Epilepsy
Conditions
Brief summary
To evaluate the effect of rufinamide on total partial seizure frequency in adolescent and adult participants (12 to 80 years, inclusive) with refractory partial onset seizures maintained on a maximum of 3 stable antiepileptic drugs (AEDs).
Interventions
DRUGPlacebo
For the 12-day Titration Phase, one matching placebo tablet will be administered twice daily and increased by 1 matching placebo tablet every 3 days up to maximum of 4 matching placebo tablets twice daily (placebo tablet matched to rufinamide total daily dose of 3200 mg). For the 12 week maintenance phase, 4 placebo tablets matching to rufinamide maintenance doses of 1600 mg twice daily (3200 mg total daily dose) will be administered. Similar to the dose reduction permitted in the rufinamide group, participants in placebo group will be allowed only during the Titration Phase to have the dose reduced to 3 placebo tablets twice daily.
DRUGRufinamide
For the titration phase, Rufinamide will be administered orally in doses starting with 400 mg twice daily and increased every 3 days in 400 mg twice daily increments up to 1600 mg twice daily (total daily dose 3200 mg). For the Maintenance Phase, maintenance doses of 1600 mg twice daily (3200 mg total daily dose) will be administered. Participants unable to tolerate the target dose (3200 mg/day) will be allowed only during the Titration Phase to have the dose reduced to 3 tablets twice daily (corresponding to a dose of 2400 mg/day in the rufinamide group).
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female patients between 12 and 80 years of age, inclusive. 2. Diagnosis of epilepsy with partial-onset seizures with or without secondarily generalized seizures according with the International League Against Epilepsy Classification of Epileptic Seizures (1981). Diagnosis should have been established by clinical history, electroencephalogram (EEG) and computed tomography/magnetic resonance imaging (CT/MRI) of the brain performed within the last 10 years and consistent with localization-related epilepsy. 3. Non-controlled partial seizures despite having been treated with at least two different antiepileptic drugs (given concurrently or sequentially) for at least two years. 4. Patient willing to participate and written consent signed by patient or legal guardian prior to entering the study or undergoing any study procedures. If the written consent is provided by a legal guardian because the patient is unable to do so, assent of the patient must also be obtained. 5. Reliability and willingness of patients to make themselves available for the study period, and ability to record seizures and report adverse events themselves or have a caregiver who can record seizures and report adverse events. 6. Female patients of non-childbearing potential by reason of surgery, radiation, or menopause (at least one year post onset); or of childbearing potential using two approved methods of contraception (such as an intrauterine device \[IUD\], implant, oral contraceptive, or barrier method plus spermicide). Use of a low-dose estrogen oral contraceptive (minipill) alone will not be permitted. Female patients of childbearing potential must have a confirmed negative serum pregnancy test at screening and a negative urine pregnancy test prior to randomization, and agree to continue to use two approved methods of contraception through the follow-up visit (Visit 8) or for 30 days after their final dose of study medication, whichever is longer. 7. At least six seizures during the prospective Baseline Phase (56 days) with no 21-day seizure-free periods. Simple partial seizures without motor signs will not be included in determining this criterion. 8. Current treatment with a maximum of three approved antiepileptic drugs, and no evidence of non-compliance with ongoing AED therapy. 9. Stable dose(s) of the same AED(s) for one month prior to screening. 10. If using a vagal nerve stimulator, it must have been implanted for at least six months prior to randomization. Stimulator parameters may not be changed for at least one month prior to screening or thereafter during the study. Magnet use will be allowed, but must be documented throughout the study. A vagal nerve stimulator will not be counted as an AED for the purpose of inclusion into the trial.
