Exploring the Safety And Tolerability of Doses of E2007 up to a Maximum of 12 mg In Patients With Refractory Partial Seizures
Condition: Epilepsy
MeSH terms: Seizures
Intervention: E2007; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      This is a randomized, double-blind, placebo-controlled, parallel group study to determine the
      maximum tolerated dose of E2007. Epilepsy patients with refractory partial seizures will be
      divided into two groups of 24 patients each. One group will be patients who take concomitant
      inducing AEDs (anti-epileptic drugs) and the second group will be patients who do not take
      concomitant inducing AEDs. In each group, 18 patients will receive E2007 (dose escalating to
      a maximum of 12 mg per day) and six will receive placebo.
    

Eligibility criteria:

        INCLUSION CRITERIA

          1. Provide written informed consent signed by patient or legal guardian prior to entering
             the study or undergoing any study procedures.

          2. Are reliable and willing to make themselves available for the study period and are
             able to record seizures and report AEs themselves or have a caregiver who can record
             and report the events.

          3. Male and female patients will be eligible for enrollment. Females should be either of
             nonchildbearing potential as a result of surgery or menopause (1 year after onset), or
             of childbearing potential and practicing a medically acceptable method of
             contraception (e.g., abstinence, a barrier method plus spermicide, or intrauterine
             device [IUD]) for at least 1 month before Visit 1 (Screening) and for 1 month after
             the end of the study. They must also have a negative serum beta-human chorionic
             gonadotropin (B-hCG) at Screening. Those females using hormonal contraceptives must
             also be using an additional approved method of contraception (e.g., a barrier method
             plus spermicide or IUD) starting with the Baseline Phase and continuing throughout the
             entire study period.

          4. Are between the ages of 18 and 70 years of age, inclusive.

          5. Are of 40 kg (88 pounds) of weight or more.

          6. Have the diagnosis of epilepsy with partial seizures with or without secondarily
             generalized seizures according with the International League Against Epilepsy's
             Classification of Epileptic Seizures (1981). Diagnosis should have been established by
             clinical history, electroencephalogram and computed tomography/magnetic resonance
             imaging of the brain performed within the last 10 years and consistent with
             localization-related epilepsy.

          7. Have uncontrolled partial seizures despite having been treated with at least three
             different AEDs (given concurrently or sequentially) for at least 2 years.

          8. Have averaged at least three partial seizures per month, with no 21-day seizure-free
             period during the 2 months preceding randomization. This should be documented in the
             form of medical history, medical records, or photocopied records of the patient
             diary/patient chart. Simple partial seizures without motor signs will not be counted
             towards this inclusion criterion.

          9. Are currently being treated with one to three (maximum) marketed and approved AEDs and
             are known to take their medications as directed. Use of a vagal nerve stimulator is
             not considered an AED by this criterion.

         10. Are on a stable dose of the same AEDs for the 1 month prior to Visit 1.

         11. If using a vagal nerve stimulator, it must have been implanted at least 5 months prior
             to Visit 1. Stimulator parameters may not be changed for at least 1 month prior to
             Visit 1 or during the study. Magnet use will be allowed and documented throughout the
             study.

        EXCLUSION CRITERIA

          1. Have participated in a study involving administration of an investigational compound
             within 3 months of Visit 1 (Screening), or within 5 half-lives of the previous
             investigational compound, whichever is longer, or who have been previously treated
             with E2007.

          2. Presence of nonmotor simple partial seizures only.

          3. Presence of primary generalized epilepsies or seizures, such as absences, myoclonic
             epilepsies, Lennox-Gastaut syndrome.

          4. History of status epilepticus in the past year or seizure clusters where individual
             seizures cannot be counted.

          5. Show evidence of clinically significant disease (cardiac, respiratory,
             gastrointestinal, renal disease, etc) that, in the opinion of the investigator, could
             affect either the patient's safety or the conduct of the study.

          6. Show evidence of significant, active, hepatic disease. Stable elevations of liver
             enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) due to
             concomitant medications will be allowed if they are less than 2 times the ULN.

          7. Show evidence of significant active hematological disease such as a white blood cell
             (WBC) count <= 2500/µL (2.50 1E+09/L), an absolute neutrophil count <= 1000/µL (1.00
             1E+09/L), or a platelet count <100,000/mm^3.

          8. Patients with clinically significant ECG abnormality, including prolonged QTc (defined
             as QTc >=450 msec using Fridericia's correction).

          9. Presence of major active psychiatric disease. Patients taking a stable dose of
             selective serotonin reuptake inhibitor antidepressant (except fluvoxamine) will be
             allowed.

         10. Presence of a progressive central nervous system (CNS) disease, including degenerative
             CNS diseases and progressive tumors.

         11. Have a history of psychogenic seizures in the past 2 years.

         12. Pregnant or lactating females.

         13. Have a history of drug abuse in the past 2 years and/or positive finding on urinary
             drug screening, other than prescribed medication.

         14. Have a history of alcohol abuse in the past 2 years, and/or positive finding on
             urinary drug screen.

         15. Have had multiple drug allergies (dermatological, hematological, or organ toxicity) or
             one or more severe drug reactions.

         16. Allergy to lactose.

         17. Concomitant use of felbamate or use of felbamate within 2 months prior to Visit 1.

         18. Concomitant use or use within the 4 weeks prior to Visit 1 of neuroleptics, monoamine
             oxidase (MAO) inhibitors, barbiturates (except for seizure control indication),
             benzodiazepines (other than occasional intermittent use), and narcotic analgesics.

         19. Frequent need of rescue benzodiazepines (two or more times a month).