Clinical trial NCT01393743: A Efficacy and Safety Study of Adjunctive Perampanel in Primary Generalized Tonic Clonic Seizures
Official title: A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Adjunctive Perampanel in Primary Generalized Tonic Clonic Seizures
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Seizure Disorder Generalized Tonic Clonic
Keywords: Central Nervous System
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2011-07-13
Enrollment: 163
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: 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)
timeFrame: Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
measure: 50% Responder Rate for Primary Generalized Tonic Clonic Seizure During Maintenance - LOCF - (for Core Study)
timeFrame: Baseline (4 or 8 weeks) and Maintenance (13 weeks)
measure: 50% Responder Rate in Primary Generalized Tonic-Clonic Seizure Frequency Per 28 Days Relative to the Core Study Prerandomization Phase - (for Extension Phase)
timeFrame: Week 1 of perampanel treatment to date of last dose of perampanel in the Extension Phase
Secondary outcomes:
measure: Median Percent Change in All Seizure Frequency Per 28 Days During the Titration and Maintenance Periods (Combined) Relative to Baseline (Prerandomization) - (for Core Study)
timeFrame: Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
measure: 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)
timeFrame: Baseline (4 or 8 weeks), Titration (4 weeks), and Maintenance (13 weeks)
measure: 50% Responder Rate for All Seizures During Maintenance-LOCF - (for Core Study)
timeFrame: Baseline (4 or 8 weeks) and Maintenance (13 weeks)
measure: 50% Responder Rate for Primary Generalized Seizure Subtype During Maintenance Period - LOCF - (for Core Study)
timeFrame: Baseline (4 or 8 weeks) and Maintenance (13 weeks)
measure: Percent Change From Core Study Prerandomization Phase in Primary Generalized Tonic-Clonic (PGTC) Seizure Frequency Per 28 Days - (for Extension Phase)
timeFrame: Date of first dose of study drug to date of last dose of study drug in the Extension Phase
measure: Summary of Percent Change From Pre-Perampanel Baseline in Seizure Frequency Per 28 Days - (for Extension Phase)
timeFrame: 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
measure: 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)
timeFrame: 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.
Other outcomes:
Locations:
Study officials:
affiliation: Eisai Inc.
name: Francesco Bibbiani
role: STUDY_DIRECTOR
References:
citation: Kerr WT, Brandt C, Ngo LY, Patten A, Cheng JY, Kramer L, French JA. Time to exceed pre-randomization monthly seizure count for perampanel in participants with primary generalized tonic-clonic seizures: A potential clinical end point. Epilepsia. 2022 Nov;63(11):2994-3004. doi: 10.1111/epi.17411. Epub 2022 Sep 30.
citation: French JA, Krauss GL, Wechsler RT, Wang XF, DiVentura B, Brandt C, Trinka E, O'Brien TJ, Laurenza A, Patten A, Bibbiani F. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial. Neurology. 2015 Sep 15;85(11):950-7. doi: 10.1212/WNL.0000000000001930.