Seizure Disorder Generalized Tonic Clonic
Conditions
Keywords
Central Nervous System
Brief summary
This study is designed to evaluate the efficacy, safety, and pharmacokinetics (PK) of perampanel on Primary Generalized Tonic Clonic (PGTC) seizure frequency in adolescents and adults maintained on one to two stable antiepileptic drugs (AED).
Detailed description
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, adjunctive-therapy study with an open-label Extension Phase. The Core Study consists of 2 phases: Prerandomization and Randomization. The Prerandomization Phase consisted of 2 periods: Screening (up to 4 weeks) and Baseline (4 or 8 weeks, depending on the accuracy of diary-documented seizures during Screening), during which participants will be assessed for eligibility to participate in the study. The Randomization Phase consisted of 3 periods: Titration (4 weeks), Maintenance (13 weeks), and Follow-up (4 weeks; only for those participants not entering into the Extension Phase). At the start of the Randomization Phase, eligible participants will be randomized to the perampanel or placebo treatment groups in a 1:1 ratio. The extension phase consists of 142 weeks.
Interventions
DRUGPerampanel
DRUGPlacebo comparator
Sponsors
Eisai Inc.
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
Inclusion: 1. Clinical diagnosis of PGTC seizures (with or without other subtypes of primary generalized seizures) and experiencing greater than or equal to 3 PGTC seizures during the 8-week period prior to randomization 2. Have had a routine electroencephalogram (EEG) prior to or during the Baseline Period with electroencephalographic features consistent with primary generalized epilepsy; other concomitant anomaly should be explained by adequate past medical history 3. On a fixed dose of one to a maximum of three concomitant antiepileptic drugs (AEDs) for a minimum of 30 days prior to Baseline; only one inducer AED (i.e., carbamazepine, oxcarbazepine, or phenytoin) out of the maximum of two AEDs will be allowed 4. A vagal nerve stimulator (VNS) will be allowed, but it must have been implanted greater than or equal to 5 months prior to Baseline (stimulator parameters cannot be changed for 30 days prior to Baseline and for the duration of the study). 5. Have had a computed tomography (CT) or magnetic resonance imaging (MRI) within the last 10 years (for adults) and 5 years (for adolescents) that ruled out a progressive cause of epilepsy 6. A ketogenic diet will be allowed as long as the participant has been on this diet for 5 weeks prior to randomization Exclusion: 1. A history of status epilepticus that required hospitalization within 12 months prior to Baseline 2. Seizure clusters where individual seizures cannot be counted 3. A history of psychogenic seizures 4. Concomitant diagnosis of Partial Onset Seizures (POS) 5. Progressive neurological disease 6. Clinical diagnosis of Lennox-Gastaut syndrome 7. If felbamate is used as a concomitant AED, participants must be on felbamate for at least 2 years, with a stable dose for 60 days prior to Baseline. They must not have a history of white blood cell (WBC) count below less than or equal to 2500/microL (2.50 1E+09/L), platelets less than 100,000/microL, liver function tests (LFTs) greater than 3 times the upper limit of normal (ULN), or other indication of hepatic or bone marrow dysfunction while receiving felbamate. 8. Concomitant use of vigabatrin: Participants who took vigabatrin in the past must be discontinued for approximately 5 months prior to Baseline, and must have documentation showing no evidence of a vigabatrin-associated clinically significant abnormality in an automated visual perimetry test 9. Concomitant use of barbiturates (except for seizure control indication) within 30 days prior to Baseline 10. Use of intermittent rescue benzodiazepines (i.e., one to two doses over a 24-hour period considered one-time rescue) two or more times within the 30 days prior to Baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Percent Change in Primary Generalized Tonic Clonic Seizure Frequency (PGTC) Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks) | Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days (as determined from participant diaries) was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change from baseline in PGTC seizure was analyzed over the Titration and Maintenance Periods combined, while baseline was defined as seizure frequency per 28 days based on all valid diary data during the Prerandomization Phase. |
| 50% Responder Rate for Primary Generalized Tonic Clonic Seizure During Maintenance - LOCF - (for Core Study) | Baseline (4 or 8 weeks) and Maintenance (13 weeks) | A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance-last observation carried forward (LOCF) from prerandomization. The data was presented as the percentage of participants. |
