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.

项目概要/摘要 克罗恩病是一种慢性疾病，会导致肠道炎症和胃肠道不适 症状。唯一被批准用于治疗儿童中度至重度克罗恩病的生物制剂（单克隆抗体） （<18岁）是那些拮抗肿瘤坏死因子-α（抗TNF）的人。虽然初始值较高 对标记英夫利昔单抗（抗 TNF）给药的反应率，只有一半英夫利昔单抗暴露患者能够达到临床效果 治疗一年后，病情缓解，不到 40% 的患者会实现内镜下愈合。多项研究已 研究表明，当患者接受抗 TNF 剂量时，持续无皮质类固醇缓解率会提高 反应性或主动性治疗药物监测后的优化。此外，抗TNF剂量强化 药效学监测可提高内镜（肠）愈合率。所以， 鉴于患有活动性克罗恩病的儿童的治疗选择有限，因此迫切需要未得到满足的治疗 开发数据驱动、个性化且可扩展的抗 TNF 剂量干预措施，从药物开始使用 并在整个治疗过程中持续优化药物暴露，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，利用创新的医生决策支持 仪表板可立即应用基于药代动力学模型的精确剂量来生成 个体英夫利昔单抗给药方案从诱导开始并针对特定阶段的药代动力学和 整个治疗过程中的药效学终点。中心假设是精确剂量（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）。中心假设将通过两个具体目标进行检验。目标1：进行 整群随机（按中心）临床试验，评估克罗恩病第一年的深度缓解率 接受精确剂量英夫利昔单抗治疗的疾病患者与传统治疗相比。目标2：细化模型- 使用持续学习方法获得知情的精确剂量并确定抗 TNF PK/PD 靶点 从诱导到与深度缓解相关的维持。我们的方法在概念上是创新的 并注重实际落实。这是第一个针对儿童提供抗 TNF 剂量的临床试验 在诱导期间进行优化，以达到特定的早期（第 6 周）谷浓度，同时维持 治疗方案是根据特定的治疗目标药代动力学和药效生物标志物来选择的。此外， 精确的给药方案是通过一个新颖的基于网络的决策支持仪表板制定的，该研究是 在 ImproveCareNow 网络内进行，以简化临床试验后勤工作。在 Aim2 中，连续 学习方法将应用于我们发布的药代动力学模型，以迭代地完善模型 捕获新的现实世界数据，以更好地描述特定患者群体并进一步减少预测误差。 长期目标是使精确剂量策略产生范式转变，成为首选剂量 优化所有生物制剂的暴露并改变克罗恩病自然史的方法。