Department of Epidemiology and Health Statistics, School of Public Health, Xi'an Jiaotong University Health Science Centre, Xi'an, China.
Tropical Clinical Trials Unit, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
JAMA Netw Open. 2019 Jul 3;2(7):e197242. doi: 10.1001/jamanetworkopen.2019.7242.
Primary outcome change could threaten the validity of a clinical trial; however, evidence about the consequences on the reported intervention effect size is unclear.
To examine the status of randomized clinical trials whose primary outcome changed between trial registration and publication and to quantify the association of this change with the reported intervention effect size.
DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study on the primary report of randomized clinical trials with clear prospectively registered primary outcomes, PubMed and Embase were searched for articles published between January 1, 2011, and December 31, 2015. The search was conducted in January 2016, identifying randomized clinical trials and the combination of keywords and text words related to registry.
Based on the developed approach, trials were classified as having primary outcome change when there was a major discrepancy between the registered and published primary outcomes. Intervention effect was estimated or recalculated using the odds ratio (OR) for each comparison. Each component OR is structured so that an OR is less than 1 if the intervention group has a more favorable result than the control group. The ratio of ORs (ROR), which is the summary OR for trials with primary outcome change divided by those without, and its 95% CI were calculated, with a value less than 1 indicating a larger reported intervention effect size in trials with primary outcome change than those without.
Among 29 749 searched articles (28 810 MEDLINE and 939 Embase), 1488 articles were randomly selected for review. Of 389 trials with clear primary outcomes prospectively described in the registry (416 outcomes reported), 33.4% (130 of 389) of trials had at least 1 primary outcome change. Most (66 of 130) of the changes were either not reporting or omitting the primary outcome. In total, 338 trials (365 outcomes and 487 comparisons) were available for quantitative analysis on the reported intervention effect size bias assessment. Compared with those without primary outcome change, trials with primary outcome change showed a 16% (pooled ROR, 0.84; 95% CI, 0.73-0.96) larger reported intervention effect size. The result persisted after adjustment for potential confounders (ROR, 0.81; 95% CI, 0.71-0.93) and other sensitivity and subgroup analyses.
Results of this study suggest that inconsistencies between registered and published primary outcomes of clinical trials are common, and trials with primary outcome change are likely to have a larger intervention effect than those without.
主要结局的改变可能会威胁临床试验的有效性；然而，关于这种改变对报告的干预效果大小的影响的证据尚不清楚。
研究主要结局在试验注册和发表之间发生改变的随机临床试验的现状，并定量评估这种改变与报告的干预效果大小之间的关系。
设计、设置和参与者：在这项对主要报告为前瞻性注册的主要结局的随机临床试验的横断面研究中，我们检索了 2011 年 1 月 1 日至 2015 年 12 月 31 日之间发表的文章，检索范围包括 PubMed 和 Embase。检索于 2016 年 1 月进行，确定了随机临床试验以及与注册相关的关键词和文本词的组合。
根据既定方法，如果注册和发表的主要结局之间存在重大差异，则将试验分类为主要结局改变。使用每个比较的比值比（OR）估计或重新计算干预效果。每个组成部分的 OR 结构为，如果干预组的结果优于对照组，则 OR 小于 1。比值比（ROR）的比值是主要结局改变的试验的汇总 OR 除以没有主要结局改变的试验，其 95%置信区间（CI）为 1，表明主要结局改变的试验的报告干预效果大小大于没有主要结局改变的试验。
在检索到的 29749 篇文章（28810 篇 MEDLINE 和 939 篇 Embase）中，随机选择了 1488 篇进行审查。在 389 项前瞻性描述了明确主要结局的注册试验中（报告了 416 项结局），33.4%（130/389）的试验至少有 1 项主要结局改变。大多数（130 项中的 66 项）改变要么未报告，要么遗漏了主要结局。共有 338 项试验（365 项结局和 487 项比较）可用于定量分析报告的干预效果大小偏差评估。与没有主要结局改变的试验相比，主要结局改变的试验报告的干预效果大小增加了 16%（汇总 ROR，0.84；95%CI，0.73-0.96）。调整潜在混杂因素（ROR，0.81；95%CI，0.71-0.93）和其他敏感性及亚组分析后，结果仍然存在。
本研究结果表明，临床试验注册和发表的主要结局之间的不一致是常见的，并且主要结局改变的试验可能比没有主要结局改变的试验具有更大的干预效果。
