Pregnenolone for the Treatment of Alcohol Use Disorder

孕烯醇酮用于治疗酒精使用障碍

• 批准号: 10681961
• 负责人: VERICA MILIVOJEVIC
• 金额: $ 75.2万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681961
• 关键词: Address; Aftercare; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anxiety; Biological Markers; Biology; Characteristics; Chemosensitization; Chronic; Clinical Research; Cognitive; Cues; Data; Development; Dose; Double-Blind Method; FDA approved; Functional disorder; Glucuronides; Health Care Costs; Heavy Drinking; Human; Individual; Laboratories; Mental Depression; Mental Health; Mental disorders; Neurosecretory Systems; Outcome; Pathway interactions; Patient Self-Report; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Placebo Control; Placebos; Play; Prefrontal Cortex; Pregnenolone; Prevalence; Public Health; Randomized; Randomized, Controlled Trials; Recording of previous events; Regulation; Relapse; Reporting; Research; Role; Safety; Self Assessment; Self-control as a personality trait; Severities; Stress; Surgeon; Testing; Time; Trauma; Up-Regulation; Woman; alcohol abuse therapy; alcohol craving; alcohol relapse; alcohol use disorder; anxiety symptoms; chronic alcohol ingestion; clinical efficacy; craving; depressive symptoms; drinking; efficacious treatment; efficacy evaluation; efficacy study; efficacy testing; executive function; flexibility; follow-up; functional improvement; gamma-Aminobutyric Acid; hypothalamic-pituitary-adrenal axis; improved; innovation; men; neurosteroids; novel; physical conditioning; primary outcome; receptor; reduced alcohol use; safety assessment; secondary outcome; sex; stress reduction; treatment duration; treatment effect

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.

项目概要/摘要 酒精使用障碍 (AUD) 是一种慢性复发性疾病，复发率很高，因此， 非常需要开发和评估新的治疗方法以减少复发和改善饮酒 结果以澳元计算。我们之前进行了一项新剂量探索人体实验室、安全性和试点功效 研究评估神经活性类固醇 (NAS) 前体孕烯醇酮 (PREG) 是否会影响 GABAergic 功能可以使酒精相关的压力干扰正常化并改善酒精使用结果 澳元。试验数据显示，每天 300 毫克的 PREG 可减少压力和提示引起的酒精渴望、焦虑 使应激生物学中与慢性酒精相关的破坏正常化，并减少每天的饮酒量 (AvgD)、饮酒天数百分比和重度饮酒天数 (%DD 和 %HDD) 与安慰剂 (PBO) 相比，在 8- 周临床研究。根据这些发现，该项目提出了为期 12 周的双盲、随机 II 期临床试验，在 150 名患者中评估 PREG 治疗（300 毫克/天）与 PBO 的安全性和有效性 男性和女性澳元。将解决以下具体目标： 目标#1：建立安全和 在 12 周治疗期内，患有 AUD 的男性和女性对 PREG（300 毫克/天）与 PBO 的耐受性 以及1个月的随访。目标#2：测试 PREG 与 PBO 对主要酒精使用的功效 试验期间 PSNHDD 的结果以及 HDD%、DD% 和 AvgD 的二次饮酒结果。目标#3： 评估 PREG 与 PBO 对其他次要压力相关结果（如渴望酒精、焦虑、 试验期间的抑郁症和患者相关功能。目标#4：评估 PREG 与 PBO 对 PREG 和其他 NAS 水平，并检查它们与主要和次要酒精使用及相关的关系 结果。探索性目标 1：评估 PREG 与 PBO 对原发性乳腺癌的持久短期治疗效果 以及治疗后 1 个月随访时的其他次要结果。探索性目标 2：探索是否 治疗前患者特征（性别、创伤史、AUD 严重程度和并发精神疾病） 影响 PREG 对主要和次要结果的影响。众所周知，长期饮酒 下调 GABA，GABA 在 AUD 的应激病理生理学以及丧失 控制饮酒。拟议的研究基于我们新颖的初步发现，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 澳元结果。如果成功，拟议的研究将确立 PREG 和神经活性类固醇作为关键 AUD 治疗的目标，还提供神经活性类固醇水平的数据以及它们是否可能 作为 AUD 治疗中的生物标志物。