Adjunctive Zonisamide in Primary Generalised Tonic Clonic Seizures
Condition: Epilepsy
MeSH terms: Seizures
Intervention: Zonisamide; Placebo
Intervention description: 25-400 mg capsules orally once daily in the evening.
Maximum study duration of 28 weeks comprising:
Baseline Period (Week-8/-4 to Week 0) no treatment
Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg; >= 12 years old: 50 mg daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4
Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events)
Down Titration Period (4 weeks); 25-400 mg Zonisamide Placebo capsules orally once daily in the evening.
Maximum study duration of 28 weeks comprising:
Baseline Period (Week-8/-4 to Week 0) no treatment
Titration Period (Week 0 to Week 4) <12 years old: 1 mg/kg Zonisamide Placebo; >= 12 years old: 50 mg Zonisamide Placebo capsules daily titrated weekly until a dose of 5 mg/kg or 300 mg was reached by Week 4
Maintenance Period (Week 4 to Week 16) dose from Week 4 to be maintained (4 mg/kg or 200 mg in the event of dose limiting adverse events)
Down Titration Period (4 weeks)
Intervention MeSH terms: Zonisamide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 21.0
Sex: All
Minimum age: 6 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      Zonisamide is already marketed for the treatment of partial seizures in epilepsy. This study
      is intended to provide evidence that zonisamide is safe and effective in the treatment of
      primary generalised tonic-clonic seizures. The total trial duration will be 5.5-6.5 months.
      After that subjects who have completed the study will be eligible to enrol in an open-label
      extension study until zonisamide is marketed for this indication or further development in
      this indication stops. This extension study will be described in a separate protocol
      (E2090-E044-316).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject is male or female and aged 6-65 years.

          2. Subject has ≥ 3 PGTCS over the two months before screening and during the eight weeks
             Baseline Period with at least one seizure in each one month period. PGTCS must occur
             in the context of Idiopathic Generalized Epilepsy (IGE) and may be accompanied by
             other primary generalized seizures, provided these are also consistent with a
             diagnosis of IGE.

          3. Subject (or parent/caregiver, for subjects below the age of consent) is willing to
             sign an informed consent form. For subjects below the age of consent in their country,
             where appropriate they must be willing to give informed (written or verbal) assent.
             Subjects from the age specified in local regulations will be required to sign an
             appropriate informed consent form.

          4. Subject is taking a stable regimen of one or two other Antiepileptic Drugs (AEDs) for
             at least two weeks prior to Visit 1 (start of the Baseline Period).

          5. Subject has a clinical diagnosis of any type of idiopathic generalized epilepsy which
             has PGTCS (and which may be accompanied by other generalized seizure types), according
             to the International League Against Epilepsy (ILAE) Classification of Epileptic
             Seizures (1981) and the ILAE Classification of Epilepsies and Epileptic Syndromes
             (1989). Diagnosis should have been established by clinical history,
             electroencephalogram (EEG) and computed tomography/magnetic resonance imaging (CT/MRI)
             of the brain consistent with idiopathic generalized epilepsy. CT/MRI scan should have
             been performed within five years of the screening visit or, if not available from this
             period, should be performed in the Baseline Period.

          6. EEG should have been performed within one year of the screening visit or, if not
             available from this period, should be performed in the Baseline Period.

          7. Female subjects are pre-menarchal, or if of childbearing potential, are not pregnant
             or lactating or are post-menopausal.

          8. Female subjects of childbearing potential must abide by the one of the following
             medically acceptable contraceptive measures: oral contraception pill, contraceptive
             injections, implants or patches, intrauterine device in place for at least three
             months or vasectomised partner or abstinence throughout the study.

          9. Subject has a body weight ≥ 20 kg.

        Exclusion Criteria:

          1. Subject has progressive or focal neurological disease (as determined by pre-existing
             brain imaging such as CT or MRI performed maximally five years before the screening
             visit), or clinically significant organic disease.

          2. Subject has a history of, or results of clinical investigations (including EEG data)
             that are suggestive of, partial seizures as defined by the ILAE, including generalized
             tonic clonic seizures which are suspected to be secondarily generalized.

          3. Subjects with cryptogenic or symptomatic generalized epilepsy.

          4. Subjects with psychogenic seizures.

          5. Subject has a history of status epilepticus within a year of screening while complying
             with AEDs.

          6. Subject has seizures that only occur in clustered patterns.

          7. Subject has a history of renal calculi or renal insufficiency (above the upper normal
             limits of creatinine).

          8. Subject has a known diagnosis of human immunodeficiency virus (HIV) or hepatitis B or
             C.

          9. Subject had a predisposing condition that might interfere with absorption,
             distribution, or excretion of zonisamide.

         10. Subject has a history of sensitivity to sulfonamide drugs or zonisamide and its
             excipients.

         11. Subject has a recent history of excessive alcohol use or drug abuse.

         12. Subject has a history of suicide attempt in the five years before the screening
             visit..

         13. Subject has abnormal screening laboratory values that were clinically significant.

         14. Subject has a history of demonstrated non-compliance with treatment or the subject or
             parent/caregiver can be reasonably expected not to be compliant with study procedures
             or to complete the study.

         15. Subject has participated in a study of an investigational drug or device within 30
             days prior to screening.

         16. Subject has received previous treatment with zonisamide.

         17. Subject is treated with ketogenic diet or vagus nerve stimulator.

         18. Subject has a history of necessary treatment with rescue benzodiazepines which is
             foreseen to continue during the study. Rescue benzodiazepines will not be allowed in
             this study (stable dosing with a benzodiazepine as (one of the) baseline
             anti-epileptic drug(s) is allowed).

         19. Current psychosis or moderate to severe depression, or use of anti-psychotic drugs,
             MAOIs, tricyclic antidepressants, benzodiazepine or barbiturate treatment for
             disorders other than epilepsy, and stimulants (amphetamine derivatives) within 28 days
             before the screening visit.

         20. Concomitant use of acetazolamide, carbonic anhydrase inhibitors such as topiramate and
             drugs with anticholinergic activity.

         21. Concomitant use of felbamate or use of felbamate within two months prior to Visit 1.

         22. Subject is not able to swallow capsules.

         23. Subject is not in general good health as determined by medical history, physical exam
             and screening laboratory results.