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盐酸洛非昔定的安全性和有效性特征，以解决fda定义的临床开发项目中的空白，盐酸洛非昔定是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。该项目包括在同一地点连续进行的两项相关研究：研究1将在600名即将完全或突然戒断短效阿片类药物的受试者中生成两种剂量盐酸洛非昔定的关键疗效/安全性数据，这些受试者将在双盲条件下随机分配到安慰剂（N=150）或洛非昔定（每日总剂量2.4 mg或3.2 mg； N=225/组）进行7天的住院治疗。随后，所有受试者将被允许在开放标签条件下继续进行最多7天的住院/门诊可变剂量治疗，这取决于现场调查员和受试者的意愿。安全性将通过不良事件评估（AE）、临床实验室、心电图（特别注意）来评估

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.