Adjunctive Zonisamide in Primary Generalised Tonic Clonic Seizures

Study Overview
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Brief Summary
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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).

Official Title
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A Double-blind, Randomised, Placebo-controlled Multi-centre Study to Assess the Efficacy and Safety of Adjunctive Zonisamide in Primary Generalised Tonic Clonic Seizures

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: Zonisamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is male or female and aged 6-65 years. 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. 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. 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). 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. 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. Female subjects are pre-menarchal, or if of childbearing potential, are not pregnant or lactating or are post-menopausal. 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. Subject has a body weight ≥ 20 kg. Exclusion Criteria: 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. 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. Subjects with cryptogenic or symptomatic generalized epilepsy. Subjects with psychogenic seizures. Subject has a history of status epilepticus within a year of screening while complying with AEDs. Subject has seizures that only occur in clustered patterns. Subject has a history of renal calculi or renal insufficiency (above the upper normal limits of creatinine). Subject has a known diagnosis of human immunodeficiency virus (HIV) or hepatitis B or C. Subject had a predisposing condition that might interfere with absorption, distribution, or excretion of zonisamide. Subject has a history of sensitivity to sulfonamide drugs or zonisamide and its excipients. Subject has a recent history of excessive alcohol use or drug abuse. Subject has a history of suicide attempt in the five years before the screening visit.. Subject has abnormal screening laboratory values that were clinically significant. 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. Subject has participated in a study of an investigational drug or device within 30 days prior to screening. Subject has received previous treatment with zonisamide. Subject is treated with ketogenic diet or vagus nerve stimulator. 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). 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. Concomitant use of acetazolamide, carbonic anhydrase inhibitors such as topiramate and drugs with anticholinergic activity. Concomitant use of felbamate or use of felbamate within two months prior to Visit 1. Subject is not able to swallow capsules. Subject is not in general good health as determined by medical history, physical exam and screening laboratory results.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Zonisamide<br> | Drug: Zonisamide<br>* 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)<br>* Other names: Zonegran;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Considered Responders as Assessed During the Maintenance Period | The number of participants who were considered responders during the 12 week Maintenance Period (Week 4 to Week 16). A responder was defined as a participant with a decrease from baseline in Primary Generalised Tonic-Clonic Seizures (PGTCS) frequency of >= 50% (i.e. 28-day PGTC seizure frequency in the period from Week 4 to the Week 16 visit compared to Week -8/-4 to randomization at Week 0). Each participant's response to treatment was assessed on the basis of their seizure diaries. The diary was dispensed at the Screening Visit and maintained by the participant (parent/caregiver) through out the titration and maintenance treatment periods until the Early termination Visit at Week 16. Due to early termination of the study by the Sponsor, no formal analyses were conducted. | Baseline (Week -8/-4 to Week 0) and Maintenance Phase (Week 4 to Week 16) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in 28-day PGTC Seizure Frequency | Absolute Change from Baseline in 28-day PGTC Seizure Frequency was assessed both for the Maintenance Period alone (Week 4 to Week 16) and for the entire double-blind treatment period (Week 0 to Week 16). Due to early termination of the study by the Sponsor, no formal analyses were conducted. | Baseline and up to 16 weeks |