Partial-onset Seizures
Conditions
Keywords
Partial-onset Seizures, partial seizures, seizure, epilepsy
Brief summary
The purpose of this study is to confirm the efficacy and safety of perampanel compared to placebo in patients with refractory partial-onset seizures
Interventions
DRUGPerampanel
Core study: 4 milligram (mg) group- Week 0 Once daily 2 milligram per day (mg/day), Week 1 to Week 18 Once daily 4 mg/day; 8 mg group- Week 0 Once daily 2 mg/day, Week 1 Once daily 4 mg/day, Week 2 Once daily 6 mg/day, Week 3 to Week 18 Once daily 8 mg/day; 12 mg group- Week 0 Once daily 2 mg/day, Week 1 Once daily 4 mg/day, Week 2 Once daily 6 mg/day, Week 3 Once daily 8 mg/day, Week 4 Once daily 10 mg/day, Week 5 to Week 18 Once daily 12 mg/day. Extension study: 4 mg group- Week 19 to Week 22 Once daily 4 mg/day, Week 23 Once daily 6 mg/day, Week 24 Once daily 8 mg/day, Week 25 Once daily 10 mg/day, Week 26 to Week 75 or more Once daily 12 mg/day; 8 mg group- Week 19 to Week 22 Once daily 8 mg/day, Week 23 Once daily 10 mg/day, Week 24 to Week 75 or more Once daily 12 mg/day; 12 mg group- Week 19 to Week 75 or more Once daily 12 mg/day.
DRUGPlacebo
Core study: Week 0 to Week 18 Once daily placebo. Extension study: Week 19 to Week 22 Once daily placebo, Week 23 Once daily perampanel 2 mg/day, Week 24 Once daily perampanel 4 mg/day, Week 25 Once daily perampanel 6 mg/day, Week 26 Once daily perampanel 8 mg/day, Week 27 Once daily perampanel 10 mg/day, Week 28 to Week 75 or more Once daily perampanel 12 mg/day.
Sponsors
Eisai Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female and greater than or equal to 12 years of age; 2. Have a diagnosis of epilepsy with partial seizures with or without secondarily generalized seizures 3. Participants with computed tomography (CT) or magnetic resonance imaging (MRI) diagnosis within the last 10 years (for adults) and 5 years (for adolescents) prior to visit 1 that ruled out progressive central nervous system (CNS) disorders, example, neurodegenerative disorders, brain tumors. For participants without existing CT or MRI results, CT or MRI was performed at or after Visit 1 but results evaluation was performed by Visit 2 4. Participants who had been treated for at least 12 weeks but confirmed to be uncontrolled with more than one standard antiepileptic drug (AED) for 2 years before enrollment 5. During the 6-week Prerandomization Phase participants must have had greater than or equal to 5 partial seizures per 6-week 6. Are currently being treated with stable doses and administrations of 1, 2, or a maximum of 3 approved AEDs. Only 1 inducer AED (defined as carbamazepine, phenytoin or oxcarbazepine only) out of the maximum of 3 AEDs is allowed
Exclusion criteria
1. Presence of nonmotor simple partial seizures only; 2. Presence of primary generalized epilepsies or seizures, such as absences and/or myoclonic epilepsies; 3. Presence or previous history of Lennox-Gastaut syndrome; 4. A history of status epilepticus within 1 year prior to screening 5. Seizure clusters where individual seizures cannot be counted 6. A history of psychogenic seizures within 5 years prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Core Phase: Percent Change in Seizure Frequency (For All Partial Seizures) Per 28 Days in the Randomization Phase Relative to Pre-randomization Phase (Baseline) | Baseline, Week 19 | Seizure frequency was based on number of seizures per 28 days, calculated as the number of seizures over the entire time interval divided by the number of days in the interval and multiplied by 28. All partial seizure included simple partial seizures without motor signs, simple partial with motor signs, complex partial, and complex partial with secondary generalized seizures. A simple partial seizure takes place on one side of the brain. Usually, people experiencing a simple partial seizure do not lose consciousness or awareness. A complex partial seizure is a type of seizure that arises in one lobe of the brain, rather than the whole brain. The seizure affects people's awareness and may cause them to lose consciousness. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Core Phase: Responder Rate During the Maintenance Period of the Randomization Phase Relative to the Prerandomization Phase (Baseline)- Last Observation Carried Forward (LOCF) | Baseline, Week 19 | Responder rate was percentage of participants with greater than or equal to (\>=) 50% reduction in seizure frequency during maintenance period of the randomization phase relative to prerandomization phase (baseline). If the reduction in seizure frequency is less than (\<) 50%, then the participants are considered as non-responders. |
