D'Onofrio Gianluca, Kuchenbuch Mathieu, Hachon-Le Camus Caroline, Desnous Béatrice, Staath Véronique, Napuri Sylvia, Ville Dorothée, Pedespan Jean-Michel, Lépine Anne, Cances Claude, de Saint-Martin Anne, Teng Théo, Chemaly Nicole, Milh Mathieu, Villeneuve Nathalie, Nabbout Rima
Department of Pediatric Neurology, Reference Centre for Rare Epilepsies, Hôpital Necker-Enfants Malades, APHP, Paris, France.
Pediatric Residency, Department of Women and Child Health, University of Padua, Padua, Italy.
Front Neurol. 2020 Aug 12;11:829. doi: 10.3389/fneur.2020.00829. eCollection 2020.
To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice. We conducted a prospective, open-label, multicenter study in seven French reference centers for rare epilepsies. Patients had slow titration to reach a target dose of 10 mg/kg/day within at least 1 month and then gradually increased to a maximum dose of 20 mg/kg/day. We analyzed AEs and efficacy at M1 (month 1), M2, and M6, comparing two sets of subgroups: Dravet syndrome (DS) vs. Lennox-Gastaut (LGS) and patients with clobazam (CLB+) vs. patients without (CLB-). One hundred and twenty-five patients were enrolled (62 LGS, 48 DS, 5 Tuberous sclerosis, and 10 other etiologies). Median concomitant antiepileptic drugs (AEDs) was three (25th percentile: 3, 75th percentile: 4). Patients received a dose of 10 (10-12), 14 (10-20), and 15.5 mg/kg/day (10-20) at M1, M2, and M6, respectively. Twenty-six patients discontinued CBD, 19 due to lack of efficacy, 2 due to AEs, 4 for both, and 1 had a sudden unexpected death in epilepsy. AEs were reported in 61 patients (48.8%), mainly somnolence ( = 26), asthenia ( = 20), and behavior disorders ( = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 ( = 0.03) and increased with the number of AEDs ( = 0.03). At M6, total seizure frequency change from baseline was -41% ± 37.5% (mean ± standard deviation), and 28 patients (37.8%) had a reduction ≥50%. AE and efficacy did not differ between DS vs. LGS and CLB+ vs. CLB- patients. A slower titration of CBD dose delivered better tolerance with comparable efficacy to previous trials. Concomitant CLB did not increase efficacy rates but in a few cases increased AEs. This slow titration scheme should help guide clinicians prescribing CBD and allow patients to benefit from its potential efficacy.
在儿科临床实践中，采用较慢滴定方案评估添加大麻二酚（CBD）的不良事件（AE）和疗效。我们在法国七个罕见癫痫参考中心进行了一项前瞻性、开放标签、多中心研究。患者以较慢的滴定速度在至少1个月内达到目标剂量10mg/kg/天，然后逐渐增加至最大剂量20mg/kg/天。我们分析了第1个月（M1）、第2个月和第6个月时的不良事件和疗效，比较了两组亚组：德雷维特综合征（DS）与伦诺克斯 - 加斯托综合征（LGS），以及使用氯巴占的患者（CLB +）与未使用氯巴占的患者（CLB -）。共纳入125例患者（62例LGS、48例DS、5例结节性硬化症和10例其他病因）。抗癫痫药物（AED）的中位数为3种（第25百分位数：3，第75百分位数：4）。患者在M1、M2和M6时分别接受的剂量为10（10 - 12）、14（10 - 20）和15.5mg/kg/天（10 - 20）。26例患者停用CBD，19例因无效，2例因不良事件，4例两者皆有，1例在癫痫发作时突然意外死亡。61例患者（48.8%）报告了不良事件，主要是嗜睡（n = 26）、乏力（n = 20）和行为障碍（n = 16）。11例同时接受丙戊酸盐和氯巴占治疗的患者报告了转氨酶异常（≥3倍）。不良事件在M₂时显著更高（P = 0.03），并随AED数量增加而增加（P = 0.03）。在M6时，总发作频率相对于基线的变化为 - 41% ± 37.5%（平均值 ± 标准差），28例患者（37.8%）发作减少≥50%。DS与LGS患者以及CLB +与CLB -患者之间的不良事件和疗效无差异。CBD剂量的较慢滴定带来了更好的耐受性，疗效与先前试验相当。同时使用氯巴占并未提高有效率，但在少数情况下增加了不良事件。这种缓慢滴定方案应有助于指导临床医生开具CBD处方，并使患者受益于其潜在疗效。
