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: 8917076
• 负责人: BARBARA J MASON
• 金额: $ 54.74万
• 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/8917076
• 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 Polymorphism; Glucocorticoid Receptor; Glucocorticoids; Health; 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; genetic predictors; men; neurogenetics; novel; pre-clinical; response; targeted treatment; 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(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。我们解决了方法和可行性问题，提供了最近完成的米非司酮(600 mg/d)人体实验室研究的结果，该研究对50名患有AUD的非治疗男性和女性进行了米非司酮(600 mg/d)的治疗，并纳入了与本项目目标直接相关的IND(#114497)中包含的米非司酮概念验证研究的入院标准和安全参数。开发更有效和耐受性更好的AUD药物疗法，使患者和临床医生更容易接受，是NIAAA的优先事项。在这项建议中接受检验的假设是，糖皮质激素受体拮抗剂是治疗AUD的有效方法。糖皮质激素受体是与AUD的发病、维持和复发相关的大脑应激反应所不可或缺的。我们建议测试一种有效的糖皮质激素受体拮抗剂米非司酮的有效性，它能迅速恢复和维持大脑应激系统的正常音调。我们建议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的人体实验室模型中获得的积极结果。在我们的POC研究中，服用米非司酮600 mg/d的1周显著减少了实验室中由线索和压力引起的渴望；与安慰剂相比，50名患有AUD的非治疗寻求者在治疗后1个月显著减少了饮酒、渴望和GGT，并改善了学习、记忆和执行功能的测试。我们建议将我们的POC研究结果扩展到寻求治疗的样本，用1周的米非司酮通过重新设置HPA轴来提高初始应答率，并用8周的咨询来巩固和维持150名患有中度DSM-V AUD的男性和女性的米非司酮效果。在我们的600毫克POC研究中，我们发现更好的饮酒结果与较高的米非司酮血浆浓度之间存在显著的相关性，同时没有安全性或耐受性问题，我们建议进行一项三组剂量范围研究，随机双盲治疗600或1200 mg/d米非司酮或匹配的安慰剂，以确定治疗AUD的最佳剂量。我们的主要目标是确定与安慰剂相比，米非司酮治疗是否与AUD患者饮酒结果的显著改善有关。我们假设米非司酮与以下因素有关：1)每周大量饮酒天数和每周饮酒次数与剂量相关的显著线性减少，以及2.)在这项为期8周的研究中，与安慰剂相比，与剂量相关的显著线性不酗酒比率上升。我们的次要目标是确定与安慰剂相比，米非司酮是否与显著降低渴求和改善神经认知功能有关。我们的探索性目的是确定米非司酮对饮酒结局的影响是否通过FKBP5基因的多态性来预测，FKBP5基因是糖皮质激素复合体和皮质反应的重要调节因子，以提供更有针对性和更有效的AUD治疗。