Inhaled Tissue Plasminogen Activator for Acute Plastic Bronchitis
Condition: Plastic Bronchitis; Protein-Losing Enteropathies; Healthy
MeSH terms: Bronchitis; Protein-Losing Enteropathies; Acute Disease
Intervention: Treatment-inhaled tPA
Intervention description: 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.
Intervention MeSH terms: Tissue Plasminogen Activator
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 5 Years
Maximum age: 24 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: children, congenital heart disease, metabolomics

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
    

Eligibility criteria:

        Inclusion Criteria (patients with plastic bronchitis):

          1. ≥ 5 years of age but ≤24 years of age and weigh at least 18.6 kg (41 lbs).

          2. Patients with CHD that have a history of PB with previous airway cast production
             and/or present with symptoms of an acute exacerbation (e.g., difficulty breathing,
             dyspnea) of PB that requires hospitalization. An acute exacerbation of PB is defined
             as either respiratory symptoms suspicious for airway cast formation and/or the
             expectoration of, or a bronchoscopy retrieved, fibrin PB cast.

          3. Patients without CHD that present with an acute exacerbation of PB, defined as the
             expectoration of, or a bronchoscopy retrieved, fibrin PB cast that causes acute
             respiratory distress (e.g., severe coughing, difficulty breathing, dyspnea) or a
             history of PB with pathologic evidence of fibrin airway cast production. Either a cast
             sample (at least ½ inch (~4cm)) or a pathology report that documents PB cast fibrin
             content must be submitted to the UM pathology core.

          4. Must be able to use a mouthpiece nebulizer.

          5. Informed consent (with parental if age ≥14 years) or assent for age ≥10 and < 14 years
             old with parental informed consent.

        Exclusion Criteria (patients with plastic bronchitis):

          1. Known contraindication(s) to the use of tPA, including:

               -  active internal bleeding;

               -  history of cerebrovascular accident;

               -  recent intracranial or intraspinal surgery or trauma;

               -  intracranial neoplasm, intracranial arteriovenous malformation or intracranial
                  aneurysm;

               -  known bleeding diathesis;

               -  and/or severe uncontrolled hypertension

          2. Body weight >/= 100th percentile or BMI > 30

          3. Known cystic fibrosis

          4. Currently receiving dornase-alfa and/or inhaled unfractionated or low molecular weight
             heparin and/or a direct acting oral anticoagulant (e.g., dabigatran, rivaroxaban)

               -  Inhaled unfractionated or low molecular weight heparin must be discontinued at
                  least 72h. Inhaled dornase alfa should be discontinued no later than the time of
                  the start of enrollment in the treatment phase. If the patient is receiving
                  inhaled tPA, this regimen must be discontinued and transitioned to the inpatient
                  dosing regimen (5mg Q6h) of study drug.

               -  Direct acting oral anticoagulants must be discontinued one week prior to the
                  start of enrollment in the treatment phase.

          5. Protein losing enteropathy

          6. Liver dysfunction (defined as ≥ 3X the normal levels of one or both liver
             transaminases, AST and AST)

             • Transaminase levels acquired within the last 9 months can be used to assess liver
             function. If previously normal and there is no clinical indication that liver function
             has worsened, the patient can be enrolled. If there are no transaminase values within
             the last 9 months, they need to be acquired as part of screening

          7. Need for concomitant intravenous or sub-cutaneous anti-coagulation with resulting
             anti- Xa levels > 0.5 (low molecular weight heparins) or > 0.3 (unfractionated
             heparin)

          8. International normalized ratio (INR) > 2.0 if not receiving warfarin

          9. Patients being actively treated for thrombosis

         10. Concomitant use of a thienopyridine class antiplatelet agent (e.g., clopidogrel)

         11. A platelet count of < 100,000 platelets/µL

         12. A hematocrit <30%

         13. Gross hematuria on screening urinalysis

         14. Pregnant or lactating women (negative pregnancy test required for girls/women of
             childbearing potential at the time of inhaled tPA administration). All women of child-
             bearing potential must be willing to practice appropriate contraception throughout the
             study.

         15. Subjects who are known positive for, or are hospitalized with COVID-19 caused by the
             new coronavirus, SARS CoV-2, at the start of the treatment phase.

         16. Suspected or active concurrent infectious illness.

        Inclusion Criteria for Healthy Controls

          1. Healthy children ≥ 5 years of age but ≤18 years of age with no other underlying
             concomitant illness or chronic medication use (with the exception of vitamin
             supplements)

          2. Weigh at least 18.6 kg (41 lbs)

        Inclusion Criteria for Healthy non-PB Fontan Controls

          1. Children ≥ 5 years of age but ≤18 years of age with uncomplicated Fontan physiology
             with no history of PB, other Fontan-associated complications (e.g., hepatopathy, PLE),
             or other concomitant illnesses (e.g., asthma).

          2. Weigh at least 18.6 kg (41 lbs)

        Inclusion Criteria for PLE Fontan Controls

          1. Children ≥ 5 years of age but ≤18 years of age with Fontan physiology, no history of
             PB and a diagnosis of PLE defined as clinically symptomatic hypoproteinemia and/or
             enteral protein loss.

          2. Weigh at least 18.6 kg (41 lbs)

        Exclusion Criteria for Healthy, non-PB Fontan Controls and PLE Fontan Controls

          1. Exceed the 100th percentile for body weight or have a BMI greater than 30.

          2. History of post-operative chylothorax following any palliation surgery (except for PLE
             controls).

          3. Known liver dysfunction per medical record review (e.g., defined as ≥ 3X the normal
             levels of one or both liver transaminases [ALT & AST])

          4. COVID-19 positive within the last 14 days prior to the scheduled visit and/or the
             presence of symptoms consistent with COVID-19 at the time of the visit

          5. Suspected or active concurrent infectious illness