一项关于阿片受体拮抗剂LY2196044治疗酒精依赖的2期安慰剂对照研究。
A phase 2, placebo-controlled study of the opioid receptor antagonist LY2196044 for the treatment of alcohol dependence.
作者信息
Wong Conrad J, Witcher Jennifer, Mallinckrodt Craig, Dean Robert A, Anton Raymond F, Chen Yunfei, Fijal Bonnie A, Ouyang Haojun, Dharia Sweta, Sundseth Scott S, Schuh Kory J, Kinon Bruce J
机构信息
Eli Lilly and Company and/or one of its wholly owned subsidiaries, Indianapolis, Indiana, USA.
出版信息
Alcohol Clin Exp Res. 2014 Feb;38(2):511-20. doi: 10.1111/acer.12257. Epub 2013 Sep 6.
BACKGROUND
Endogenous opioid-mediated reward pathways may play a role in the development and maintenance of alcohol dependence. This study tested whether LY2196044, an opioid receptor antagonist, in combination with medical management would reduce drinking in alcohol-dependent patients.
METHODS
This was a multicenter, outpatient, randomized, double-blind, parallel, and placebo-controlled trial with a 16-week treatment period. Patients (N = 375) were alcohol-dependent, treatment-seeking adults. Patients were randomly assigned to once-daily LY2196044 (final doses of 125 or 250 mg/d) or placebo. DNA samples were collected at baseline. At each visit, patients underwent safety assessments, laboratory testing, efficacy measures, and medical management. Blood samples were also obtained for pharmacokinetic testing. The primary measure was the change from baseline in the percent heavy drinking days (HDD). Secondary efficacy measures were percent days abstinent per month and number of drinks per day.
RESULTS
The treatment difference in change from baseline in % HDD between LY2196044 and placebo was not statistically significant (-43.02 vs. -38.72%, respectively; p = 0.12). There was a trend toward greater change from baseline in the percent days abstinent per month for the LY2196044 group compared with the placebo group (33.49 vs. 28.12%, respectively; p = 0.051). The decrease from baseline for mean number of drinks per day was statistically significantly greater in the LY2196044 group compared with the placebo group (-5.37 vs. -4.66 drinks per day, respectively; p = 0.013). LY2196044-treated patients who were dopamine receptor type 4-variable number tandem repeat L carriers had greater reductions in % HDD (p = 0.0565), increased percent days abstinent (p = 0.0496), and reduced drinks per day (p = 0.0069) than placebo-treated L carriers. The safety profile for LY2196044 appeared similar to that of other opioid antagonists.
CONCLUSIONS
The results from this proof-of-concept clinical trial warrant further evaluation of LY2196044 for the treatment of alcohol dependence.
背景
内源性阿片介导的奖赏通路可能在酒精依赖的发生和维持中起作用。本研究测试了阿片受体拮抗剂LY2196044联合药物治疗是否会减少酒精依赖患者的饮酒量。
方法
这是一项多中心、门诊、随机、双盲、平行和安慰剂对照试验，治疗期为16周。患者（N = 375）为寻求治疗的酒精依赖成年患者。患者被随机分配至每日一次的LY2196044（最终剂量为125或250 mg/d）或安慰剂组。在基线时采集DNA样本。每次就诊时，患者接受安全性评估、实验室检查、疗效测量和药物治疗。还采集血样进行药代动力学检测。主要测量指标是重度饮酒日（HDD）百分比相对于基线的变化。次要疗效指标是每月戒酒天数百分比和每日饮酒量。
结果
LY2196044与安慰剂相比，HDD百分比相对于基线的变化的治疗差异无统计学意义（分别为-43.02%和-38.72%；p = 0.12）。与安慰剂组相比，LY2196044组每月戒酒天数百分比相对于基线的变化有更大的趋势（分别为33.49%和28.12%；p = 0.051）。与安慰剂组相比，LY2196044组每日平均饮酒量相对于基线的减少在统计学上显著更大（分别为-5.37杯/天和-4.66杯/天；p = 0.013）。与接受安慰剂治疗的L携带者相比，接受LY2196044治疗的多巴胺受体4型可变数目串联重复L携带者的HDD百分比降低幅度更大（p = 0.0565），戒酒天数百分比增加（p = 0.0496），每日饮酒量减少（p = 0.0069）。LY2196044的安全性与其他阿片拮抗剂相似。
结论
这项概念验证临床试验的结果值得对LY2196044治疗酒精依赖进行进一步评估。
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