Article
Author: Moore, David ; Owen, Meriem Bensalem ; Krauss, Gregory L. ; Kalra, Arun ; Knowlton, Robert ; Herrman, Craig ; Morales, Sarug Reyes ; Lasso, Jorge ; Barroso, Noe ; Davis, Ronald ; Charlet, Michael ; Clement, Jean-Francois ; Cristalli, Diana ; Nieto, Flavia ; Thomson, Alfredo ; Goodpasture, Hewitt ; Ali, Imran ; Consalvo, Damián E. ; Jain, Sanjay ; Rodríguez, Ildefonso ; Biton, Victor ; Armstrong, Robert ; Shneker, Bassel ; Mitchell, Wendy ; Hwang, Paul ; Klein, Pavel ; Nofal, Pedro ; Flamini, J. ; Bautista, Ramon ; Enlow, Thomas ; Campanille, Verónica ; Kankirawatana, Pongkiat ; Ayala, Ricardo ; Renfroe, Ben ; Miller, John ; Zuin, Daniel ; Silva, Walter ; French, Jacqueline A. ; Lesch, David ; Krauss, Gregory ; Hogan, Robert ; Rogawski, Michael A. ; Squillacote, David ; Floridia, Jorge ; Halford, Jonathan ; Steiner, David ; Firstenfeld, Alfredo ; Modur, Pradeep ; Teasley, Jean ; Hernandez, Marcelo Leiva ; McLachlan, Richard ; Yang, Haichen ; Ferreira, Jose ; Yerby, Mark ; Webb, Randall ; Sosa, Veronica ; Aung-Din, Ronald ; Sperling, Michael ; Klapper, Jack ; Chung, Steve ; Elterman, Roy ; Brown, Lawrence ; Kumar, Dinesh ; Ilari, Rita ; Wheless, James ; Wilfong, Angus ; Pillay, Neelan ; Sfaello, Ignacio ; Pociecha, Juan ; Puri, Vinay ; Mesri, Jacobo ; Milian, Albino Contreras ; Miranda, Fernando ; Fessler, Albert ; Gruenthal, Michael ; Leroy, Robert ; Conry, Joan ; Szaflarski, Jerzy ; Laurenza, Antonio ; Tenhamm, Eugenio ; Brower, Richard ; Peralta, Balduin Lawson ; King-Stephens, David
OBJECTIVETo assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures.METHODSThis was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (≥12 years, with ongoing seizures despite 1-3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration.RESULTSOf 388 patients randomized and treated, 387 provided seizure frequency data. Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was -21.0%, -26.3%, and -34.5% for placebo and perampanel 8 and 12 mg, respectively (p = 0.0261 and p = 0.0158 for 8 and 12 mg vs placebo, respectively). Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p = 0.0760) or 12 mg (p = 0.0914). Sixty-eight (17.5%) patients discontinued, including 40 (10.3%) for adverse events. Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia.CONCLUSIONSThis trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures. Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable.CLASSIFICATION OF EVIDENCEThis study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures.