Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease

精确的英夫利昔单抗暴露和药效学控制可实现小儿克罗恩病的深度缓解

• 批准号: 10417405
• 负责人: Phillip P Minar
• 金额: $ 78.97万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417405
• 关键词: 10 year old; 17 year old; 18 year old; Adrenal Cortex Hormones; Adverse event; Age of Onset; Antibodies; Biological; Biological Markers; Biological Products; Caring; Child; Chronic; Chronic Disease; Clinical; Clinical Trials; Computer software; Crohn' s disease; Data; Development; Disease; Disease remission; Dose; Drug Exposure; Drug Kinetics; Drug Monitoring; Drug Targeting; Drug usage; Effectiveness; Enrollment; Exposure to; Flare; Fostering; Goals; Growth; Hospitalization; Immunosuppressive Agents; Incidence; Individual; Intervention; Intestines; Kidney Transplantation; Label; Lead; Leukocyte L1 Antigen Complex; Logistics; Maintenance; Maintenance Therapy; Measures; Modeling; Modification; Monitor; Monoclonal Antibodies; Natural History; North America; Online Systems; Operative Surgical Procedures; Outcome; Patients; Pediatric Crohn' s disease; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physicians; Population; Prednisone; Publishing; Quality of life; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recurrent disease; Regimen; Relapse; Reporting; Risk; Serum; Severities; Statistical Computing; Symptoms; TNF gene; Testing; Therapeutic; Treatment Failure; United States Food and Drug Administration; Validation; adalimumab; arm; base; clinical decision support; clinical remission; cohort; dashboard; drug clearance; early adolescence; gastrointestinal symptom; gut inflammation; healing; improved; improved outcome; infliximab; innovation; learning progression; multidisciplinary; neutrophil; novel; novel therapeutics; patient population; peripheral blood; pharmacodynamic biomarker; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pragmatic implementation; response; support tools; treatment arm; young adult

Project Summary/Abstract Crohn's disease is a chronic illness that results in intestinal inflammation and unwanted gastrointestinal symptoms. The only biologic (monoclonal antibody) approved for moderate to severe Crohn's disease in children (<18 years old) are those that antagonize tumor necrosis factor-alpha (anti-TNF). While there is a high initial response rate to labeled infliximab (anti-TNF) dosing, only half of infliximab exposed patients will achieve clinical remission and less than 40% will achieve endoscopic healing after one year on therapy. Several studies have shown that rates of sustained corticosteroid-free remission are improved when patients receive anti-TNF dose optimizations following reactive or proactive therapeutic drug monitoring. Moreover, anti-TNF dose intensification following pharmacodynamic monitoring has led to improved rates of endoscopic (intestinal) healing. Therefore, given the limited therapeutic options for children with active Crohn's disease, there is a critical unmet need for the development of a data-driven, individualized, and scalable anti-TNF dosing intervention used from drug start and continued throughout therapy to optimize drug exposure and ultimately, improve rates of intestinal healing. Our team has developed a precision dosing strategy that uses an innovative physician decision support dashboard that instantaneously applies pharmacokinetic model-informed precision dosing to generate an individual infliximab dosing regimen starting with induction and targeting phase-specific pharmacokinetic and pharmacodynamic endpoints throughout therapy. The central hypothesis is precision dosing (intervention arm) with infliximab during induction and maintenance will improve rates of deep remission vs. conventional care (pragmatic dosing; control arm). The central hypothesis will be tested with two specific aims. Aim1: Conduct a cluster-randomized (by center) clinical trial to assess rates of deep remission at year1 between Crohn's disease patients receiving infliximab with precision dosing vs. conventional care. Aim2: Refine model- informed precision dosing using a continuous learning approach and identify anti-TNF PK/PD targets from induction to maintenance associated with deep remission. Our approach is conceptually innovative with an emphasis on practical implementation. This is the first clinical trial in children to provide anti-TNF dose optimization during induction to target a specific early (week6) trough concentration while the maintenance regimen is selected by specific treat-to-target pharmacokinetic and pharmacodynamic biomarkers. Additionally, precision dosing regimens are produced with a novel web-based decision support dashboard and the study is being performed within the ImproveCareNow Network to streamline clinical trial logistics. In Aim2, a continuous learning approach will be applied to our published pharmacokinetic model to iteratively refine the model by capturing new real-world data to better describe specific patient populations and further reduce prediction error. The long-term goal is for the precision dosing strategy to generate a paradigm shift as the preferred dosing approach to optimize exposure to all biologics and change the natural history of Crohn's disease.

项目摘要/摘要 克罗恩病是一种慢性疾病，会导致肠道炎症和不想要的胃肠道 症状。唯一被批准用于儿童中到重度克罗恩病的生物学(单抗) (&lt；18岁)是那些能拮抗肿瘤坏死因子-α(抗肿瘤坏死因子)的药物。虽然有一个很高的首字母 对标记英夫利昔单抗(抗肿瘤坏死因子)剂量的应答率，只有一半英夫利昔单抗暴露的患者将达到临床疗效 缓解率不到40%，治疗一年后内窥镜下痊愈。几项研究已经 结果显示，当患者接受抗肿瘤坏死因子的剂量时，持续的非皮质类固醇缓解率得到改善。 反应性或主动性治疗药物监测后的优化。此外，抗肿瘤坏死因子的剂量增强 随后的药效学监测提高了内窥镜(肠道)治愈率。因此， 鉴于活动性克罗恩病儿童的治疗选择有限，存在严重的未得到满足的需求 从药物开始使用的数据驱动的、个性化的、可扩展的抗肿瘤坏死因子剂量干预的开发 并在整个治疗过程中继续优化药物暴露，最终提高肠道愈合率。 我们的团队开发了一种精确剂量策略，它使用创新的医生决策支持 仪表板，即时应用药代动力学模型通知的精确剂量，以生成 英夫利昔单抗个体化给药方案从诱导和靶向阶段特定的药代动力学和 整个治疗过程中的药效学终点。中心假设是精确给药(干预臂) 与传统护理相比，在诱导和维持期间使用英夫利昔单抗将提高深度缓解率 (实用剂量；控制臂)。核心假设将通过两个具体目标进行检验。目标1：开展一项 整群随机(按中心)评估第1年克罗恩病深度缓解率的临床试验 疾病患者接受英夫利昔单抗精确剂量与常规护理的比较。AIM2：优化模型- 使用连续学习方法的知情精确给药和识别抗肿瘤坏死因子PK/PD靶点 从诱导到维持与深度缓解相关。我们的方法在概念上是创新的 注重实际执行。这是第一次在儿童中提供抗肿瘤坏死因子剂量的临床试验。 在诱导期间进行优化，以在维护期间针对特定的早期(6周)谷底浓度 根据特定的治疗靶点药代动力学和药效学生物标志物来选择方案。另外， 精确给药方案是用一个新的基于网络的决策支持仪表板产生的，这项研究是 在ImproveCareNow网络内进行，以简化临床试验后勤。在AIM2中，连续的 学习方法将应用于我们已发表的药代动力学模型，通过以下方式迭代改进模型 捕获新的真实数据，以更好地描述特定的患者群体，并进一步减少预测错误。 长期目标是实现精确配药策略，使其成为首选配药模式的转变 优化接触所有生物制品的方法，改变克罗恩病的自然病史。