Evaluation of Atomoxetine for Cocaine Dependence: A Pilot Trial

描述（由申请人提供）：本申请是根据标题为“药物治疗物质相关疾病的初步临床试验”的申请请求DA-06-002编写的。“可卡因滥用和依赖已被认为是一个重大的公共卫生问题，目前还没有广泛有效的药物。最近从采用激动剂替代或替代方法的研究中获得了有希望的结果，包括对d-苯丙胺和莫达非尼的研究。该试点项目拟评估托莫西汀（Strattera），一种目前上市用于治疗青少年和成人ADHD的化合物，用于治疗可卡因依赖。托莫西汀是一种去甲肾上腺素再摄取阻滞剂，对多巴胺和5-羟色胺转运位点的亲和力相对较低。它在临床实践中已被安全耐受，并且与低滥用可能性相关。初步数据表明，其药效学效应与原型兴奋剂部分重叠，托莫西汀维持治疗可降低可卡因滥用志愿者对可卡因的主观反应和自我报告的可卡因欲望评级。本申请拟进行一项单次、安慰剂对照、双盲、随机化初步临床试验，以评价托莫西汀（Stattera）治疗可卡因依赖的疗效。正在寻求药物滥用治疗的可卡因依赖性健康个体将在经过仔细的医学和精神病学筛选后入组，以确保他们在两周内适合本研究。在随机分配到两组之一之前，将根据已知影响可卡因滥用治疗结果的变量对患者进行分层（n=25/组）。在持续12周的试验期间，患者将随机接受托莫西汀（80 mg/天，有一个简短的导入期）或匹配的安慰剂。所有患者将参加每周一次的认知行为咨询会议。将采用应急管理程序，以增加出席率，减少审判人员的流失。在整个试验过程中，将收集一系列广泛的指标，包括药物使用、安全性、情绪、心理社会功能和药物依从性（包括核黄素检测和药丸计数）以及可卡因渴望的指标。主要结局指标将是苯甲酰爱子碱随时间推移的尿液毒理学结果和连续三周禁欲的实现。次要结局指标将包括门诊出勤率、药物依从性、心理社会功能和其他药物使用。将使用PROC混合、一般估计方程和参数ANOVA方法分析数据。组大小基于从其他试验中获得的把握度分析，这些试验在该人群中获得了阳性药物信号。本研究将提供关于托莫西汀潜在效用的初步安全性和疗效数据，并确定是否需要进行更大规模的评价。

DESCRIPTION (provided by applicant): This application is written in response to Request for Applications DA-06-002 entitled, "Pilot Clinical Trials of Pharmacotherapies for Substance Related Disorders." Cocaine abuse and dependence has been recognized as a significant public health problem, and no broadly effective medications are available. Recent promising results have been obtained from studies employing the agonist substitution or replacement approach, including studies of d-amphetamine and modafinil. This pilot project proposes to evaluate atomoxetine (Strattera), a compound presently marketed for the treatment of ADHD in adolescents and adults, for the treatment of cocaine dependence. Atomoxetine is a norepinephrine reuptake blocker, which has relatively low affinity for the dopamine and serotonin transport sites. It has been safely tolerated in clinical practice and is associated with low abuse potential. Preliminary data suggest that its pharmacodynamic effects overlap partially with prototypic stimulants, and that maintenance on atomoxetine can reduce the subjective response to cocaine and self-reported ratings of desire for cocaine in cocaine abusing volunteers. This application proposes to conduct a single, placebo-controlled, double blind, randomized pilot clinical trial to evaluate atomoxetine (Stattera) for the treatment of cocaine dependence. Cocaine-dependent healthy individuals, who are seeking treatment for their substance abuse, will be enrolled after careful medical and psychiatric screening to ensure their suitability for the study over a two- week period. Patients will be stratified on variables known to impact cocaine abuse treatment outcomes prior to randomization to one of two groups (n=25/group). Patients will be randomized to receive either atomoxetine (80 mg/day with a brief lead-in) or a matched-placebo during a trial lasting 12 weeks. All patients will participate in weekly cognitive behavioral counseling sessions. A contingency management procedure will be employed to reinforce attendance and decrease attrition from the trial. A broad array of measures, including measures of drug use, safety, mood, psychosocial functioning, and medication compliance (including riboflavin testing and pill counts) and cocaine craving will be collected throughout the course of the trial. The primary outcome measures will be urine toxicology results for benzoylecgonine over time and achievement of three consecutive weeks of abstinence. Secondary outcome measures will include clinic attendance, medication adherence, psychosocial functioning, and other drug use. Data will be analyzed using PROC Mix, General Estimating Equations and parametric ANOVA approaches. The group size was based upon power analyses derived from other trials in which positive medications signals were obtained in this population. This study will provide preliminary safety and efficacy data on the potential utility of atomoxetine and determine whether a larger-scale evaluation is warranted.