| 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Week 1 of perampanel treatment to date of last dose of perampanel in the Extension Phase | Responder rate was defined as the percentage of participants who experienced a 50% or greater reduction in PGTC and total seizure frequency during treatment per 28 days relative to baseline (responder). Week 1 began on the date of first dose of the perampanel treatment regardless of whether it occurred in the Core Study or Extension Phase and continued to and included the date of the last dose of perampanel in the Extension Phase. For any given analysis window and seizure type(s), a 50% response from Core Study Prerandomization is a participant whose seizure frequency per 28 days for that seizure type(s) during that analysis window is 50% to 100% lower than his or her Core Study Prerandomization baseline seizure frequency per 28 days for that same seizure type(s). In Part B of the Extension Phase (after Visit 15), the seizure diary is only completed for days on which a seizure occurred and missing days were imputed as non-seizure days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 50% Responder Rate for Primary Generalized Seizure Subtype During Maintenance Period - LOCF - (for Core Study) | Baseline (4 or 8 weeks) and Maintenance (13 weeks) | Primary generalized seizure subtype included absence and myoclonic seizures. A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance - (LOCF) from prerandomization. The data was presented as the percentage of participants. |
| Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Date of first dose of study drug to date of last dose of study drug in the Extension Phase | Week 1 began on the date of first dose of the perampanel treatment regardless of whether it occurred in the Core Study or Extension Phase and continued to and included the date of the last dose of perampanel in the Extension Phase. For any given analysis window and seizure type(s), a 50% responder from Core Study Randomization is a participant whose seizure frequency per 28 days for that seizure type(s) during that analysis window is 50% to 100% lower than his or her Core Study Prerandomization baseline seizure frequency per 28 days for that same seizure type(s). In Part B of the Extension Phase (after Visit 15), the seizure diary is only completed for days on which a seizure occurred and missing days were imputed as non-seizure days. |
| Median Percent Change in All Seizure Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks) | Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change in seizure frequency relative to baseline (prerandomization) for all seizures (PGTC, myoclonic, absence and all other seizures that occur during the study) per 28 days during the Titration and Maintenance Periods combined was analyzed. |
| Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events as a Measure of Safety and Tolerability of Perampanel in Subjects With Inadequately Controlled PGTC Seizures - (for Core Study) | For each participant, from the first treatment dose till 30 days after the last dose or up to 21 weeks for core study and 142 weeks for extension phase. | An Adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered an investigational product. A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening (i.e., the subject was at immediate risk of death from the AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect (in the child of a subject who was exposed to the study drug). In this study, treatment emergent adverse events (TEAEs) (defined as an AE that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication) were assessed. |
| Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks: 1 to 13, 14 to 26, 27 to 39, 40 to 52, 53 to 65, 66 to 78, 79 to 91, 92 to 104, 105 to 117, 118 to 130, 131 to 143, greater than or equal to 144 | Efficacy assessments included seizure counts from participant diaries. The percent change in seizure frequency was assessed during the perampanel treatment duration, with the pre-perampanel baseline being used for evaluating the change. The pre-perampanel baseline was defined as follows: 1) for all participants who had been assigned to placebo treatment in the Core Study, the pre-perampanel baseline was computed from all valid seizure diary data during the Core Study, and 2) for participants who had been assigned to perampanel in the Core Study, the pre-perampanel baseline was computed from all valid seizure diary data during the Prerandomization Phase plus the 4 weeks prior to the Prerandomization Phase of the Core Study. The perampanel treatment duration consisted of: 1) the Randomization Phase of the Core Study plus the Extension Phase for participants assigned to perampanel in the Core Study, and 2) the Extension Phase for participants assigned to placebo in the Core Study. |
