A Phase 2 Randomized Controlled Trial of the Efficacy and Safety of Cannabidivarin as Add-on Therapy in Participants with Inadequately Controlled Focal Seizures.
A Phase 2 Randomized Controlled Trial of the Efficacy and Safety of Cannabidivarin as Add-on Therapy in Participants with Inadequately Controlled Focal Seizures.
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DOI：
10.1089/can.2020.0075
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发表时间：
2021-12
影响因子：
3.8
通讯作者：
GWEP1330 Study Group
中科院分区：
文献类型：
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作者：
Brodie MJ;Czapinski P;Pazdera L;Sander JW;Toledo M;Napoles M;Sahebkar F;Schreiber A;GWEP1330 Study Group
目的：我们评估了cannabidivarin（CBDV）作为局部癫痫发作控制不佳的成人添加治疗的有效性，安全性和耐受性。材料和方法：162名参与者（CBDV n=81;安慰剂n=81）入组。在4周基线后，参与者从400至800 mg CBDV滴定，每日两次（b.i.d.）(or安慰剂），随后稳定给药6周（800 mg b.i.d.）还有12天的减量期主要终点是8周治疗期间局灶性癫痫发作频率较基线的变化。次要终点包括与癫痫发作相关的其他疗效指标、医生和参与者报告的结局、急救药物使用的变化、认知评估和安全性。结果如下：两组中基线局灶性癫痫发作频率的中位数为每28天17-18次，CBDV组中观察到频率降低相似（40.5%）和安慰剂（37.7%）组在治疗期间（CBDV/安慰剂治疗比[降低%]：0.95 [4.6];置信区间：0.78-1.17 [-16.7至21.9]; p=0.648）。CBDV组和安慰剂组之间的任何癫痫发作亚型均无差异。对于任何次要疗效结局指标，CBDV组和安慰剂组之间均无显著治疗差异。总体而言，CBDV组59例（72.8%）受试者和安慰剂组39例（48.1%）受试者发生≥1起治疗后出现的不良事件（AE）;最常见的3起为腹泻、恶心和嗜睡。严重AE的发生率较低（CBDV组3.7% vs安慰剂组1.2%）。CBDV对生命体征、体格检查或心电图结果的影响很小或没有影响。血清转氨酶（丙氨酸转氨酶或天冬氨酸转氨酶）升高至>3×正常上限的水平发生在服用CBDV的3名参与者（其中2名因此停药）和服用安慰剂的1名参与者中;然而，没有一名符合潜在海氏法则病例的标准。结论：CBDV的癫痫发作减少40.5%可能代表了该局灶性癫痫发作人群的适当药理学应答。然而，安慰剂的反应很高，这可能反映了参与者对CBDV的期望，并且没有观察到与安慰剂的治疗差异。CBDV通常耐受良好。临床试验注册号：NCT 02365610。
Objective: We assessed the efficacy, safety, and tolerability of cannabidivarin (CBDV) as add-on therapy in adults with inadequately controlled focal seizures. Materials and Methods: One hundred and sixty-two participants (CBDV n=81; placebo n=81) were enrolled. After a 4-week baseline, participants titrated from 400 to 800 mg CBDV twice daily (b.i.d.) (or placebo) over 2 weeks, followed by 6 weeks stable dosing (at 800 mg b.i.d.) and a 12-day taper period. The primary endpoint was the change from baseline in focal seizure frequency during the 8-week treatment period. Secondary endpoints included additional efficacy measures relating to seizures, physician- and participant-reported outcomes, change in the use of rescue medication, cognitive assessments, and safety. Results: Median baseline focal seizure frequencies were 17–18 per 28 days in both groups, and similar reductions in frequency were observed in the CBDV (40.5%) and placebo (37.7%) groups during the treatment period (treatment ratio [% reduction] CBDV/placebo: 0.95 [4.6]; confidence interval: 0.78–1.17 [−16.7 to 21.9]; p=0.648). There were no differences between the CBDV and placebo groups for any seizure subtype. There were no significant treatment differences between CBDV and placebo groups for any of the secondary efficacy outcome measures. Overall, 59 (72.8%) of participants in the CBDV group and 39 (48.1%) in the placebo group had ≥1 treatment-emergent adverse event (AE); the 3 most common were diarrhea, nausea, and somnolence. The incidence of serious AEs was low (3.7% in the CBDV group vs. 1.2% in the placebo group). There was little or no effect of CBDV on vital signs, physical examination, or electrocardiogram findings. Elevations in serum transaminases (alanine aminotransferase or aspartate aminotransferase) to levels >3×upper limit of normal occurred in three participants taking CBDV (two discontinued as a result) and one taking placebo; however, none met the criteria for potential Hy's Law cases. Conclusion: It is likely the 40.5% seizure reduction with CBDV represents an appropriate pharmacological response in this population with focal seizures. The placebo response was, however, high, which may reflect the participants' expectations of CBDV, and a treatment difference from placebo was not observed. CBDV was generally well tolerated. Clinical Trial Registration number: NCT02365610.