1/2-Multicenter Trial of Combined Pharmacotherapy to Treat Cocaine Dependence

描述（由申请人提供）：可卡因依赖在美国仍然是一个重大的公共卫生问题，并且没有fda批准的药物治疗可卡因使用障碍。对可卡因依赖的标准社会心理治疗产生小到中等的效果，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、阿片类药物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，单独已证明有限的疗效。这两种药物有不同的作用机制：安非他明增加多巴胺的传递，托吡酯减少伏隔核多巴胺的释放。这种组合可能会降低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，混合安非他明盐缓释（MAS-ER）和托吡酯的组合对促进可卡因依赖个体的戒断是有效的，特别是对那些在基线时使用频率较高的个体。这一有希望的结果值得在更大的随机安慰剂对照研究中得到证实。采用PAR-10-099“药物滥用协同临床试验”机制，拟建项目为双盲随机试验。我们的目标是研究经常使用可卡因的可卡因依赖个体，对他们来说，MAS-ER和托吡酯的组合是有效的。这个III期临床试验的目标是建立在

DESCRIPTION (provided by applicant): Cocaine dependence continues to be a significant public health problem in the United States and there are no FDA-approved pharmacotherapy's 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 pharmacotherapy's for alcohol, opioid, and nicotine use disorders, the development of effective pharmacotherapy's for cocaine use disorders remains an important public health goal. Promising separate developing lines of research suggest that amphetamine and topiramate are potential pharmacotherapy's 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.