Predicting Response to Standardized Pediatric Colitis Therapy: The 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。此外，长期存在的疾病还具有患结肠癌的高风险。虽然目前的药物治疗通常可以缓解症状，但目前还没有治愈方法，许多患者需要皮质类固醇（类固醇）或强效免疫抑制药物（IM），这些药物具有重大风险，或者最终手术切除结肠。关于儿童UC治疗的对照数据很少，几乎没有研究为临床医生提供指导，以确定哪些儿童会做得好，哪些儿童会做得不好，需要增加药物暴露和可能的手术。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17个儿童IBD中心对410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，我们将对该队列进行2年随访，主要临床结局为1年时临床缓解，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获得生物标本，包括血液、粪便和结肠组织，并确定和检测预先指定的临床、遗传、环境和免疫因素对粘膜炎症的影响，以及无类固醇缓解的主要临床结局。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）提供关于标准化治疗反应的数据和更优化的适应性研究设计，用于在单用美沙拉嗪不太可能实现无类固醇缓解的儿童UC患者中进行早期IM使用的临床试验，2）发现关于常见遗传和环境因素在效应和调节淋巴细胞的分化和功能中的作用的基本新知识，以及3）建立临床，基因、免疫数据和生物样本，这些数据可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1000名儿童克罗恩病（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。 公共卫生相关性：该研究的目的是通过发现指导临床决策来改善溃疡性结肠炎儿童的长期结局。我们计划开发一种临床、遗传和免疫学信息模型，使临床医生能够制定个性化的治疗计划，以实现临床缓解，并尽可能减少毒性药物或手术需求的暴露。

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 in addition carries a high risk of colon cancer. While current medical therapies often relieve symptoms, there is currently no cure and many patients require corticosteroids (steroids) or potent immunsuppressive medications (IM) with major risks, or, ultimately surgery to remove the colon. There is a paucity 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 and who is going to do poorly and need increasing medication exposure and possible 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 410 children newly diagnosed with UC at 17 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 follow this cohort for 2 years with a primary clinical outcome of clinical remission at one year without the concurrent use of steroid medications or the need for more potent immunsuppressive 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 mucosal inflammation, and the primary clinical outcome of steroid-free remission. 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 and a more optimal adaptive study design for a clinical trial of early IM use in pediatric UC patients unlikely to achieve steroid-free remission with mesalamine alone, 2) discovering fundamental new knowledge regarding the role of common genetic and environmental factors in the differentiation and function of effector and regulatory lymphocytes, and 3) establishing a repository of clinical, genetic, and immune data, and biospecimens, which can be used by for future ancillary studies. Ultimately, results of PROTECT will be integrated with those of an ongoing prospective study of 1000 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. PUBLIC HEALTH RELEVANCE: The goal of the PROTECT study is improve the long-term outcome of children with ulcerative colitis by discoveries to guide clinical decision making. We plan to develop a model of clinical, genetic, and immunologic information that will allow clinicians to formulate individualized treatment plans to achieve clinical remission and minimize exposure when possible to toxic medications or the need of surgery.