| Median Percent Change in Primary Generalized Seizure Subtype Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks) | Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change in seizure frequency relative to baseline (prerandomization) for primary generalized seizure subtype (myoclonic and absence) per 28 days during the Titration and Maintenance Periods combined was analyzed. |
| 50% Responder Rate for All Seizures During Maintenance-LOCF - (for Core Study) | Baseline (4 or 8 weeks) and Maintenance (13 weeks) | All seizures included PGTC, myoclonic, absence and all other seizures that occur during the study. A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance- LOCF from prerandomization. The data was presented as percentage of participants. |
Participant flow
Pre-assignment details
Of the 307 participants who were screened, 143 participants were screen failures and 164 participants were eligible to continue in the study but 1 participant withdrew prior to receiving treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Core Study) Participants received 6 tablets of perampanel matched placebo, once a day, before bedtime and with food. | 82 |
| Perampanel (Core Study) Participants received 6 tablets (initially ,1 tablet of 2 mg perampanel plus 5 tablets of perampanel matched placebo) and up-titrated weekly in 2 mg increments to a target dose range of 8 mg per day maintaining the blind with administration of 6 tablets per day of either perampanel/perampanel matched placebo. | 81 |
| Total | 163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Study | Adverse Event | 5 | 9 | 0 |
| Core Study | Inadequate therapeutic effect | 2 | 0 | 0 |
| Core Study | Lost to Follow-up | 1 | 1 | 0 |
| Core Study | Participant's Choice | 2 | 3 | 0 |
| Extension Phase | Adverse Event | 0 | 0 | 12 |
| Extension Phase | Inadequate therapeutic effect | 0 | 0 | 7 |
| Extension Phase | Lost to Follow-up | 0 | 0 | 2 |
| Extension Phase | Other | 0 | 0 | 14 |
| Extension Phase | Participant choice | 0 | 0 | 16 |
| Extension Phase | Pregnancy | 0 | 0 | 1 |
| Extension Phase | Withdrawal by Subject | 0 | 0 | 8 |
Baseline characteristics
| Characteristic | Placebo (Core Study) | Perampanel (Core Study) | Total |
|---|---|---|---|
| Age, Continuous | 26 Years | 26 Years | 26 Years |
| Sex: Female, Male Female | 46 Participants | 46 Participants | 92 Participants |
| Sex: Female, Male Male | 36 Participants | 35 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 56 / 82 | 67 / 81 | 106 / 138 |
| serious Total, serious adverse events | 7 / 82 | 6 / 81 | 18 / 138 |
Outcome results
Primary
50% Responder Rate for Primary Generalized Tonic Clonic Seizure During Maintenance - LOCF - (for Core Study)
A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance-last observation carried forward (LOCF) from prerandomization. The data was presented as the percentage of participants.
Time frame: Baseline (4 or 8 weeks) and Maintenance (13 weeks)
Population: Full Analysis Set included all randomized participants who received as least 1 dose of study drug and had any postbaseline seizure frequency data. Last observation carried forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Core Study) | 50% Responder Rate for Primary Generalized Tonic Clonic Seizure During Maintenance - LOCF - (for Core Study) | 39.5 Percentage of participants |
| Perampanel (Core Study) | 50% Responder Rate for Primary Generalized Tonic Clonic Seizure During Maintenance - LOCF - (for Core Study) | 64.2 Percentage of participants |
p-value: 0.0019Cochran-Mantel-Haenszel
Primary
50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase)
Responder rate was defined as the percentage of participants who experienced a 50% or greater reduction in PGTC and total seizure frequency during treatment per 28 days relative to baseline (responder). Week 1 began on the date of first dose of the perampanel treatment regardless of whether it occurred in the Core Study or Extension Phase and continued to and included the date of the last dose of perampanel in the Extension Phase. For any given analysis window and seizure type(s), a 50% response from Core Study Prerandomization is a participant whose seizure frequency per 28 days for that seizure type(s) during that analysis window is 50% to 100% lower than his or her Core Study Prerandomization baseline seizure frequency per 28 days for that same seizure type(s). In Part B of the Extension Phase (after Visit 15), the seizure diary is only completed for days on which a seizure occurred and missing days were imputed as non-seizure days.
