Adjunctive cenobamate in people with focal onset seizures: Insights from the Italian Expanded Access Program

Objective This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. Methods This was a retrospective study at 21 centers particip...

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Published in:	Epilepsia (Copenhagen) Vol. 65; no. 10; pp. 2909 - 2922
Main Authors:	Roberti, Roberta, Assenza, Giovanni, Bisulli, Francesca, Boero, Giovanni, Canafoglia, Laura, Chiesa, Valentina, Di Bonaventura, Carlo, Di Gennaro, Giancarlo, Elia, Maurizio, Ferlazzo, Edoardo, Giordano, Alfonso, La Neve, Angela, Liguori, Claudio, Meletti, Stefano, Operto, Francesca Felicia, Pietrafusa, Nicola, Puligheddu, Monica, Pulitano, Patrizia, Rosati, Eleonora, Sammarra, Ilaria, Tartara, Elena, Vatti, Giampaolo, Villani, Flavio, Bartalini, Sabina, Calabrese, Costanza, Irelli, Emanuele Cerulli, Coa, Roberta, Didato, Giuseppe, Falcicchio, Giovanni, Fernandes, Mariana, Fortunato, Francesco, Frangiosa, Renato, Fronzoni, Edoardo, Lomonaco, Domenico, Matrullo, Roberto, Micalizzi, Elisa, Morano, Alessandra, Muccioli, Lorenzo, Panzini, Chiara, Pascarella, Angelo, Ricci, Emilia, Salimbene, Licia, Tombini, Mario, Vaudano, Anna Elisabetta, Russo, Emilio, Lattanzi, Simona
Format:	Journal Article
Language:	English
Published:	United States Wiley Subscription Services, Inc 01-10-2024
Subjects:	antiseizure medication cenobamate clobazam Convulsions & seizures drug daily dose Epilepsy focal seizures Pharmacokinetics Seizures Statistical analysis epilepsy focal seizures antiseizure medication clobazam drug daily dose cenobamate
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Summary:	Objective This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. Methods This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses. Results A total of 236 subjects with a median age of 38 (Q1–Q3 = 27–49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1–Q3 = 2.50–4.47) at baseline to 2.50 (Q1–Q3 = 1.67–3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ‐aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel. Significance Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult‐to‐treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam.
Bibliography:	Cenobamate Expanded Access Program Italy Study Group: Sabina Bartalini: UOC Neurology and Clinical Neurophysiology, University Hospital of Siena, Siena, Italy; Costanza Calabrese: Clinical and Experimental Neurology, full member of European Reference Network EpiCARE, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Emanuele Cerulli Irelli: Department of Human Neurosciences, Sapienza University, Rome, Italy; Roberta Coa: Epilepsy Center, Neurology Unit AOU, Cagliari, Italy; Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Alfredo D'Aniello: IRCCS NEUROMED, Pozzilli, Italy; Giuseppe Didato: Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Costanza Calabrese: Science of Health Department, Magna Graecia University, Catanzaro, Italy; Giovanni Falcicchio: “FM Puca” Neurology Unit, University Hospital Consortium Corporation Polyclinic of Bari, Bari, Italy; DiBraiN Department, University of Bari “A. Moro,” Bari, Italy; Mariana Fernandes: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Francesco Fortunato: Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Renato Frangiosa: Department of Human Neurosciences, Sapienza University, Rome, Italy; Edoardo Fronzoni: Department of Neurosciences, Psychology, Drug Research, and Child Health (NEUROFARBA), Neurosciences Section, University of Florence, Florence, Italy; Domenico Lomonaco: Department of Brain and Behavioral Sciences, University of Pavia, IRCCS Mondino Foundation, Pavia, Italy; Roberto Matrullo: Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli,” Naples, Italy; Elisa Micalizzi: Division of Clinical Neurophysiology and Epilepsy Center, IRCCS Policlinico San Martino, Genoa, Italy; Alessandra Morano: Department of Human Neurosciences, Sapienza University, Rome, Italy; Lorenzo Muccioli: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, full member of the European Reference Network EpiCARE, Bologna, Italy; Chiara Panzini: IRCCS NEUROMED, Pozzilli, Italy; Angelo Pascarella: Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Great Metropolitan Bianchi‐Melacrino‐Morelli Hospital, Reggio Calabria, Italy; Pier Paolo Quarato: IRCCS NEUROMED, Pozzilli, Italy; Emilia Ricci: Epilepsy Center, ASST Santi Paolo Carlo, Milan, Italy; Department of Health Sciences, Università degli Studi di Milano, Milan, Italy; Licia Salimbene: Clinical and Experimental Neurology, full member of European Reference Network EpiCARE, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Mario Tombini: Research Unit of Neurology, Department of Medicine and Surgery, Università Campus Bio‐Medico, Rome, Italy; Operative Research Unit of Neurology, Fondazione Policlinico Universitario Campus Bio‐Medico, Rome, Italy; Anna Elisabetta Vaudano: Neurophysiology Unit and Epilepsy Center, AOU Modena, Italy; Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena and Reggio Emilia, Italy. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0013-9580 1528-1167 1528-1167
DOI:	10.1111/epi.18091