www.thelancet.com/child-adolescent Published online May 23, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30099-3 1 Articles Lancet Child Adolesc Health 2018 Published Online May 23, 2018 http://dx.doi.org/10.1016/ S2352-4642(18)30099-3 See Online/Comment http://dx.doi.org/10.1016/ S2352-4642(18)30128-7 Tor Vergata University Hospital, Rome, Italy (Prof P Curatolo MD); Department of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA (Prof D N Franz MD); Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children’s Hospital, Sydney, NSW, Australia (J A Lawson MD); Division of Child Neurology, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey (Prof Z Yapici MD); National Hospital Organization Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan (H Ikeda MD); Paediatric Epileptology, Mara Hospital, Bethel Epilepsy Center, Bielefeld, Germany (T Polster MD); Hospital Necker-Enfants Malades, Paris Descartes University, Paris, France (R Nabbout MD); Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa (Prof P J de Vries PhD); Departments of Neurology and Pediatrics, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA (D J Dlugos MD); Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (J Fan MD, D Pelov MS, M Voi MD); Novartis Pharmaceuticals SAS, Paris,France (A Ridolfi MS); and Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial Paolo Curatolo, David N Franz, John A Lawson, Zuhal Yapici, Hiroko Ikeda, Tilman Polster, Rima Nabbout, Petrus J de Vries, Dennis J Dlugos, Jenna Fan, Antonia Ridolf, Diana Pelov, Maurizio Voi, Jacqueline A French Summary Background Epilepsy occurs in 70–90% of patients with tuberous sclerosis complex. We aimed to assess the efcacy and safety of adjunctive everolimus for treatment-refractory seizures associated with tuberous sclerosis complex in paediatric patients enrolled in the EXIST-3 trial, a double-blind, placebo-controlled, randomised, phase 3 study. Methods This post-hoc analysis focused on paediatric patients (age <18 years) in the EXIST-3 trial, which consisted of baseline (8 weeks), core (18 weeks), and extension phases (≥48 weeks) and was done at 99 centres in 25 countries worldwide. Briefy, patients with tuberous sclerosis complex-associated treatment-refractory seizures, who were receiving a stable dose of one to three antiepileptic drugs, were randomly assigned (1:1:1) to receive placebo, low-exposure everolimus (3–7 ng/mL), or high-exposure everolimus (9–15 ng/mL). Following the core phase, patients could enter the extension phase to receive everolimus at a targeted exposure range of 3–15 ng/mL up to 48 weeks after the last patient had completed the core phase. Efcacy endpoints were response rate (≥50% of reduction from baseline in average weekly seizure frequency) and median percentage reduction in seizure frequency during the 12-week maintenance period of the core phase, and at 12-week intervals throughout the extension phase. This study is registered with ClinicalTrials.gov, number NCT01713946. Findings Between July 3, 2013, and May 29, 2015, 299 paediatric patients enrolled in the trial. In the younger subgroup (<6 years; n=104), 34 received placebo, 33 low-exposure everolimus, and 37 high-exposure everolimus; in the older subgroup (≥6 years to <18 years; n=195), 62 received placebo, 63 low-exposure everolimus, and 70 high-exposure everolimus. At the end of the core phase, response rate was higher in the treatment groups than placebo in both the younger subgroup (17·6% [6·8–34·5] for placebo vs 30·3% [95% CI 15·6–48·7; p=0·2245] for low-exposure everolimus vs 59·5% [42·1–75·2; p=0·0003] for high-exposure everolimus) and the older subgroup (12·9% [5·7–23·9] vs 27·0% [16·6–39·7; p=0·0491] vs 30·0% [19·6–42·1; p=0·0179]), as were median reduction in seizure frequency (12·3% [95% CI −10·1 to 24·8] vs 29·3% [95% CI 13·4 to 46·3; p=0·0474] vs 54·7% [43·5 to 73·1; p<0·0001] in younger patients; 13·5% [−3·0 to 26·8] vs 31·0% [16·1 to 42·9; p=0·0128] vs 34·8% [26·7 to 41·3; p=0·0006] in older patients). The efcacy persisted, with sustained seizure reduction after 1 year of treatment across both paediatric subgroups (response rate 48·9% [95% CI 38·1–59·8] for the younger subgroup vs 47·2% [39·3–55·2] for the older subgroup; median percentage reduction in seizure frequency 48·4% [95% CI 34·3–73·6] vs 48·0% [38·2–57·5]). At the cutof date for the extension phase, grade 3 or 4 adverse events were reported in 45 (45%) younger patients (commonly pneumonia [n=16]) and 74 (38%) older patients (commonly pneumonia [n=8] and stomatitis [n=6]). Two deaths (pneumonia, which was suspected to be treatment- related, and sudden unexplained death due to epilepsy) were reported. Interpretation Adjunctive everolimus resulted in sustained reductions in seizure frequency after 1 year and was well tolerated in paediatric patients with treatment-refractory seizures associated with tuberous sclerosis complex. Funding Novartis Pharmaceuticals Corporation. Copyright © 2018 Elsevier Ltd. All rights reserved. Introduction Epilepsy is the most common presenting feature of tuberous sclerosis complex, afecting 70–90% of pa- tients. 1–4 The onset of seizures occurs within the frst year of life in roughly 60% of patients, and can even be observed in the neonatal period. 1–5 Adults with tuberous sclerosis complex without a history of seizures continue to be at risk (12%) for developing seizures in later years. 1 Furthermore, patients with tuberous sclerosis complex have an 84–92% chance of having at least one seizure during their lifetime. 6 Early seizure onset is associated with an increased risk of refractory epilepsy, as well as