Glucocorticoid Antagonist Treatment of Alcohol Use Disorder

糖皮质激素拮抗剂治疗酒精使用障碍

• 批准号: 8803452
• 负责人: BARBARA J MASON
• 金额: $ 56.67万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803452
• 关键词: Abstinence; Address; Admission activity; Affinity; Aftercare; Alcoholism; Animal Model; Brain; Chronic; Clinical; Clinical Trials; Collaborations; Complex; Counseling; Cues; DSM-V; Development; Dose; Double-Blind Method; Evaluation; FDA approved; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Glucocorticoid Receptor; Glucocorticoids; Health Personnel; Heavy Drinking; Human; Hydrocortisone; Laboratories; Laboratory Study; Learning; Liver Function Tests; Maintenance; Managed Care; Memory; Mifepristone; Modeling; National Institute on Alcohol Abuse and Alcoholism; Neurocognitive; Neurosecretory Systems; Outcome; Outpatients; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Placebos; Plasma; Randomized; Relapse; Relative (related person); Resources; Risk; Safety; Sampling; Severities; Stress; Subjects Selections; System; Testing; Titrations; Validation; Woman; alcohol seeking behavior; alcohol use disorder; arm; base; biological adaptation to stress; clinical application; craving; drinking; effective therapy; efficacy testing; executive function; men; neurogenetics; novel; pre-clinical; public health relevance; response; treatment response

DESCRIPTION (provided by applicant): This is a revised application of Glucocorticoid Antagonist Treatment of Alcohol Use Disorder (AUD). We addressed approach and feasibility concerns by providing results from our recently completed proof-of-concept (POC) human laboratory study of mifepristone (600 mg/d) in 50 non treatment-seeking men and women with AUD, and by incorporating the admission criteria and safety parameters included in our IND (#114497) for the mifepristone POC study, which are directly relevant to the aims of the present project. The development of more effective and better tolerated pharmacotherapies for AUD that have greater acceptability to patients and clinicians is a NIAAA priority. The hypothesis under test in this proposal is that antagonism of the glucocorticoid receptor is an effective treatment fr AUD. The glucocorticoid receptor is integral to the brain stress response associated with onset, maintenance and relapse in AUD. We propose to test the efficacy of a potent glucocorticoid receptor antagonist, mifepristone that acts to rapidly restore and maintain normal tone in the brain stress system. Our proposed clinical trial of mifepristone is based on positive results obtained with mifepristone in pre-clinical and human laboratory models of protracted abstinence. In our POC study, 1-week of treatment with mifepristone 600 mg/d significantly reduced cue- and stress-induced craving in the lab; significant decreases in drinking, craving and GGT, and improvement on tests of learning, memory and executive function persisted for 1-month post treatment relative to placebo in 50 non treatment seekers with AUD. We propose to extend our POC study results to a treatment seeking sample, with 1-week of mifepristone to increase rate of initial response by re-setting the HPA axis and 8 weeks of counseling to consolidate and sustain mifepristone effects in 150 men and women with DSM-V AUD of e moderate severity. Based on the significant association between better drinking outcome and higher mifepristone plasma concentration found in our 600 mg POC study in conjunction with no safety or tolerability concerns, we propose to conduct a 3-arm dose-ranging study with randomization to double-blind treatment with 600 or 1200 mg/d of mifepristone or matched placebo in order to identify optimal dosing for AUD. Our Primary Aim is to determine if mifepristone treatment is associated with significant improvement in drinking outcomes in AUD relative to placebo. We hypothesize mifepristone will be associated with: 1.) significant linear dose-related reductions in the number of heavy drinking days per week and the number of drinks consumed per week, and 2.) a significant linear dose- related increase in rates of no heavy drinking over the 8-week study relative to placebo. Our Secondary Aims are to determine if mifepristone is associated with a significantly greater reduction in craving and improvement in neurocognitive functioning than placebo. Our Exploratory Aim is to determine whether mifepristone effects on drinking outcome are predicted by polymorphisms in the FKBP5 gene, an important regulator of the glucocorticoid complex and cortical response, to provide more targeted and effective treatment of AUD.

描述（由申请人提供）：这是糖皮质激素拮抗剂治疗酒精使用障碍（AUD）的修订申请。我们通过提供最近完成的米非司酮（600 毫克/天）概念验证 (POC) 人体实验室研究的结果，解决了方法和可行性问题，该研究对 50 名非寻求治疗的 AUD 男性和女性进行了研究，并纳入了入院标准以及米非司酮 POC 研究的 IND (#114497) 中包含的安全参数，这些参数与当前项目的目标直接相关。 NIAAA 的首要任务是开发更有效、耐受性更好的 AUD 药物疗法，使患者和临床医生更容易接受。本提案中所测试的假设是糖皮质激素受体的拮抗作用是 AUD 的有效治疗方法。糖皮质激素受体是与 AUD 发病、维持和复发相关的大脑应激反应不可或缺的一部分。我们建议测试有效的糖皮质激素受体拮抗剂米非司酮的功效，米非司酮可快速恢复和维持大脑应激系统的正常张力。我们提出的米非司酮临床试验是基于米非司酮在临床前和长期戒断人体实验室模型中获得的积极结果。在我们的 POC 研究中，米非司酮 600 毫克/天治疗 1 周，在实验室中显着降低了线索和压力引起的渴望；与安慰剂相比，50 名未寻求治疗的 AUD 患者在治疗后 1 个月内饮酒、渴望和 GGT 显着下降，学习、记忆和执行功能测试持续改善。我们建议将我们的 POC 研究结果扩展到寻求治疗的样本，在 150 名患有以下疾病的男性和女性中，使用 1 周的米非司酮，通过重新设定 HPA 轴来提高初始反应率，并进行 8 周的咨询，以巩固和维持米非司酮的效果。 DSM-V AUD 的严重程度为中等。基于在我们的 600 mg POC 研究中发现更好的饮酒结果和更高的米非司酮血浆浓度之间的显着关联，并且没有安全性或耐受性问题，我们建议进行一项 3 组剂量范围研究，随机化至双盲治疗600 或 1200 mg/d 米非司酮或匹配的安慰剂，以确定 AUD 的最佳剂量。我们的主要目标是确定米非司酮治疗是否与 AUD 相对于安慰剂的饮酒结果的显着改善相关。我们假设米非司酮与以下因素相关：1.) 每周重度饮酒天数和每周饮酒次数与剂量相关的显着线性减少，以及 2.) 不饮酒率与剂量相关的显着线性增加。与安慰剂相比，在为期 8 周的研究中大量饮酒。我们的次要目标是确定米非司酮是否比安慰剂更能显着减少食欲并改善神经认知功能。我们的探索性目标是确定米非司酮对饮酒结果的影响是否可以通过 FKBP5 基因（糖皮质激素复合物和皮质反应的重要调节因子）的多态性来预测，从而为 AUD 提供更有针对性和更有效的治疗。