy Patients With Difficult to Treat, Partial-onset Seizures.

Double-Blind Parallel Comparison of Topiramate 200 mg Twice Daily to Placebo in Patients With Refractory Partial Epilepsy

The purpose of the study is to evaluate the efficacy and safety of topiramate in epilepsy patients with difficult to treat, partial-onset seizures who are taking one or two standard antiepileptic drugs.

Epilepsy is characterized by seizures, which are abnormal electrical discharges in the brain that temporarily disrupt normal brain function. Seizures are classified as "generalized," originating in both sides of the brain simultaneously, or "partial-onset," starting in one area of the brain. Antiepilepsy medications, such as topiramate, are selected based on seizure type. This is a double-blind, placebo-controlled study to evaluate topiramate efficacy and safety as add-on therapy in partial epilepsy patients. This study includes a baseline phase and a treatment phase. During the baseline phase (8 weeks duration), patients receive one or two standard antiepileptic drugs (AEDs), such as phenytoin, carbamazepine, phenobarbital, primidone, or valproic acid. Patients who continue to have seizures during treatment with standard AEDs proceed into the double-blind treatment phase. Patients then receive topiramate or placebo at a dosage of 100 milligrams once daily, increasing gradually over 3 weeks to 2 tablets twice daily (400 mg/day) or maximum tolerated dose, and maintained on that dose for 8 weeks (11 weeks is the total duration of the double-blind phase), while continuing on their standard AED regimen. Assessments of effectiveness include the percent reduction in the average monthly seizure rate, percent of patients responding to treatment (having equal to or greater than 50% reduction in seizure rate), and, the patient's and investigator's global assessments of medication at end of study. Safety assessments include the incidence of adverse events throughout the study, clinical laboratory tests (hematology, serum chemistry, urinalysis), neurologic examinations, and vital sign measurements (blood pressure, pulse, temperature) weekly during the treatment phase. The study hypothesis is that topiramate, taken as add-on therapy to treatment with AEDs, will significantly reduce seizure frequency, compared with placebo, in patients with refractory partial epilepsy: that is, in patients who continue to have seizures despite treatment with a first-line AEDs. In addition, it is hypothesized that topiramate is well tolerated. Topiramate, 100 milligrams (mg) oral tablets (or placebo). Dosage begins at 100 mg once daily and increases gradually over 3 weeks to 2 tablets twice daily (400 mg/day, maximum) or maximum tolerated dose for an additional 8 weeks.

Inclusion Criteria:

• History of simple or complex partial epilepsy that has been documented or witnessed
• an electroencephalogram (EEG) during the preceding 5 years that has a pattern consistent with the diagnosis of partial epilepsy
• during an 8-week baseline phase, patient must have at least 8 partial seizures while maintaining therapeutic levels of antiepileptic drugs (AEDs) and have no more than one seizure-free interval of up to 3 weeks
• and no seizure-free interval longer than 3 weeks
• good physical health.

Exclusion Criteria:

• Patients having solely generalized seizures or lacking documentation of partial epilepsy
• patients with generalized tonic-clonic seizures or other generalized epilepsies in the absence of an EEG consistent with partial epilepsy
• generalized seizures, which are defined by the EEG wave pattern
• seizures that lack an abnormal pulsation pattern on EEG
• female patients who are pregnant or nursing, or those not using adequate birth control if capable of having children