Inhaled Tissue Plasminogen Activator for Acute Plastic Bronchitis

Plastic bronchitis (PB) is a rare, most often pediatric disease characterized by the formation of obstructive airway casts primarily composed of fibrin. There is presently no FDA-approved pharmacotherapy for PB, but acute exacerbations of the illness are often treated with inhaled tissue plasminogen activator (tPA). To date, this is done somewhat anecdotally because there has been no safety or efficacy testing of this treatment. In addition, there is presently no reliable surrogate marker of adverse drug events. Nevertheless, in the absence of inhaled tPA treatment, PB-induced respiratory distress can be severe, often warranting urgent or emergent bronchoscopy for cast removal, or can sometimes result in respiratory failure. As such there is a significant unmet need for safety and efficacy testing of inhaled tPA and for biomarkers of drug response. Objectives and Endpoints: The objectives of this protocol are to: 1) test the safety and efficacy of an inhaled tPA regimen in children with PB; and 2) identify potential candidate biomarkers of inhaled tPA drug response. Safety endpoints will consist of the development of new, active bleeding that is systemic and/or pulmonary and/or new hematuria (defined as gross hematuria). Secondary endpoints of efficacy will also be measured (e.g., frequency of cast production). Urine and blood will also be collected for the development of potential biomarkers of inhaled tPA drug response. Funding source- FDA OOPD

Background and Rationale: Plastic bronchitis (PB) is a rare, disease characterized by the formation of obstructive fibrin airway casts. Presently, acute exacerbations of the illness are often treated with inhaled tissue plasminogen activator (tPA), in part, because there are no FDA approved treatments. To date, there has been no safety or efficacy testing of inhaled tPA. In addition, there is presently no reliable marker that could be used to assess adverse drug events. However, in the absence of inhaled tPA treatment, PB-induced respiratory distress can be severe, often warranting urgent or emergent bronchoscopy for cast removal, or can sometimes result in respiratory failure. This clinical trial will address the unmet need for safety and efficacy testing of inhaled tPA and for assessing biomarkers of drug response. Objectives and Endpoints: This is an open-label, multi-center clinical trial of inhaled tPA for the treatment of acute PB. The objectives of this protocol are to: 1) test the safety and efficacy of an inhaled tPA regimen in children with PB; and 2) identify potential candidate biomarkers of inhaled tPA drug response. Safety endpoints will consist of the development of new, active bleeding that is systemic and/or pulmonary and/or new hematuria (defined as gross hematuria). Secondary endpoints of efficacy will also be measured (e.g., frequency of cast production). Urine and blood will also be collected for the development of potential biomarkers of inhaled tPA drug response. Assessments: Enrolled subjects will be routinely clinically monitored and blood work will be assessed for the development of new, active bleeding that is systemic and/or pulmonary or new gross hematuria. Levels of oxygenation and pulmonary function will be assessed during the study period. We will also include the incidence of expectorated casts as a measurement of efficacy. Statistical Methods: This is an open-label study of up to 13 subjects with PB that will serve as their own controls. A group of healthy subjects (n=12), Fontan subjects without PB (n=12), and Fontan subjects with protein losing enteropathy (PLE) (n=12) will serve as controls for biomarker assay development. The incidence of new, active bleeding events and the frequency of airway cast expectoration will be assessed in subjects with PB. PLE is another illness that is associated with congenital heart disease in children that has been surgically remedied by the Fontan procedure. The active treatment arm (inhaled tPA) will be conducted across six clinical centers. In addition, these centers will enroll PLE control patients. All other control subjects will only be enrolled at the University of Michigan. The outcome measures only pertain to tPA treated patients. Since the control subjects are not included in the outcome analysis, recruitment/enrollment status pertains to the PB patients. The University of Michigan has initiated enrollment of healthy control subjects and there have been consented subjects.