PRISM

棱镜

• 批准号: 10749441
• 负责人: Daniel Gonzalez
• 金额: $ 76.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749441
• 关键词: Adrenal Cortex Hormones; Adverse event; Age; Age Months; Alveolar; Anti-Inflammatory Agents; Bronchopulmonary Dysplasia; Childhood; Clinical; Data; Development; Diffuse; Doctor of Pharmacy; Doctor of Philosophy; Dose; Drug Kinetics; Edema; FDA approved; Fibrosis; Frequencies; Gestational Age; Health Care Costs; Hospitalization; Hyperoxia; Impairment; Infant; Inflammation; Inflammatory; Lead; Leukotriene Receptor; Leukotrienes; Life; Linear Regressions; Maintenance; Measures; Modeling; National Institute of Child Health and Human Development; Nature; Neonatal; Neonatology; Oral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebos; Population; Pregnancy; Premature Infant; Prevalence; Production; Public Health; Pulmonary Inflammation; Pulmonary Surfactants; Quality of life; Recording of previous events; Research; Research Personnel; Resort; Risk; Risk Reduction; Safety; Severity of illness; Site; Testing; Therapeutic; Training; Trauma; Ventilator; cohort; design; drug clearance; efficacy trial; experience; high risk; improved; indexing; montelukast; neonatal care; neurodevelopment; open label; overtreatment; oxygen toxicity; pharmacokinetics and pharmacodynamics; pharmacometrics; phase III trial; postnatal; pre-clinical; premature; pressure; prevent; primary outcome; pulmonary function; respiratory; response; secondary outcome; side effect; stem; treatment duration; trend; ventilation

Project Summary / Abstract Bronchopulmonary dysplasia (BPD) is the most common respiratory sequelae of prematurity and is often fatal. Montelukast is FDA-approved and already shows promise in small neonatal trials. Because of limited pharmacokinetic (PK)/pharmacodynamics (PD) research, the optimal montelukast dose for premature infants to avoid BPD is unknown. We propose the Pharmacokinetic and pharmacodynamic study of montelukast in infants with developing BPD (PRISM) trial, a dose-escalating open-label pharmacokinetic, safety and preliminary efficacy trial in premature infants (born < 29 weeks’ gestation) at high risk for BPD (requiring positive pressure ventilation between 29-33 weeks). Our central premise is that re-purposing a non-steroid anti-inflammatory agent will be safe and show preliminary efficacy in preventing BPD. Our objective is to perform population-specific PK/PD analyses under FDA regulatory guidance to identify the optimal montelukast dose to use in a definitive phase III trial. The trial will begin with a low-dose (0.75 mg/kg/day) cohort, and will proceed sequentially to the medium- (1.5 mg/kg/day) and high-dose (2.25 mg/kg/day) cohorts after safety reviews. Dosing will last 4 weeks involving 90 infants (30/cohort) at up to 8 experienced neonatal sites. A comparator cohort of placebo-treated NICHD-trial infants with similar age and disease severity will serve as historical controls. The primary outcome will be the drug clearance (CL/F), which is the key determinant of maintenance dosing. Secondary outcomes will include safety (determined by total adverse events) and exposure-response relationships between montelukast and change in BPD risk over the treatment period. Our first aim will be to characterize the PK of montelukast in premature infants. We hypothesize that the clearance in the infants ≤ 28 weeks post-menstrual age (PMA) (i.e. PMA = gestational age + postnatal age) will be at least 30% reduced compared to infants > 28 weeks. Our second aim is to characterize the safety profile of montelukast in premature infants; we hypothesize that the montelukast adverse event rate will not increase with montelukast exposure. Lastly, we aim to determine preliminary efficacy of montelukast in premature infants; we hypothesize that the change in moderate-severe BPD risk calculated from a population PK/PD linear regression model will decrease by 30% with increasing montelukast AUC0-24.The PRISM PK/PD results will be submitted to the FDA, and will help determine the optimal dose of montelukast to reduce BPD. The impact of the PRISM trial could be monumental in the field of neonatology.

项目摘要 /摘要 支气管肺发育不良（BPD）是早产的最常见呼吸道后遗症，通常是致命的。 Monterukast是FDA批准的，并且在小型新生儿试验中已经显示出希望。因为有限 药代动力学（PK）/药效学（PD）研究，最佳蒙特鲁克斯特剂量过早婴儿 避免BPD是未知的。我们提出了Montelukast的药代动力学和药效学研究 患有BPD（PRISM）试验的婴儿，剂量升级的开放标签药代动力学，安全性和 早产婴儿的初步效率试验（出生于29周的妊娠<29周），以BPD高风险（需要 正压通风在29-33周之间）。我们的中心前提是重新使用非类固醇 抗炎剂将是安全的，并在防止BPD方面显示出初步效率。我们的目标是 在FDA监管指导下进行特定人群的PK/PD分析，以识别最佳的Montelukast 在确定的III期试验中使用剂量。试验将以低剂量（0.75 mg/kg/day）的同类开始，将开始 在安全后，依次继续进行培养基（1.5 mg/kg/day）和高剂量（2.25 mg/kg/day） 评论。剂量将持续4周，涉及多达8个经验丰富的新生儿部位，涉及90名婴儿（30个/队列）。一个 与年龄相似的安慰剂治疗的NICHD试验婴儿的比较者队列将作为 历史控制。主要结果将是药物清除率（CL/F），这是关键的确定器 维护剂量。次要结果将包括安全性（由总广告事件确定）和 在治疗期间，Montelukast与BPD风险变化之间的暴露反应关系。 我们的第一个目的是表征早产儿中蒙特鲁卡斯特的PK。我们假设 月经后年龄≤28周的婴儿清除（PMA）（即PMA =胎龄 +产后年龄）将 与婴儿> 28周相比，至少降低了30％。我们的第二个目的是表征安全性 早产婴儿的蒙特鲁卡斯特（Montelukast）；我们假设Montelukast不良事件率不会增加 与Montelukast暴露。最后，我们旨在确定Montelukast的初步效率 婴儿；我们假设现代重度BPD风险的变化是由人口PK/PD计算的 随着Montelukast AUC0-22的增加，线性回归模型将降低30％。PrismPK/PD结果 将提交给FDA，并将有助于确定Montelukast的最佳剂量以减少BPD。 在新生儿学领域，棱镜试验的影响可能是巨大的。