Abstract
Perampanel for Tonic–Clonic Seizures in Idiopathic Generalized Epilepsy: A Randomized Trial
French JA, Krauss GL, Wechsler RT, Wang XF, DiVentura B, Brandt C, Trinka E, O'Brien TJ, Laurenza A, Patten A, Bibbiani F. Neurology 2015;85:950–957.
OBJECTIVE: To assess efficacy and safety of adjunctive perampanel in patients with drug-resistant, primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE). METHODS: In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743; funded by Eisai Inc.), patients 12 years or older with PGTC seizures and IGE were randomized to placebo or perampanel during a 4-week titration period (perampanel uptitrated from 2 to 8 mg/d, or highest tolerated dose) and 13-week maintenance period. The primary endpoint was percent change in PGTC seizure frequency per 28 days (titration plus maintenance vs baseline). The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving ≥50% reduction in PGTC seizure frequency; maintenance vs baseline). Treatment-emergent adverse events were monitored. RESULTS: Of 164 randomized patients, 162 comprised the full analysis set (placebo, 81; perampanel, 81). Compared with placebo, perampanel conferred a greater median percent change in PGTC seizure frequency per 28 days (−38.4% vs −76.5%; p < 0.0001) and greater 50% PGTC seizure responder rate (39.5% vs 64.2%; p = 0.0019). During maintenance, 12.3% of placebo-treated patients and 30.9% of perampanel-treated patients achieved PGTC seizure freedom. For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%). CONCLUSIONS: Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE.
Commentary
Idiopathic generalized epilepsy syndromes are presumably genetic and manifested by multiple seizure types, including primary generalized tonic–clonic, absence, and myoclonic seizures. Primary generalized tonic–clonic seizures may precipitate numerous adverse outcomes, such as seizure-related injuries and SUDEP. The primary treatment of these seizures is antiepileptic drug (AED) therapy. In contrast to focal seizures, surgical therapies. Unfortunately, even though AED therapy is the mainstay of treatment, AED options are limited. Since 1993, 15 AEDs have been approved in the United States, and yet among these new generation AEDs, only three—lamotrigine, levetiracetam, and topiramate—have received approval for the treatment of primary generalized tonic–clonic seizures. These AEDs have all demonstrated efficacy in randomized double-blind, placebo-controlled trials of adjunctive treatment for drug resistant primary generalized tonic–clonic seizures (1). Evidence also supports the use of valproic acid (1). Clearly, we need more options to treat refractory generalized tonic–clonic seizures in idiopathic generalized epilepsy. Perampanel, as reported by French and colleagues, is a promising option as adjunctive therapy.
Perampanel, a noncompetitive α-amino-3hydroxy-5-methy-4-isoxazole-propionic acid (AMPA) receptor antagonist, is structurally novel, and has been studied extensively in both preclinical studies and in clinical trials of focal seizures (2). It has antiepileptic properties in multiple animal models of seizures and epilepsy including in the rat amygdala kindling model. Efficacy in this model suggests that perampanel may be able to treat primary generalized seizures. Both blinded short-term and open-label long-term extension trials have revealed significant reductions in focal seizures in doses ranging from 4 to 12 mg per day. Reported adverse events in these trials include dizziness, somnolence, and neuropsychiatric disturbances.
