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（AUD）治疗的金标准，使用减少饮酒终点作为主要结局。然而，如何最好地定义减少饮酒的结果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禁欲是治疗效果的最佳指标，但现在这被视为一个过度限制的结果。FDA目前关注的是在规定的治疗期内没有重度饮酒日（HDD ≥5次饮酒，或男性≥5次，女性≥4次）的受试者比例，以确定治疗疗效。世界卫生组织（WHO）制定的另一项指标，即平均每日摄入量（ADV;平均ETOH gm/天），用于定义研究目的的饮酒水平，已被欧洲药品管理局（EMA，相当于FDA的欧盟）采用，用于定义治疗成功。然而，由于HOD和ADV作为临床试验结果的证据基础存在许多严重的局限性，因此饮酒结果指标被认为是开发更有效的酒精治疗方法的关键方法障碍。饮酒结果效用的实证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和其他饮酒结果的不同定义的实证支持，大型的、有代表性的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，包括饮酒和后果措施的丰富性和一致性。在本研究中，我们将利用NESARC Wave 1（2001-2002; N= 43，093）和Wave 2（Wave 1参与者的3年随访，N= 34，653）以及NESARC-111（2012-2013; N= 36，318名新参与者）的数据。我们将使用回归样条来确定HOD，ADV和后果之间最具信息性的函数关系，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)3年内HOD和ADV的变化水平如何预测同期后果的变化？(3)这些关联是否会受到酒精诊断和其他酒精特征（潜在的临床试验资格、治疗史、早期重度饮酒）的影响？(4)这些关系在年轻人和其他成年人（18-25岁vs. 26岁以上）之间是否有差异，性别，种族/民族，或精神病合并症？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？HOD或ADV是否提供优势作为结果？结果如何与其他常见的临床试验结果相关：戒酒天数%;每个饮酒日的平均饮酒量？研究结果将有助于确定不同的潜在饮酒结果措施的关系。该研究旨在通过定义最具临床意义的结果指标来提高识别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重大影响。

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.