| Core Phase: Percent Change in Seizure Frequency Per 28 Days For Complex Partial Seizures Plus Secondary Generalized Seizures in the Randomization Phase Relative to the Prerandomization Phase (Baseline) | Baseline, Week 19 | Seizure frequency was based on number of seizures per 28 days, calculated as the number of seizures over the entire time interval divided by the number of days in the interval and multiplied by 28. A complex partial seizure is a type of seizure that arises in one lobe of the brain, rather than the whole brain and it affects awareness and may cause in loss of consciousness. Secondary generalized seizures begin in one part of the brain, but then spread to both sides of the brain. |
| Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Baseline, Week 19 | The investigator evaluated each participant for CGIC questionnaire to assess change in participant's disease clinical status from baseline. Assessment evaluated frequency of seizures, severity of seizures, occurrence of adverse events (AEs), and overall functional status of the participant using the 7-point scale. The evaluation used a 7-point scale with the scores 1: Very much improved, 2: Much improved, 3: Minimally improved, 4: No change, 5: Minimally worse, 6: Much worse, 7: Very much worse. Lower score indicated improvement and higher score indicated worsening. |
Countries
Australia, China, Japan, Malaysia, South Korea, Taiwan, Thailand
Participant flow
Recruitment details
Participants took part in the study at 119 investigative sites in Australia, China, Korea, Japan, Malaysia, Taiwan, and Thailand from 15th May 2012 to 28th May 2020. A total of 940 participants were enrolled and screened, of which 230 participants were screen failures, 710 participants were randomized and 707 participants were treated in this study.
Pre-assignment details
This study included Core and Extension Phase. Core Phase consisted of 2 phases: Prerandomization (Baseline) and Randomization (Titration, Maintenance Period). Extension Phase consisted of 3 periods: Preconversion, Conversion, Maintenance Period. Participants received varying doses depending on which dose level they were assigned to in Core Phase and their individual tolerance but in Extension Phase, all participants were up-titrated to single target dose level of 12 milligram (mg) per day.
Participants by arm
| Arm | Count |
|---|---|
| Core Phase: Placebo Participants received perampanel-matched placebo tablets (6 tablets), orally, once daily before bedtime from Week 0 up to Week 18 (up to 19 weeks). | 176 |
| Core Phase: Perampanel 4 mg Participants received perampanel 2 mg tablet, orally once daily before bedtime in Week 0 and then titrated up to maximum dose of 4 mg orally once daily from Week 1 up to Week 5 (titration period), followed by perampanel 4 mg, orally once daily from Week 6 up to Week 18 (maintenance period). Total duration of titration and maintenance period is 19 weeks. | 176 |
| Core Phase: Perampanel 8 mg Participants received perampanel 2 mg tablet, orally once daily before bedtime in Week 0 and then titrated up to maximum dose of 8 mg (weekly increment of 2 mg from Week 1 up to Week 3) orally once daily for up to Week 5 (titration period), followed by perampanel 8 mg, orally once daily from Week 6 up to Week 18 (maintenance period). Total duration of titration and maintenance period is 19 weeks. | 175 |
| Core Phase: Perampanel 12 mg Participants received perampanel 2 mg tablet, orally once daily before bedtime in Week 0 and then titrated up to maximum dose of 12 mg (weekly increment of 2 mg from Week 1 up to Week 5) orally once daily for up to Week 5 (titration period), followed by perampanel 12 mg, orally once daily from Week 6 up to Week 18 (maintenance period). Total duration of titration and maintenance period is 19 weeks. | 180 |
| Total | 707 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Core Phase | Adverse Event | 4 | 5 | 15 | 20 |
| Core Phase | Lack of Efficacy | 1 | 2 | 1 | 1 |
| Core Phase | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Core Phase | Not treated | 1 | 0 | 2 | 0 |
| Core Phase | Other than specified | 1 | 2 | 2 | 2 |
| Core Phase | Pregnancy | 2 | 0 | 0 | 0 |
| Core Phase | Withdrawal by Subject | 16 | 11 | 9 | 13 |
