Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome Devinsky O, Patel AD, Cross JH, et al; GWPCARE3 Study Group. N Engl J Med. 2018;378:1888-1897. BACKGROUND Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy. METHODS In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2-55 years) who had had 2 or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of 20 mg/kg of body weight (20-mg cannabidiol group) or 10 mg/kg (10-mg cannabidiol group) or matching placebo, administered in 2 equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. RESULTS A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percentage reduction from baseline in drop seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group ( P = .005 for the 20-mg cannabidiol group vs placebo group, and P = .002 for the 10-mg cannabidiol group vs placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. CONCLUSIONS Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 or 20 mg/kg/d to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560.) Long-Term Safety and Treatment Effects of Cannabidiol in Children and Adults With Treatment-Resistant Epilepsies: Expanded Access Program Results Szaflarski JP, Bebin EM, Comi AM, et al; CBD EAP Study Group. Epilepsia. 2018;59(8):1540-1548. OBJECTIVE Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2 to 10 mg/kg/d, titrated to a maximum dose of 25 to 50 mg/kg/d. Patient visits were every 2 to 4 weeks through 16 weeks and every 2 to 12 weeks thereafter. Efficacy end points included the percentage change from baseline in median monthly convulsive and total seizure frequency and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures versus baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS Of 607 patients in the safety data set, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. Cannabidiol was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE Results from this ongoing EAP support previous observational and clinical trial data, showing that add-on CBD may be an efficacious long-term treatment option for TRE. Randomized, Dose-Ranging Safety Trial of Cannabidiol in Dravet Syndrome Devinsky O, Patel AD, Thiele EA, et al; GWPCARE1 Part A Study Group. Neurology. 2018;90(14):e1204-e1211. OBJECTIVE To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. METHODS Patients aged 4 to 10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, electrocardiograms, adverse events (AEs), seizure frequency, and suicidality. RESULTS Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose proportional (AUC0-t). Cannabidiol did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed. CONCLUSIONS Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. Cannabidiol resulted in more AEs than placebo but was generally well tolerated. CLASSIFICATION OF EVIDENCE This study provides class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well tolerated.

