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/文摘