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.

项目概要/摘要 支气管肺发育不良（BPD）是早产儿最常见的呼吸道后遗症，通常是致命的。 孟鲁司特已获得 FDA 批准，并已在小型新生儿试验中显示出前景。由于有限 药代动力学（PK）/药效学（PD）研究，早产儿孟鲁司特最佳剂量 避免 BPD 的方法尚不清楚。我们提出孟鲁司特的药代动力学和药效学研究 患有 BPD 的婴儿 (PRISM) 试验，一项剂量递增的开放标签药代动力学、安全性和 针对 BPD 高风险早产儿（妊娠 < 29 周出生）的初步疗效试验（需要 正压通气 (29-33 周)。我们的中心前提是重新利用非类固醇 抗炎剂在预防 BPD 方面是安全的并且显示出初步疗效。我们的目标是 在 FDA 监管指导下进行人群特异性 PK/PD 分析，以确定最佳孟鲁司特 在最终的 III 期试验中使用的剂量。该试验将从低剂量（0.75 毫克/公斤/天）队列开始，并将 安全后依次进行中剂量（1.5 mg/kg/天）和高剂量（2.25 mg/kg/天）队列 评论。给药将持续 4 周，涉及最多 8 个有经验的新生儿中心的 90 名婴儿（30 名/队列）。一个 具有相似年龄和疾病严重程度的接受安慰剂治疗的 NICHD 试验婴儿的比较队列将作为 历史控制。主要结果是药物清除率 (CL/F)，这是药物清除率的关键决定因素 维持剂量。次要结果包括安全性（由不良事件总数决定）和 孟鲁司特与治疗期间 BPD 风险变化之间的暴露-反应关系。 我们的首要目标是表征孟鲁司特在早产儿中的 PK。我们假设 月经后年龄 (PMA) ≤ 28 周的婴儿的清除率（即 PMA = 孕龄 + 产后年龄） 与 28 周以上的婴儿相比，至少减少 30%。我们的第二个目标是描述安全状况 早产儿中的孟鲁司特；我们假设孟鲁司特不良事件发生率不会增加 与孟鲁司特暴露。最后，我们的目的是确定孟鲁司特对早产儿的初步疗效 婴儿；我们假设根据人群 PK/PD 计算得出中重度 BPD 风险的变化 线性回归模型将随着孟鲁司特 AUC0-24 的增加而降低 30%。PRISM PK/PD 结果 将提交给 FDA，并将有助于确定孟鲁司特降低 BPD 的最佳剂量。这 PRISM 试验对新生儿学领域的影响可能是巨大的。