Perampanel as adjunctive therapy for treatment of drug resistant primary generalized tonic–clonic seizures in adults and adolescents with refractory idiopathic generalized epilepsy was investigated in a multicenter, international, double-blind, placebo-controlled, parallel-group study. Eligible subjects included patients aged 12 and older diagnosed with primary generalized tonic–clonic seizures and idiopathic epilepsy who had ≥ three primary generalized tonic–clonic seizures during baseline and were taking one to three approved AEDs. Diagnoses were confirmed by independent reviewers and were based on age at onset, EEG data, IQ, MRI, and seizure descriptions. After randomization, the study was divided into three periods: titration, maintenance, and follow-up. The goal dose of perampanel was 8 mg/day or the highest tolerated dose. The primary efficacy endpoint was the percent change in primary generalized tonic–clonic seizure frequency per 28 days (titration and maintenance vs baseline). The key secondary endpoint was 50% primary generalized tonic–clonic seizure responder rate (percentage of patients achieving ≥ 50% reduction of primary generalized tonic–clonic seizure frequency during maintenance vs baseline). Of 307 patients screened, 143 were not included, primarily because they did not meet inclusion criteria, such as misdiagnosis or insufficient evidence to confirm diagnosis. One hundred sixty-three subjects were randomized; 82 to the placebo group and 81 to perampanel. Baseline characteristics were similar between the groups. Perampanel treatment resulted in a significantly greater median percent reduction in primary generalized tonic–clonic seizure frequency per 28 days (76.5% vs 38.4%; p < 0.0001). As well, perampanel had a greater 50% responder rate (64.2% vs 39.5%; p = 0.0019). Seizure freedom was obtained in 30.9% of perampanel treated patients compared to 12.3% of placebo treated subjects. Perampanel treatment was associated with dizziness (32.1%) and fatigue (14.8%). Prior studies reported high percentages of irritability at higher doses. In the perampanel-treated group, irritability was reported in 9% of subjects compared to 2% of the placebo group.
The results of this randomized controlled study support the efficacy (class I evidence) of perampanel as adjunctive therapy for the treatment of primary generalized tonic–clonic seizures for subjects with idiopathic epilepsy. As perampanel has a novel mechanism, these results provide another option and hope for patients with refractory primary generalized tonic–clonic seizures. In clinical practice, treating persons with refractory primary generalized tonic–clonic seizures is extremely disheartening. Many of these patients begin having seizures during the vulnerable period of adolescence, and their education and social development are often significantly impacted. Studies demonstrate that seizure freedom is the most significant factor that improves quality of life and contributes to whether patients perceive themselves as disabled, yet for patients with idiopathic generalized epilepsy, we have so few options to successfully treat their seizures (3). Perampanel as adjunctive therapy is now another option.
In addition to the results, another significant point of this study is how the investigators defined study eligibility. Idiopathic generalized epilepsy is as previously mentioned a presumably genetic form of epilepsy characterized by seizure-type presentation, abnormal EEG, MRI, and IQ. When studying different aspects of idiopathic generalized epilepsy, including response to medication, it is important to include a well-defined group. Prior studies have not been as stringent in their definition, often rendering the results difficult to interpret with limited generalizability. By using multiple criteria to define idiopathic generalized epilepsy and eliminating subjects who do not meet the predefined criteria, these results are more generalizable to other subjects with refractory idiopathic generalized epilepsy. This methodology should be included in future studies of idiopathic generalized epilepsy.
The side effects found in this study were similar to prior studies in patients with refractory focal seizures. Following those studies, a black box warning was released in 2012 by the FDA, alerting practitioners and patients about the risk of serious neuropsychiatric events, including irritability, aggression, anger, anxiety, paranoia, euphoric mood, agitation, and mental status changes (4). In this study, irritability was seen more commonly in perampanel-treated patients when compared to the placebo group. A dose-dependent effect is likely, as in this study, most side effects resolved after reducing the dose. Among the nine patients who discontinued the study because of side effects, five were because of psychiatric disorders. Practitioners need to be aware of these effects and counsel patients appropriately; they are, however, more common at higher doses.
Perampanel, as evidenced by the results of this study by French et al., is a novel antiepileptic agent that is effective in the treatment of refractory generalized tonic–clonic seizures in idiopathic epilepsy. We do not, however, know its effects on the treatment of other seizure types associated with idiopathic generalized epilepsy. Future studies will hopefully elucidate whether this drug is effective against all seizure types associated with idiopathic generalized epilepsy syndromes.