A Six-Month, RCT of Probuphine Safety and Efficacy in Opioid Addiction

描述（由申请人提供）：本申请涉及研究和研究基础设施重大机遇（RC2） （RFA-OD-09-004）优先领域：“物质相关疾病的小分子开发”。海洛因和处方阿片类药物成瘾是一种全球性的健康和社会危机。美国有超过160万人，全球有1500万人（占全球人口的0.2%）滥用或依赖阿片类药物。丁丙诺啡用于治疗阿片类药物成瘾现已得到充分确认，并被认为是一种安全有效的阿片类药物成瘾办公室治疗方法。尽管每日服用舌下丁丙诺啡片已被证明是有效的，但这种治疗方法有几个缺点，导致了重大的公共卫生问题。首先，由于需要频繁给药，成瘾行为的性质，以及一些患者高度不稳定的生活方式，患者的依从性很低。更具体地说，药物依从性差是这一人群复发、治疗失败和死亡的主要原因。除了依从性问题，丁丙诺啡片剂也存在严重滥用和非法转移，这是美国日益严重的公共卫生问题。Probuphine（盐酸丁丙诺啡/醋酸乙烯酯）是一种小剂量的皮下植入丁丙诺啡制剂，可在单次治疗后持续给药6个月，目前正处于治疗阿片类药物成瘾的3期临床开发阶段。先前对普罗布啡的研究表明，它与舌下丁丙诺啡具有相同的功效，但潜在地消除了舌下片剂的两个最大问题：依从性差和转移。为了满足FDA的要求，并且为了让普罗布芬（Probuphine）对患者可用，必须完成额外的安慰剂对照试验。这项为期6个月的研究将比较Probuphine（与安慰剂以及丁丙诺啡的舌下片剂Suboxone）的安全性和有效性。它将在美国大约20个成瘾治疗中心进行，目标招募250名参与者。筛选成功的患者将按2:1:2的比例随机接受Probuphine(植入物、安慰剂植入物或舌下丁丙诺啡（12-18mg/天）。所有参与者还将接受标准化（手动驱动）的每周个人药物咨询。参与者将在前16周每周见三次，在后8周每周见一次，然后在第25周进行一次额外的安全访问。主要的具体目的是比较各组在第16周阿片类药物阴性尿样的比例。次要的具体目的包括评估成瘾治疗的其他重要临床参数，包括戒断症状、药物渴望和治疗依从性。本研究将在允许的2年时间框架内开始并完成。

DESCRIPTION (provided by applicant): This application addresses Research and Research Infrastructure Grand Opportunities (RC2) (RFA-OD-09-004) priority area: "Small Molecule Development for Substance Related Disorders." Addiction to heroin and prescription opioids represents a worldwide health and social crisis. Over 1.6 million people in the United States (US) and 15 million people globally (0.2% of the global population) are abusing or dependent on opioids. The use of buprenorphine for the treatment of opioid addiction is now well established and accepted as a safe and useful office-based treatment for opioid addiction. Though the daily dosing of sublingual buprenorphine tablets has proven effective, this treatment has several shortcomings that have lead to significant public health concerns. First, patient compliance is low due to the need for frequent dosing, the nature of addictive behavior, and the highly unstable lifestyle of some patients. More specifically, poor medication adherence is the leading cause of relapse, treatment failure, and mortality in this population. In addition to issues with compliance, there is also significant abuse and illicit diversion of the tablet form of buprenorphine, a growing public health issue in the US. Probuphine( (buprenorphine hydrochloride/ethylene vinyl acetate) is a small, subcutaneous, implant formulation of buprenorphine that provides continuous delivery of drug for 6 months following a single treatment, and is under Phase 3 clinical development for the treatment of opioid addiction. Previous studies with Probuphine( have shown that it offers the same benefits as sublingual buprenorphine, but potentially eliminates two of the biggest problems with sublingual tablets: poor adherence and diversion. In order to meet FDA requirements, and for Probuphine( to become available to patients, an additional placebo-controlled trial must be completed. This six-month study will compare the safety and effectiveness of Probuphine( to placebo and also to the sublingual tablet form of buprenorphine, Suboxone(. It will be conducted in approximately 20 addiction treatment centers across the US, with a target enrollment of 250 participants. Successful screeners will be randomized in a 2:1:2 ratio to receive Probuphine( implants, placebo implants, or sublingual buprenorphine (12-18mg/day). All participants will also receive standardized (manual-driven), individual weekly drug counseling. Participants will be seen thrice weekly for the first 16 weeks and weekly for the last 8 weeks, followed by one additional safety visit at week 25. The primary specific aim is to compare the proportion of opioid-negative urine samples between groups at week 16. Secondary specific aims include evaluation of other important clinical parameters of addiction treatment including withdrawal symptoms, drug craving, and treatment compliance. This study will begin and complete within the 2-year time frame allowed. PUBLIC HEALTH RELEVANCE: Despite the well-established effectiveness and safety of sublingual buprenorphine (Suboxone() in the treatment of opioid addiction, significant therapeutic and public health issues exist due to poor medication adherence, and diversion and misuse of the sublingual tablets. This research project will evaluate an innovative new treatment, Probuphine(, which is a subcutaneous implant formulation of buprenorphine that delivers medication for six months following a single treatment. The significance of this research is that once approved and available to patients, Probuphine( will substantially address the important public health issues of compliance to treatment and diversion.