Epilepsy
Conditions
Keywords
Epilepsy, Monotherapy
Brief summary
The purpose of this study is to assess the long-term safety and tolerability and to explore the long-term efficacy of zonisamide as monotherapy treatment in subjects with newly diagnosed partial seizures.
Interventions
DRUGZonisamide
Subjects will start on the same dose that was achieved at the end of study E2090-E044-310. Maximum daily dose allowable is 500 mg; the minimum daily dose allowable is 200 mg. During the study, subjects will be titrated up or down depending on seizure-free status or intolerability/adverse events, respectively. Should a dose outside of the maximum be required the subject will be with drawn and gradually down titrated by 100 mg per week.
DRUGCarbamazepine
Subjects will start on the same dose that was achieved at the end of study E2090-E044-310. Maximum daily dose allowable is 1200 mg; the minimum daily dose allowable is 400 mg. During the study, subjects will be titrated up or down depending on seizure-free status or intolerability/adverse events respectively. Should a dose outside of the maximum be required the subject will be with drawn and gradually down titrated by 200 mg per week.
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
Inclusion criteria
1. Subject has completed study E2090-E044-310. 2. Subject is able and willing to give written informed consent. 3. Female subjects without childbearing potential (two years post-menopausal, bilateral oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects of childbearing potential must be non-pregnant, non-lactating and abide by one of the following medically acceptable contraceptive measures: oral contraceptive pill, contraceptive injections, implants or patches, intrauterine device in place for at least three months, vasectomised partner or abstinence throughout the study and for one month after discontinuation of study medication. When the contraceptive pill is used, this should contain no less than 50 μg oestrogen. 4. The subject is able and willing to follow the investigational study procedures, maintain a seizure diary and report adverse events.
Exclusion criteria
1. Subject has a history of a significant or currently uncontrolled disease that will contraindicate the use of the study drugs or interfere with the conduct of this study and/or the assessment of safety and efficacy of the study drugs. 2. Subject has a body weight \<40 kg. 3. Subject has a newly occurring progressive malignancy during study E2090-E044-310 (excluding a history of non-metastasized and adequately treated cutaneous squamous cell carcinoma). 4. Subject has developed a psychiatric illness or mood disorder requiring electro-convulsive or drug therapy within the previous 6 months and is considered uncontrolled; history of suicide attempt, alcohol or drug abuse, chronic treatment with benzodiazepines or barbiturates. 5. Subject is currently taking carbonic anhydrase inhibitors. 6. Subject developed pancreatitis, nephrolithiasis or hypercalcuria, clinically significant laboratory abnormalities, stroke or uncontrolled hypertension during study E2090-E044-310. 7. Subject is currently taking monoamine oxidase inhibitors (MAOIs) or any other excluded medications (see protocol section 9.9.3). 8. Subject has a history of allergy to carbamazepine or to zonisamide or to any of their ingredients or to sulphonamides. 9. Subject has developed a bone marrow depression, low platelet count or other blood dyscrasias.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Remaining in the Study at Each Visit | At 3, 6, 9, 12, 15, 18, 21, 24, and 27 months | The retention rate is defined as the percentage of subjects remaining on the study at each visit, starting from the first dose of study drug in the extension phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Drop-out Due to Lack of Efficacy | Week 1 to Week 109 (in core study) and Month 1 to Month 27 (in extension study) | Lack of efficacy was if the subject had poor seizure control (defined as experiencing a seizure despite being on the maximum dose for = 2 weeks). The subject could withdraw at any time due to lack of efficacy. |
| Time to Drop-out Due to Adverse Event (AE) | Week 1 to Week 109 (in base study) and Month 1 to Month 27 (in extension study) | Adverse events in study subjects included any change in the subject's condition. This includes symptoms, physical findings, or clinical syndromes. All AEs that occurred after signing of informed consent through the last visit and for 15 days following study drug discontinuation were captured on the AE Case Report Form (CRF). |
| Percentage of Participants That Are Seizure Free for at Least 24 Month Consecutive Period in the Base Study and Extension Phase | Week 5 to Week 109 (in base study) and Month 1 to Month 27 (in extension phase) | The number of participants that have remained seizure free for at least a 24 month consecutive period from the start of the Flexible Dosing Period (FDP: the period following the Titration Period and leading into the Maintenance Period) in the base study through the treatment period of this study. Seizure freedom was defined as the absence of all seizure regardless of seizure type. |
| Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Weeks 0, 26, 52, 78 and 117 | The QOLIE-31-P is a 31-item questionnaire evaluating a participant's QOL perception in 7 domains: seizure worry,emotional well being,energy/fatigue, cognitive functioning, medication effects, social functioning,overall QOL. The overall score is derived by weighing and then summing the 7 domain scores. Precoded numeric values for some domains are such that a higher number reflects a more favorable health state; others are such that a higher number reflects a less favorable state. Precoded values are converted to 0-100 point scores; higher converted scores always reflect better QOL. |
Countries
Australia, Denmark, France, Germany, Greece, Hungary, India, Italy, Montenegro, Poland, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom
Participant flow
Recruitment details
E2090-E044-314 is a double-blind extension of E2090-E044-310 (NCT00477295) base study. Assessment of eligibility took place at the Study Entry Visit (SEV), which was the same day as their final visit of Study 310. Subjects remained on the same investigational product as they were randomized to in Study 310 until unblinding of that study.
