Drinking levels (binge, volume) and alcohol consequences: using national data to identify clinical trial endpoints

项目摘要 随机对照试验是评估酒精使用障碍(AUDS)治疗的金标准，使用减少饮酒的终点作为主要结果。然而，对于如何最好地定义减少饮酒的结果，仍然存在相当大的不确定性。尽管临床医生和食品和药物管理局(FDA)长期以来一直认为完全戒烟是衡量治疗效果的最佳指标，但现在这被视为过于严格的结果。美国食品和药物管理局目前关注的是在规定的治疗期内没有大量饮酒的受试者的比例(HDD≥5饮品，男性为≥5，女性为≥4)，以确定治疗效果。世界卫生组织(WHO)开发的另一种衡量标准--平均每日饮酒量(ADV；Mean Etoh gm/day)--已被欧洲药品管理局(EMA)采用，以定义治疗成功。然而，由于HOD和ADV作为临床试验结果的证据基础有许多严重的局限性，饮酒结果测量被认为是在开发更有效的酒精治疗方面取得进展的关键方法学障碍。对饮酒结果效用的经验支持包括其与临床相关后果的关系，包括人际和职业功能、医疗状况和酒精使用障碍。为了检验对HOD、ADV和其他饮酒后果的不同定义的经验支持，具有代表性的大型NESARC调查(全国酒精及相关疾病流行病学调查)提供了重要的优势，包括饮酒和后果衡量的丰富性和一致性。在这项研究中，我们将使用NESARC第一波(2001-2002年；N=43,093)和第二波(第一波参与者的3年跟踪，N=34,653)和NESARC-111(2012-2013；N=36,318名新参与者)的数据。我们将使用回归样条法来确定HOD、ADV和后果之间最有信息的函数关系，并确定这些关系中的关键变化点，以解决以下关键问题：(1)什么水平的HOD和ADV与更高的后果风险相关？(2)在过去3年中，HOD和ADV的变化水平预示着同一时期后果的变化？(3)这些关联是否因酒精诊断和其他酒精特征(潜在的临床试验资格、治疗史、早期大量饮酒)而改变？(4)这些关系在年轻人和其他成年人(18-25岁与26岁以上)之间是否存在性别差异，种族/民族，还是精神疾病的共病？我们还将探讨以下问题：HOD和ADV的其他定义是否会影响研究结果？作为结果，HOD或ADV是否具有优势？结果与其他常见的临床试验结果有何关系：禁酒天数百分比；平均每天饮酒量？研究结果将有助于确定不同的潜在饮酒结果指标与结果的关系。这项研究旨在通过定义最具临床意义的结果衡量标准，提高确定酒精使用障碍有效治疗方法的能力，从而对酒精中毒治疗研究产生实质性影响。

Project Summary Randomized controlled trials, the gold standard in evaluating treatments for alcohol use disorders (AUDs), use drinking-reduction endpoints as the main outcomes. However, considerable uncertainty exists about how best to define drinking-reduction outcomes. Although clinicians and the Food and Drug Administration (FDA) long considered total abstinence as the best indicator of treatment efficacy, this is now seen as an overly restrictive outcome. The FDA presently focuses on the proportion of subjects with no Heavy-Drinking Days (HDD ≥5 drinks, or ≥5 for men, ≥4 for women) during a defined treatment period to define treatment efficacy. Another measure, Average Daily Volume (ADV; mean ETOH gm/day) developed by the World Health Organization (WHO) to define drinking levels for research purposes, has been adopted by the European Medicines Agency (EMA, the EU equivalent of the FDA), to define treatment success. However, because the evidence base for both HOD and ADV as clinical trial outcomes has many serious limitations, drinking outcome measures are considered a key methodological barrier to progress in developing more effective alcohol treatments. Empirical support for a drinking outcome's utility consists of its relationship to clinically relevant consequences, including interpersonal and occupational functioning, medical status, and alcohol use disorders. To examine empirical support for varying definitions of HOD, ADV and other drinking outcomes, the large, representative NESARC surveys (National Epidemiologic Survey on Alcohol and Related Conditions) offer important advantages, including richness and consistency of drinking and consequence measures. For this study, we will utilize data from NESARC Wave 1 (2001-2002; N=43,093) and Wave 2 (3-year follow-ups of Wave 1 participants, N=34,653) and NESARC-111 (2012-2013; N=36,318 new participants). We will use regression splines to determine the most informative functional relationships between HOD, ADV and consequences and identify key change-points in these relationships, to address the following key questions: (1) What levels of HOD and ADV are associated with higher risk of consequences? (2) What level of change in HOD and ADV over 3 years predicts change in consequences over the same period? (3) Are these associations modified by alcohol diagnoses and other alcohol characteristics (potential clinical trial eligibility, treatment history, early heavy drinking)? (4) Do these relationships differ between young and other adults (18-25 vs. 26+), by gender, race/ethnicity, or psychiatric comorbidity? We will also explore the following: Do alternative definitions of HOD and ADV influence findings? Does HOD or ADV offer advantages as outcomes? How do consequences relate to other common clinical trial outcomes: % days abstinent; mean drinks per drinking day? Study findings will help to define the relationship of different potential drinking outcome measures to consequences. The study is positioned to have a substantial impact on alcoholism treatment research by improving the ability to identify effective treatments for alcohol use disorders by defining the most clinically meaningful outcome measures.