Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada.
Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.
Clin Gastroenterol Hepatol. 2018 May;16(5):637-647.e13. doi: 10.1016/j.cgh.2017.08.025. Epub 2017 Aug 24.
BACKGROUND & AIMS: Advances in development of therapeutic agents for ulcerative colitis (UC) have been paralleled by innovations in trial design. It would be useful to identify a core outcome set, to standardize outcome definitions for efficacy and safety in clinical trials. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled randomized controlled trials of patients with UC.
We searched MEDLINE, EMBASE, and the Cochrane Library from inception through March 1, 2017, for placebo-controlled randomized controlled trials of adult patients with UC treated with aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules. We collected information on efficacy and safety outcomes, definitions, and measurement tools, stratified by decade of publication.
We analyzed data from 83 randomized controlled trials (68 induction and 15 maintenance) comprising 17,737 patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the UC Disease Activity Index and Mayo Clinic Score were frequently used to determine clinical response or remission. We found substantial variation in definitions of clinical or composite-clinical endpoints, with more than 50 definitions of response or remission. Endoscopic factors, histologic features, and fecal or serum biomarkers were used to determine outcomes in 83.1% (69 of 83), 24.1% (20 of 83), and 24.1% (20 of 83) of trials, respectively. A greater proportion of trials published after 2007 reported objective outcomes (96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized definitions of histologic or biomarker endpoints were found. Patient-reported efficacy and quality-of-life outcomes were described in 25 trials (30.1%) and safety outcomes were reported in 77 trials (92.8%).
In a systematic review, we found that despite recent advances in clinical trials methods, there is a great deal of variation in definitions of endpoints, including response and remission, in randomized controlled trials of patients with UC. Researchers should identify a core set of outcomes to standardize efficacy and safety reporting in UC clinical trials.
溃疡性结肠炎（UC）治疗药物的发展取得了进步，临床试验设计也随之创新。确定一个核心结局集，将有助于对临床试验中的疗效和安全性结局定义进行标准化。我们对 UC 患者接受氨基水杨酸盐、免疫抑制剂、皮质类固醇、生物制剂和口服小分子药物治疗的安慰剂对照随机对照试验报告的疗效和安全性结局进行了系统评价。
我们检索了 MEDLINE、EMBASE 和 Cochrane 图书馆，检索时间从建库至 2017 年 3 月 1 日，以获取成人 UC 患者接受氨基水杨酸盐、免疫抑制剂、皮质类固醇、生物制剂和口服小分子药物治疗的安慰剂对照随机对照试验。我们收集了疗效和安全性结局、定义和测量工具的信息，并按发表年代进行分层。
我们分析了 83 项随机对照试验（68 项诱导治疗和 15 项维持治疗）的数据，共纳入 17737 例患者。所有试验均报告了临床或综合临床疗效结局；UC 疾病活动指数和 Mayo 评分常用于确定临床反应或缓解。我们发现，临床或综合临床终点的定义存在很大差异，有 50 多种反应或缓解的定义。83.1%（83 项中的 69 项）、24.1%（83 项中的 20 项）和 24.1%（83 项中的 20 项）的试验分别使用内镜因素、组织学特征和粪便或血清生物标志物来确定结局。2007 年后发表的试验报告客观结局的比例更高（96.5%的内镜结局、26.3%的组织学结局和 36.8%的生物标志物结局），但未发现组织学或生物标志物终点的标准化定义。25 项试验（30.1%）描述了患者报告的疗效和生活质量结局，77 项试验（92.8%）报告了安全性结局。
在系统评价中，我们发现，尽管临床试验方法最近取得了进展，但 UC 患者的随机对照试验中，包括反应和缓解在内的终点定义存在很大差异。研究人员应确定一套核心结局，以标准化 UC 临床试验的疗效和安全性报告。
