PRISM

棱镜

基本信息

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
项目类别：
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

项目摘要

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，并且由于有限，已经在小型新生儿试验中显示出前景。药代动力学（PK）/药效学（PD）研究，早产儿孟鲁司特最佳剂量我们建议对孟鲁司特进行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（需要我们的中心前提是重新使用非类固醇药物。抗炎剂将是安全的，并且在预防 BPD 方面显示出初步功效。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确定性 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）。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。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。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性特征。孟鲁司特在早产儿中的应用；我们追求孟鲁司特不良事件发生率不会增加最后，我们的目的是确定孟鲁司特对早产儿的初步疗效。婴儿；我们追求根据人群 PK/PD 计算得出的中度至重度 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。 PRISM 试验对新生儿学领域的影响可能是巨大的。