Glucocorticoid Antagonist Treatment of Alcohol Use Disorder

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。我们通过提供我们最近完成的米非司酮（600mg /d）在50名非寻求治疗的AUD患者中进行的概念验证（POC）人体实验室研究的结果，并通过纳入米非司酮POC研究的IND（#114497）中包含的入院标准和安全参数，解决了方法和可行性问题，这与本项目的目标直接相关。开发更有效和耐受性更好的药物治疗AUD，使患者和临床医生更容易接受是NIAAA的优先事项。本研究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发病、维持和复发相关的脑应激反应的组成部分。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功效，米非司酮的作用是迅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人类实验室长期戒断模型中获得的积极结果。在我们的POC研究中，在实验室中，米非司酮600毫克/天治疗1周显著减少了线索和压力引起的渴望；在50名未寻求治疗的AUD患者中，饮酒、渴望和GGT显著减少，学习、记忆和执行功能测试的改善持续了1个月。我们建议将我们的POC研究结果扩展到寻求治疗的样本中，在150名患有DSM-V中度AUD的男性和女性中，使用1周的米非司酮以通过重新设置HPA轴来提高初始缓解率，并进行8周的咨询以巩固和维持米非司酮的效果。基于我们在600 mg POC研究中发现的更好的饮用结果和更高的米非司酮血浆浓度之间的显著关联，并且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AUD的最佳剂量。我们的主要目的是确定相对于安慰剂，米非司酮治疗是否与AUD患者饮酒结局的显著改善相关。我们假设米非司酮将与：1.)每周重度饮酒天数和每周饮酒数量的显著线性剂量相关减少，以及2.)与安慰剂相比，8周研究期间无重度饮酒率的显著线性剂量相关增加。我们的次要目的是确定米非司酮是否比安慰剂更能显著减少渴望和改善神经认知功能。我们的探索性目的是确定米非司酮对饮酒结果的影响是否可以通过FKBP5基因的多态性来预测，FKBP5基因是糖皮质激素复合物和皮质反应的重要调节因子，从而为AUD提供更有针对性和更有效的治疗。

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.