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

描述（由申请人提供）：可卡因依赖仍然是美国的一个重大公共卫生问题，目前尚无FDA批准的可卡因使用障碍药物治疗。可卡因依赖的标准心理社会治疗产生小到中等的效果大小，但对许多可卡因依赖患者无效。 鉴于近年来在开发针对酒精、阿片类和尼古丁使用障碍的有效药物疗法方面取得的成功，开发针对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。有希望的独立发展的研究表明，安非他明和托吡酯是潜在的药物治疗可卡因依赖，单独已证明疗效有限。 这两种药物有不同的作用机制-安非他明增加多巴胺的传输和托吡酯减少脑桥核多巴胺的释放。这种组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试点研究（N=81）发现，混合安非他明盐缓释（MAS-ER）和托吡酯的组合可有效促进可卡因依赖者的戒断，特别是在基线时使用频率较高的人群中。这一有希望的结果需要在一项更大规模的随机安慰剂对照研究中得到证实。 使用PAR-10-099“药物滥用合作临床试验”机制，拟定项目是一项双中心随机双盲试验。我们的目的是研究可卡因依赖的个人谁使用可卡因频繁，并为他们的MAS-ER和托吡酯的组合被证明是有效的。这项III期临床试验的目标是建立在 我们的有前途的试点研究结果，并检查MAS-ER和托吡酯的组合对可卡因消费使用的禁欲启动模型的疗效。 具体目的：确定MAS-ER和托吡酯在可卡因依赖患者中促进可卡因戒断的疗效。主要假设：与安慰剂相比，MAS-ER和托吡酯将显著促进可卡因使用的戒断。主要结局指标为试验结束时连续3周的可卡因戒断，通过时间轴随访方法记录，并通过肌酐标准化定量尿苯甲酰爱子碱（BE）水平确认。次要假设：MAS-ER和托吡酯将1）在研究期间的任何连续三周内显著促进戒断，并且在降低2）BE阴性的尿液毒理学样品的比例~ 3）可卡因戒断症状~和4）可卡因渴望方面上级安慰剂。我们的研究小组非常适合进行这项研究，因为我们在进行可卡因依赖药物治疗临床试验方面有丰富的经验，并且在使用MAS-ER和托吡酯治疗可卡因依赖门诊患者方面有直接经验。

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.