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

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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.