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（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）的修订应用。我们通过在50名具有AUD的50种非治疗方法的男性和女性中提供了最近完成的概念证明（POC）人类实验室研究（600 mg/d）的结果来解决方法和可行性问题，并将其纳入我们的IND（＃114497）中的录取标准和安全参数（包括PORVINCTISSONE SPOCTISS），并将其纳入了我们的IND（＃114497）中，这是POCCRISTISS PORTISTIS的录取标准和安全参数。 NIAAA的优先事项是对患者和临床医生具有更大可接受性的AUD的更有效和耐受性的耐受性的开发。该提议中检验的假设是糖皮质激素受体的拮抗作用是一种有效的治疗方法。糖皮质激素受体是与AUD发作，维持和复发相关的脑应力反应不可或缺的。我们建议测试有效的糖皮质激素受体拮抗剂，米非酮的疗效，该米非酮可迅速恢复和维持脑应力系统中的正常音调。我们提出的米非司酮的临床试验基于在临床前和人类实验室的长期禁欲模型中用米非司酮获得的阳性结果。在我们的POC研究中，用600 mg/d治疗的1周治疗可显着降低实验室中的提示和应力诱导的渴望；饮酒，渴望和GGT的显着减少以及对学习，记忆和执行功能的测试的改善持续了1个月的治疗，相对于安慰剂，在50位具有AUD的非治疗者中，其安慰剂。我们建议将我们的POC研究结果扩展到寻求样本的治疗方法，米非司酮为1周，通过重新设置HPA轴和8周的咨询率来巩固和维持米非司酮在150名男性和女性中的米非司酮效应，以提高初始反应的速度。基于在我们的600 mg POC研究中发现的更好的饮酒结果和较高的米非生血浆浓度之间的显着关联，而没有安全性或耐受性的问题，我们建议进行3臂剂量范围的研究，随机分组以与600或1200 mg/d的双倍处理，以识别Mifepristone或匹配的地理位置的双重治疗，以识别最佳的地理位置，以识别均可供应量的量子。我们的主要目的是确定Mifepristone治疗是否与安慰剂相对于安慰剂的饮酒结果显着改善。我们假设Mifepristone将与：1。）相关，每周饮酒天数和每周消耗的饮料数量和2.）与安慰剂相对于8周的研究，无重量饮酒率的显着线性剂量率增加。我们的次要目的是确定米非酮是否与安慰剂相比，神经认知功能的渴望和改善明显更大。我们的探索性目的是确定米非酮对饮酒结果的影响是否由FKBP5基因中的多态性预测，FKBP5基因是糖皮质激素复合物和皮质反应的重要调节剂，以提供更有针对性的AUD治疗方法。