Adjunctive Transdermal Cannabidiol for Adults With Focal Epilepsy: A Randomized Clinical Trial.
Adjunctive Transdermal Cannabidiol for Adults With Focal Epilepsy: A Randomized Clinical Trial.
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DOI：
10.1001/jamanetworkopen.2022.20189
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发表时间：
2022-07-01
影响因子：
13.8
通讯作者：
Gutterman, Donna L.
中科院分区：
文献类型：
--
作者：
O'Brien, Terence J.;Berkovic, Samuel F.;French, Jacqueline A.;Messenheimer, John A.;Sebree, Terri B.;Bonn-Miller, Marcel O.;Gutterman, Donna L.
这项随机临床试验评估了经皮大麻二酚与安慰剂在成人耐药局灶性癫痫中的应用。经皮给药大麻二酚治疗成人耐药局灶性癫痫的疗效、安全性和耐受性如何？在一项随机、双盲、安慰剂对照、多中心临床试验中，188名患者在双盲期的第12周，安慰剂、195毫克大麻二酚和390毫克大麻二酚治疗组的癫痫发作频率没有差异。开放标签扩展证明了经皮给药大麻二酚的长期安全性、耐受性和可接受性，在试验的第6个月，超过一半的患者癫痫发作减少至少50%。虽然大麻二酚在本试验中的表现并不明显优于安慰剂，但它具有良好的耐受性和安全性；未来评估高剂量影响的研究可能是有必要的。大麻二酚在随机临床试验中显示出对主要影响儿童的特定综合征的耐药癫痫的疗效。然而，缺乏大麻二酚治疗成人最常见的耐药癫痫（局灶性癫痫）的有效性和安全性的高水平证据。研究经皮给药大麻二酚治疗成人耐药局灶性癫痫的疗效、安全性和耐受性。在澳大利亚和新西兰的14个癫痫试验中心进行的一项随机、双盲、安慰剂对照、多中心临床试验。参与者是患有耐药局灶性癫痫的成年人，接受多达3种抗癫痫药物的稳定治疗。数据分析时间为2017年7月至2018年11月。符合条件的参与者被随机分配（1:1:1）到195毫克或390毫克透皮大麻二酚或安慰剂，每天两次，持续12周，之后他们可以参加长达2年的开放标签扩展研究。癫痫发作频率用每日日记自我报告。主要疗效终点是在12周的治疗期间，每28天的对数变换总发作频率的最小二乘平均差，调整为共同基线对数发作率。共有188例患者（45%男性[85例]，54.8%女性[103例]），平均（SD）年龄为39.2（12.78）岁，进行随机、治疗和分析（195 mg大麻二酚，63例；390 mg大麻二酚，62例；安慰剂，63例）。在双盲期的第12周，安慰剂组（平均[SD] 2.49[1.31]次/ 28天）和195 mg大麻二酚组（平均[SD] 2.51[1.15]次/ 28天）的癫痫发作频率无差异，最小二乘平均差为0.014,95% CI为- 0.175 ~ 0.203,P =。89)或390毫克大麻二酚（平均[SD] 2.59[1.12]次/ 28天；最小二乘平均差为0.096；95% CI为- 0.093 ~ 0.285;P = 0.32）。到开放标签扩展的第6个月，115例患者（60.8%）癫痫发作减少至少50%。大麻二酚组治疗后出现的不良事件发生率为50.4%（125名参与者中的63名），安慰剂组为41.3%（63名参与者中的26名），治疗差异为9.1% (95% CI, - 6.0%至23.6%)，大麻二酚组的发生率相似。少数受试者停止治疗（7%[188名受试者中的14名]），大多数（98%[174名受试者中的171名]）继续进行开放标签延长治疗。两种剂量的透皮大麻二酚耐受性良好且安全。在双盲治疗期间，大麻二酚和安慰剂的疗效无显著差异。开放标签扩展证明了经皮大麻二酚输送的长期安全性，耐受性和可接受性。ACTRN12616000510448(双盲);ACTRN12616001455459(项)。
This randomized clinical trial evaluates the use of transdermal cannabidiol vs placebo for adults with drug-resistant focal epilepsy. What is the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy? In a randomized, double-blind, placebo-controlled, multicenter clinical trial of 188 patients, no difference was found in seizure frequency at week 12 of the double-blind period among the placebo, 195-mg cannabidiol, and 390-mg cannabidiol treatments. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery, with a seizure reduction of at least 50% in more than half of the patients by month 6 of the trial. Although cannabidiol did not perform significantly better than placebo in this trial, it was well tolerated and safe; future studies to assess the effect of higher doses may be warranted. Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants; 390-mg cannabidiol, 62 participants; placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days; least squares mean difference, 0.014; 95% CI, −0.175 to 0.203; P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days; least squares mean difference, 0.096; 95% CI, −0.093 to 0.285; P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, −6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. ACTRN12616000510448 (double-blind); ACTRN12616001455459 (open-label).
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影响因子：
13.8
作者：
Scheffer IE;Hulihan J;Messenheimer J;Ali S;Keenan N;Griesser J;Gutterman DL;Sebree T;Sadleir LG
通讯作者：
Sadleir LG
影响因子：
5.6
作者：
Chung, Steve;Sperling, Michael R.;Doty, Pamela
通讯作者：
Doty, Pamela
影响因子：
2.9
作者：
CARLINI, EA;CUNHA, JM
通讯作者：
CUNHA, JM
影响因子：
4.2
作者：
Brown, EG;Wood, L;Wood, S
通讯作者：
Wood, S
影响因子：
2.9
作者：
Mechoulam, R;Parker, LA;Gallily, R
通讯作者：
Gallily, R