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

摘要 虽然开发治疗AUD的新型药物仍然是一个高度优先的研究领域，但主要 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 研究新的化合物对AUD，是如何有效地确定一种新的药物是否有足够的 初步疗效的证据，以保证后续临床试验的进行。筛选小说的过程 用于初始功效的化合物，称为药物开发的早期阶段2，通常由以下组成： 人类实验室研究评估推定的临床相关性的结构，如酒精渴望， 对酒精的主观反应和实验室条件下的酒精自我给药。然而，尽管如此， 这些受控的人类实验室模型缺乏临床试验的生态有效性， 通过有动机改变其饮酒的个体中的临床意义的终点来确定效果。的 这项建议的科学前提是，筛选新的AUD药物可以是有效的， 如果早期2期研究联合收割机将实验室测试的内部效度与 临床试验的外部效度。为此，我们提出了一种新的早期疗效检测范式， 通过了解戒烟药物开发文献，筛选有前景的AUD药物。 具体来说，这种新的人类实验室协议涉及安慰剂对照，受试者内，交叉 设计，其中具有当前AUD的个体报告改变其饮酒的内在动机， 两周的“练习戒烟尝试”和线索-反应性范例，间隔1周的清除期。的 主要结果是每个戒烟练习周的戒烟天数。拟议的实验室 已经制定并验证了用于筛选戒烟药物疗法的方案。客观 该提案的目的是调整和验证这种新方法来筛选AUD的药物治疗。

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.