Time frame: Week 1 of perampanel treatment to date of last dose of perampanel in the Extension Phase
Population: The Extension Phase FAS included participants who were eligible to participate in the Extension Phase, received at least 1 dose of study drug in this phase, and had baseline seizure frequency data and at least 1 observation of valid seizure diary data during study drug treatment duration.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Core Study Maintenanace Period | 55.1 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Conversion Period | 74.6 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Maintenance Weeks 1 to 13 | 75.9 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Maintenance Weeks 14 to 26 | 78.4 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Maintenance Weeks 27 to 39 | 78.1 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Maintenance Weeks 40 to 52 | 79.8 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Maintenance Weeks 53 to 65 | 81.8 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Maintenance Weeks 66 to 78 | 76.5 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Maintenance Weeks 79 to 91 | 80.3 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase) | Extension Maintenance Weeks 92 to 104 | 91.4 Percentage of participants |
Primary
Median Percent Change in Primary Generalized Tonic Clonic Seizure Frequency (PGTC) Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study)
Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days (as determined from participant diaries) was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change from baseline in PGTC seizure was analyzed over the Titration and Maintenance Periods combined, while baseline was defined as seizure frequency per 28 days based on all valid diary data during the Prerandomization Phase.
Time frame: Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
Population: The Full Analysis Set included participants who were randomized to study drug, received at least 1 dose of study drug, and had any postbaseline seizure frequency data during the Randomization Phase.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo (Core Study) | Median Percent Change in Primary Generalized Tonic Clonic Seizure Frequency (PGTC) Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | -38.38 Percent change |
| Perampanel (Core Study) | Median Percent Change in Primary Generalized Tonic Clonic Seizure Frequency (PGTC) Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | -76.47 Percent change |
Comparison: The median difference to placebo and the 95% confidence interval are based on the Hodges-Lehmann method.p-value: 0.000195% CI: [-45.49, -15.244]ANCOVA
Secondary
50% Responder Rate for All Seizures During Maintenance-LOCF - (for Core Study)
All seizures included PGTC, myoclonic, absence and all other seizures that occur during the study. A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance- LOCF from prerandomization. The data was presented as percentage of participants.
Time frame: Baseline (4 or 8 weeks) and Maintenance (13 weeks)
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Core Study) | 50% Responder Rate for All Seizures During Maintenance-LOCF - (for Core Study) | 34.6 Percentage of participants |
| Perampanel (Core Study) | 50% Responder Rate for All Seizures During Maintenance-LOCF - (for Core Study) | 45.7 Percentage of participants |
p-value: 0.1826Cochran-Mantel-Haenszel
Secondary
50% Responder Rate for Primary Generalized Seizure Subtype During Maintenance Period - LOCF - (for Core Study)
Primary generalized seizure subtype included absence and myoclonic seizures. A responder was a participant who experienced a 50% or greater reduction in seizure frequency per 28 days during Maintenance - (LOCF) from prerandomization. The data was presented as the percentage of participants.
Time frame: Baseline (4 or 8 weeks) and Maintenance (13 weeks)
Population: Only a subset of participants in the Full Analysis Set who experienced these seizure types during the Prerandomization Phase of the study were included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Core Study) | 50% Responder Rate for Primary Generalized Seizure Subtype During Maintenance Period - LOCF - (for Core Study) | Absence | 39.4 Percentage of participants |
| Placebo (Core Study) | 50% Responder Rate for Primary Generalized Seizure Subtype During Maintenance Period - LOCF - (for Core Study) | Myoclonic | 60.9 Percentage of participants |
| Perampanel (Core Study) | 50% Responder Rate for Primary Generalized Seizure Subtype During Maintenance Period - LOCF - (for Core Study) | Absence | 48.1 Percentage of participants |
| Perampanel (Core Study) | 50% Responder Rate for Primary Generalized Seizure Subtype During Maintenance Period - LOCF - (for Core Study) | Myoclonic | 41.7 Percentage of participants |
Comparison: P Value Compared to Placebo for Absence Seizuresp-value: 0.4653Cochran-Mantel-Haenszel
Comparison: P Value Compared to Placebo for Myoclonic Seizuresp-value: 0.3694Cochran-Mantel-Haenszel
Secondary
Median Percent Change in All Seizure Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study)
Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change in seizure frequency relative to baseline (prerandomization) for all seizures (PGTC, myoclonic, absence and all other seizures that occur during the study) per 28 days during the Titration and Maintenance Periods combined was analyzed.
