Clinical, Imaging, and Endoscopic Outcomes of Children Newly Diagnosed with Crohn's Disease

新诊断克罗恩病儿童的临床、影像学和内窥镜结果

• 批准号: 10560015
• 负责人: LEE ARMISTEAD DENSON
• 金额: $ 280万
• 依托单位: CONNECTICUT CHILDREN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560015
• 关键词: Algorithms; Ancillary Study; Anti-Tumor Necrosis Factor Therapy; Biological; Biological Factors; Budgets; Characteristics; Child; Childhood; Clinical; Clinical Treatment; Clinical/Radiologic; Cohort Studies; Colon; Colonoscopy; Crohn' s disease; Data; Data Management Resources; Data Set; Development; Diagnosis; Disease; Disease remission; Dose; Drug Exposure; Drug Monitoring; Erythrocyte Sedimentation Rate; Exhibits; Fibroblasts; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Genomics; Genotype; Goals; Health Expenditures; Hospitalization; Image; Immune response; Inflammatory; Institutional Review Boards; Intestines; Logistic Regressions; Macrophage; Magnetic Resonance; Manuals; Measures; Microbe; Microbial Taxonomy; Modeling; Mucous Membrane; Multiomic Data; Neoadjuvant Therapy; Newly Diagnosed; Nutritional status; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Pediatric Crohn' s disease; Pharmaceutical Preparations; Predictive Factor; Probability; Procedures; Process; Prospective, cohort study; Protocols documentation; Quality of life; Radiology Specialty; Reading; Refractory; Regimen; Reporting; Risk; Serology; Services; Severities; Specific qualifier value; TNF gene; Testing; Therapeutic; Translating; Validation; antimicrobial; biobank; clinical practice; clinical remission; clinical research site; experience; genetic signature; genotyped patients; healing; hospitalization rates; image archival system; improved; infliximab; insight; microbial; microbial community; microbial genomics; microbiota; novel; operation; predictive modeling; primary endpoint; response; secondary endpoint; seropositive; targeted treatment; transcriptome; transcriptomics

PROJECT SUMMARY/ABSTRACT Therapeutic goals in pediatric Crohn's Disease (CD) have shifted from clinical improvement or remission to endoscopic healing (EH) by ileocolonoscopy and transmural healing (TH) by magnetic resonance enterography (MRE). Patients achieving complete healing (CH, EH and TH) experience fewer hospitalizations or surgery. We hypothesize that specific pre-treatment clinical, radiologic, transcriptomic, genomic, and microbial factors along with attainment of targeted anti-TNF biologic exposure will be associated with the primary endpoint, CH, and the major secondary endpoints, EH and TH, 52 weeks after anti-TNF start. We will test this hypothesis in a prospective cohort study of 550 newly diagnosed pediatric-onset CD subjects treated with anti-TNF medication within 6 months of diagnosis guided by therapeutic drug monitoring (TDM). Aim 1. Evaluate putative associations and explore novel associations between CH and baseline measures of clinical and radiologic severity. We hypothesize that pre-treatment nutritional status, antimicrobial serologies, and MRE findings will be associated with year 1 CH. Formal hypothesis tests will be carried out with appropriately controlled Type I error probabilities to confirm the predictive power of a set of pre- specified baseline measures using a logistic regression model based on the year 1 CH outcome. Aim 2. Evaluate putative associations and explore novel associations between anti-TNF drug levels, CH, and host and microbial genomic and transcriptomic factors. We hypothesize that pre-treatment gene expression signatures and microbial factors will be associated with early anti-TNF drug levels and year 1 CH. We will characterize the host genotype, baseline mucosal and longitudinal fecal microbial taxonomic profile, and baseline ileal and colon host transcriptome. Those variables identified as significantly associated will be candidates for the final prediction model determined in Aim 3. Aim 3. Use a k-fold cross-validation procedure to determine the optimal predictive model of year 1 CH. We hypothesize that a model which includes host gene signatures and microbes will improve prediction of CH beyond one based on clinical and imaging factors alone. The model will include clinical and imaging predictors from Aim 1 and host and microbial characteristics found to be potentially explanatory in Aim 2. Impact. The proposed inception cohort study, CAMEO, will provide a robust platform to study factors that contribute to healing in pediatric CD that can then be translated into practice, as well as guiding future therapies targeting the host immune response and microbiota in patients unlikely to achieve healing. .

项目总结/摘要 儿童克罗恩病（CD）的治疗目标已从临床改善或缓解转向 通过回结肠镜检查进行内镜下愈合（EH），通过磁共振小肠造影检查进行透壁愈合（TH （MRE）。实现完全愈合的患者（CH、EH和TH）经历较少的住院或手术。我们 假设特定治疗前临床、放射学、转录组、基因组和微生物因素沿着 达到靶向抗TNF生物制剂暴露将与主要终点CH相关， 主要次要终点，EH和TH，抗TNF治疗开始后52周。我们将在一个 在550例接受抗TNF药物治疗的新诊断儿童发病CD受试者中开展的前瞻性队列研究 在治疗药物监测（TDM）指导下诊断的6个月内。 目标1.评估CH和基线之间的假定关联并探索新的关联 临床和放射学严重程度的测量。我们假设治疗前的营养状况， 抗菌血清学和MRE结果将与第1年CH相关。 进行了适当控制的I型错误概率，以确认一组预- 使用基于第1年CH结果的逻辑回归模型指定基线测量。 目标2.评价抗TNF药物水平、CH、 以及宿主和微生物基因组和转录因子。我们假设治疗前基因 表达特征和微生物因子将与早期抗TNF药物水平和1年CH相关。 我们将描述宿主基因型、基线粘膜和纵向粪便微生物分类特征， 基线回肠和结肠宿主转录组。被确定为显著相关的变量将是 目标3中确定的最终预测模型的候选者。 目标3.使用k折交叉验证程序确定第1年CH的最佳预测模型。 我们假设一个包括宿主基因签名和微生物的模型将改善CH的预测 而不仅仅是基于临床和成像因素。该模型将包括临床和成像预测因子 目标1和目标2中发现的宿主和微生物特征可能具有解释性。 冲击拟议的初始队列研究CAMEO将提供一个强大的平台来研究 有助于儿科CD的愈合，然后可以转化为实践，并指导未来的治疗 靶向不太可能实现愈合的患者的宿主免疫反应和微生物群。 .