Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies: A Nonrandomized Controlled Trial.
Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies: A Nonrandomized Controlled Trial.
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DOI：
10.1001/jamanetworkopen.2021.23930
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发表时间：
2021-09-01
影响因子：
13.8
通讯作者：
Sadleir LG
中科院分区：
文献类型：
--
作者：
Scheffer IE;Hulihan J;Messenheimer J;Ali S;Keenan N;Griesser J;Gutterman DL;Sebree T;Sadleir LG
患有发育性和癫痫性脑病的儿童是否可以耐受大麻二酚（CBD）透皮凝胶，CBD凝胶是否与癫痫发作频率降低有关？在这项非随机对照试验中，CBD透皮凝胶在6.5个月的治疗中耐受性良好，60%的患者发生了治疗相关的不良事件，其中96%为轻度或中度。在局灶性意识障碍性癫痫发作和强直阵挛性癫痫发作中观察到癫痫发作频率降低43.5%。这些结果表明，CBD透皮凝胶在患有发育性和癫痫性脑病的儿童中具有良好的耐受性，并且可能与癫痫发作的减少有关。这项非随机对照试验检查了经皮大麻二酚（CBD）凝胶在发育性和癫痫性脑病儿童中的安全性和耐受性，并评估了CBD凝胶治疗与癫痫发作频率之间的相关性。发育性和癫痫性脑病（DEE）是最严重的耐药性癫痫。迫切需要替代口服治疗的药物，以减少癫痫发作，改善这一医学复杂人群的发育结局和合并症。评估大麻二酚（CBD）透皮凝胶在DEE儿童中的安全性和耐受性，并评估癫痫发作频率、睡眠和生活质量。这项非随机对照试验于2018年4月至2019年7月在澳大利亚和新西兰的2家中心进行。接受1 - 4种抗癫痫药物稳定治疗方案的3 - 18岁DEE儿童和青少年有资格参加本研究。在1个月的基线期和滴定期后，患者进入5.5个月的灵活给药维持期，共治疗6.5个月。在整个6.5个月治疗期间分析数据。每日两次应用CBD透皮凝胶，剂量为125至500 mg，持续6.5个月。安全性和耐受性评估包括不良事件（AE）和皮肤检查。癫痫发作的结局是6.5个月内局灶性意识障碍癫痫发作（FIAS）和强直阵挛性癫痫发作（TCS）的每月（28天）癫痫发作频率较基线的中位百分比变化。在48名患者中（平均[SD]年龄，10.5 [3.8]岁; 26名[54%]男孩），29名（60%）在6.5个月内至少发生1起治疗相关AE; 46起治疗相关AE中有44起（96%）为轻度或中度。至少5%患者发生的治疗相关AE为给药部位干燥、给药部位疼痛和嗜睡（各有4例患者[8%]报告）。唯一的治疗相关胃肠道AE是腹泻，在1例患者中报告。CBD治疗与FIAS和TCS频率的降低相关。对33例FIAS和TCS患者的分析显示，5个月时癫痫发作的中位（四分位距）每月减少58%（−5.3%至81.8%），整个6.5个月研究期间减少43.5%（−23.8%至57.5%）。父母和照顾者注意到社交或人际交往和易怒（43名参与者中的33名[77%]）;警觉性，精力和睡眠（43名参与者中的23名[53%]）;以及认知或注意力（43名参与者中的20名[47%]）的改善。在这项研究中，CBD透皮凝胶是安全的，耐受性良好，并与FIAS和TCS频率和疾病负担的减少有关。ClinicalTrials.gov标识符：ACTRN 12618000516280
Can children with developmental and epileptic encephalopathies tolerate adjunctive cannabidiol (CBD) transdermal gel, and is CBD gel associated with reduced seizure frequency? In this nonrandomized controlled trial, CBD transdermal gel was well tolerated over 6.5 months of treatment, with 60% of patients experiencing a treatment-related adverse event, 96% of which were mild or moderate. A 43.5% reduction in seizure frequency was observed in focal impaired awareness seizures and tonic-clonic seizures. These results suggest that CBD transdermal gel is well tolerated in children with developmental and epileptic encephalopathies and may be associated with a reduction in epileptic seizures. This nonrandomized controlled trial examines the safety and tolerability of transdermal cannabidiol (CBD) gel among children with developmental and epileptic encephalopathies and assesses the association between treatment with CBD gel and seizure frequency. Developmental and epileptic encephalopathies (DEEs) are the most severe group of drug-resistant epilepsies. Alternatives to oral therapies are urgently needed to reduce seizures and improve developmental outcomes and comorbidities in this medically complex population. To assess the safety and tolerability of cannabidiol (CBD) transdermal gel in children with DEEs and to evaluate seizure frequency, sleep, and quality of life. This nonrandomized controlled trial was conducted in 2 centers in Australia and New Zealand from April 2018 to July 2019. Children and adolescents aged 3 to 18 years with DEEs who were receiving a stable regimen of 1 to 4 antiseizure medications were eligible for this study. After 1-month baseline and titration periods, patients entered a 5.5-month flexible-dosing maintenance period for a total of 6.5 months of treatment. Data were analyzed throughout the 6.5-month treatment period. Twice-daily applications of CBD transdermal gel at doses of 125 to 500 mg for 6.5 months. Safety and tolerability assessments included adverse events (AEs) and examination of skin. The outcome for seizures was the median percentage change from baseline in monthly (28-day) seizure frequency of focal impaired awareness seizures (FIAS) and tonic-clonic seizures (TCS) over 6.5 months. Of 48 patients (mean [SD] age, 10.5 [3.8] years; 26 [54%] boys), 29 (60%) had at least 1 treatment-related AE over 6.5 months; 44 of 46 treatment-related AEs (96%) were mild or moderate. Treatment-related AEs that occurred in at least 5% of patients were application-site dryness, application-site pain, and somnolence (each reported by 4 patients [8%]). The only treatment-related gastrointestinal AE was diarrhea, reported in a single patient. CBD treatment was associated with reductions in FIAS and TCS frequency. Analysis of the 33 patients with FIAS and TCS showed a median (interquartile range) monthly reduction in seizures of 58% (−5.3% to 81.8%) at 5 months and 43.5% (−23.8% to 57.5%) over the entire 6.5-month study period. Parents and caregivers noted improvements in social or interpersonal engagement and irritability (33 of 43 [77%] participants); alertness, energy, and sleep (23 of 43 [53%]); and cognition or concentration (20 of 43 [47%]). In this study, CBD transdermal gel was safe, well tolerated, and was associated with reductions in FIAS and TCS frequency and disease burden. ClinicalTrials.gov Identifier: ACTRN12618000516280
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