Time frame: Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
Population: Full Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo (Core Study) | Median Percent Change in All Seizure Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | -22.87 Percent Change |
| Perampanel (Core Study) | Median Percent Change in All Seizure Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | -43.4 Percent Change |
Comparison: The median difference to placebo and the 95% confidence interval are based on the Hodges-Lehmann method.p-value: 0.001895% CI: [-40.668, -8.518]ANCOVA
Secondary
Median Percent Change in Primary Generalized Seizure Subtype Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study)
Seizure frequency per 28 days was derived from the information recorded in the participant diaries. PGTC seizure frequency per 28 days was calculated as the number of PGTC seizures divided by the number of days in the interval and multiplied by 28. The percent change in seizure frequency relative to baseline (prerandomization) for primary generalized seizure subtype (myoclonic and absence) per 28 days during the Titration and Maintenance Periods combined was analyzed.
Time frame: Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo (Core Study) | Median Percent Change in Primary Generalized Seizure Subtype Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | Absence | -7.58 Percent Change |
| Placebo (Core Study) | Median Percent Change in Primary Generalized Seizure Subtype Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | Myoclonic | -52.54 Percent Change |
| Perampanel (Core Study) | Median Percent Change in Primary Generalized Seizure Subtype Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | Absence | -41.18 Percent Change |
| Perampanel (Core Study) | Median Percent Change in Primary Generalized Seizure Subtype Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study) | Myoclonic | -24.47 Percent Change |
Comparison: Median Difference to Placebo for Absence Seizuresp-value: 0.347895% CI: [-53.054, 26.989]ANCOVA
Comparison: Median Difference to Placebo for Myoclonic Seizurep-value: 0.6195% CI: [-15.338, 59.938]ANCOVA
Secondary
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events as a Measure of Safety and Tolerability of Perampanel in Subjects With Inadequately Controlled PGTC Seizures - (for Core Study)
An Adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered an investigational product. A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening (i.e., the subject was at immediate risk of death from the AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect (in the child of a subject who was exposed to the study drug). In this study, treatment emergent adverse events (TEAEs) (defined as an AE that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication) were assessed.
Time frame: For each participant, from the first treatment dose till 30 days after the last dose or up to 21 weeks for core study and 142 weeks for extension phase.
Population: The Safety Analysis Set included participants who were randomized to study drug, received at least 1 dose of study drug, and had at least 1 postbaseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo (Core Study) | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events as a Measure of Safety and Tolerability of Perampanel in Subjects With Inadequately Controlled PGTC Seizures - (for Core Study) | Treatment emergent adverse events | 59 Participants |
| Placebo (Core Study) | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events as a Measure of Safety and Tolerability of Perampanel in Subjects With Inadequately Controlled PGTC Seizures - (for Core Study) | Treatment emergent serious adverse events | 7 Participants |
| Perampanel (Core Study) | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events as a Measure of Safety and Tolerability of Perampanel in Subjects With Inadequately Controlled PGTC Seizures - (for Core Study) | Treatment emergent adverse events | 67 Participants |
| Perampanel (Core Study) | Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events as a Measure of Safety and Tolerability of Perampanel in Subjects With Inadequately Controlled PGTC Seizures - (for Core Study) | Treatment emergent serious adverse events | 6 Participants |
Secondary
Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase)
Week 1 began on the date of first dose of the perampanel treatment regardless of whether it occurred in the Core Study or Extension Phase and continued to and included the date of the last dose of perampanel in the Extension Phase. For any given analysis window and seizure type(s), a 50% responder from Core Study Randomization is a participant whose seizure frequency per 28 days for that seizure type(s) during that analysis window is 50% to 100% lower than his or her Core Study Prerandomization baseline seizure frequency per 28 days for that same seizure type(s). In Part B of the Extension Phase (after Visit 15), the seizure diary is only completed for days on which a seizure occurred and missing days were imputed as non-seizure days.
