Predicting Response to Standardized Pediatric Colitis Therapy: PROTECT Study

预测标准化小儿结肠炎治疗的反应：PROTECT 研究

• 批准号: 8458111
• 负责人: LEE ARMISTEAD DENSON
• 金额: $ 252.23万
• 依托单位: CONNECTICUT CHILDREN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458111
• 关键词: Abdominal Pain; Accounting; Adherence; Adrenal Cortex Hormones; Adult; Affect; Age; Algorithms; American; Americas; Aminosalicylate; Ancillary Study; Antibodies; Antineutrophil Cytoplasmic Antibodies; Automobile Driving; Benefits and Risks; Biological Markers; Blood; Body Weight decreased; Caring; Cell Maturation; Child; Child health care; Childhood; Chronic; Clinical; Clinical Protocols; Clinical Trials; Cohort Studies; Colectomy; Colitis; Colon; Colon Carcinoma; Crohn' s disease; Data; Dendritic Cells; Diagnosis; Diarrhea; Disease; Disease remission; Electronics; Enrollment; Exhibits; Exposure to; Feces; Foundations; Future; Gender; Gene Expression Profile; Genes; Genetic; Genomics; Genotype; Granulocyte-Macrophage Colony-Stimulating Factor; Healed; Hemorrhage; Immune; Immunologic Tests; Immunomodulators; Immunosuppressive Agents; Individual; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Intestinal Diseases; Leukocyte L1 Antigen Complex; Maintenance; Maintenance Therapy; Measures; Medical; Mesalamine; Microarray Analysis; Modeling; Monitor; Mucosal Immunity; Myeloid Cells; Names; Neoadjuvant Therapy; Newly Diagnosed; North America; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patient Noncompliance; Patients; Pharmaceutical Preparations; Prospective Studies; Provider; Race; Rectum; Relative (related person); Reporting; Risk; Serologic tests; Serum; Severity of illness; Sigmoidoscopy; Specific qualifier value; Steroids; Structure; System; Technology; Testing; Time; Tissues; Toxic effect; Translating; Tumor necrosis factor receptor 11b; Ulcerative Colitis; Variant; Vitamin D; Vitamins; antimicrobial; clinical practice; clinical remission; cohort; design; follow-up; healing; high risk; improved; indexing; insight; large bowel Crohn' s disease; medication compliance; novel; prospective; rectal; repository; response; transcriptome sequencing; treatment response

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.

描述（由申请人提供）：溃疡性结肠炎（UC）是一种称为炎症性肠病（IBD）的慢性肠道疾病。它影响着数十万美国人，其中约 25-30% 是儿童。 UC 会造成相当大的痛苦，包括腹痛、腹泻、出血和体重减轻，并且由于未知原因，儿童的病情往往比成人更严重。长期患病会带来患结肠癌的高风险。理想情况下，UC 可通过美沙拉嗪（一种 5-氨基水杨酸盐​​）得到充分控制，具有良好的益处：风险特征。不幸的是，单独使用美沙拉嗪通常是不够的，需要使用皮质类固醇（类固醇）、具有重大风险的强效免疫抑制药物 (IM) 进行升级治疗，或进行结肠切除手术。缺乏关于儿童 UC 治疗的对照数据，而且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，诊断时进行的临床、遗传和免疫学测试的结合可能允许构建个体化治疗模型，从而改善当前的结果。具体来说，我们将在北美 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：PROTECT 研究）。使用旨在提供最佳护理并响应疾病严重程度的临床方案，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嗪一年后临床缓解的主要临床结果，无需同时使用类固醇药物或不需要更有效的免疫抑制药物或手术。将在诊断和随访期间获取包括血液、粪便和结肠组织在内的生物样本，并将确定和测试预先指定的临床、遗传、环境和免疫因素，并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，将对患者进行一年以上的随访，最长可达 2-5 年，具体取决于进入研究的时间。 PROTECT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）提供有关标准化治疗反应的数据，最大限度地提高对美沙拉嗪反应的可能性，2）确定与治疗反应相关的新生物途径，3）建立临床、遗传和免疫数据以及生物样本的存储库，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) 赞助的一项对 1100 名儿科克罗恩病 (CD) 患者进行的前瞻性研究（即 RISK 研究）相结合，为发现驱动儿科 IBD 发病机制和临床结果的机制提供一个强大的新平台。