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

Background Epilepsy occurs in 70-90% of patients with tuberous sclerosis complex. We aimed to assess the efficacy 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. Briefly, 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. Efficacy 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 efficacy 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 cutoff 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. Copyright (C) 2018 Elsevier Ltd. All rights reserved.