Time frame: Date of first dose of study drug to date of last dose of study drug in the Extension Phase
Population: Full analysis set included all participants who were eligible to participate in the Extension Phase, received at least 1 dose of perampanel in this phase, and had baseline seizure frequency data and at least 1 observation of valid seizure diary data during the perampanel treatment duration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Core Study Titration Period | -57.72 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Core Study Maintenance Period | -57.40 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Conversion Period | -100.00 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Maintenance Period, Weeks 1 to 13 | -84.62 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Maintenance Period, Weeks 14 to 26 | -86.81 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Maintenance Period, Weeks 27 to 39 | -86.62 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Maintenance Period, Weeks 40 to 52 | -100.00 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Maintenance Period, Weeks 53 to 65 | -100.00 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Maintenance Period, Weeks 66 to 78 | -100.00 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Maintenance, Weeks 79 to 91 | -100.00 Percent change in PGTC seizure frequency |
| Placebo (Core Study) | Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase) | Extension Phase Maintenance, Weeks 92 to 104 | -100.00 Percent change in PGTC seizure frequency |
Secondary
Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase)
Efficacy assessments included seizure counts from participant diaries. The percent change in seizure frequency was assessed during the perampanel treatment duration, with the pre-perampanel baseline being used for evaluating the change. The pre-perampanel baseline was defined as follows: 1) for all participants who had been assigned to placebo treatment in the Core Study, the pre-perampanel baseline was computed from all valid seizure diary data during the Core Study, and 2) for participants who had been assigned to perampanel in the Core Study, the pre-perampanel baseline was computed from all valid seizure diary data during the Prerandomization Phase plus the 4 weeks prior to the Prerandomization Phase of the Core Study. The perampanel treatment duration consisted of: 1) the Randomization Phase of the Core Study plus the Extension Phase for participants assigned to perampanel in the Core Study, and 2) the Extension Phase for participants assigned to placebo in the Core Study.
Time frame: Weeks: 1 to 13, 14 to 26, 27 to 39, 40 to 52, 53 to 65, 66 to 78, 79 to 91, 92 to 104, 105 to 117, 118 to 130, 131 to 143, greater than or equal to 144
Population: Full Analysis Set, which comprised all participants who were eligible to participate in the Extension Phase, received at least 1 dose of perampanel in this phase, and had baseline seizure frequency data and at least 1 observation of valid seizure diary data during the perampanel treatment duration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 1 to 13 | -77.45 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 14 to 26 | -74.21 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 27 to 39 | -84.62 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 40 to 52 | -89.65 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 53 to 65 | -92.45 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 66 to 78 | -100.00 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 79 to 91 | -100.00 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 92 to 104 | -100.00 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 105 to 117 | -100.00 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 118 to 130 | -100.00 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 131 to 143 | -100.00 Percent change in seizure frequency |
| Placebo (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks greater than or equal to 144 | -100.00 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 131 to 143 | -91.70 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 1 to 13 | -56.54 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 79 to 91 | -90.28 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 14 to 26 | -63.53 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 118 to 130 | -96.58 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 27 to 39 | -79.49 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 92 to 104 | -98.96 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 40 to 52 | -83.38 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks greater than or equal to 144 | -82.09 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 53 to 65 | -83.33 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 105 to 117 | -96.42 Percent change in seizure frequency |
| Perampanel (Core Study) | Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase) | Weeks 66 to 78 | -88.71 Percent change in seizure frequency |