Sullivan, J.Gunning, B.Zafar, M.Guerrini, R.Gecz, J.Kolc, K.L.Zhao, Y.Gasior, M.Aimetti, A.A.Samanta, D.2024-08-132024-08-132023Epilepsy Research, 2023; 191:107112-1-107112-70920-12111872-6844https://hdl.handle.net/2440/141894Introduction: Protocadherin-19 (PCDH19)-clustering epilepsy is a distinct developmental and epileptic encephalopathy characterized by early-onset seizures that are often treatment refractory. Caused by a mutation of the PCDH19 gene on the X chromosome, this rare epilepsy syndrome primarily affects females with seizure onset commonly in the first year of life. A global, randomized, double-blind, placebo-controlled, phase 2 trial was conducted to evaluate the efficacy, safety, and tolerability of ganaxolone compared with placebo as adjunctive therapy to a standard antiseizure medication regimen in patients with PCDH19-clustering epilepsy (VIOLET; NCT03865732). Methods: Females aged 1–17 years with a molecularly confirmed pathogenic or likely pathogenic PCDH19 variant who were experiencing ≥12 seizures during a 12-week screening period were stratified by baseline allopregnanolone sulfate (Allo-S) levels (low: ≤2.5 ng/mL; high: >2.5 ng/mL) at screening and randomized 1:1 within each strata to receive ganaxolone (maximum daily dose of 63 mg/kg/day if ≤28 kg or 1800 mg/day if >28 kg) or matching placebo in addition to their standard antiseizure treatment for the 17-week double-blind phase. The primary efficacy endpoint was the median percentage change in 28-day seizure frequency from baseline to the 17-week double-blind phase. Treatment-emergent adverse events (TEAEs) were tabulated by overall, system organ class, and preferred term. Results: Of the 29 patients screened, 21 (median age, 7.0 years; IQR, 5.0–10.0 years) were randomized to receive either ganaxolone (n = 10) or placebo (n = 11). After the 17-week double-blind phase, the median (IQR) percentage change in 28-day seizure frequency from baseline was − 61.5% (− 95.9% to − 33.4%) among patients in the ganaxolone group and − 24.0% (− 88.2% to − 4.9%) among patients in the placebo group (Wilcoxon ranksum test, p = 0.17). TEAEs were reported by 7 of 10 (70.0%) patients in the ganaxolone group and 11 of 11 (100%) patients in the placebo group. Somnolence was the most common TEAE (40.0% ganaxolone vs 27.3% placebo); serious TEAEs were more common in the placebo group (10.0% ganaxolone vs 45.5% placebo); and 1 (10.0%) patient in the ganaxolone group discontinued the study versus none in the placebo group. Conclusions: Ganaxolone was generally well tolerated and led to a greater reduction in the frequency of PCDH19- clustering seizures compared to placebo; however, the trend did not reach statistical significance. Novel trial designs are likely needed to evaluate the effectiveness of antiseizure treatments for PCDH19-clustering epilepsy.en© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Seizures; Pediatric; Safety; Encephalopathy; GanaxoloneHumansEpilepsy, GeneralizedSeizuresPregnanoloneAnticonvulsantsTreatment OutcomeCluster AnalysisChildFemaleProtocadherinsJournal article10.1016/j.eplepsyres.2023.1071122024-02-28636613Gecz, J. [0000-0002-7884-6861]Kolc, K.L. [0000-0001-6247-5544]