Inhaled Tissue Plasminogen Activator for Acute Plastic Bronchitis
Condition: Plastic Bronchitis; Protein-Losing Enteropathies; Healthy
MeSH terms: Bronchitis; Protein-Losing Enteropathies; Acute Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      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
    

Detailed description: 
      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.
    

Intervention name(s): Treatment-inhaled tPA
Intervention type(s): Drug
Intervention description(s): Enrolled patients with acute plastic bronchitis (fibrin airway casts) will receive inhaled tPA treatment. The tPA regimen will consist of 5mg every six hours for a total of 72 hours.
Other intervention name(s): alteplase; Activase
Intervention MeSH terms: Tissue Plasminogen Activator
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: children, congenital heart disease, metabolomics