Defining predictors of responsiveness to advanced therapies in Crohn’s disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine

Introduction Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient’s quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients. Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures. IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. Methods and analysis This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. Ethics and dissemination Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. Trial registration number ISRCTN96296121.

引言 炎症性肠病（IBD）以胃肠道慢性炎症为特征，其症状包括腹泻、腹痛和疲劳，会显著影响患者的生活质量。过去20年的治疗进展使治疗发生了革命性变化。然而，临床试验和实际数据显示，原发性无应答率高达40%。一个重大挑战是无法预测哪种治疗对个体患者有益。目前对IBD发病机制的理解涉及宿主遗传学和肠道微生物组之间的复杂相互作用。迄今为止，大多数研究肠道微生物群的队列样本量不足，只研究了单一治疗方法，且结果各异。缺乏跨治疗比较和有足够样本量的独立重复队列，阻碍了推断预测特征在实际应用中的能力。IBD - RESPONSE项目将利用多组学数据创建一个治疗反应的预测工具。未来患者可能受益于基于生物标志物的治疗分层的发展或肠道微生物靶点的调控。IBD - RESPONSE项目及其后续研究有可能提高生活质量、降低患者风险并减少无效治疗的支出。 方法与分析 这项前瞻性、多中心、观察性研究将确定并验证一个对先进IBD疗法反应的预测模型，该模型纳入肠道微生物组、代谢组、单细胞转录组、人类基因组、饮食和临床数据。将从英国约40个地点招募1325名开始接受先进疗法的参与者。数据将在基线、第14周和第54周收集。主要结局是第14周的临床反应。次要结局包括临床缓解、第14周有反应者的反应丧失、无糖皮质激素反应/缓解、治疗升级时间以及患者报告结局指标的变化。 伦理与传播 已从威尔士研究伦理委员会5获得伦理批准（参考编号：21/WA/0228）。招募正在进行中。研究完成后，结果将提交给同行评审期刊发表，并在科学会议上展示。研究结果将在www.ibd - response.co.uk上总结。试验注册号为ISRCTN96296121。