Objective: To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice. Methods: 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-). Results: 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 (n = 26), asthenia (n = 20), and behavior disorders (n = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 (p = 0.03) and increased with the number of AEDs (p = 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. Significance: 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.

中文翻译：

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在开放标签研究中，缓慢滴定抗药性癫痫中卡那比二醇的添加量可以提高安全性，并保持疗效。

目的：在儿科临床实践中以较慢的滴定方案评估不良事件（AEs）和附加大麻素（CBD）的疗效。方法：我们在法国的七个罕见癫痫病参考中心进行了一项前瞻性，开放标签，多中心研究。患者需缓慢滴定以在至少1个月内达到目标剂量10 mg / kg /天，然后逐渐增加至最大剂量20 mg / kg /天。我们分析了M1，M1（第1个月），M2和M6的AE和疗效，比较了两组亚组：Dravet综合征（DS）与Lennox-Gastaut（LGS）以及患有Clobazam的患者（CLB +）与未治疗的患者（CLB- ）。结果：招募了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）。中位数同时使用的抗癫痫药（AED）为3（第25个百分点：3，第75个百分点：4）。患者分别在M1，M2和M6分别接受10（10-12），14（10-20）和15.5 mg / kg /天（10-20）的剂量。26例患者停用CBD，其中19例由于缺乏疗效而停药，2例由于AEs，两者均4例，1例癫痫猝死。据报道有61名患者（48.8％）发生AE，主要是嗜睡（n = 26），乏力（n = 20）和行为障碍（n = 16）。据报道11例同时接受丙戊酸盐和氯巴沙姆治疗的患者转氨酶异常（≥3次）。AE在M2时显着更高（p = 0.03），并随着AED的数量增加（p = 0.03）。在M6时，总癫痫发作频率相对于基线的变化为-41％±37.5％（平均值±标准差），并且28例患者（37.8％）的缓解率≥50％。DS与LGS，CLB +与CLB-患者之间的AE和疗效无差异。意义：CBD剂量的较慢滴定可提供更好的耐受性，且疗效与以前的试验相当。伴随的CLB并没有增加疗效，但是在少数情况下增加了AE。这种缓慢的滴定方案应有助于指导临床医生开具CBD处方，并使患者从其潜在疗效中受益。