IND119678 Phase II Safety & Efficacy of Inhaled Activase for Acute Plastic Bronchitis 12-10-14

IND119678 第二阶段安全

• 批准号: 9631306
• 负责人: KATHLEEN A STRINGER
• 金额: $ 50万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9631306
• 关键词: IND119678; Phase; II; Safety; Efficacy

Plastic bronchitis (PB), in which exudative cellular fibrin casts form in the airways, is a complex, rare, pediatric disease with high morbidity and mortality but for which there are no FDA-approved therapies. It most often oc- curs in children with congenital heart disease that have undergone surgical palliation with the Fontan proce- dure. Critically, in the absence of inhaled tPA treatment, the risk of PB-induced respiratory distress can be se- vere, often warranting urgent or emergent bronchoscopy for cast removal. In fact, PB is considered a life- threatening condition because mortality approaches 50%. As such there is a significant unmet need for safety and efficacy testing of inhaled tPA and for biomarkers of drug response. Here, we propose to fill this major gap in knowledge that hinders the advancement of this much needed therapy for these critically ill children by proposing a phase II clinical trial of inhaled tPA (IND119670; NCT02315898). The objective of this Clinical Study of Safety and Effectiveness of Orphan Products Research Project Grant (R01) application is to test the safety and effectiveness of the designated orphan drug, inhaled tPA (#14-4314), for the treatment of acute exacerbations of PB. To achieve this goal, we will address three specific aims: 1) To test the safety of an inhaled tPA regimen for the treatment of acute exacerbations of PB. To accomplish this aim we will count bleeding events and monitor parameters of bleeding such as hematocrit, international normalized ratio (INR), prothrombin time (PTT), and urinalysis of children with fibrin confirmed PB who receive an inhaled tPA regimen of 5mg every 6h for up to 96 h; 2) To assess the efficacy of an inhaled tPA regimen for the treatment of acute exacerbations of PB. To accomplish this aim we will monitor the frequency of airway cast production, cast size, pulmonary function tests and assess the need for bronchoscopy in children with fibrin confirmed PB who receive an inhaled tPA reg- imen of 5mg every 6h for up to 96h; 3) Metabolically characterize differences in children with and without PB and following inhaled tPA treatment. To accomplish this aim we will collect blood and urine samples from healthy, age-matched children, children with CHD, and children with PB for metabolomics assay. At the comple- tion of this clinical trial, it is our expectation that we will have: 1) knowledge of the safety of an inhaled tPA regi- men for the treatment of acute pediatric PB; 2) evidence of inhaled tPA treatment efficacy; and 3) a panel of me- tabolites linked to PB and inhaled tPA treatment response. Collectively, we expect these data will: 1) inform of the safe and 2) efficacious use of inhaled tPA in pediatric PB which will permit its confident use for PB treatment and allow us to optimally design a phase III clinical trial that will be needed for drug approval; and 3) direct a tar- geted metabolomics approach for the clinical monitoring of inhaled tPA drug response. These data will have a positive impact on the field of pediatric orphan drug development because they will support the approval of the only therapeutic for these patients and will advance understanding of the mechanisms that dictate the PB and tPA drug response phenotypes.

可塑性支气管炎（PB），其中渗出性细胞纤维蛋白管型形成的气道，是一种复杂的，罕见的，儿科 高发病率和死亡率的疾病，但没有FDA批准的治疗方法。它通常是O-O- 先天性心脏病患儿接受Fontan手术姑息治疗后， dure.重要的是，在没有吸入性tPA治疗的情况下，PB诱导的呼吸窘迫的风险可能是安全的。 通常需要紧急或紧急支气管镜检查以取出管型。事实上，PB被认为是一种生活- 因为死亡率接近50%因此，存在显著的未满足的安全需求 以及吸入tPA的功效测试和药物反应的生物标志物。在这里，我们建议填补这一重大空白， 这些知识阻碍了这些重症儿童急需的治疗的进展， 吸入性tPA的II期临床试验（IND 119670; NCT 02315898）。本安全性临床研究的目的 孤儿产品研究计划资助（R 01）的申请是为了测试孤儿产品的安全性和有效性， 指定孤儿药吸入型tPA（#14-4314）治疗急性加重的有效性 PB.为了实现这一目标，我们将解决三个具体目标：1）测试吸入tPA方案的安全性 用于治疗PB的急性加重。为了实现这一目标，我们将统计出血事件， 监测出血参数，如红细胞压积、国际标准化比值（INR）、凝血酶原时间（PTT）， 和尿分析的儿童纤维蛋白确诊的PB谁接受吸入tPA方案5毫克每6小时， 96 h; 2）评估吸入tPA方案治疗PB急性加重的疗效。 为了实现这一目标，我们将监测气道铸型制作的频率、铸型尺寸、肺功能 测试并评估接受吸入tPA注册的纤维蛋白确诊PB儿童的支气管镜检查需求- 每6小时5 mg，持续96小时; 3）有和无代谢特征的儿童差异 PB和吸入tPA治疗后。为了实现这一目标，我们将收集血液和尿液样本， 健康、年龄匹配儿童、患有CHD的儿童和患有PB的儿童进行代谢组学测定。在完成- 通过这项临床试验，我们期望：1）了解吸入tPA给药方案的安全性， 男性用于治疗急性儿科PB; 2）吸入tPA治疗有效性的证据;和3）一组ME-PA 与PB和吸入性tPA治疗反应相关的Tablets。总的来说，我们预计这些数据将：1）告知 吸入性tPA在儿童PB中的安全性和2）有效性，这将使其有信心用于PB治疗 并使我们能够优化设计药物批准所需的III期临床试验; 3）指导焦油- 代谢组学方法用于临床监测吸入tPA药物反应。这些数据将有一个 对儿科孤儿药开发领域产生积极影响，因为它们将支持 仅对这些患者有治疗作用，并将促进对决定PB的机制的理解， tPA药物反应表型。