Exclusion criteria
1. Participation in a study involving administration of an investigational compound within one month of Visit 1 (Screening), or within five half-lives of the previous investigational compound, whichever is longer; or any prior exposure to rufinamide. 2. Presence of non-motor simple partial seizures only. 3. Presence of generalized epilepsies or seizures, such as absences, myoclonic epilepsies, Lennox-Gastaut syndrome. 4. History of status epilepticus in the past year or seizure clusters where individual seizures cannot be counted. 5. Evidence of clinically significant disease (cardiac, respiratory, gastrointestinal, hepatic, hematologic or renal disease, etc.) that in the opinion of the Investigator could affect the patient's safety or trial conduct. 6. Clinically significant ECG abnormality. 7. Patients with a diagnosis of major active psychiatric disease will be excluded from the study. However, those patients who are only taking a stable dose of either a selective serotonin reuptake inhibitor (SSRI) antidepressant drug or a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant drug for a diagnosed depressive disorder can be included as long as they have been on the SSRI or SNRI for a period of two months or longer before randomization. Other antidepressant medications will not be allowed. 8. Progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors. 9. Occurrence of psychogenic seizures in the previous year. 10. History of drug abuse and/or positive finding on urinary drug screening, other than prescribed medication 11. History of alcohol abuse in the past two years. 12. History of suicide attempt within the previous 10 years. 13. Multiple drug allergies (dermatological, hematological or organ toxicity) or more than one severe drug reaction(s). 14. Concomitant use of felbamate or use of felbamate within two months prior to Visit 1. 15. Frequent need of rescue benzodiazepines (more than once a month). 16. Patients with a known hypersensitivity to rufinamide, triazole derivatives, or to any excipients used in the formulation. 17. Concomitant use of vigabatrin. Patients who took vigabatrin in the past must be off vigabatrin for at least five months prior to Visit 1 and must not have evidence of a clinically significant abnormality in a visual perimetry test. 18. All Patients with a diagnosis of Congenital Short QT Syndrome. Patients with a family history of Congenital Short QT Syndrome may be excluded on the basis of the Investigator's clinical judgment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Total Partial Seizure Frequency Per 28 Days During Maintenance Phase Relative to the Baseline Phase | Baseline, Days 13 to 96 | Seizure data was collected via patient diary, which was used to record daily seizure count and type. Intent-to-treat (ITT) population: All randomized participants who had baseline Patient Seizure Diary data and had at least completed the titration period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 50% or Greater Reduction in Total Partial Seizure Frequency Per 28 Days During the Maintenance Phase Relative to the Baseline Phase | Baseline, Days 13 to 96 | Seizure data was collected via patient diary, which was used to record daily seizure count and type. |
| Log10 Transformed Total Partial Seizure Frequency Per 28 Days During the Baseline Phase and Maintenance Phase | Days 13 to 96 | Total partial seizure frequencies per 28 days during the double-blind Maintenance and Baseline Phases were transformed using logarithms to the base 10 (log10), because it was expected from previous studies that the results would not be normally distributed. |
| Reduction From Baseline in Total Partial Seizure Frequency Rate (RRATIO) During Maintenance Phase | Baseline, Days 13 to 96 | RRATIO= 100\*(T-B)/(T+B) where T= total seizure frequency per 28 days during the Maintenance Phase, and B=total seizure frequency per 28 days during the Baseline Phase. |
Countries
United States
Participant flow
Pre-assignment details
Participants were screened at 75 centers (69 in the United States and 6 in Canada). Participants were enrolled at 65 centers (61 in the United States and 4 in Canada).
Participants by arm
| Arm | Count |
|---|---|
| Rufinamide For the 12-day Titration Phase, rufinamide were administered orally in doses starting with 400 mg twice daily and increased every 3 days in 400 mg twice daily increments up to 1600 mg twice daily (total daily dose 3200 mg). For the 12 week Maintenance Phase, maintenance doses of 1600 mg twice daily (3200 mg total daily dose) were administered. Participants unable to tolerate the target dose (3200 mg/day) were allowed only during the Titration Phase to have the dose reduced to 3 tablets twice daily (corresponding to a dose of 2400 mg/day in the rufinamide group). | 176 |
| Placebo For 12-day Titration Phase and 12 week Maintenance Phase, placebo tablets matching to rufinamide 400 mg oral tablets were administered according to the same regimen scheme as described for rufinamide. For 12-day Titration Phase, 1 matching placebo tablet were administered twice daily and increased by 1 tablet every 3 days up to maximum of 4 matching placebo tablets twice daily (placebo tablet matched to rufinamide total daily dose of 3200 mg). For the 12 week maintenance phase, 4 placebo tablets matching to rufinamide maintenance doses of 1600 mg twice daily (3200 mg total daily dose) were administered. Similar to the dose reduction permitted in the rufinamide group, participants in placebo group were allowed only during the Titration Phase to have the dose reduced to 3 tablets twice daily. | 180 |
