A Novel Human Laboratory Model for Screening Medications for Alcohol Use Disorder

用于筛选酒精使用障碍药物的新型人体实验室模型

• 批准号: 10019310
• 负责人: LARA A. RAY
• 金额: $ 18.53万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019310
• 关键词: Alcohol consumption; Alcohols; Area; Clinical; Clinical Research; Clinical Trials; Cross-Over Studies; Crossover Design; Cues; DSM-V; Detection; Development; Disease; Double-Blind Method; FDA approved; Human; Individual; Laboratories; Laboratory Study; Literature; Methods; Modeling; Naltrexone; Outcome; Participant; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebos; Procedures; Process; Protocols documentation; Randomized; Reading; Reporting; Research Priority; Self Administration; Signal Transduction; Testing; Translations; Treatment Efficacy; United States; Woman; alcohol craving; alcohol cue; alcohol response; alcohol screening; alcohol use disorder; breath alcohol measurement; clinically relevant; cost; cue reactivity; drinking; drinking behavior; improved; intrinsic motivation; men; novel; novel strategies; phase 2 study; phase 2 testing; primary outcome; screening; smoking cessation

ABSTRACT While developing novel medications to treat AUD remains a high priority research area, there are major opportunities to refine the process of screening novel compounds. To that end, a key question in clinical studies of novel compounds for AUD, is how to efficiently determine whether a novel medication has sufficient evidence of initial efficacy to warrant the conduct of subsequent clinical trials. The process of screening novel compounds for initial efficacy, known as the early phase 2 of medications development, often consists of human laboratory studies assessing constructs of putative clinical relevance, such as alcohol craving, subjective response to alcohol, and alcohol self-administration under laboratory conditions. Nevertheless, these controlled human laboratory models lack the ecological validity of clinical trials in which medication effects are established via clinically meaningful endpoints in individuals motivated to change their drinking. The scientific premise of this proposal is that screening novel AUD medications can be efficient and clinically meaningful if early phase 2 studies combine the internal validity of experimental laboratory testing with the external validity of clinical trials. To that end, we proposed to conduct a novel early efficacy detection paradigm informed by the smoking cessation medication development literature, to screen a promising AUD medication. Specifically, this novel human laboratory protocol involves a placebo-controlled, within-subjects, crossover design, in which individuals with current AUD reporting intrinsic motivation to change their drinking complete two week-long “practice quit attempts” and cue-reactivity paradigm separated by a 1 week washout period. The primary outcome is the number of abstinent days during each practice quit week. The proposed laboratory protocol has been developed and validated for screening smoking cessation pharmacotherapies. The objective of this proposal is to adapt and validate this novel approach to screen pharmacotherapies for AUD.

摘要 虽然开发治疗AUD的新药仍然是一个高度优先的研究领域，但有一些主要的 有机会改进筛选新化合物的过程。为此，临床上的一个关键问题 对治疗AUD的新化合物的研究，是如何有效地确定一种新药物是否有足够的 初步疗效的证据，以保证后续临床试验的进行。小说的筛选过程 最初疗效的化合物，也就是药物开发的早期阶段2，通常包括 人体实验室研究评估可能与临床相关的结构，如酒精渴求， 对酒精的主观反应和实验室条件下的酒精自我给药。不过， 这些受控人体实验室模型缺乏临床试验的生态有效性，在临床试验中，药物 影响是通过临床上有意义的终点在有动机改变饮酒的个人身上建立的。这个 这一建议的科学前提是筛选新的AUD药物可以有效并在临床上使用 如果早期的第二阶段研究将实验室实验的内部有效性与 临床试验的外部有效性。为此，我们提出了一种新的早期疗效检测范式 通过了解戒烟药物的发展文献，筛选出一种很有前途的AUD药物。 具体地说，这项新的人体实验室方案涉及受试者内安慰剂对照的交叉试验 设计，在这种设计中，目前患有AUD的人报告了改变饮酒的内在动机 两个星期的“练习戒烟尝试”和线索反应范式被一个星期的冲洗期隔开。这个 主要结果是每周戒除练习的禁欲天数。拟建的实验室 已经开发并验证了用于筛选戒烟药物疗法的方案。目标是 这项建议的目的是适应和验证这一新的方法来筛选AUD的药物疗法。