Epilepsy
Conditions
Brief summary
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).
Interventions
DRUGPlacebo administered to match targeted daily doses of 100-500 mg/day
matching placebo
DRUGZonisamide at targeted daily doses of 100-500 mg/day
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
Sponsors
Eisai Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. 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. 2. Able to complete the questionnaires used in this study. 3. 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. 4. 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. 5. 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
1. Seizures attributed to metabolic causes (e.g., electrolyte disturbances, hyperglycaemia). 2. Seizures which could be attributed to use of a drug. 3. Presence of primary generalised epilepsies or seizures, such as absences, myoclonic epilepsies, Lennox-Gastaut syndrome. 4. A history of eating disorders or a body weight below 40 kg. 5. A history of blood dyscrasias. 6. A history of renal stones or having risk factors for nephrolithiasis such as a family history of nephrolithiasis or hypercalciuria. 7. An increased risk factor for rhabdomyolysis such as uncontrolled hypothyroidism, personal or family history of muscle disorders. 8. Taking concomitant medication associated with nephrolithiasis and medications increasing the risk of rhabdomyolysis. 9. Taking rifampicin or drugs with anticholinergic effects. 10. Taking carbonic anhydrase inhibitors or topiramate. 11. A history of pancreatitis. 12. A history of Stevens Johnson Syndrome. 13. Elevated levels of serum creatinine \>165 Umol, or known severe hepatic impairment to the extent that the protocol dose titration schedule cannot be followed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Baseline, Week 4, Week 8, Week 12, Week 16 | 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. |
| Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Baseline, Week 4, Week 8, Week 12, Week 16 | The Bond-Lader mood rating scale measured sedation, with scores ranging from 0 to 100. A high score reflects a high level of sedation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Seizure Frequency From Baseline to the Last 28 Days of the Maintenance Period | Baseline and Month 4 | Seizure frequency was assessed by a seizure diary, maintained daily from Baseline, in which the subject recorded the occurrence of any seizure. |
| Percentage of Responders During Last 28 Days of Maintenance Period | Baseline and Month 4 | 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. |
Countries
Germany, Hungary, Italy, Netherlands, Poland, Switzerland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects took matching doses of placebo during both the Titration Period and Maintenance Period. | 18 |
| Zonisamide Subjects started the Titration Period on a Total Daily Dose (TDD) of zonisamide 50mg (25mg capsules twice daily in the morning and evening) for a total of 8 weeks. Doses increased in 100mg increments up to a targeted TDD of 300mg with a range of 100mg to 500mg. Subjects entered the Maintenance Period on the same dose they were on at the end of the titration phase, taking the dose once daily (in the evening) or twice daily for a total of 8 weeks. Subjects were withdrawn if they required a TDD outside of the suggested range. | 33 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 4 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Zonisamide | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 72.5 Years STANDARD_DEVIATION 5.63 | 72.0 Years STANDARD_DEVIATION 5.29 | 71.1 Years STANDARD_DEVIATION 4.61 |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 31 Participants | 48 Participants | 17 Participants |
| Race/Ethnicity, Customized White | 33 Participants | 51 Participants | 18 Participants |
| Sex: Female, Male Female | 19 Participants | 30 Participants | 11 Participants |
| Sex: Female, Male Male | 14 Participants | 21 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 18 | 17 / 33 |
| serious Total, serious adverse events | 1 / 18 | 6 / 33 |
Outcome results
Primary
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.
Time frame: Baseline, Week 4, Week 8, Week 12, Week 16
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Week 4 | -1.337 Scores on a Scale | Standard Deviation 22.2976 |
| Placebo | Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Week 8 | 7.688 Scores on a Scale | Standard Deviation 17.0998 |
| Placebo | Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Week 12 | 1.386 Scores on a Scale | Standard Deviation 13.613 |
| Placebo | Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Week 16 | 2.502 Scores on a Scale | Standard Deviation 17.6228 |
| Zonisamide | Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Week 16 | 3.943 Scores on a Scale | Standard Deviation 21.0086 |
| Zonisamide | Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Week 4 | 1.654 Scores on a Scale | Standard Deviation 16.4085 |
| Zonisamide | Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Week 12 | -0.682 Scores on a Scale | Standard Deviation 18.0567 |
| Zonisamide | Change From Baseline in Bond and Lader Visual Analogue Scale (VAS) Mood Sub-Scores for Sedation by Visit During Titration and Maintenance Period | Week 8 | 1.990 Scores on a Scale | Standard Deviation 16.0172 |
Primary
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.
Time frame: Baseline, Week 4, Week 8, Week 12, Week 16
Population: Intent-to-Treat Population: All randomized subjects who received at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Week 4 | -3.448 Seconds | Standard Deviation 10.212 |
| Placebo | Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Week 8 | -2.776 Seconds | Standard Deviation 9.984 |
| Placebo | Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Week 12 | -7.223 Seconds | Standard Deviation 11.949 |
| Placebo | Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Week 16 | -3.324 Seconds | Standard Deviation 14.995 |
| Zonisamide | Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Week 16 | -5.102 Seconds | Standard Deviation 11.526 |
| Zonisamide | Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Week 4 | -3.898 Seconds | Standard Deviation 13.149 |
| Zonisamide | Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Week 12 | -2.731 Seconds | Standard Deviation 14.084 |
| Zonisamide | Change From Baseline in CVST of the FePsy Test (Mean Reaction Time) by Visit During Titration and Maintenance Period | Week 8 | -0.650 Seconds | Standard Deviation 10.14 |
Secondary
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.
Time frame: Baseline and Month 4
Population: Intent-to-Treat Population. Percentages are based on the number of subjects present in the Maintenance Phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Responders During Last 28 Days of Maintenance Period | Responders (Yes) | 62.5 Percentage of Participants |
| Placebo | Percentage of Responders During Last 28 Days of Maintenance Period | Non-Responders (No) | 12.5 Percentage of Participants |
| Placebo | Percentage of Responders During Last 28 Days of Maintenance Period | Missing | 25 Percentage of Participants |
| Zonisamide | Percentage of Responders During Last 28 Days of Maintenance Period | Responders (Yes) | 75 Percentage of Participants |
| Zonisamide | Percentage of Responders During Last 28 Days of Maintenance Period | Non-Responders (No) | 14.3 Percentage of Participants |
| Zonisamide | Percentage of Responders During Last 28 Days of Maintenance Period | Missing | 10.7 Percentage of Participants |
Secondary
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.
Time frame: Baseline and Month 4
Population: Intent-to-Treat Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percent Change in Seizure Frequency From Baseline to the Last 28 Days of the Maintenance Period | -100 Percent Change |
| Zonisamide | Percent Change in Seizure Frequency From Baseline to the Last 28 Days of the Maintenance Period | -100 Percent Change |