Genomic Predictors of Placebo response in Phase II AUD trials

项目总结 安慰剂反应是一种重要且鲜为人知的治疗反应现象。一个大的和 在长达十年的安慰剂对照双盲临床试验中，可变安慰剂反应已经很明显 测试了酒精使用障碍(AUD)的各种治疗方法。大的安慰剂效应使检测变得复杂 研究药物的可量化治疗效果，特别是对适度有效的精神病患者 毒品。安慰剂反应来自患者、临床试验人员和治疗的复杂交互作用 环境因素。因为安慰剂反应在个体之间错综复杂且多种多样，所以它是 在登记参加临床试验之前，要识别这些人是有挑战性的。拟议的项目旨在 探索基因组学在ІІ期AUD治疗试验中识别安慰剂反应者的效用。到目前为止，到 就我们所知，还没有进行全面的基因组研究来评估 与AUD治疗结果或安慰剂反应的关系。基因组分析需要大量的样本， 在与寻求治疗的个人进行的中小型临床试验中不容易收集 患有AUD或其他药物使用障碍。为了解决这个问题，我们将利用来自六家公司的资源 已完成和正在进行的两项由NIAAA资助的ІІ期AUD治疗试验。我们将首先检查以下方面的变化 在AUD治疗期间，登记的寻求治疗的澳大利亚人的饮酒模式 安慰剂(AimІ)。然后我们将探索这些饮酒变化是如何影响基因表达的，仔细阅读 每个个体的整个基因组(AimІІ)。其表达水平被发现发生变化的基因 一个人的饮酒行为，或者这个人戒酒的频率，都是可以的- 梳理以确定DNA序列(遗传)变异，使它们对不同数量的 酒精(AimІІІ)。接下来，我们将探索这些遗传变异及其表达模式 基因，可以预测患有AUD人群的安慰剂反应(以禁酒率衡量)，以及 其他精神疾病(可卡因成瘾和创伤后应激障碍；探索性目标І)。最后，我们将探索是否 已识别的遗传变异和基因在那些接受了 积极用药(恩丹西酮/托吡酯/纳曲酮)治疗他们的AUD(探索性目标ІІ)， 这可能有助于我们理解对有效药物的反应中嵌入的安慰剂成分，在 分子水平。总而言之，我们提议的项目在概念和方法上都是创新的 通过检测与饮酒量相关的基因表达差异来探索遗传变异 在安慰剂治疗期间。作为首次研究ІІ期安慰剂反应的基因组学特征 试验结果将为今后的翻译研究和宣传提供丰富的信息 个性化医疗。利用安慰剂反应并知道如何优化它将使我们能够：a) 改善总体结果；b)确定谁需要额外治疗，以及c)确定 AUD特定亚组的治疗指数(疗效/副作用)。

PROJECT SUMMARY Placebo response is an important and poorly understood phenomenon of treatment response. A large and variable placebo response has been evident in decade’s long placebo-controlled double blind clinical trials that tested various treatments for alcohol use disorders (AUD). Large placebo effects complicate detection of quantifiable treatment effects for investigational medications, especially for the modestly effective psychiatric drugs. Placebo response arise from a complex interaction of patient, clinical trial staff, and treatment environment factors. Because the placebo response is intricate, complex and variable among individuals, it is challenging to identify these individuals prior to enrollment in a clinical trial. The proposed project seeks to explore the utility of genomics to identify placebo responders in phase ІІ AUD treatment trials. To date, to the best of our knowledge, comprehensive genomic studies have not been conducted to assess genetic variation in relation to outcomes of AUD treatment or placebo response. Genomic analyses require large sample sizes that are not easy to gather in small to medium scale clinical trials conducted with treatment seeking individuals with an AUD or other drug use disorder. To address this issue, we will leverage the resources from six completed and two ongoing NIAAA-funded phase ІІ AUD treatment trials. We will first examine changes in patterns of drinking among the enrolled treatment-seeking individuals with AUD, during treatment with a placebo (Aim І). We will then explore how these changes in drinking affect expression of genes, perusing the entire genome of each individual (Aim ІІ). The genes whose expression levels are found to be changed according to a person’s drinking behavior or how frequent the person was able to abstain from alcohol, will be fine- combed to identify DNA sequence (genetic) variations that rendered them susceptible to varying amounts of alcohol (Aim ІІІ). Next, we will explore whether these genetic variations and the expression patterns of their genes, can predict placebo response (as measured by abstinence rates) in populations with AUD together with other psychiatric conditions (cocaine addiction and PTSD; Exploratory Aim І). Finally, we will explore whether the identified genetic variants and genes are expressed in the same manner in those who have received an active medication (ondansetron/topiramate/naltrexone) for the treatment of their AUD (Exploratory Aim ІІ), which may help us understand the placebo component embedded within response to an active medication, at a molecular level. In summary, our proposed project is conceptually and methodologically innovative in exploring genetic variations by examining gene expression differences associated with amounts of drinking during placebo treatment. As the first study to characterize genomics of placebo response in phase ІІ AUD trials, findings will provide a wealth of information for future translational research and propagate personalized medicine. Harnessing the placebo response and knowing how to optimize it will allow us to: a) improve overall outcomes; b) determine who is in need of additional treatment, and c) characterize the therapeutic index (efficacy/side effects) for particular subgroups with AUD.