Partial Seizures
Conditions
Keywords
Epilepsy, Partial seizures
Brief summary
The objectives of this trial are to evaluate the safety and efficacy of Zonisamide as adjunctive therapy in medically refractory patients receiving other antiepileptic drugs (AEDs).
Interventions
DRUGZonisamide
Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient.
DRUGPlacebo
Patients in placebo group were titrated with placebo in the same way as in zonisamide group.
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
According to the International League Against Epilepsy (ILAE) classification of seizure type (1981) and international classification of epilepsies and epileptic syndromes (ILAE, 1989), definite diagnosis of partial seizures (with or without secondary generalized seizures) refractory to current anti epilepsy drug (AED) therapy. Inclusion criteria: 1. Adult male or female, 16 to 70 years old; 2. Classified according to the ILAE classification of seizure type (1981) and international classification of epilepsy and epileptic syndromes (ILAE, 1989) into partial seizures (with or without secondary generalized seizures); 3. Based on the retrospective subject diary, at least 4 partial seizures per month ( 4 weeks ) within 12 weeks prior to entry; 4. No more than 8 secondary generalized tonic, clonic, or tonic-clonic seizures per month within 12 weeks prior to entry; 5. Antiepileptic therapy including at least 1-2 concomitant AEDs and were on a stable dose(s) of the same AEDs for the 3 months prior to enrollment; 6. Had performed electro encephalogram (EEG) within 6 months prior to entry, and computer tomography (CT) or magnetic resonance imaging (MRI) examination to mainly exclude space-occupying disease; 7. Was able to count seizure frequencies; 8. Women with child bearing potential, were not to be pregnant or nursing, and must have agreed to practice during the study a reliable form of contraception (oral contraceptive, condom, intrauterine device or diaphragm). 9. Signed written informed consent and agreed to comply with the protocol.
Exclusion criteria
1. History or evidence of a progressive central nervous system (CNS) disease; 2. Nonepileptic seizures and pseudoepileptic seizures; 3. Severe mental retardation or unstable psychical status; 4. Clinically significant cardiac, hepatic, renal, or hematological disease, uncontrolled hypertension (systolic blood pressure (SBP) ≥150 and/or diastolic blood pressure (DBP) ≥100mmHg), Symptomatic ischemic heart disease, cerebral infarction or atherosclerosis obliterans; 5. History of malignant neoplastic disease; 6. Any condition that might interfere the pharmacokinetics (absorption, distribution, and/or excretion) of drugs, such as liver or kidney dysfunction, hypoproteinemia; 7. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or history of hemolytic anemia or acute intermittent porphyria. 8. History of kidney stone; 9. History of alcohol or drug abuse within 2 years; 10. Sensitivity to sulfonamide medications or history of severe drug allergy; 11. Administration of monoamine oxidase inhibitor (MAOI), antidepressants or antipsychotic a psycho-tropic within 14 days prior to entry; 12. History of status epileptics in the past years or seizure clusters where individual seizures cannot be counted ; 13. History of zonisamide administration; 14. History of acetazolamide administration to treat epilepsy within 2 months prior to entry; 15. Joined the clinical trial of other AEDs within 30 days prior to entry; 16. Pregnant women or women in lactation; 17. Abnormal clinical laboratory values with clinical significance judged by investigators (for example, if abnormal hepatic function is caused by concurrent other AEDs, the abnormal value within 2 times of normal could be acceptable); 18. Inability of subject to return for scheduled visits or to comply with any other aspect of the protocol. 19. Subjects who, in the opinion of the investigator, were poor medical candidates or pose any other risk for therapy with an investigational drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Percent Change From Baseline in All Partial Seizure Frequency (Complex Partial Seizures (CP)+ Simple Partial Seizures (SP) + Secondary Generalization Seizures (SGS)) During the Fixed-dose Phase | Baseline and 16 weeks | The median percent change in seizure frequency of all partial seizures (CP+SP+SGS) from baseline during the fixed-dose phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Mean Percent Change From Baseline in Simple Partial (SP) Seizure Frequency | Baseline and 16 weeks | The Mean percent change in seizure frequency of SP from baseline during the fixed-dose phase. |
