Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial

Jacqueline A French, Gregory L Krauss, Robert T Wechsler, Xue-Feng Wang, Bree DiVentura, Christian Brandt, Eugen Trinka, Terence J O'Brien, Antonio Laurenza, Anna Patten, Francesco Bibbiani, Jacqueline A French, Gregory L Krauss, Robert T Wechsler, Xue-Feng Wang, Bree DiVentura, Christian Brandt, Eugen Trinka, Terence J O'Brien, Antonio Laurenza, Anna Patten, Francesco Bibbiani

Abstract

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 up titrated 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 (238.4%vs 276.5%; p , 0.0001) and greater 50%PGTC seizure responder rate (39.5% vs 64.2%; p 5 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.

Figures

Figure 1. Patient disposition
Figure 1. Patient disposition
Figure 2. Median percent change in PGTC…
Figure 2. Median percent change in PGTC seizure frequency and 50% PGTC seizure responder rates
(A) Median percent change in seizure frequency per 28 days (full analysis set). (B) Fifty percent PGTC seizure responder rates (percentage of patients achieving ≥50% reduction in PGTC seizure frequency during maintenance vs baseline; full analysis set). *Versus placebo. PGTC = primary generalized tonic-clonic.

References

    1. Rheims S, Ryvlin P. Pharmacotherapy for tonic-clonic seizures. Expert Opin Pharmacother 2014;15:1417–1426.
    1. Hanada T, Yang H, Ido K, Laurenza A. AMPA Receptor Antagonists for the Treatment of CNS Disorders: Antiepileptics and Beyond. Frontiers in Clinical Drug Research (Volume 3): CNS and Neurological Disorders. Sharjah, UAE: Bentham Science Publishers; 2015:34–76.
    1. Durmuller N, Craggs M, Meldrum BS. The effect of the non-NMDA receptor antagonist GYKI 52466 and NBQX and the competitive NMDA receptor antagonist D-CPPene on the development of amygdala kindling and on amygdala-kindled seizures. Epilepsy Res 1994;17:167–174.
    1. Kodama M, Yamada N, Sato K, et al. Effects of YM90K, a selective AMPA receptor antagonist, on amygdala-kindling and long-term hippocampal potentiation in the rat. Eur J Pharmacol 1999;374:11–19.
    1. Wu T, Nagaya Y, Hanada T. Pharmacodynamic and pharmacokinetic interactions of perampanel and other antiepileptic drugs in a rat amygdala kindling model. Seizure 2014;23:732–739.
    1. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 2012;79:589–596.
    1. French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2013;54:117–125.
    1. Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408–1415.
    1. Steinhoff BJ, Ben-Menachem E, Ryvlin P, et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia 2013;54:1481–1489.
    1. European Medicines Agency. Fycompa summary of product characteristics. Available at: . Accessed August 7, 2015.
    1. Food and Drug Administration. Fycompa prescribing information. Available at: . Accessed August 7, 2015.
    1. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:489–501.
    1. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30:389–399.
    1. Berg AT, Millichap JJ. The 2010 revised classification of seizures and epilepsy. Continuum 2013;19:571–597.
    1. Holtkamp M, Kowski AB, Merkle H, Janz D. Long-term outcome in epilepsy with grand mal on awakening: forty years of follow-up. Ann Neurol 2014;75:298–302.
    1. Senf P, Schmitz B, Holtkamp M, Janz D. Prognosis of juvenile myoclonic epilepsy 45 years after onset: seizure outcome and predictors. Neurology 2013;81:2128–2133.
    1. Trinka E, Baumgartner S, Unterberger I, et al. Long-term prognosis for childhood and juvenile absence epilepsy. J Neurol 2004;251:1235–1241.
    1. Unterberger I, Trinka E, Luef G, Bauer G. Idiopathic generalized epilepsies with pure grand mal: clinical data and genetics. Epilepsy Res 2001;44:19–25.
    1. Höfler J, Unterberger I, Dobesberger J, Kuchukhidze G, Walser G, Trinka E. Seizure outcome in 175 patients with juvenile myoclonic epilepsy: a long-term observational study. Epilepsy Res 2014;108:1817–1824.
    1. Asadi-Pooya AA, Nikseresht A, Yaghoubi E, Nej M. Physical injuries in patients with epilepsy and their associated risk factors. Seizure 2012;21:165–168.
    1. Hesdorffer DC, Tomson T, Benn E, et al. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52:1150–1159.
    1. Hesdorffer DC, Tomson T, Benn E, et al. Do antiepileptic drugs or generalized tonic-clonic seizure frequency increase SUDEP risk? A combined analysis. Epilepsia 2012;53:249–252.
    1. Monte CP, Arends JB, Tan IY, Aldenkamp AP, Limburg M, de Krom MC. Sudden unexpected death in epilepsy patients: risk factors. A systematic review. Seizure 2007;16:1–7.
    1. Tomson T, Beghi E, Sundqvist A, Johannessen SI. Medical risks in epilepsy: a review with focus on physical injuries, mortality, traffic accidents and their prevention. Epilepsy Res 2004;60:1–16.
    1. Ryvlin P, Nashef L, Lhatoo SD, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 2013;12:966–977.
    1. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 2007;69:1751–1760.
    1. Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology 1999;52:1330–1337.
    1. Biton V, Sackellares JC, Vuong A, Hammer AE, Barrett PS, Messenheimer JA. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Neurology 2005;65:1737–1743.
    1. Biton V, Di Memmo J, Shukla R, et al. Adjunctive lamotrigine XR for primary generalized tonic-clonic seizures in a randomized, placebo-controlled study. Epilepsy Behav 2010;19:352–358.
    1. Trevathan E, Kerls SP, Hammer AE, Vuong A, Messenheimer JA. Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic-clonic seizures. Pediatrics 2006;118:e371–e378.
    1. Gelisse P, Genton P, Kuate C, Pesenti A, Baldy-Moulinier M, Crespel A. Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies. Epilepsia 2004;45:1282–1286.
    1. Genton P, Gelisse P, Thomas P, Dravet C. Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy? Neurology 2000;55:1106–1109.
    1. Thomas P, Valton L, Genton P. Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy. Brain 2006;129:1281–1292.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa