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，被称为炎症性肠病（IBD）。它影响了成千上万的美国人，其中约25-30%是儿童。UC会引起腹痛、腹泻、出血和体重减轻等相当大的痛苦，并且由于未知的原因，儿童通常比成人更严重。长期患病的人患结肠癌的风险很高。理想情况下，UC可以用美沙拉胺充分控制，美沙拉胺是一种具有良好益处的5-氨基水杨酸盐：风险概况。不幸的是，单独使用美沙拉胺通常是不够的，需要皮质类固醇（类固醇）、具有重大风险的强效免疫抑制药物（IM）或手术切除结肠的加强治疗。缺乏关于儿童UC治疗的对照数据，实际上也没有研究为临床医生提供指导，说明哪些儿童单独使用美沙拉胺效果好，哪些效果差，需要增加药物暴露或手术。我们假设在诊断时进行的临床、遗传和免疫测试的结合可能允许构建个体化治疗的模型，从而改善当前的结果。具体来说，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（预测对标准化儿童结肠炎治疗的反应：The PROTECT研究）。采用旨在提供最佳护理和对疾病严重程度作出反应的临床方案，以及监测药物依从性的最先进技术，我们随后将确定仅使用美沙拉胺一年的临床缓解的主要临床结果，而不同时使用类固醇药物或需要更有效的免疫抑制药物或手术。生物标本包括血液、粪便和结肠组织将在诊断和随访期间获得，预先指定的临床、遗传、环境和免疫因素将被确定和测试，以确定它们对主要临床结果的影响，并在一年内进行粘膜愈合。在可能的情况下，根据进入研究的时间，患者将被随访超过一年，最长可达2-5年。PROTECT研究的整体结果将对该领域产生重大和持续的影响：1)提供有关标准化治疗反应的数据，最大限度地提高对美萨拉明反应的可能性；2)确定与治疗反应相关的新生物学途径；3)建立临床、遗传和免疫数据库，以及生物标本，可用于未来的辅助研究。最终，PROTECT的结果将与美国克罗恩病和结肠炎基金会（CCFA）正在进行的一项针对1100名儿童克罗恩病（CD）患者的前瞻性研究（RISK研究）相结合，为发现推动儿童IBD发病机制和临床结果的机制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. PUBLIC HEALTH RELEVANCE: The PROTECT Study will, for the first time; describe the course of children newly diagnosed with ulcerative colitis treated with standardized therapy that has been devised to minimize exposure to more toxic drugs. By concomitantly obtaining biospecimens at diagnosis and during the first year following therapy PROTECT will facilitate the understanding of inter-patient variability in response to therapy and provide insights into the pathways that sustain colonic inflammation. This effort will not only improve the health of children newly diagnosed with ulcerative colitis, but will also lessen the likelihood of medication toxicity and the need for colectomy.