Pregnenolone for the Treatment of Alcohol Use Disorder

项目摘要/摘要 酒精使用障碍(AUD)是一种与高复发率相关的慢性复发性疾病，因此， 迫切需要开发和评估新的治疗方法来减少复发和改善酒精使用 以澳元计算的结果。我们之前进行了一项新的剂量发现人体实验室、安全性和试验效果 评估神经活性类固醇(NAS)前体孕烯醇酮(PREG)是否影响 GABA能功能可能使酒精相关的应激障碍正常化并改善酒精使用结果 澳元。试点数据显示，每天300毫克的PREG可以减少压力和线索诱导的酒精渴求、焦虑 以及压力生物学中与酒精相关的慢性干扰的正常化，以及每天减少饮酒量 (AvgD)、饮酒天数和重度饮酒天数(%DD和%HDD)与安慰剂(PBO)的比较 每周临床研究。在这些发现的基础上，本项目提出了为期12周的双盲、随机 第二阶段临床试验，评估PREG(300 mg/d)与PBO治疗150人的安全性和有效性 所有的男人和女人。将实现以下具体目标：目标1：建立安全和 男性和女性AUD患者在12周治疗期间对PREG(300 mg/d)和PBO的耐受性 在1个月的随访期。目的#2：测试PREG与PBO对初次饮酒的疗效 在试验期间，PSNHDD的结果和HDD%、DD%和AvgD的二次饮酒结果。目标3：达到 评估PREG与PBO对酒精渴求、焦虑、 试验期间的抑郁和患者相关功能。目的#4：评估PREG与PBO对 PRG和其他NAS水平，并检查它们与初次和二次饮酒的关系以及相关 结果。探索性目标1：评价PREG与PBO治疗原发性肺癌的远期疗效 以及治疗后1个月随访的其他次要结果。探索性目标2：探索 治疗前患者特征(性别、创伤病史、AUD严重程度和共生精神障碍) 影响PREG对初级和次级结局的影响。众所周知，长期饮酒 下调在AUD应激病理生理学中起重要作用的GABA，也在AUD的 控制饮酒。拟议的研究是基于我们新的初步发现，并将测试我们的创新 提高内源性神经活性类固醇水平以增强其功能从而改善其功能的方法 AUD结果。如果成功，这项拟议的研究将确立PREG和神经活性类固醇为关键 治疗AUD的靶点，还提供了神经活性类固醇水平的数据，以及它们是否可以 作为AUD治疗的生物标志物。

PROJECT SUMMARY/ABSTRACT Alcohol Use Disorder (AUD) is a chronic relapsing illness associated with high rates of relapse, and thus, there is great need to develop and evaluate novel treatments to decrease relapse and improve alcohol use outcomes in AUD. We previously conducted a novel dose finding human laboratory, safety and pilot efficacy study to assess whether the neuroactive steroid (NAS) precursor pregnenolone (PREG) that influences GABAergic functioning may normalize alcohol-related stress disruption and improve alcohol use outcomes in AUD. Pilot data showed that PREG at 300mg/day reduced stress- and cue- induced alcohol craving, anxiety and normalized chronic alcohol-related disruption in stress biology and also reduced alcohol drinks/day (AvgD), percent drinking days and heavy drinking days (%DD and %HDD) compared to placebo (PBO) in an 8- week clinical study. On the basis of these findings, this project proposes a 12-week double blind, randomized Phase II clinical trial to evaluate the safety and efficacy of PREG treatment (300 mg/day) versus PBO in 150 AUD men and women. The following specific aims will be addressed: Aim #1: To establish the safety and tolerability of PREG (300mg/day) vs. PBO in men and women with AUD over the 12-week treatment period and at the 1-month follow up. Aim #2: To test the efficacy of PREG vs. PBO on the primary alcohol use outcome of PSNHDD and secondary drinking outcomes of HDD%, DD% and AvgD during the trial. Aim #3: To assess the effects of PREG vs. PBO on other secondary stress-related outcomes of alcohol craving, anxiety, depression and patient-related functioning during the trial. Aim #4: To assess the effects of PREG vs. PBO on PREG and other NAS levels and examine their relationship to primary and secondary alcohol use and related outcomes. Exploratory Aim 1: To assess enduring short-term treatment effect of PREG vs. PBO on primary and other secondary outcomes at a 1-month post-treatment follow-up. Exploratory Aim 2: To explore whether pre-treatment patient characteristics (sex, trauma history, AUD severity and co-occurring psychiatric disorders) influence PREG effects on primary and secondary outcomes. It is well known that chronic alcohol use downregulates GABA which plays a significant role in the stress pathophysiology of AUD and also in loss of control drinking. The proposed study is based on our novel preliminary findings and will test our innovative approach of boosting endogenous neuroactive steroid levels to increase their function and thereby improve AUD outcomes. If successful, the proposed research will establish PREG and neuroactive steroids as key targets in the treatment of AUD, and also provide data on neuroactive steroid levels and whether they may serve as biomarkers in AUD treatment.