A multivariable prediction model of a major treatment response for focal-onset seizures: A post-hoc analysis of Phase III trials of perampanel

• Published in: Epilepsy research 2021-08, Vol.174, p.106649-106649, Article 106649
• Main Authors: Krauss, Gregory L., Ben-Menachem, Elinor, Wechsler, Robert T., Patten, Anna, Williams, Betsy, Laurenza, Antonio, Malhotra, Manoj
• Format: Article
• Language: English
• Subjects: adjunctive perampanel; Anticonvulsants - therapeutic use; Antiepileptic drugs; childhood; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Therapy, Combination; drugs; Epilepsy; Focal-onset seizures; Humans; intractability; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; Nitriles; people; Perampanel; Predictive factors; prognosis; Pyridones - therapeutic use; Quality of Life; remission; risk; Seizures - diagnosis; Seizures - drug therapy; sudden unexpected death; Treatment Outcome; Treatment response
• ISSN: 0920-1211; 1872-6844
• DOI: 10.1016/j.eplepsyres.2021.106649

•Patients with focal-onset seizures may exhibit resistance to antiepileptic drugs.•Analyses identified predictive factors of a major response to placebo/perampanel.•Baseline FBTC seizures and low baseline seizure frequency were predictive factors.•Higher perampanel plasma concentration was also a predictive factor.•The findings may help to guide clinicians when optimizing patients’ treatment. Although 50 % reduction in seizure frequency is a common efficacy endpoint in clinical trials of antiepileptic drugs (AEDs), 75 % or greater reductions may be required to improve patients’ health-related quality of life. Identification of clinical factors that are associated with high responder rates may help to inform clinicians on which patients may optimally benefit from treatment. We evaluated potential predictive factors for achieving major treatment responses (≥75 % reduction in seizure frequency per 28 days from study baseline) in patients with drug-resistant focal-onset seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures in perampanel trials designed for regulatory approval. Univariate analyses using logistic regression were performed using data from three double-blind, placebo-controlled Phase III studies of adjunctive perampanel (Studies 304 [NCT00699972], 305 [NCT00699582], 306 [NCT00700310]), and their open-label extension study (OLEx; Study 307 [NCT00735397]). For the double-blind studies, baseline seizure frequency, number of baseline AEDs, baseline seizure type, baseline concomitant enzyme-inducing AEDs (EIAEDs), baseline carbamazepine, lamotrigine, or valproic acid, age at diagnosis, time since diagnosis, etiology, and perampanel plasma concentration were included individually with study treatment. The same factors were included for the OLEx analysis except for plasma concentration and treatment. Variables found to be significant predictors for a major treatment response in univariate analyses were subsequently included in multivariable analyses using backwards and forwards selection. In the double-blind studies, 175/1374 patients had a major response to placebo (n = 25) or perampanel (n = 150). The best predictors of a major treatment response in multivariable models with forwards and backwards selection were: the presence of FBTC seizures during baseline (P = 0.0002), higher perampanel plasma concentration (P < 0.0001), older age at diagnosis (P = 0.0024 and 0.0045, respectively), and lower baseline seizure frequency (P = 0.0364 an