Epilepsy
Conditions
Brief summary
This study is intended to provide evidence that zonisamide is safe and effective in the treatment of myoclonic seizures. The total planned trial duration will be 6.5 months. After that, subjects who have completed the study will be eligible to enroll 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-E044-318).
Interventions
DRUGZonisamide
50-400 mg capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks)
DRUGPlacebo
50-400 mg Zonisamide Placebo capsules once daily in the evening orally. Maximum study duration 28 weeks comprising: Baseline Period (Week -8 to Week 0): no treatment Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4 Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 mg in the event of dose limiting adverse events) Down Titration Period (4 Weeks)
Sponsors
Eisai Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Subject is male or female and aged 12-65 years. 2. Subject has at least eight days with at least one myoclonic seizure over the two months Baseline Period. Myoclonic seizures must occur in the context of IGE and may be accompanied by other primary generalized seizures, provided these are also consistent with a diagnosis of Idiopathic Generalized Epilepsy (IGE). 3. Subject (or parent/caregiver, for subjects below the age of consent) is willing to sign an informed consent form. Subjects below the age of consent in their country, must where appropriate 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. 4. Subject is taking a stable regimen of one or two other AEDs for at least two weeks prior to Visit 1 (start of the Baseline Period). 5. Subject has a clinical diagnosis of any type of idiopathic generalised epilepsy (IGE) which has myoclonic seizures (and which may be accompanied by other generalised 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 generalised epilepsy. A 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. 6. 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. 7. Female subjects are pre-menarchal, or if of childbearing potential, are not pregnant or lactating, or are post-menopausal. 8. Female subjects of childbearing potential ≥ 18 years must abide by 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. Subjects \<18 years and of childbearing potential must be either abstinent or willing to use one of the medically appropriate forms of contraception for the duration of the study.
Exclusion criteria
1. Subject has progressive or focal neurological disease (as determined by preexisting brain imaging such as CT or MRI performed maximally five years before the screening visit), or clinically significant organic disease. 2. 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 generalised tonic clonic seizures which are suspected to be secondarily generalised. 3. Subjects with cryptogenic or symptomatic generalised epilepsy. 4. Subjects with psychogenic seizures. 5. Subject has a history of convulsive status epilepticus within a year of screening while complying with AEDs. 6. Subject has a history of renal calculi or renal insufficiency (above the upper normal limits of creatinine). 7. Subject has a known diagnosis of human immunodeficiency virus (HIV) or hepatitis B or C. 8. Subject has a predisposing condition that might interfere with absorption, distribution, or excretion of zonisamide. 9. Subject has a history of sensitivity to sulfonamide drugs or to zonisamide or any of its excipients. 10. Subject has a recent history of excessive alcohol use or drug abuse. 11. Subject has a history of suicide attempt in the five years before the screening visit. 12. Subject has abnormal screening laboratory values that are clinically significant. 13. 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. 14. Subject has participated in a study of an investigational drug or device within 30 days prior to screening. 15. Subject has received previous treatment with zonisamide. 16. Subject is treated with ketogenic diet or vagus nerve stimulator. 17. 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). 18. Concomitant use of acetazolamide, carbonic anhydrase inhibitors such as topiramate and drugs with anticholinergic activity. 19. 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. 20. Concomitant use of felbamate or use of felbamate within two months prior to Visit 1. 21. Subject is unable to swallow capsules. 22. Subject is not in general good health as determined by medical history, physical exam and screening laboratory results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Considered Responders as Assessed During the Maintenance Period | Baseline (Week -8 to Week 0) and Maintenance Period (Week 4 to Week 16) | 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 \>= 50% from baseline in the number of days with myoclonic seizures per 28 days (i.e. 28-day myoclonic seizure frequency in Period from Week 4 to the Week 16 visit compared to Week -8 to randomization at Week 0 \[Screening/ Baseline Period\]). Occurrence of seizures was documented in a seizure diary. The diary was dispensed at the Screening Visit and maintained by the participant (parent/caregiver) and reviewed at each following visit. The diary was completed daily. All seizures except myoclonic seizures were counted individually in the the diary. Due to early termination of the study by the Sponsor, no formal analyses were conducted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in the Monthly Number of Days With Myoclonic Seizures | Baseline and up to 16 weeks | Percentage Change from Baseline in the monthly number of days with myoclonic seizures 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. |
Countries
Australia, Croatia, Czechia, Estonia, Finland, Germany, Hungary, Lithuania, Poland, Romania, Russia, Serbia, Ukraine
Participant flow
Recruitment details
This study was recruited at three study centers (1 in Australia and 2 in Hungary). A further 39 study centers in Europe and Australia were initiated. A total of 12 study sites in the following countries were not initiated; (2 in Finland), (3 in Czech Republic), and (7 in Ukraine) during the period of 04 June 2008 to 05 January 2009.
Pre-assignment details
10 participants were screened for eligibility and six participants did not continue after the Screening Visit due to the Sponsor's decision to terminate the study. 4 participants were enrolled and treated during the study.
Participants by arm
| Arm | Count |
|---|---|
| Zonisamide 50-400 mg capsules once daily in the evening orally.
Maximum study duration 28 weeks comprising:
Baseline Period (Week -8 to Week 0): no treatment
Titration Period (Week 0 to Week 4): 50 mg daily titrated weekly until 300 mg was reached by Week 4
Maintenance Period (Week 4 to Week 16) 400 mg (or 350 mg in the event of dose limiting adverse events)
Down Titration Period (4 Weeks) | 2 |
| Placebo 50-400 mg Zonisamide Placebo capsules once daily in the evening orally.
Maximum study duration 28 weeks comprising:
Baseline Period (Week -8 to Week 0): no treatment
Titration Period (Week 0 to Week 4): 50 mg Zonisamide Placebo daily titrated weekly until 300 mg was reached by Week 4
Maintenance Period (Week 4 to Week 16) 400 mg Zonisamide Placebo (or 350 mg in the event of dose limiting adverse events)
Down Titration Period (4 Weeks) | 2 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Sponsor Decision | 2 | 1 |
Baseline characteristics
| Characteristic | Zonisamide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 24.0 years STANDARD_DEVIATION 16.97 | 33.5 years STANDARD_DEVIATION 23.33 | 28.8 years STANDARD_DEVIATION 17.54 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 1 / 2 |
Outcome results
Primary
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 \>= 50% from baseline in the number of days with myoclonic seizures per 28 days (i.e. 28-day myoclonic seizure frequency in Period from Week 4 to the Week 16 visit compared to Week -8 to randomization at Week 0 \[Screening/ Baseline Period\]). Occurrence of seizures was documented in a seizure diary. The diary was dispensed at the Screening Visit and maintained by the participant (parent/caregiver) and reviewed at each following visit. The diary was completed daily. All seizures except myoclonic seizures were counted individually in the the diary. Due to early termination of the study by the Sponsor, no formal analyses were conducted.
Time frame: Baseline (Week -8 to Week 0) and Maintenance Period (Week 4 to Week 16)
Secondary
Percentage Change From Baseline in the Monthly Number of Days With Myoclonic Seizures
Percentage Change from Baseline in the monthly number of days with myoclonic seizures 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.
Time frame: Baseline and up to 16 weeks