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. .

项目摘要/摘要 儿童克罗恩病(CD)的治疗目标已从临床改善或缓解转变为 回结肠镜下的内窥镜愈合(EH)和磁共振肠镜下的跨壁愈合(TH) (MRE)。完全痊愈的患者(CH、EH和TH)住院或手术次数较少。我们 假设特定的治疗前临床、放射、转录、基因组和微生物因素 随着靶向抗肿瘤坏死因子的实现，生物暴露将与主要终点、CH和 主要次要终点，EH和TH，抗肿瘤坏死因子治疗52周后。我们将在一个 550例新发CD患儿应用抗肿瘤坏死因子药物治疗的前瞻性队列研究 在治疗药物监测(TDM)的指导下，确诊后6个月内。 目标1.评估假设的关联并探索CH和基线之间的新关联 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， 抗微生物血清学和MRE结果将与第一年CH有关。正式的假设检验将是 以适当控制的类型I错误概率进行，以确认一组预编码的预测能力 使用基于第1年CH结果的Logistic回归模型指定的基线测量。 目的2.评估推测的关联，并探索抗肿瘤坏死因子药物水平、CH、 以及宿主和微生物的基因组和转录因子。我们假设治疗前的基因 表达特征和微生物因素将与早期的抗肿瘤坏死因子药物水平和第一年的CH有关。 我们将确定宿主基因型、基线粘膜和纵向粪便微生物分类图谱，以及 回肠和结肠宿主转录组基线。那些被确定为显著相关的变量将 目标3中确定的最终预测模型的候选者。 目的3.采用k重交叉验证法确定第一年慢性肝炎的最优预测模型。 我们假设，包括宿主基因签名和微生物的模型将改善对CH的预测 而不仅仅是基于临床和影像因素。该模型将包括临床和成像预测因子。 从目标1和宿主和微生物的特性中发现，在目标2中有可能解释。 冲击力。拟议的初始队列研究CAMEO将提供一个强大的平台来研究以下因素 有助于治愈儿童CD，然后可以转化为实践，以及指导未来的治疗 针对不太可能治愈的患者的宿主免疫反应和微生物区系。 。