2/2 Multicenter trial of combined pharmacotherapy to treat cocaine dependence

描述(申请人提供)：可卡因依赖在美国仍然是一个严重的公共卫生问题，目前还没有FDA批准的可卡因使用障碍的药物疗法。可卡因依赖的标准心理社会治疗产生的效果为中小型，但对许多可卡因依赖患者无效。鉴于近年来在开发治疗酒精、阿片和尼古丁使用障碍的有效药物疗法方面取得的成功，开发治疗可卡因使用障碍的有效药物疗法仍然是一个重要的公共卫生目标。有前景的单独发展的研究表明，苯丙胺和托吡酯是治疗可卡因依赖的潜在药物疗法，但单独显示的疗效有限。这两种药物有不同的作用机制，苯丙胺促进多巴胺传递，托吡酯减少伏核多巴胺释放。这种结合可能会减少基线渴望和可卡因诱导的强化。我们的研究小组进行的一项初步研究(N=81)发现，混合苯丙胺盐缓释剂(MAS-ER)和托吡酯的组合有效地促进了可卡因依赖者的戒断，特别是在基线使用频率较高的人。这一有希望的结果值得在一项更大规模的随机安慰剂对照研究中得到证实。利用PAR-10-099“药物滥用临床试验协作”机制，建议的项目是一项双部位随机双盲试验。我们的目标是研究经常使用可卡因的可卡因依赖者，对他们来说，MAS-ER和托吡酯的联合治疗被证明是有效的。这项第三阶段临床试验的目标是在 我们有希望的试验性研究结果，并使用戒断启动模型检查MAS-ER和托吡酯联合使用对可卡因消费的效果。具体目的：探讨MAS-ER和托吡酯在促进可卡因依赖患者戒断中的作用。基本假设：与安慰剂相比，MAS-ER和托吡酯将显著促进可卡因的戒断。主要结果衡量标准将是试验结束时连续三周的可卡因戒断情况，由肌酐标准化定量尿苯甲酰ecGonine(BE)确认的时间线回溯法记录。第二个假设：MAS-ER和托吡酯将在研究期间的任何连续三周内显著促进戒断，在减少BE~阴性的尿毒学样本比例方面优于安慰剂，3)可卡因戒断症状和4)可卡因渴求。鉴于我们在进行可卡因依赖药物治疗临床试验方面的丰富经验，以及在使用MAS-ER和托吡酯治疗可卡因依赖门诊患者方面的直接经验，我们的研究团队非常适合进行这项研究。

DESCRIPTION (provided by applicant): Cocaine dependence continues to be a significant public health problem in the United States and there are no FDA-approved pharmacotherapies for cocaine use disorders. Standard psychosocial treatments for cocaine dependence yield small-to-medium effect sizes, but are not effective for many cocaine-dependent patients. Given the success in recent years in developing effective pharmacotherapies for alcohol, opioid, and nicotine use disorders, the development of effective pharmacotherapies for cocaine use disorders remains an important public health goal. Promising separate developing lines of research suggest that amphetamine and topiramate are potential pharmacotherapies for cocaine dependence that individually have demonstrated limited efficacy. These two medications have distinct mechanisms of action~ amphetamine increases dopamine transmission and topiramate reduces nucleus accumbens dopamine release. This combination may decrease baseline craving and cocaine-induced reinforcement. A pilot study (N=81) conducted by our research group found that the combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate was effective for promoting abstinence among cocaine- dependent individuals, particularly among those with a greater frequency of use at baseline. This promising result warrants confirmation in a larger randomized placebo-controlled study. Using the PAR-10-099 "Collaborative Clinical Trials in Drug Abuse" mechanism, the proposed project is a two site randomized double- blind trial. We aim to study cocaine-dependent individuals who use cocaine frequently and for whom the combination of MAS-ER and topiramate was shown to be effective. The goal of this phase III clinical trial is to build on our promising pilot study results and examine the efficacy of the combination of MAS-ER and topiramate on cocaine consumption using an abstinence-initiation model. Specific Aim: To determine the efficacy of MAS-ER and topiramate in promoting cocaine abstinence among cocaine-dependent patients. Primary Hypothesis: MAS-ER and topiramate will significantly promote abstinence from cocaine use as compared to placebo. The primary outcome measure will be three consecutive weeks of cocaine abstinence at the end of the trial as recorded by the Timeline Follow-Back method confirmed by creatinine-normalized quantitative urine benzoylecgonine (BE) levels. Secondary Hypotheses: MAS-ER and topiramate will 1) significantly promote abstinence during any three consecutive weeks during the study period and be superior to placebo in reducing 2) the proportion of urine toxicology samples negative for BE~ 3) symptoms of cocaine withdrawal~ and 4) cocaine craving. Our research group is well suited to conduct this study given our extensive experience in conducting cocaine dependence pharmacotherapy clinical trials, as well as having direct experience in using MAS-ER and topiramate to treat cocaine-dependent outpatients.