A Phase 3, Double-Blind Efficacy, Safety and Dose-Response Study of Lofexidine (S

描述（由申请方提供）：拟定研究旨在表征安全性和疗效特征，以解决FDA定义的盐酸洛非西定（一种正在开发的用于治疗短效阿片类药物急性戒断的α-2肾上腺素能激动剂）临床开发项目中的空白。该计划包括在相同研究中心连续进行的两项相关研究：研究1将生成600名受试者中两种剂量盐酸洛非西定的关键疗效/安全性数据，这些受试者将接受短效阿片类药物的完全和突然戒断，并将在双盲条件下随机分配至安慰剂（N=150）或洛非西定组（2.4 mg或3.2 mg每日总剂量; N=225/组），持续7天住院治疗。随后，根据研究中心研究者和受试者的意愿，允许所有受试者在开放标签条件下继续接受最多7天的住院/门诊可变剂量治疗。将通过评价不良事件（AE）、临床实验室检查、心电图（特别注意 QTc）、生命体征和体格检查数据。每天将通过受试者和患者完成的量表评价疗效，包括简短的Gossop阿片类戒断量表（SOWS-G）（主要结局指标为第1-7天的SOWS-G评分曲线下面积）、客观阿片类戒断量表（OOWS-Handelsman）、疗效视觉模拟量表（VAS-E）和改良的临床总体疗效量表（疗效和副作用）。还将通过研究保留率、完成率、合并用药使用、退出相关AE的发生率和出院后30天的受试者治疗状态评价疗效。研究2将遵循类似的14天给药形式，但将是完全开放标签的; 200至400名受试者（与研究1中的受试者不同）将以不超过 根据入组研究中心的正常标准治疗，在住院患者、门诊患者或组合情况下，每天总计3.2 mg或单次给药0.8 mg。研究2是一项转化研究设计，旨在收集“真实世界”的有效性和安全性数据，以补充现有的洛非西定安全性数据库，并为最终用户提供适当的产品标签。将对所有接受治疗的受试者和两个队列（尿液药物滥用阴性和尿液药物滥用阳性的受试者）进行安全性评价，以便考虑报告AE的所有可能原因进行分析。将通过临床阿片类戒断量表（COWS）、脱毒完成率和出院后30天的受试者治疗状态评价有效性。研究2中计划的开放标签、可变剂量、真实世界设计在III期药物开发中很常见，并且与研究1一起将提供支持拟定产品适应症所需的关键疗效数据，该项目旨在满足洛非西定的FDA注册要求。在NDA获批后，洛非西定将成为美国首个获批用于治疗阿片类戒断的非麻醉性、非成瘾性药物，为该适应症提供重要的替代疗法。 公共卫生相关性：随着数百万美国人越来越依赖处方药和其他短效阿片类药物，对新的解毒治疗的医疗需求尚未得到满足。FDA批准用于该适应症的唯一药物（美沙酮和丁丙诺啡）是阿片类替代或替代疗法，其本身具有滥用潜力。拟定的盐酸洛非西定研究计划将：i）通过检查两种不同剂量的洛非西定的安全性和有效性来确定剂量范围; ii）确认洛非西定可以使用至阿片类药物戒断的急性期完成（即，最多14天）;以及iii）通过采用“真实世界”策略来研究额外的受试者并增加识别可能仅存在于一小部分用户中的潜在安全问题的可能性来增加安全数据库。NIDA对洛非西定开发工作的支持对于FDA批准第一个非麻醉性、非成瘾性阿片类药物戒断治疗是必要的。

DESCRIPTION (provided by applicant): The proposed research is aimed at characterizing the safety and efficacy profiles to address FDA-defined gaps in the clinical development program for lofexidine hydrochloride, an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short-acting opioids. The program includes two linked studies to be conducted consecutively at the same sites: Study 1 will generate pivotal efficacy/safety data for two doses of lofexidine hydrochloride in 600 subjects about to undergo total and abrupt withdrawal from short- acting opioids who will be randomized under double-blind conditions to either placebo (N=150) or lofexidine (2.4 mg or 3.2 mg total daily dose; N=225/group) for 7 days of inpatient treatment. Subsequently, all subjects will be permitted to continue under open-label conditions for up to an additional 7 days of inpatient/outpatient, variable-dose treatment depending on the wishes of the Site Investigator and subject. Safety will be assessed by evaluation of adverse event (AE), clinical laboratory, electrocardiogram (with special attention to QTc), vital signs, and physical exam data. Efficacy will be evaluated daily by subject- and observer-completed scales including the Short Opiate Withdrawal Scale of Gossop (SOWS-G) (the primary outcome measure is SOWS-G score area under the curve for Days 1-7), the Objective Opiate Withdrawal Scale (OOWS-Handelsman), the Visual Analog Scale for Efficacy (VAS-E), and the Modified Clinical Global Impressions scales for efficacy and side effects. Efficacy will also be evaluated by study retention, completion rates, concomitant medication use, incidence of withdrawal-related AEs, and subject treatment status 30 days post discharge. Study 2 will follow a similar 14-day dosing format but will be entirely open-label; and 200 to 400 subjects (different from those in Study 1) will receive lofexidine at a variable dose not to exceed a total of 3.2 mg per day or a single dose of 0.8 mg in an inpatient, outpatient, or a combination of settings as per the normal standard of care at the enrolling site. Study 2 is a translational research design aimed at gathering "real-world" effectiveness and safety data to supplement the existing lofexidine safety database and enable appropriate product labeling for end-users. Safety will be evaluated for all treated subjects and for two cohorts: those with urines negative and those with urines positive for drugs of abuse so that all possible causes of reported AEs may be considered for analysis. Effectiveness will be evaluated by the Clinical Opiate Withdrawal Scale (COWS), rate of detoxification completion, and subject treatment status 30 days post discharge. An open-label, variable-dose, real-world design as planned in Study 2 is common in Phase 3 drug development, and together with Study 1, which will provide pivotal efficacy data needed to support the proposed product indication, the program has been designed to address FDA registration requirements for lofexidine. On approval of an NDA, lofexidine will be the first approved non-narcotic, non-addictive drug indicated for treatment of opioid withdrawal in the US, providing an important alternative therapy for this indication. PUBLIC HEALTH RELEVANCE: With a growing trend of millions of Americans becoming dependent on prescription and other short-acting opioid narcotics, there is an unmet medical need for new detoxification treatments. The only drugs approved by the FDA for this indication (methadone and buprenorphine) are opioid replacement or substitution therapies which themselves have abuse potential. The proposed research program on lofexidine hydrochloride will: i) establish the dose range by examining the safety and efficacy of two different doses of lofexidine; ii) confirm that lofexidine may be used until the acute phase of opioid withdrawal is complete (i.e., up to 14 days); and iii) increase the safety database by employing a "real-world" strategy to study additional subjects and increase the likelihood of identifying potential safety issues that may be present in only a small percentage of users. NIDA's support of this development work on lofexidine is necessary to enable FDA approval of the first non-narcotic, non-addictive treatment for opioid withdrawal.