Predicting Response to Standardized Pediatric Colitis Therapy: PROTECT Study

描述（由申请人提供）：溃疡性结肠炎（UC）是一种慢性肠道疾病，称为炎症性肠病（IBD）。它影响了数十万美国人，其中约25-30%是儿童。UC引起相当大的痛苦，腹痛，腹泻，出血和体重减轻，并且由于未知原因，儿童通常比成人更严重。长期患病会带来结肠癌的高风险。理想情况下，美沙拉嗪（一种5-氨基水杨酸盐）可以充分控制UC，具有良好的获益：风险特征。不幸的是，单独的美沙拉嗪通常是不够的，需要用皮质类固醇（类固醇）、具有重大风险的强效免疫抑制药物（IM）或手术切除结肠进行逐步治疗。缺乏关于儿童UC治疗的对照数据，几乎没有研究为临床医生提供指导，以确定哪些儿童单独使用美沙拉嗪效果良好，哪些儿童效果不佳，需要增加药物暴露或手术。我们假设，在诊断时进行的临床，遗传和免疫学测试的组合可能会允许构建一个模型，用于个性化治疗，从而改善当前的结果。具体而言，我们将在北美24个儿童IBD中心对430名新诊断为UC的儿童进行标准化药物治疗的临床试验（预测标准化儿童结肠炎治疗的反应：CRTOT研究）。使用旨在提供最佳护理并对疾病严重程度做出反应的临床方案，以及监测药物依从性的最新技术，我们随后将确定仅使用美沙拉嗪1年时临床缓解的主要临床结局，而无需同时使用类固醇药物或需要更强效的免疫抑制药物或手术。将在诊断时和随访期间采集生物标本，包括血液、粪便和结肠组织，并确定和检测预先规定的临床、遗传、环境和免疫因素对主要临床结局以及1年时粘膜愈合的影响。如果可能，将对患者进行超过1年和长达2-5年的随访，具体取决于进入研究的时间。联合国气候变化技术研究的集体结果将通过以下方式对该领域产生重大和持续的影响：1）提供关于对标准化疗法的响应的数据，该标准化疗法使对美沙拉嗪的响应的可能性最大化，2）鉴定与治疗响应相关的新的生物学途径，以及3）建立临床、遗传和免疫数据以及生物样本的储存库，可以用于未来的辅助研究。最终，将把CCPT的结果与美国克罗恩病和结肠炎基金会（CCFA）赞助的1100例儿童克罗恩病（CD）患者的前瞻性研究（RISK研究）的结果整合在一起，为发现儿童IBD的发病机制和临床结局提供一个强大的新平台。

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is one of the chronic intestinal disorders known as inflammatory bowel disease (IBD). It affects hundreds of thousands of Americans with about 25-30% being children. UC causes considerable suffering with abdominal pain, diarrhea, bleeding, and weight loss and for unknown reasons is often more severe in children than adults. Longstanding disease carries a high risk of colon cancer. Ideally, UC is adequately controlled with mesalamine, a 5-aminosalicylate with a favorable benefit: risk profile. Unfortunately, mesalamine alone is often not sufficient requiring step-up therapy with corticosteroids (steroids), potent immunosuppressive medications (IM) with major risks, or surgery to remove the colon. There are a lack of controlled data on the treatment of UC in children and virtually no studies that provide guidance to clinicians as to which children are going to do well with mesalamine alone and who is going to do poorly and need increasing medication exposure or surgery. We hypothesize that a combination of clinical, genetic, and immunologic tests performed at diagnosis may allow construction of a model for individualized treatment and thereby improvement of current outcomes. Specifically, we will conduct a clinical trial of standardized medical therapy for 430 children newly diagnosed with UC at 24 pediatric IBD centers in North America (Predicting Response to Standardized Pediatric Colitis Therapy: The PROTECT Study). Using a clinical protocol that is designed to provide optimal care and be responsive to disease severity, as well as state of the art technology to monitor medication adherence, we will subsequently determine the primary clinical outcome of clinical remission at one year on mesalamine only without the concurrent use of steroid medications or the need for more potent immunosuppressive medications or surgery. Biospecimens including blood, stool, and colonic tissue will be obtained at diagnosis and during follow-up, and pre-specified clinical, genetic, environmental, and immune factors will be determined and tested for their impact upon the primary clinical outcome as well as mucosal healing at one year. When possible patients will be followed beyond one year and up to 2-5 years depending upon time of entry into the study. The collective results of the PROTECT study will have a significant and sustained impact upon the field by: 1) providing data regarding response to standardized therapy maximizing the likelihood of response to mesalamine, 2) identifying novel biologic pathways associated with treatment response, and 3) establishing a repository of clinical, genetic, and immune data, as well as biospecimens, that can be used by for future ancillary studies. Ultimately, results of PROTECT will be integrated with those of an ongoing prospective study of 1100 pediatric Crohn's Disease (CD) patients sponsored by the Crohn's and Colitis Foundation of America (CCFA), the RISK study, to provide a powerful new platform for discovering mechanisms which drive pathogenesis and clinical outcomes in pediatric IBD.