Participants by arm
| Arm | Count |
|---|---|
| Zonisamide Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 200 mg and 500 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range. | 282 |
| Carbamazepine Subjects received the same study drug to which they had been randomized in the core study phase and remained on their final dose for the start of the extension phase (between 400 mg and 1200 mg per day). Flexible dosing was permitted as symptoms changed as long as it stayed within the dosing range. | 301 |
| Total | 583 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| E2090-E044-310 (Base Study) Disposition | Adverse Event | 31 | 35 |
| E2090-E044-310 (Base Study) Disposition | Lack of Efficacy | 23 | 23 |
| E2090-E044-310 (Base Study) Disposition | Lost to Follow-up | 21 | 11 |
| E2090-E044-310 (Base Study) Disposition | Other | 4 | 3 |
| E2090-E044-310 (Base Study) Disposition | Physician Decision | 4 | 5 |
| E2090-E044-310 (Base Study) Disposition | Protocol Violation | 3 | 8 |
| E2090-E044-310 (Base Study) Disposition | Withdrawal by Subject | 35 | 24 |
| E2090-E044-310 (Base Study) Transition | Chose not to enter 314 Extension study | 24 | 34 |
| E2090-E044-314 (Extension Study) | Adverse Event | 2 | 1 |
| E2090-E044-314 (Extension Study) | Lack of Efficacy | 1 | 1 |
| E2090-E044-314 (Extension Study) | Other | 5 | 6 |
| E2090-E044-314 (Extension Study) | Physician Decision | 0 | 2 |
| E2090-E044-314 (Extension Study) | Protocol Violation | 1 | 2 |
| E2090-E044-314 (Extension Study) | Withdrawal by Subject | 8 | 12 |
Baseline characteristics
| Characteristic | Zonisamide | Total | Carbamazepine |
|---|---|---|---|
| Age, Continuous Base Study 310 (NCT00477295, n=583) | 37.1 years STANDARD_DEVIATION 16.33 | 36.35 years STANDARD_DEVIATION 15.92 | 35.6 years STANDARD_DEVIATION 15.5 |
| Age, Continuous Extension Study 314 (NCT00848549, n=295) | 37.8 years STANDARD_DEVIATION 16.13 | 36.1 years STANDARD_DEVIATION 15.53 | 34.4 years STANDARD_DEVIATION 14.93 |
| Sex/Gender, Customized Female (Base Study 310, NCT00477295) | 107 participants | 235 participants | 128 participants |
| Sex/Gender, Customized Female (Extension Study 314, NCT00848549) | 57 participants | 116 participants | 59 participants |
| Sex/Gender, Customized Male (Base Study 310, NCT00477295) | 174 participants | 346 participants | 172 participants |
| Sex/Gender, Customized Male (Extension Study 314, NCT00848549) | 80 participants | 179 participants | 99 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 137 | 10 / 158 | 72 / 281 | 69 / 300 |
| serious Total, serious adverse events | 7 / 137 | 7 / 158 | 15 / 281 | 17 / 300 |
Outcome results
Primary
Percentage of Participants Remaining in the Study at Each Visit
The retention rate is defined as the percentage of subjects remaining on the study at each visit, starting from the first dose of study drug in the extension phase.
