Efficacy and Safety of Adjunctive Zonisamide in Myoclonic Seizures Associated With Idiopathic Generalised Epilepsy
Condition: Epilepsy
MeSH terms: Epilepsy; Seizures; Epilepsies, Myoclonic; Epilepsy, Generalized
Intervention: Zonisamide; Placebo
Intervention description: 50-400 mg capsules once daily in the evening orally.
Maximum study duration 28 weeks comprising:
Baseline Period (Week -8 to Week 0): no treatment
Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4
Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events)
Down Titration Period (4 Weeks); 50-400 mg Zonisamide Placebo capsules once daily in the evening orally.
Maximum study duration 28 weeks comprising:
Baseline Period (Week -8 to Week 0): no treatment
Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4
Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 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: 10.0
Sex: All
Minimum age: 12 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      This study is intended to provide evidence that zonisamide is safe and effective in the
      treatment of myoclonic seizures. The total planned trial duration will be 6.5 months. After
      that, subjects who have completed the study will be eligible to enroll 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-E044-318).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject is male or female and aged 12-65 years.

          2. Subject has at least eight days with at least one myoclonic seizure over the two
             months Baseline Period. Myoclonic seizures must occur in the context of IGE and may be
             accompanied by other primary generalized seizures, provided these are also consistent
             with a diagnosis of Idiopathic Generalized Epilepsy (IGE).

          3. Subject (or parent/caregiver, for subjects below the age of consent) is willing to
             sign an informed consent form. Subjects below the age of consent in their country,
             must where appropriate 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 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 generalised epilepsy (IGE)
             which has myoclonic seizures (and which may be accompanied by other generalised
             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 generalised epilepsy. A 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 ≥ 18 years must abide by 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.
             Subjects <18 years and of childbearing potential must be either abstinent or willing
             to use one of the medically appropriate forms of contraception for the duration of the
             study.

        Exclusion Criteria:

          1. Subject has progressive or focal neurological disease (as determined by preexisting
             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 generalised
             tonic clonic seizures which are suspected to be secondarily generalised.

          3. Subjects with cryptogenic or symptomatic generalised epilepsy.

          4. Subjects with psychogenic seizures.

          5. Subject has a history of convulsive status epilepticus within a year of screening
             while complying with AEDs.

          6. Subject has a history of renal calculi or renal insufficiency (above the upper normal
             limits of creatinine).

          7. Subject has a known diagnosis of human immunodeficiency virus (HIV) or hepatitis B or
             C.

          8. Subject has a predisposing condition that might interfere with absorption,
             distribution, or excretion of zonisamide.

          9. Subject has a history of sensitivity to sulfonamide drugs or to zonisamide or any of
             its excipients.

         10. Subject has a recent history of excessive alcohol use or drug abuse.

         11. Subject has a history of suicide attempt in the five years before the screening visit.

         12. Subject has abnormal screening laboratory values that are clinically significant.

         13. 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.

         14. Subject has participated in a study of an investigational drug or device within 30
             days prior to screening.

         15. Subject has received previous treatment with zonisamide.

         16. Subject is treated with ketogenic diet or vagus nerve stimulator.

         17. 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).

         18. Concomitant use of acetazolamide, carbonic anhydrase inhibitors such as topiramate and
             drugs with anticholinergic activity.

         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 felbamate or use of felbamate within two months prior to Visit 1.

         21. Subject is unable to swallow capsules.

         22. Subject is not in general good health as determined by medical history, physical exam
             and screening laboratory results.