Predicting Response to Standardized Pediatric Colitis Therapy: PROTECT Study

描述(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)。它影响着数十万美国人，其中约25%-30%是儿童。UC会引起相当大的痛苦，包括腹痛、腹泻、出血和体重减轻，而且由于不明原因，儿童的病情往往比成年人更严重。长期的疾病具有患结肠癌的高风险。理想情况下，UC可以用美沙拉明充分控制，美沙拉明是一种5-氨基水杨酸酯，有一个有利的好处：风险概况。不幸的是，仅靠美沙拉明往往是不够的，需要加强皮质类固醇(类固醇)治疗、有重大风险的有效免疫抑制药物(IM)或手术切除结肠。关于儿童UC的治疗缺乏受控数据，而且几乎没有研究向临床医生提供指导，说明哪些儿童单独使用美沙拉明效果良好，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允许构建个体化治疗的模型，从而改善当前的结果。具体地说，我们将在北美的24个儿科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(预测标准化儿科结肠炎治疗的反应：保护性研究)。使用旨在提供最佳护理和对疾病严重程度做出反应的临床方案，以及监测服药依从性的最新技术，我们随后将确定仅在一年内临床缓解美沙拉明的主要临床结果，而无需同时使用类固醇药物或更有效的免疫抑制药物或手术。在诊断时和随访期间将获得包括血液、粪便和结肠组织在内的生物标本，并将确定和测试预先指定的临床、遗传、环境和免疫因素，以确定和测试它们对主要临床结果以及一年后粘膜愈合的影响。如果可能，根据进入研究的时间，患者将被跟踪观察一年以上，最长可达2-5年。PROTECT研究的集体结果将通过以下方面对该领域产生重大而持久的影响：1)提供有关标准化治疗反应的数据，最大限度地提高对美沙拉明的反应可能性；2)确定与治疗反应相关的新的生物途径；3)建立临床、遗传和免疫数据以及生物标本的储存库，可用于未来的辅助研究。最终，PROTECT的结果将与由美国克罗恩和结肠炎基金会(CCFA)赞助的对1100名儿童克罗恩病(CD)患者进行的前瞻性研究(风险研究)的结果相结合，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。 公共卫生相关性：PROTECT研究将首次描述新诊断为溃疡性结肠炎的儿童接受标准化治疗的过程，该治疗方法旨在最大限度地减少接触更有毒药物的机会。通过在诊断时和治疗后第一年同时获得生物检材，PROTECT将促进对治疗反应的患者间变异性的理解，并提供对 维持结肠炎症的途径。这一努力不仅将改善新诊断为溃疡性结肠炎的儿童的健康，还将减少药物治疗的可能性。 毒性和结肠切除术的必要性。

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.