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

塑料支气管炎(PB)是一种复杂、罕见的儿科疾病，其特征是在呼吸道内形成渗出性细胞纤维蛋白铸型。 发病率和死亡率高，但没有FDA批准的治疗方法的疾病。最常见的情况是- 接受丰坦手术姑息治疗的先天性心脏病儿童的术后并发症-- 在此期间。关键的是，在没有吸入tPA治疗的情况下，铅引起的呼吸窘迫的风险可能会降低。 在此，通常需要紧急或紧急支气管镜检查以摘除管型。事实上，PB被认为是一种生命- 危险的情况，因为死亡率接近50%。因此，对安全的需求还远远没有得到满足。 以及吸入tPA的疗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 知识阻碍了这些危重儿童急需的治疗方法的进展，因为他们提出了 吸入tPA的II期临床试验(IND119670；NCT02315898)。这项安全性临床研究的目的 孤儿产品研究项目资助(R01)申请的有效性是为了测试安全性和 指定的孤儿药物吸入tPA(#14-4314)治疗急性加重期的疗效 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 用于治疗慢性阻塞性肺疾病急性加重。为了实现这一目标，我们将统计出血事件和 监测出血参数如红细胞压积、国际标准化比率(INR)、凝血酶原时间(PTT)、 对患有纤维蛋白的儿童进行尿液分析，确诊为PB，他们每6小时吸入5 mg tPA方案，最长可达 96小时；2)评价吸入tPA方案治疗PB急性加重期的疗效。 为了实现这一目标，我们将监测气道管型产生的频率、管型大小、肺功能 纤维蛋白确诊为PB的儿童接受吸入tPA检测和评估支气管镜检查的必要性 IMAN每隔6小时服用5毫克，持续96小时；3)患有和不患有糖尿病的儿童的代谢特征不同 PB和吸入tPA治疗后。为了实现这一目标，我们将从 健康、年龄匹配的儿童、冠心病儿童和PB儿童进行代谢组学检测。在复杂的情况下- 在这项临床试验中，我们期望：1)了解吸入性tPA规则的安全性。 用于治疗儿童急性PB的男性；2)吸入tPA治疗效果的证据；以及3)一组我- 代谢物与PB和吸入tPA治疗反应有关。总体而言，我们预计这些数据将：1) 吸入tPA在儿童PB中的安全和有效使用将使其能够放心地用于PB的治疗 并使我们能够以最佳方式设计药物批准所需的第三阶段临床试验；以及3)指导TAR- GET代谢组学方法用于吸入性tPA药物反应的临床监测。这些数据将具有 对儿科孤儿药物开发领域产生积极影响，因为它们将支持批准 只对这些患者有治疗作用，并将促进对决定PB和 TPA药物反应表型。

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.