| Extension Phase | Adverse Event | 18 | 16 | 9 | 20 |
| Extension Phase | Lack of Efficacy | 17 | 33 | 26 | 24 |
| Extension Phase | Lost to Follow-up | 2 | 1 | 1 | 1 |
| Extension Phase | Other than specified | 13 | 18 | 13 | 18 |
| Extension Phase | Pregnancy | 2 | 0 | 1 | 1 |
| Extension Phase | Withdrawal by Subject | 43 | 48 | 42 | 33 |
Baseline characteristics
| Characteristic | Core Phase: Placebo | Core Phase: Perampanel 4 mg | Core Phase: Perampanel 8 mg | Core Phase: Perampanel 12 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 34.5 years STANDARD_DEVIATION 13.21 | 33.1 years STANDARD_DEVIATION 13.18 | 33.6 years STANDARD_DEVIATION 14.11 | 32.3 years STANDARD_DEVIATION 12.3 | 33.4 years STANDARD_DEVIATION 13.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 176 Participants | 175 Participants | 175 Participants | 179 Participants | 705 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 169 Participants | 168 Participants | 159 Participants | 171 Participants | 667 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 7 Participants | 7 Participants | 14 Participants | 7 Participants | 35 Participants |
| Sex: Female, Male Female | 90 Participants | 94 Participants | 84 Participants | 93 Participants | 361 Participants |
| Sex: Female, Male Male | 86 Participants | 82 Participants | 91 Participants | 87 Participants | 346 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 176 | 0 / 176 | 1 / 175 | 0 / 180 | 7 / 679 |
| other Total, other adverse events | 114 / 176 | 119 / 176 | 127 / 175 | 155 / 180 | 618 / 679 |
| serious Total, serious adverse events | 10 / 176 | 6 / 176 | 7 / 175 | 12 / 180 | 113 / 679 |
Outcome results
Primary
Core Phase: Percent Change in Seizure Frequency (For All Partial Seizures) Per 28 Days in the Randomization Phase Relative to Pre-randomization Phase (Baseline)
Seizure frequency was based on number of seizures per 28 days, calculated as the number of seizures over the entire time interval divided by the number of days in the interval and multiplied by 28. All partial seizure included simple partial seizures without motor signs, simple partial with motor signs, complex partial, and complex partial with secondary generalized seizures. A simple partial seizure takes place on one side of the brain. Usually, people experiencing a simple partial seizure do not lose consciousness or awareness. A complex partial seizure is a type of seizure that arises in one lobe of the brain, rather than the whole brain. The seizure affects people's awareness and may cause them to lose consciousness.
Time frame: Baseline, Week 19
Population: Intent-to-treat (ITT) Analysis Set included all participants who signed informed consent, were randomized, received at least one dose of study medication, and had at least one postdose seizure frequency data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Core Phase: Percent Change in Seizure Frequency (For All Partial Seizures) Per 28 Days in the Randomization Phase Relative to Pre-randomization Phase (Baseline) | -10.76 percent change |
| Perampanel 4 mg | Core Phase: Percent Change in Seizure Frequency (For All Partial Seizures) Per 28 Days in the Randomization Phase Relative to Pre-randomization Phase (Baseline) | -17.32 percent change |
| Perampanel 8 mg | Core Phase: Percent Change in Seizure Frequency (For All Partial Seizures) Per 28 Days in the Randomization Phase Relative to Pre-randomization Phase (Baseline) | -28.95 percent change |
| Perampanel 12 mg | Core Phase: Percent Change in Seizure Frequency (For All Partial Seizures) Per 28 Days in the Randomization Phase Relative to Pre-randomization Phase (Baseline) | -38.03 percent change |
p-value: 0.23395% CI: [-14.112, 4.519]ANCOVA
p-value: 0.000395% CI: [-25.683, -7.251]ANCOVA
p-value: <0.000195% CI: [-33.878, -16.235]ANCOVA
Secondary
Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores
The investigator evaluated each participant for CGIC questionnaire to assess change in participant's disease clinical status from baseline. Assessment evaluated frequency of seizures, severity of seizures, occurrence of adverse events (AEs), and overall functional status of the participant using the 7-point scale. The evaluation used a 7-point scale with the scores 1: Very much improved, 2: Much improved, 3: Minimally improved, 4: No change, 5: Minimally worse, 6: Much worse, 7: Very much worse. Lower score indicated improvement and higher score indicated worsening.