| Total | 356 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 27 | 12 |
| Overall Study | Medication Noncompliance | 0 | 3 |
| Overall Study | Other | 1 | 2 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Request of the investigator or sponsor | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 4 |
Baseline characteristics
| Characteristic | Rufinamide | Placebo | Total |
|---|---|---|---|
| Age, Customized 12 to < 18 years | 15 participants | 21 participants | 36 participants |
| Age, Customized 18 to <65 years | 155 participants | 153 participants | 308 participants |
| Age, Customized >=65 years | 6 participants | 6 participants | 12 participants |
| Race/Ethnicity, Customized Asian/Pacific Islander | 4 participants | 2 participants | 6 participants |
| Race/Ethnicity, Customized Black | 14 participants | 19 participants | 33 participants |
| Race/Ethnicity, Customized Hispanic | 13 participants | 14 participants | 27 participants |
| Race/Ethnicity, Customized Native American | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Other | 0 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized White | 145 participants | 140 participants | 285 participants |
| Sex: Female, Male Female | 92 Participants | 97 Participants | 189 Participants |
| Sex: Female, Male Male | 84 Participants | 83 Participants | 167 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 176 | 0 / 180 |
| other Total, other adverse events | 101 / 176 | 66 / 180 |
| serious Total, serious adverse events | 6 / 176 | 7 / 180 |
Outcome results
Primary
Percentage Change in Total Partial Seizure Frequency Per 28 Days During Maintenance Phase Relative to the Baseline Phase
Seizure data was collected via patient diary, which was used to record daily seizure count and type. Intent-to-treat (ITT) population: All randomized participants who had baseline Patient Seizure Diary data and had at least completed the titration period.
Time frame: Baseline, Days 13 to 96
Population: Intent-to-treat (ITT) population: All randomized participants who had baseline Patient Seizure Diary data and had at least completed the titration period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rufinamide | Percentage Change in Total Partial Seizure Frequency Per 28 Days During Maintenance Phase Relative to the Baseline Phase | -23.25 Percentage change |
| Placebo | Percentage Change in Total Partial Seizure Frequency Per 28 Days During Maintenance Phase Relative to the Baseline Phase | -9.80 Percentage change |
Secondary
Log10 Transformed Total Partial Seizure Frequency Per 28 Days During the Baseline Phase and Maintenance Phase
Total partial seizure frequencies per 28 days during the double-blind Maintenance and Baseline Phases were transformed using logarithms to the base 10 (log10), because it was expected from previous studies that the results would not be normally distributed.
Time frame: Days 13 to 96
Population: ITT population: All randomized participants who had baseline Patient Seizure Diary data and had at least completed the titration period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rufinamide | Log10 Transformed Total Partial Seizure Frequency Per 28 Days During the Baseline Phase and Maintenance Phase | 0.98 Seizures per 28-days (log-transformed) | Standard Deviation 0.675 |
| Placebo | Log10 Transformed Total Partial Seizure Frequency Per 28 Days During the Baseline Phase and Maintenance Phase | 1.13 Seizures per 28-days (log-transformed) | Standard Deviation 0.52 |
Secondary
Percentage of Participants With 50% or Greater Reduction in Total Partial Seizure Frequency Per 28 Days During the Maintenance Phase Relative to the Baseline Phase
Seizure data was collected via patient diary, which was used to record daily seizure count and type.
Time frame: Baseline, Days 13 to 96
Population: ITT population: All randomized participants who had baseline Patient Seizure Diary data and had at least completed the titration period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rufinamide | Percentage of Participants With 50% or Greater Reduction in Total Partial Seizure Frequency Per 28 Days During the Maintenance Phase Relative to the Baseline Phase | 32.5 Percentage of Participants |
| Placebo | Percentage of Participants With 50% or Greater Reduction in Total Partial Seizure Frequency Per 28 Days During the Maintenance Phase Relative to the Baseline Phase | 14.3 Percentage of Participants |
Secondary
Reduction From Baseline in Total Partial Seizure Frequency Rate (RRATIO) During Maintenance Phase
RRATIO= 100\*(T-B)/(T+B) where T= total seizure frequency per 28 days during the Maintenance Phase, and B=total seizure frequency per 28 days during the Baseline Phase.
Time frame: Baseline, Days 13 to 96
Population: ITT population: All randomized participants who had baseline Patient Seizure Diary data and had at least completed the titration period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rufinamide | Reduction From Baseline in Total Partial Seizure Frequency Rate (RRATIO) During Maintenance Phase | -18.76 RRATIO | Standard Deviation 37.841 |
| Placebo | Reduction From Baseline in Total Partial Seizure Frequency Rate (RRATIO) During Maintenance Phase | -6.90 RRATIO | Standard Deviation 24.869 |