Reduction in frequency of drug use as a primary outcome and its relation to changes in health-related and other functional outcomes in stimulant use disorder trials

项目概要/摘要： 兴奋剂使用障碍临床试验的设计和分析中存在的几个问题阻碍了 开发和批准新的治疗方案。一个关键问题是依赖禁欲， 主要成果。虽然禁欲是一个临床相关的终点，相对较少的试验参与者曾经 在治疗期间或治疗后6 - 12个月内实现持久禁欲。此外，使用 相对于减少使用频率的定量措施， 信息和统计能力的重大损失。这一损失的一个重要影响是， 需要更大的样本量，这对征聘和留用都造成了更大的挑战。此外该 这些试验的统计分析提出了一些具有挑战性的问题，迄今为止，这些问题尚未得到充分的研究。 处理。首先，丢失数据是一个可怕的问题，通常用权宜之计来处理， 产生治疗效果的有偏估计。拟议研究的总体目标是确定， 根据尿液药物筛查确定的治疗内使用频率降低是（i）更敏感的 终点评估治疗兴奋剂使用障碍的好处，和（ii）预测的长期 治疗后对药物使用和功能的随访措施。为此，我们提出了一个严格的统计 克服缺失数据挑战的兴奋剂使用障碍试验分析方法 上面强调。具体来说，使用五个现有的临床试验数据集，拟议的研究将提供两个 统计和经验证据表明，减少使用频率（基于尿液药物筛选），而不是 禁欲是确定治疗效果的更敏感的终点。此外，研究将 检查治疗内使用频率降低与长期随访之间的关系 改进具有重大社会影响的五个问题领域的措施：㈠法律的，㈡ （iii）家庭问题;（iv）心理问题;及（v）医疗问题。最后，研究将确定 是否可以从这些问题域中选择一组关键的度量， 减少使用频率，为临床试验提供最显著和有临床意义的终点 兴奋剂使用障碍 此外，我们计划使非政府组织广泛了解为每个目标制定的统计方法， 统计学家。具体来说，我们将创建可用于现有统计数据的宏和过程， 软件包（例如，SAS、Stata和R）。统计宏指令和程序将被记录并制定 通过我们的网站向科学界的其他研究人员公开和免费提供， 有关如何将这些宏应用于在最终出版物中分析的示例数据集的文档。

Project summary/Abstract: Several issues in the design and analysis of clinical trials of stimulant use disorders have impeded the development and approval of new treatment options. A key issue concerns the reliance on abstinence as the primary outcome. Although abstinence is a clinically relevant endpoint, relatively few trial participants ever achieve enduring abstinence either during treatment or in the 6-12 months post treatment. Moreover, the use of a binary measure of abstinence, relative to a quantitative measure of reduction in frequency of use, entails a significant loss of information and statistical power. One important implication of this loss is that trials with larger sample sizes are required, creating greater challenges for both recruitment and retention. In addition, the statistical analyses of these trials pose a number of challenging issues that, so far, have not been adequately addressed. Primarily, missing data is a formidable problem that is often handled with stopgap methods that yield biased estimates of treatment effects. The overarching goal of the proposed research is to establish that within-treatment reduction in frequency of use, as determined from urine drug screens, is (i) a more sensitive endpoint for assessing the benefits of treatments for stimulant use disorders, and (ii) predictive of longer term post-treatment follow-up measures of drug use and functioning. In doing so, we propose a rigorous statistical approach to the analyses of stimulant use disorder trials that overcomes the missing data challenges highlighted above. Specifically, using five existing clinical trial datasets, the proposed research will provide both statistical and empirical evidence that reduction in frequency of use (based on urine drug screens), rather than abstinence, is a more sensitive endpoint for determining treatment efficacy. In addition, the research will examine the association between within-treatment reduction in frequency of use and longer-term follow-up improvements in measures from five problem domains that have significant societal consequence: (i) legal, (ii) employment, (iii) family, (iv) psychological and (v) medical problems. Finally, the research will determine whether a key set of measures from these problem domains can be selected for use in conjunction with reduction in frequency of use to provide the most salient and clinically meaningful endpoints for clinical trials of stimulant use disorders. Additionally, we plan to make the statistical methodology developed for each aim widely accessible to non- statisticians. Specifically, we will create macros and procedures which can be used with existing statistical software packages (e.g., SAS, Stata, and R). Statistical macros and procedures will be documented and made publicly and freely available to other researchers in the scientific community via our website, together with documentation on how to apply these macros to the example datasets analyzed in the resulting publications.