Time frame: At 3, 6, 9, 12, 15, 18, 21, 24, and 27 months
Population: The Intent-to-Treat (ITT) Population is defined as all subjects who received at least one dose of investigational product(IP)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 6 months | 87.6 Percentage of Participants |
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 18 months | 27.7 Percentage of Participants |
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 12 months | 58.4 Percentage of Participants |
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 21 months | 13.1 Percentage of Participants |
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 9 months | 76.6 Percentage of Participants |
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 24 months | 5.8 Percentage of Participants |
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 15 months | 38.7 Percentage of Participants |
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 27 months | 1.5 Percentage of Participants |
| Zonisamide | Percentage of Participants Remaining in the Study at Each Visit | 3 months | 95.6 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 27 months | 0.6 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 3 months | 93.7 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 6 months | 84.2 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 9 months | 75.3 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 12 months | 61.4 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 15 months | 43.7 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 18 months | 27.8 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 21 months | 12.7 Percentage of Participants |
| Carbamazepine | Percentage of Participants Remaining in the Study at Each Visit | 24 months | 2.5 Percentage of Participants |
Secondary
Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit
The QOLIE-31-P is a 31-item questionnaire evaluating a participant's QOL perception in 7 domains: seizure worry,emotional well being,energy/fatigue, cognitive functioning, medication effects, social functioning,overall QOL. The overall score is derived by weighing and then summing the 7 domain scores. Precoded numeric values for some domains are such that a higher number reflects a more favorable health state; others are such that a higher number reflects a less favorable state. Precoded values are converted to 0-100 point scores; higher converted scores always reflect better QOL.
Time frame: Weeks 0, 26, 52, 78 and 117
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zonisamide | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 117 | -0.292 Score on a scale | Standard Deviation 17.332 |
| Zonisamide | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 0 | 4.697 Score on a scale | Standard Deviation 16.254 |
| Zonisamide | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 26 | 6.101 Score on a scale | Standard Deviation 16.566 |
| Zonisamide | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 52 | 8.602 Score on a scale | Standard Deviation 14.326 |
| Zonisamide | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 78 | 4.287 Score on a scale | Standard Deviation 15.566 |
| Carbamazepine | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 78 | 1.902 Score on a scale | Standard Deviation 13.495 |
| Carbamazepine | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 52 | 11.687 Score on a scale | Standard Deviation 13.653 |
| Carbamazepine | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 0 | 7.101 Score on a scale | Standard Deviation 13.781 |
| Carbamazepine | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 117 | 15.849 Score on a scale | Standard Deviation 12.302 |
| Carbamazepine | Change From Baseline in Quality of Life Assessed by Quality of Life in Epilepsy-Problems Questionnaire (QOLIE-31-P) Overall Score at Each Visit | Week 26 | 10.956 Score on a scale | Standard Deviation 14.94 |
Secondary
Percentage of Participants That Are Seizure Free for at Least 24 Month Consecutive Period in the Base Study and Extension Phase
The number of participants that have remained seizure free for at least a 24 month consecutive period from the start of the Flexible Dosing Period (FDP: the period following the Titration Period and leading into the Maintenance Period) in the base study through the treatment period of this study. Seizure freedom was defined as the absence of all seizure regardless of seizure type.
Time frame: Week 5 to Week 109 (in base study) and Month 1 to Month 27 (in extension phase)
Population: 310 ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zonisamide | Percentage of Participants That Are Seizure Free for at Least 24 Month Consecutive Period in the Base Study and Extension Phase | 32.3 Percentage of Participants |
| Carbamazepine | Percentage of Participants That Are Seizure Free for at Least 24 Month Consecutive Period in the Base Study and Extension Phase | 35.2 Percentage of Participants |
Secondary
Time to Drop-out Due to Adverse Event (AE)
Adverse events in study subjects included any change in the subject's condition. This includes symptoms, physical findings, or clinical syndromes. All AEs that occurred after signing of informed consent through the last visit and for 15 days following study drug discontinuation were captured on the AE Case Report Form (CRF).
Time frame: Week 1 to Week 109 (in base study) and Month 1 to Month 27 (in extension study)
Population: 310 ITT Population (33 participants were discontinued in the Zonisamide arm and 35 were discontinued in the Carbamazepine arm; these were the participants evaluated for this outcome)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | Time to Drop-out Due to Adverse Event (AE) | 131.9 Days | Standard Deviation 166.9 |
| Carbamazepine | Time to Drop-out Due to Adverse Event (AE) | 97.2 Days | Standard Deviation 114.47 |
Secondary
Time to Drop-out Due to Lack of Efficacy
Lack of efficacy was if the subject had poor seizure control (defined as experiencing a seizure despite being on the maximum dose for = 2 weeks). The subject could withdraw at any time due to lack of efficacy.
Time frame: Week 1 to Week 109 (in core study) and Month 1 to Month 27 (in extension study)
Population: 310 ITT Population (combined ITT Population from basecore study and extension phase). 24 participants were discontinued in each arm due to lack of efficacy; these were the participants that were evaluated in this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | Time to Drop-out Due to Lack of Efficacy | 297.9 Days | Standard Deviation 170.03 |
| Carbamazepine | Time to Drop-out Due to Lack of Efficacy | 289.0 Days | Standard Deviation 108.93 |