| The Mean Percent Change From Baseline in Partial Seizures With Secondary Generalization (SGS) | Baseline and 16 weeks | The mean percent change in seizure frequency of SGS from baseline during the fixed-dose phase. |
| Responder Rate | Baseline and 16 weeks | Responder rate is defined as percentage of participants with \>=50% reduction in seizure frequency from baseline. |
| Mean Number of Seizure Free Days | 12 weeks | Mean number of seizure free days per 28 day period during fixed dose phase |
| The Mean Percent Change From Baseline in Complex Partial (CP) Seizure Frequency | Baseline and 16 weeks | The Mean Percent Change in seizure frequency of CP from baseline during the fixed-dose phase. |
| Mean Time to First Seizure (Days) | 16 weeks | Mean time to first seizure during fixed dose phase |
| Percentage of Seizure-free Participants During Fixed-dose Phase | 16 weeks | Percentage of seizure-free participants during fixed-dose phase |
| Drop - Out Rate | 16 weeks | Number of Participants who dropped out of the study. In the Study drop-out rate is defined as number of participants. |
| Mean Percentage of Change in Seizure Free Days | 16 weeks | — |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zonisamide 100 mg Tablet Patients entered a 4-week titration period, during which zonisamide dosing began at 100 mg/day for the first 2 weeks, increased to 200 mg/day for the 3rd week, and to 300 mg/day for the 4th week, reaching 300 mg/d at the end of the titration period. 300 mg/d was the target dose in the titration period and must be reached. Dose increment was continued to 400 mg/d if this was tolerated by the patient. | 111 |
| Placebo Patients in placebo group were titrated with placebo in the same way as in zonisamide group. | 106 |
| Total | 217 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 6 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Placebo | Total | Zonisamide 100 mg Tablet |
|---|---|---|---|
| Age, Continuous | 30.69 years STANDARD_DEVIATION 11.59 | 31.73 years STANDARD_DEVIATION 11.89 | 32.72 years STANDARD_DEVIATION 12.18 |
| Race/Ethnicity, Customized Asian | 97 participants | 217 participants | 120 participants |
| Region of Enrollment China | 106 participants | 217 participants | 111 participants |
| Sex: Female, Male Female | 43 Participants | 97 Participants | 54 Participants |
| Sex: Female, Male Male | 63 Participants | 120 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 95 / 120 | 75 / 118 |
| serious Total, serious adverse events | 0 / 120 | 0 / 118 |
Outcome results
Primary
Median Percent Change From Baseline in All Partial Seizure Frequency (Complex Partial Seizures (CP)+ Simple Partial Seizures (SP) + Secondary Generalization Seizures (SGS)) During the Fixed-dose Phase
The median percent change in seizure frequency of all partial seizures (CP+SP+SGS) from baseline during the fixed-dose phase.
Time frame: Baseline and 16 weeks
Population: Full analysis set (FAS)
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Zonisamide 100 mg Tablet | Median Percent Change From Baseline in All Partial Seizure Frequency (Complex Partial Seizures (CP)+ Simple Partial Seizures (SP) + Secondary Generalization Seizures (SGS)) During the Fixed-dose Phase | -48.42 Percent Change | Full Range 73.83 |
| Placebo | Median Percent Change From Baseline in All Partial Seizure Frequency (Complex Partial Seizures (CP)+ Simple Partial Seizures (SP) + Secondary Generalization Seizures (SGS)) During the Fixed-dose Phase | -26.58 Percent Change | Full Range 157.22 |
p-value: 0.028ANOVA
Secondary
Drop - Out Rate
Number of Participants who dropped out of the study. In the Study drop-out rate is defined as number of participants.
