Masashi Mizuguchi1, Hiroko Ikeda2, Kuriko Kagitani-Shimono3, Harumi Yoshinaga4, Yasuhiro Suzuki5, Makoto Aoki6, Masae Endo6, Masataka Yonemura6, Masaya Kubota7. 1. Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: mizuguchi-tky@umin.net. 2. Department of Pediatrics, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO, Shizuoka, Japan. 3. United Graduate School of Child Development, Osaka University, Osaka, Japan. 4. Department of Child Neurology, Okayama University Hospital, Okayama, Japan; Department of Severely Disabled Children Center, Minami Okayama Medical Center, Okayama, Japan. 5. Department of Pediatric Neurology, Osaka Women's and Children's Hospital, Osaka, Japan. 6. Novartis Pharma K.K, Tokyo, Japan. 7. Division of Neurology, National Center for Child Health and Development, Tokyo, Japan.
Abstract
BACKGROUND:Epilepsy and autism spectrum disorder (ASD) are the common neurological manifestations of tuberous sclerosis complex (TSC). EXIST-3 study has recently demonstrated that everolimus reduces seizures in patients with TSC and refractory epilepsy. Here we report the efficacy and safety of everolimus for treatment-refractory seizures in Japanese patients of EXIST-3, along with the exploratory analysis evaluating the everolimus effect on comorbid ASD symptoms in these patients. METHODS: Primary endpoint was change in seizure frequency from baseline defined as response rate (≥50% reduction) and median percentage reduction in the seizure frequency. Pervasive Developmental Disorders AutismSociety JapanRating Scale (PARS) scores were assessed at baseline and at week-18 for ASD symptoms. RESULTS: Overall, 35 Japanese patients were randomized to everolimus low-exposure (LE; n = 10), everolimus high-exposure (HE; n = 14), or placebo (n = 11). The response rate was 30.0% and 28.6% versus 0% with the everolimus LE and HE versus placebo arm, respectively. Similarly, the median percentage reduction in seizure frequency was 6.88% and 38.06% versus -6.67%. Stomatitis was the most frequently reported adverse event (everolimus LE, 100%; HE, 78.6%; placebo, 9.1%). Four of 11 patients with ASD in the everolimus arms and 1 of 8 patients with ASD in the placebo arm showed ≥5 point decrease in PARS scores. CONCLUSIONS:Adjunctive everolimus treatment improved seizure frequency with a tolerable safety relative to placebo among 35 Japanese patients with TSC-associated refractory seizures, consistent with the results of overall EXIST-3 study involving 366 patients. A favorable trend towards the improvement of ASD symptoms was observed.
RCT Entities:
BACKGROUND:Epilepsy and autism spectrum disorder (ASD) are the common neurological manifestations of tuberous sclerosis complex (TSC). EXIST-3 study has recently demonstrated that everolimus reduces seizures in patients with TSC and refractory epilepsy. Here we report the efficacy and safety of everolimus for treatment-refractory seizures in Japanese patients of EXIST-3, along with the exploratory analysis evaluating the everolimus effect on comorbid ASD symptoms in these patients. METHODS: Primary endpoint was change in seizure frequency from baseline defined as response rate (≥50% reduction) and median percentage reduction in the seizure frequency. Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores were assessed at baseline and at week-18 for ASD symptoms. RESULTS: Overall, 35 Japanese patients were randomized to everolimus low-exposure (LE; n = 10), everolimus high-exposure (HE; n = 14), or placebo (n = 11). The response rate was 30.0% and 28.6% versus 0% with the everolimus LE and HE versus placebo arm, respectively. Similarly, the median percentage reduction in seizure frequency was 6.88% and 38.06% versus -6.67%. Stomatitis was the most frequently reported adverse event (everolimus LE, 100%; HE, 78.6%; placebo, 9.1%). Four of 11 patients with ASD in the everolimus arms and 1 of 8 patients with ASD in the placebo arm showed ≥5 point decrease in PARS scores. CONCLUSIONS: Adjunctive everolimus treatment improved seizure frequency with a tolerable safety relative to placebo among 35 Japanese patients with TSC-associated refractory seizures, consistent with the results of overall EXIST-3 study involving 366 patients. A favorable trend towards the improvement of ASD symptoms was observed.
Authors: Maria Jimena Salcedo-Arellano; Ana Maria Cabal-Herrera; Ruchi Harendra Punatar; Courtney Jessica Clark; Christopher Allen Romney; Randi J Hagerman Journal: Neurotherapeutics Date: 2020-11-19 Impact factor: 7.620