PRISM

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，往往是致命的。 孟鲁司特是FDA批准的，已经在小型新生儿试验中显示出希望。由于有限的 药代动力学（PK）/药效学（PD）研究，早产儿的最佳孟鲁司特剂量 避免BPD是未知的。我们建议进行孟鲁司特的药代动力学和药效学研究， BPD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 在BPD高风险早产儿（出生< 29周妊娠）中进行的初步疗效试验（需要 29-33周之间的正压通气）。我们的中心假设是，重新利用非类固醇 抗炎药是安全的，对预防BPD有初步疗效。我们的目标是 在FDA监管指导下进行人群特异性PK/PD分析，以确定最佳的孟鲁司特 在确定的III期试验中使用的剂量。试验将从低剂量（0.75 mg/kg/天）队列开始，并将 安全性后，依次进入中剂量（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个有经验的新生儿部位的90例婴儿（30例/队列）。一 年龄和疾病严重程度相似的安慰剂治疗的NICHD试验婴儿的对照队列将作为 历史控制。主要结局将是药物清除率（CL/F），这是治疗的关键决定因素。 维持剂量。次要结局将包括安全性（由总不良事件确定）和 孟鲁司特与治疗期间BPD风险变化之间的安全性-反应关系 我们的第一个目标是描述孟鲁司特在早产儿中的PK特征。我们假设 月经后≤ 28周（PMA）（即PMA =胎龄+出生后年龄）的婴儿的清除率将 与> 28周的婴儿相比，至少减少30%。我们的第二个目标是描述安全性特征 我们假设孟鲁司特的不良事件发生率不会增加， 孟鲁司特暴露。最后，我们的目的是确定孟鲁司特在早产儿中的初步疗效。 婴儿;我们假设根据人群PK/PD计算的中重度BPD风险的变化 随着孟鲁司特AUC 0 - 24的增加，线性回归模型将下降30%。PRISM PK/PD结果 将提交给FDA，并将有助于确定孟鲁司特减少BPD的最佳剂量。的 PRISM试验的影响可能在生殖医学领域具有里程碑意义。

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.