中文翻译：

---

不要害怕基于植物的大麻二酚的冷藏柜证据支架作为癫痫的治疗方法。

卡那比二醇对伦诺克斯—盖斯托综合征中癫痫发作的影响Devinsky O，Patel AD，Cross JH等；GWPCARE3研究组。N Engl J Med。2018; 378：1888-1897。背景技术大麻二酚已被用于患有严重的早发性癫痫的患者的治疗性癫痫发作。我们研究了在常规抗癫痫药物治疗方案中添加大麻素二醇治疗严重的发展性癫痫性脑病Lennox-Gastaut综合征患者的癫痫发作的疗效和安全性。方法在30个临床中心进行的这项双盲，安慰剂对照试验中，我们随机分配了Lennox-Gastaut综合征（年龄范围，（2-55岁）在28天的基线期内每周发作2次或更多次癫痫发作，接受剂量为20 mg / kg体重的大麻酚口服液（20 mg大麻双酚组）或10 mg / kg （10毫克大麻二酚组）或相匹配的安慰剂，每天2次平均分剂量服用，持续14周。主要结局是治疗期间癫痫发作频率（每28天平均值）相对于基线的百分比变化。结果共纳入225例患者。76例患者分为20毫克大麻二酚组，73例10毫克大麻二酚组和76例安慰剂组。在28天的基线期内，所有试验组的癫痫发作中位数为85。在治疗期间，癫痫发作频率与基线相比降低的中位数百分比为41。20毫克大麻二酚组为9％，10毫克大麻二酚组为37.2％，安慰剂组为17.2％（20毫克大麻二酚组与安慰剂组相比，P = .005，丙二醛对P = .002 10毫克大麻二酚组与安慰剂组）。大麻素组患者中最常见的不良事件是嗜睡，食欲下降和腹泻。这些事件在高剂量组中更频繁地发生。20毫克大麻二酚组中的6名患者和10毫克大麻二酚组中的1名患者由于不良事件而中断了试验药物的治疗，因此退出了试验。接受大麻二酚（14％）的十四名患者肝氨基转移酶浓度升高。结论在患有Lennox-Gastaut综合征的儿童和成人中，在常规抗癫痫治疗方案中以10或20 mg / kg / d的剂量添加大麻二酚会比安慰剂更大程度地降低癫痫发作的频率。大麻二酚的不良反应包括肝氨基转移酶浓度升高。（由GW Pharmaceuticals资助； GWPCARE3 ClinicalTrials.gov编号，NCT02224560。）卡那比多在患有抗药性癫痫的儿童和成人中的长期安全性和治疗效果：扩大的访问计划结果Szaflarski JP，Bebin EM，Comi AM等；CBD EAP研究小组。癫痫病。2018; 59（8）：1540-1548。目的自2014年以来，在一项正在进行的扩展访问计划（EAP）中，对患有耐药性癫痫病（TRE）的患者使用了大麻二酚（CBD）。我们报告了截至2016年12月治疗EAP患者的CBD安全性和有效性的中期结果。方法包括25个基于美国的EAP站点，这些站点招募了在基线时服用稳定剂量抗癫痫药（AED）的TRE患者。在4周的基准期内，父母/看护人会记录所有可计数的癫痫发作类型的日记。患者接受口服CBD的起始剂量为2至10 mg / kg / d，最大剂量为25至50 mg / kg / d。患者访视是每2至4周到16周，此后每2至12周一次。疗效终点包括中位数每月惊厥发作和总癫痫发作频率相对于基线的百分比变化，以及癫痫发作相对于基线降低了50％，≥75％和100％的患者百分比。对数据进行描述性分析以进行功效分析，并使用最后观察携带的方法来解释丢失的数据。每次访视均记录不良事件（AE）。结果安全性数据集中的607例患者中，有146例（24％）退出了研究；最常见的原因是缺乏疗效（89 [15％]）和不良事件（32 [5％]）。平均年龄为13岁（范围为0.4-62）。伴随的AED的中位数为3（范围为0-10）。CBD中位剂量为25 mg / kg / d；中位治疗时间为48周。附加的CBD在12周时使每月惊厥发作的中位数减少了51％，总癫痫发作减少了48％；减少到96周相似。在第12周，惊厥性发作≥50％，≥75％和100％减少的患者比例分别为52％，31％和11％，到96周的比率相似。通常，大麻二酚的耐受性良好。最常见的不良事件为腹泻（29％）和嗜睡（22％）。重要性此持续进行的EAP的结果支持以前的观察和临床试验数据，表明附加的CBD可能是TRE的有效长期治疗选择。卡那比二醇在Dravet综合征中的随机，剂量范围安全性试验Devinsky O，Patel AD，Thiele EA等；GWPCARE1 A部分研究组。神经病学。2018; 90（14）：e1204-e1211。目的评估纯化的大麻素（CBD）药物制剂在儿童Dravet综合征中的安全性和初步药代动力学。方法将4至10岁的患者按4：1的比例随机分为CBD（5、10或20 mg / kg / d）或安慰剂，每天两次。这项双盲试验包括4周的基线，3周的治疗（包括滴定），10天的锥度和4周的随访期。完成者可以继续使用开放标签扩展。在给药的第一天和治疗结束时采集了多个药代动力学血样，以测定CBD，其代谢物6-OH-CBD，7-OH-CBD和7-COOH-CBD，以及抗癫痫药（AED；氯巴沙姆和代谢物N-去甲基环丙酰胺[N-CLB]，丙戊酸酯，左乙拉西坦，托吡酯和替替米多）。安全性评估包括临床实验室检查，体格检查，生命体征，心电图，不良事件（AE），癫痫发作频率和自杀倾向。结果34例患者被随机分组​​（CBD组分别为5、10和20 mg / kg / d，分别为10、8和9，安慰剂为7）。32（94％）完成治疗。CBD及其代谢产物的暴露与剂量成正比（AUC0-t）。除N-CLB升高外，卡那比二醇不影响伴随的AED水平（除服用替比汀的患者外）。CBD上最常见的不良事件为发热，嗜睡，食欲下降，镇静，呕吐，共济失调和行为异常。六名服用CBD和丙戊酸盐的患者出现转氨酶升高；没有一个满足药物性肝损伤的标准，并且全部恢复。没有观察到其他临床相关的安全信号。结论CBD及其代谢产物的暴露随剂量成比例增加。观察到与N-CLB的相互作用，可能与CBD对细胞色素P450亚型2C19的抑制有关。卡纳比多二醇产生的AE比安慰剂多，但一般耐受性良好。证据分类这项研究提供了I类证据，对于患有Dravet综合征的儿童，CBD导致的AE比安慰剂多，但耐受性一般。结论CBD及其代谢产物的暴露随剂量成比例增加。观察到与N-CLB的相互作用，可能与CBD对细胞色素P450亚型2C19的抑制有关。卡纳比多二醇产生的AE比安慰剂多，但一般耐受性良好。证据分类这项研究提供了I类证据，对于患有Dravet综合征的儿童，CBD导致的AE比安慰剂多，但耐受性一般。结论CBD及其代谢产物的暴露随剂量成比例增加。观察到与N-CLB的相互作用，可能与CBD对细胞色素P450亚型2C19的抑制有关。卡纳比多二醇产生的AE比安慰剂多，但一般耐受性良好。证据分类这项研究提供了I类证据，对于患有Dravet综合征的儿童，CBD导致的AE比安慰剂多，但耐受性一般。