Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada.
Department of Gastroenterology, University of Ghent, Ghent, Belgium.
Gut. 2018 Jan;67(1):61-69. doi: 10.1136/gutjnl-2016-312762. Epub 2016 Oct 31.
Although several pharmacological agents have emerged as potential adjunctive therapies to a gluten-free diet for coeliac disease, there is currently no widely accepted measure of disease activity used in clinical trials. We conducted a systematic review of coeliac disease activity indices to evaluate their operating properties and potential as outcome measures in registration trials.
MEDLINE, EMBASE and the Cochrane central library were searched from 1966 to 2015 for eligible studies in adult and/or paediatric patients with coeliac disease that included coeliac disease activity markers in their outcome measures. The operating characteristics of histological indices, patient-reported outcomes (PROs) and endoscopic indices were evaluated for content and construct validity, reliability, responsiveness and feasibility using guidelines proposed by the US Food and Drug Administration (FDA).
Of 19 123 citations, 286 studies were eligible, including 24 randomised-controlled trials. Three of five PROs identified met most key evaluative criteria but only the Celiac Disease Symptom Diary (CDSD) and the Celiac Disease Patient-Reported Outcome (CeD PRO) have been approved by the FDA. All histological and endoscopic scores identified lacked content validity. Quantitative morphometric histological analysis had better reliability and responsiveness compared with qualitative scales. Endoscopic indices were infrequently used, and only one index demonstrated responsiveness to effective therapy.
Current best evidence suggests that the CDSD and the CeD PRO are appropriate for use in the definition of primary end points in coeliac disease registration trials. Morphometric histology should be included as a key secondary or co-primary end point. Further work is needed to optimise end point configuration to inform efficient drug development.
尽管有几种药物已被证明是对乳糜泻患者无麸质饮食的潜在辅助治疗方法，但目前在临床试验中尚未广泛接受用于评估疾病活动的测量方法。我们对乳糜泻活动指数进行了系统评价，以评估其在注册试验中的操作特性和作为结局指标的潜力。
从 1966 年至 2015 年，在 MEDLINE、EMBASE 和 Cochrane 中心图书馆中搜索了符合条件的研究，这些研究纳入了乳糜泻患者的乳糜泻活动标志物作为结局指标的成人和/或儿科患者。使用美国食品和药物管理局（FDA）提出的指南评估了组织学指标、患者报告结局（PRO）和内镜指标的内容和结构有效性、可靠性、反应性和可行性。
在 19233 条引用中，有 286 项研究符合条件，包括 24 项随机对照试验。确定的 5 种 PRO 中有 3 种符合大多数关键评估标准，但只有 Celiac Disease Symptom Diary（CDSD）和 Celiac Disease Patient-Reported Outcome（CeD PRO）已获得 FDA 批准。所有确定的组织学和内镜评分均缺乏内容有效性。定量形态计量组织学分析与定性量表相比具有更好的可靠性和反应性。内镜指数很少使用，只有一个指数显示对有效治疗有反应。
目前的最佳证据表明，CDSD 和 CeD PRO 适用于定义乳糜泻注册试验的主要终点。形态计量组织学应作为关键次要或共同主要终点纳入。需要进一步工作来优化终点配置，以提供有效的药物开发信息。