Time frame: Baseline, Week 19
Population: ITT Analysis Set included all participants who signed informed consent, were randomized, received at least one dose of study medication, and had at least one postdose seizure frequency data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Very much worse | 0 Participants |
| Placebo | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Minimally worse | 3 Participants |
| Placebo | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | No change | 67 Participants |
| Placebo | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Very much improved | 3 Participants |
| Placebo | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Much worse | 1 Participants |
| Placebo | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Much improved | 31 Participants |
| Placebo | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Minimally improved | 54 Participants |
| Perampanel 4 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Minimally worse | 10 Participants |
| Perampanel 4 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Minimally improved | 45 Participants |
| Perampanel 4 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Much improved | 39 Participants |
| Perampanel 4 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | No change | 56 Participants |
| Perampanel 4 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Very much worse | 0 Participants |
| Perampanel 4 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Much worse | 0 Participants |
| Perampanel 4 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Very much improved | 5 Participants |
| Perampanel 8 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Minimally improved | 53 Participants |
| Perampanel 8 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Very much worse | 0 Participants |
| Perampanel 8 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Very much improved | 11 Participants |
| Perampanel 8 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Much improved | 41 Participants |
| Perampanel 8 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | No change | 37 Participants |
| Perampanel 8 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Minimally worse | 5 Participants |
| Perampanel 8 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Much worse | 0 Participants |
| Perampanel 12 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Much improved | 54 Participants |
| Perampanel 12 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Much worse | 1 Participants |
| Perampanel 12 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Minimally worse | 4 Participants |
| Perampanel 12 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Very much improved | 9 Participants |
| Perampanel 12 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Very much worse | 1 Participants |
| Perampanel 12 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | No change | 37 Participants |
| Perampanel 12 mg | Core Phase: Number of Participants With Clinical Global Impression of Change (CGIC) Scores | Minimally improved | 40 Participants |
Secondary
Core Phase: Percent Change in Seizure Frequency Per 28 Days For Complex Partial Seizures Plus Secondary Generalized Seizures in the Randomization Phase Relative to the Prerandomization Phase (Baseline)
Seizure frequency was based on number of seizures per 28 days, calculated as the number of seizures over the entire time interval divided by the number of days in the interval and multiplied by 28. A complex partial seizure is a type of seizure that arises in one lobe of the brain, rather than the whole brain and it affects awareness and may cause in loss of consciousness. Secondary generalized seizures begin in one part of the brain, but then spread to both sides of the brain.
Time frame: Baseline, Week 19
Population: ITT Analysis Set included all participants who signed informed consent, were randomized, received at least one dose of study medication, and had at least one postdose seizure frequency data. Here overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Core Phase: Percent Change in Seizure Frequency Per 28 Days For Complex Partial Seizures Plus Secondary Generalized Seizures in the Randomization Phase Relative to the Prerandomization Phase (Baseline) | -11.70 percent change |
| Perampanel 4 mg | Core Phase: Percent Change in Seizure Frequency Per 28 Days For Complex Partial Seizures Plus Secondary Generalized Seizures in the Randomization Phase Relative to the Prerandomization Phase (Baseline) | -19.08 percent change |
| Perampanel 8 mg | Core Phase: Percent Change in Seizure Frequency Per 28 Days For Complex Partial Seizures Plus Secondary Generalized Seizures in the Randomization Phase Relative to the Prerandomization Phase (Baseline) | -33.68 percent change |
| Perampanel 12 mg | Core Phase: Percent Change in Seizure Frequency Per 28 Days For Complex Partial Seizures Plus Secondary Generalized Seizures in the Randomization Phase Relative to the Prerandomization Phase (Baseline) | -41.80 percent change |
p-value: 0.055295% CI: [-18.067, 1.671]ANCOVA
p-value: <0.000195% CI: [-30.941, -11.368]ANCOVA
p-value: <0.000195% CI: [-37.698, -19.794]ANCOVA
Secondary
Core Phase: Responder Rate During the Maintenance Period of the Randomization Phase Relative to the Prerandomization Phase (Baseline)- Last Observation Carried Forward (LOCF)
Responder rate was percentage of participants with greater than or equal to (\>=) 50% reduction in seizure frequency during maintenance period of the randomization phase relative to prerandomization phase (baseline). If the reduction in seizure frequency is less than (\<) 50%, then the participants are considered as non-responders.
Time frame: Baseline, Week 19
Population: ITT Analysis Set included all participants who signed informed consent, were randomized, received at least one dose of study medication, and had at least one postdose seizure frequency data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Core Phase: Responder Rate During the Maintenance Period of the Randomization Phase Relative to the Prerandomization Phase (Baseline)- Last Observation Carried Forward (LOCF) | 19.4 percentage of participants |
| Perampanel 4 mg | Core Phase: Responder Rate During the Maintenance Period of the Randomization Phase Relative to the Prerandomization Phase (Baseline)- Last Observation Carried Forward (LOCF) | 23.0 percentage of participants |
| Perampanel 8 mg | Core Phase: Responder Rate During the Maintenance Period of the Randomization Phase Relative to the Prerandomization Phase (Baseline)- Last Observation Carried Forward (LOCF) | 36.0 percentage of participants |
| Perampanel 12 mg | Core Phase: Responder Rate During the Maintenance Period of the Randomization Phase Relative to the Prerandomization Phase (Baseline)- Last Observation Carried Forward (LOCF) | 43.3 percentage of participants |
p-value: 0.3954Cochran-Mantel-Haenszel
p-value: 0.0005Cochran-Mantel-Haenszel
p-value: <0.0001Cochran-Mantel-Haenszel