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

洛非西定 (S) 的 3 期双盲疗效、安全性和剂量反应研究

• 批准号: 8547804
• 负责人: Charles W. Gorodetzky
• 金额: $ 554.44万
• 依托单位: US WORLDMEDS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547804
• 关键词: Abstinence; Acute; Address; Adrenergic Agonists; Adverse effects; Adverse event; Alternative Therapies; American; Applications Grants; Area Under Curve; Attention; Buprenorphine; Clinical; Data; Databases; Development; Dose; Double-Blind Method; Drug Metabolic Detoxication; Effectiveness; Electrocardiogram; Enrollment; Evaluation; FDA approved; Hydrochloride Salt; Incidence; Inpatients; Laboratories; Life; Link; Literature; Marketing; Medical; Methadone; Narcotics; Opiates; Opioid; Outcome Measure; Outpatients; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Product Labeling; Program Development; Publishing; Randomized; Reporting; Research; Research Design; Research Personnel; Safety; Severe Adverse Event; Signs and Symptoms; Site; Symptoms; Translational Research; United Kingdom; United States Food and Drug Administration; Urine; Visual; Withdrawal; Work; analog; base; cohort; design; drug development; drug of abuse; experience; impression; lofexidine; meetings; open label; opioid withdrawal; phase 3 study; primary outcome; programs; public health relevance; response; standard of care; therapy development; treatment duration; trend

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.

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 规定的盐酸洛非西定临床开发计划中的差距，洛非西定是一种正在开发的 α-2 肾上腺素能激动剂，用于治疗短期急性戒断症状。 -作用阿片类药物。该计划包括在同一地点连续进行的两项相关研究：研究 1 将在 600 名即将接受短效阿片类药物突然戒断的受试者中，生成两剂盐酸洛非西定的关键疗效/安全性数据，这些受试者将被随机分组双盲条件下住院患者接受安慰剂 (N=150) 或洛非西定（2.4 mg 或 3.2 mg 每日总剂量；N=225/组）7 天 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，具体取决于现场调查员和受试者的意愿。将通过不良事件（AE）、临床实验室、心电图评估（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评估疗效，包括 Gossop 短期阿片戒断量表 (SOWS-G)（主要结果指标是第 1-7 天的 SOWS-G 评分曲线下面积）、客观阿片戒断量表戒断量表 (OOWS-Handelsman)、功效视觉模拟量表 (VAS-E) 以及功效和副作用的改良临床总体印象量表影响。疗效还将通过研究保留率、完成率、伴随药物使用、戒断相关 AE 发生率以及出院后 30 天的受试者治疗状态进行评估。研究 2 将遵循类似的 14 天给药形式，但将完全开放标签； 200至400名受试者（与研究1中的受试者不同）将接受不超过可变剂量的洛非西定 根据入组地点的正常护理标准，在住院患者、门诊患者或组合环境中每天总共 3.2 mg 或单剂量 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进行安全性评估：尿液呈阴性的受试者和尿液滥用药物呈阳性的受试者，以便可以考虑分析报告的 AE 的所有可能原因。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来评估有效性。研究 2 中计划的开放标签、可变剂量、真实世界设计在第 3 期药物开发中很常见，并且与研究 1 一起，研究 1 将提供支持拟议产品适应症所需的关键功效数据，该计划已旨在满足洛非西定的 FDA 注册要求。新药申请获得批准后，洛非西定将成为美国第一个获批用于治疗阿片类药物戒断的非麻醉、非成瘾药物，为该适应症提供了一种重要的替代疗法。