NYU Comprehensive Epilepsy Center, New York, New York.
Necker Hospital for Sick Children, Imagine Institute, Paris, France.
Epilepsia. 2019 Feb;60(2):294-302. doi: 10.1111/epi.14628. Epub 2018 Dec 23.
Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5.
Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d.
By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale.
This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.
在一项随机、双盲、安慰剂对照试验（GWPCARE1 部分 B，NCT02091375）中，附加使用大麻二酚（CBD）可显著减少 Dravet 综合征（DS）相关的癫痫发作。完成 GWPCARE1 部分 A（NCT02091206）或部分 B 或第二项安慰剂对照试验 GWPCARE2（NCT02224703）的患者被邀请参加一项长期开放标签扩展试验 GWPCARE5（NCT02224573）。我们在此报告 GWPCARE5 的安全性、疗效和患者报告结局的中期分析结果。
患者接受口服溶液中高度纯化 CBD 的药物制剂（100mg/mL）治疗，在 2 周内滴定剂量至 2.5 至 20mg/kg/d，同时使用其现有药物。根据反应和耐受性，CBD 剂量可增加或减少至 30mg/kg/d。
截至 2016 年 11 月，共有 278 名患者完成了原始随机试验，其中 264 名（95%）患者入组了这项开放标签扩展试验。中位治疗持续时间为 274 天（范围 1-512），平均模式剂量为 21mg/kg/d，患者中位数接受 3 种抗癫痫药物治疗。93.2%的患者发生不良事件（AE），大多为轻度（36.7%）或中度（39.0%）。常见的不良事件包括腹泻（34.5%）、发热（27.3%）、食欲下降（25.4%）和嗜睡（24.6%）。17 名患者（6.4%）因不良事件而停药。GWPCARE1 中的 22 名患者（17.2%）出现了丙氨酸氨基转移酶升高≥3 倍正常值上限，所有患者均服用丙戊酸。在 GWPCARE1 部分 B 的患者中，在 12 周评估期内，每月癫痫发作频率的中位数从基线下降 38%至 44%，癫痫发作的总发作频率从基线下降 39%至 51%。治疗 48 周后，85%的患者/照护者在患者整体状况上报告了改善，在患者/照护者整体变化量表上的评分有所提高。
这项试验表明，长期 CBD 治疗具有可接受的安全性，并导致治疗抵抗性 DS 患者的癫痫发作频率持续、具有临床意义的降低。
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