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(Abst. 2.389), 2014

ADJUNCTIVE PERAMPANEL (PER) FOR TREATMENT OF DRUG-RESISTANT PRIMARY GENERALIZED TONIC-CLONIC (PGTC) SEIZURES IN PATIENTS (PTS) WITH IDIOPATHIC GENERALIZED EPILEPSY (IGE): A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE III TRIAL
Authors: Jacqueline French, Gregory Krauss, Robert Wechsler, Xuefeng Wang, Bree DiVentura, Christian Brandt, Eugen Trinka, Terence O'Brien, Antonio Laurenza, Anna Patten and Francesco Bibbiani
Content: Rationale: There are limited PGTC seizure treatments. PER, a selective noncompetitive AMPA receptor antagonist, is approved in 35+ countries for adjunctive treatment of partial-onset seizures (POS) with or without secondarily generalized (SG) seizures in epilepsy pts ≥12 years (≥18 years in Canada). Post-hoc pooled analyses of pivotal Phase III trial data suggested a potential efficacy for PER in SG seizures. Our study assessed the efficacy and safety of PER for adjunctive treatment of PGTC seizures in IGE pts. Methods: Pts (≥12 years; IGE confirmed by external Epilepsy Study Consortium review; ≥3 PGTC seizures in the 8 weeks prior to randomization; fixed doses of 1-3 concomitant antiepileptic drugs for ≥30 days prior to Baseline) were recruited from 78 sites in 16 countries. This trial (NCT01393743, Study 332) had Pre-randomization (4-week screening; Baseline 4-8 weeks), Randomization (1:1 PER or placebo followed by 4-week Titration, 13-week Maintenance, 4-week Follow-up) and Extension Phases. During Titration, pts received 2 mg/day PER or placebo followed by weekly 2-mg increases to 8 mg/day or maximum-tolerated dose. Pts entered Maintenance on their last dose level. The primary efficacy endpoints were percent change from Baseline in PGTC seizure frequency per 28 days and 50% responder rate (≥50% reduction in PGTC seizure frequency during Maintenance vs Baseline). All adverse events (AEs) were recorded. Covariance analysis was conducted on percent change data and responder rates were analyzed by Cochran-Mantel-Haenszel test. Results: Of 164 pts randomized, the full analysis set (≥1 dose; any post-Baseline seizure frequency data) included 81 pts on PER and 81 on placebo. Median percent change in PGTC seizure frequency per 28 days during Titration and Maintenance vs Baseline was greater with PER than placebo (-76.5% vs -38.4%; P<0.0001). The 50% PGTC responder rate was also higher with PER than placebo (64.2% vs 39.5%; P=0.0019). During Maintenance, 30.9% PER pts were free of tonic-clonic (TC) seizures and 23.5% free of all seizures (12.3% and 4.9% for placebo). For the Safety Set (n=163; ≥1 dose; any post-Baseline safety assessments), treatment-emergent AEs (TEAEs) occurred in 82.7% PER and 72.0% placebo pts. AEs reported for ≥10% more PER vs placebo pts were dizziness (32.1% vs 6.1%), fatigue (14.8% vs 6.1%), headache (12.3% vs 9.8%), somnolence (11.1% vs 3.7%), and irritability (11.1% vs 2.4%). Two PER and no placebo pts had serious TEAEs (1 suicidal ideation; 1 suicide attempt). There was one PER death (accidental drowning not treatment-related) and one placebo death (sudden unexpected death in epilepsy). Conclusions: Adjunctive treatment with PER up to 8 mg improved seizure control in IGE pts aged ≥12 years with inadequately controlled PGTC seizures. Almost a third of PER pts were free of TC seizures during Maintenance. PER was well tolerated with a safety profile similar to refractory POS. Support: Eisai Inc.