Time frame: 16 weeks
Population: FAS Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zonisamide 100 mg Tablet | Drop - Out Rate | 4 Number of Participants |
| Placebo | Drop - Out Rate | 6 Number of Participants |
Secondary
Mean Number of Seizure Free Days
Mean number of seizure free days per 28 day period during fixed dose phase
Time frame: 12 weeks
Population: FAS Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide 100 mg Tablet | Mean Number of Seizure Free Days | 22.31 Days | Standard Deviation 6.14 |
| Placebo | Mean Number of Seizure Free Days | 21.43 Days | Standard Deviation 7.07 |
p-value: 0.09X^2 test
Secondary
Mean Percentage of Change in Seizure Free Days
Time frame: 16 weeks
Population: FAS Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide 100 mg Tablet | Mean Percentage of Change in Seizure Free Days | 79.69 Percent Change | Standard Deviation 21.93 |
| Placebo | Mean Percentage of Change in Seizure Free Days | 76.52 Percent Change | Standard Deviation 25.26 |
p-value: 0.09X^2 test
Secondary
Mean Time to First Seizure (Days)
Mean time to first seizure during fixed dose phase
Time frame: 16 weeks
Population: FAS Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide 100 mg Tablet | Mean Time to First Seizure (Days) | 22.31 Days | Standard Deviation 6.14 |
| Placebo | Mean Time to First Seizure (Days) | 21.43 Days | Standard Deviation 7.07 |
p-value: 0.162X^2 test
Secondary
Percentage of Seizure-free Participants During Fixed-dose Phase
Percentage of seizure-free participants during fixed-dose phase
Time frame: 16 weeks
Population: FAS Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zonisamide 100 mg Tablet | Percentage of Seizure-free Participants During Fixed-dose Phase | 1.8 Percentage of Participants |
| Placebo | Percentage of Seizure-free Participants During Fixed-dose Phase | 2.8 Percentage of Participants |
p-value: 0.678X^2 test
Secondary
Responder Rate
Responder rate is defined as percentage of participants with \>=50% reduction in seizure frequency from baseline.
Time frame: Baseline and 16 weeks
Population: FAS Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zonisamide 100 mg Tablet | Responder Rate | 48.6 Percentage of Participants |
| Placebo | Responder Rate | 34.9 Percentage of Participants |
p-value: 0.044X^2 test
Secondary
The Mean Percent Change From Baseline in Complex Partial (CP) Seizure Frequency
The Mean Percent Change in seizure frequency of CP from baseline during the fixed-dose phase.
Time frame: Baseline and 16 weeks
Population: FAS population. Complex partial seizure patients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide 100 mg Tablet | The Mean Percent Change From Baseline in Complex Partial (CP) Seizure Frequency | -31.65 Percent Change | Standard Deviation 87.28 |
| Placebo | The Mean Percent Change From Baseline in Complex Partial (CP) Seizure Frequency | -25.21 Percent Change | Standard Deviation 68.23 |
p-value: 0.253ANOVA
Secondary
The Mean Percent Change From Baseline in Partial Seizures With Secondary Generalization (SGS)
The mean percent change in seizure frequency of SGS from baseline during the fixed-dose phase.
Time frame: Baseline and 16 weeks
Population: FAS Population. Secondary generalization patients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide 100 mg Tablet | The Mean Percent Change From Baseline in Partial Seizures With Secondary Generalization (SGS) | -53.2 Percent Change | Standard Deviation 54.81 |
| Placebo | The Mean Percent Change From Baseline in Partial Seizures With Secondary Generalization (SGS) | -4.08 Percent Change | Standard Deviation 178.66 |
p-value: 0.516ANOVA
Secondary
The Mean Percent Change From Baseline in Simple Partial (SP) Seizure Frequency
The Mean percent change in seizure frequency of SP from baseline during the fixed-dose phase.
Time frame: Baseline and 16 weeks
Population: FAS Population. Simple partial seizure patients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide 100 mg Tablet | The Mean Percent Change From Baseline in Simple Partial (SP) Seizure Frequency | -49.14 Percent Change | Standard Deviation 62.06 |
| Placebo | The Mean Percent Change From Baseline in Simple Partial (SP) Seizure Frequency | 56.03 Percent Change | Standard Deviation 318.43 |
p-value: 0.211ANOVA