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

描述(由申请人提供)：拟议的研究旨在描述安全性和有效性特征，以解决FDA定义的盐酸洛非西定临床开发计划中的空白，盐酸洛非西定是一种正在开发的α-2肾上腺素能激动剂，用于治疗短效阿片类药物的急性戒断。该计划包括将在同一地点连续进行的两项相互关联的研究：研究1将在600名即将完全和突然停用短效阿片类药物的受试者中产生关键的疗效/安全性数据，这些受试者将在双盲条件下随机分为安慰剂(N=150)或洛非西定(2.4毫克或3.2毫克每日总剂量；N=225/组)进行7天的住院治疗。随后，根据现场调查员和受试者的意愿，所有受试者将被允许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。安全性将通过评估不良事件(AE)、临床实验室、心电图(特别注意 QTC)、生命体征和体检数据。每天将通过受试者和观察者完成的量表进行疗效评估，包括Gossop短期阿片类药物戒断量表(SOWS-G)(主要结果衡量标准是第1-7天的SOWS-G评分曲线下的面积)、客观阿片类药物戒断量表(OOWS-Handelsman)、视觉模拟疗效量表(VAS-E)以及修改后的临床总体印象量表的疗效和副作用。疗效还将通过研究保留率、完成率、伴随用药情况、与戒断相关的不良反应发生率以及出院30天后受试者的治疗状况进行评估。研究2将遵循类似的14天剂量形式，但将完全开放标签；200至400名受试者(与研究1不同)将接受不超过的可变剂量的洛非西定。 根据登记地点的正常护理标准，每天总共3.2毫克或单次0.8毫克的剂量用于住院患者、门诊患者或两者的组合。研究2是一项翻译研究设计，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组受试者进行安全性评估：尿液阴性者和尿液药物滥用阳性者，以便可以考虑报告的不良反应的所有可能原因进行分析。疗效将通过临床阿片戒断量表(COWS)、戒毒完成率和出院后30天的受试者治疗状态进行评估。研究2中计划的开放标签、可变剂量的真实世界设计在第三阶段药物开发中很常见，研究1将提供支持建议的产品适应症所需的关键疗效数据，该计划旨在满足FDA对洛非西定的注册要求。一旦获得批准，洛非西定将成为美国第一个被批准用于治疗阿片类药物戒断的非麻醉性、非成瘾性药物，为这一适应症提供了一种重要的替代疗法。 与公共健康相关：随着数百万美国人越来越依赖处方和其他短效阿片类麻醉剂的趋势，对新的戒毒疗法的医疗需求尚未得到满足。FDA批准的唯一用于这一适应症的药物(美沙酮和丁丙诺啡)是阿片类药物替代或替代疗法，这些药物本身具有滥用潜力。拟议的盐酸洛非西定研究方案将：一)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；二)确认可以使用洛非西定直到阿片类药物戒断的急性期结束(即最多14天)；三)通过采用“真实世界”战略来增加安全数据库，以研究更多的受试者，并增加发现仅在一小部分使用者中可能存在的潜在安全问题的可能性。NIDA对洛非西定开发工作的支持是必要的，以使FDA能够批准第一种非麻醉性、非成瘾性的阿片类药物戒断治疗。

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.