A Study to Evaluate the Safety and Tolerability and Explore the Efficacy of Zonisamide as add-on Therapy in Elderly Patients With Refractory Partial Seizures

Study Overview
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Brief Summary
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A two arm, randomized, double-blind study comparing zonisamide with placebo. The zonisamide arm will consist of 100 subjects and the placebo arm of 50 subjects. Study medication will be administered as an add-on treatment to the subject's current 1 or 2 anti-epileptic (AEDs).

Official Title
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A Randomised, Double Blind, Placebo-controlled Study to Evaluate the Safety and Tolerability and to Explore the Efficacy of Zonisamide as add-on Therapy in Elderly Patients With Refractory Partial Seizures

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: Zonisamide at targeted daily doses of 100-500 mg/day
* Drug: Placebo administered to match targeted daily doses of 100-500 mg/day


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Capable of maintaining a seizure daily diary or who have access to a caregiver who is prepared to complete this on the patient's behalf. Able to complete the questionnaires used in this study. Localization related epilepsy, with simple and/or complex partial seizures with or without secondary generalized seizures as defined by the International League Against Epilepsy (ILAE) criteria. Have at least one well documented seizure in the 4 weeks preceding the Randomisation Visit (Visit 2) and are deemed to require additional AED medication. Receiving at least one, but not more than two other marketed AEDs as concomitant medication, and the dosage should be stable for at least four weeks before the Screening Visit. Key Exclusion Criteria: Seizures attributed to metabolic causes (e.g., electrolyte disturbances, hyperglycaemia). Seizures which could be attributed to use of a drug. Presence of primary generalised epilepsies or seizures, such as absences, myoclonic epilepsies, Lennox-Gastaut syndrome. A history of eating disorders or a body weight below 40 kg. A history of blood dyscrasias. A history of renal stones or having risk factors for nephrolithiasis such as a family history of nephrolithiasis or hypercalciuria. An increased risk factor for rhabdomyolysis such as uncontrolled hypothyroidism, personal or family history of muscle disorders. Taking concomitant medication associated with nephrolithiasis and medications increasing the risk of rhabdomyolysis. Taking rifampicin or drugs with anticholinergic effects. Taking carbonic anhydrase inhibitors or topiramate. A history of pancreatitis. A history of Stevens Johnson Syndrome. Elevated levels of serum creatinine >165 Umol, or known severe hepatic impairment to the extent that the protocol dose titration schedule cannot be followed.

Ages Eligible for Study
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Minimum 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Zonisamide at targeted daily doses of 100-500 mg/day<br> | Drug: Zonisamide at targeted daily doses of 100-500 mg/day<br>* Each group received 2 doses a day (in the morning and evening) during the Titration Period, once a day (in the evening) or BID during the Maintenance Phase, comprising 25 mg, 50 mg, or 100 mg of ZNS capsules<br>|
| Placebo Comparator: Placebo administered to match daily doses of 100-500 mg/day<br> | Drug: Placebo administered to match targeted daily doses of 100-500 mg/day<br>* matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | The Computer Visual Search Task (CVST) of the Ferrum Psyche (FePsy)measured cognition. A decrease from Baseline (negative change value) signifies an improvement in the mean reaction time of CVST. | Baseline, Week 4, Week 8, Week 12, Week 16 | 
| Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | The Bond-Lader mood rating scale measured sedation, with scores ranging from 0 to 100. A high score reflects a high level of sedation. | Baseline, Week 4, Week 8, Week 12, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Seizure Frequency From Baseline to the Last 28 Days of the Maintenance Period | Seizure frequency was assessed by a seizure diary, maintained daily from Baseline, in which the subject recorded the occurrence of any seizure. | Baseline and Month 4 | 
| Percentage of Responders During Last 28 Days of Maintenance Period | Seizure frequency was assessed by a seizure diary, maintained daily from Baseline, in which the subject recorded the occurrence of any seizure. A responder is a subject who had at least a 50 percent or greater reduction in the seizure frequency of all seizures during the last 28 days of the Maintenance Period compared to the Baseline Period seizure frequency. Due to the exploratory nature of the objective for efficacy and the truncated study size, analysis of efficacy was based on observed cases, without imputation for missing data. As a result, there are some variations in sample sizes for efficacy at different visits, depending on if particular efficacy variables were missing for particular visits. | Baseline and Month 4 |