Inhaled Tissue Plasminogen Activator for Acute Plastic Bronchitis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Safety and Efficacy of Inhaled Tissue Plasminogen Activator (tPA) for the Acute Treatment of Pediatric Plastic Bronchitis

Conditions
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Plastic Bronchitis, Protein-Losing Enteropathies, Healthy

Intervention / Treatment
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* Drug: Treatment-inhaled tPA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (patients with plastic bronchitis): ≥ 5 years of age but ≤24 years of age and weigh at least 18.6 kg (41 lbs). 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. 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. Must be able to use a mouthpiece nebulizer. 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): 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 Body weight >/= 100th percentile or BMI > 30 Known cystic fibrosis 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. Protein losing enteropathy 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 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) International normalized ratio (INR) > 2.0 if not receiving warfarin Patients being actively treated for thrombosis Concomitant use of a thienopyridine class antiplatelet agent (e.g., clopidogrel) A platelet count of < 100,000 platelets/µL A hematocrit <30% Gross hematuria on screening urinalysis 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. 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. Suspected or active concurrent infectious illness. Inclusion Criteria for Healthy Controls 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) Weigh at least 18.6 kg (41 lbs) Inclusion Criteria for Healthy non-PB Fontan Controls 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). Weigh at least 18.6 kg (41 lbs) Inclusion Criteria for PLE Fontan Controls 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. Weigh at least 18.6 kg (41 lbs) Exclusion Criteria for Healthy, non-PB Fontan Controls and PLE Fontan Controls Exceed the 100th percentile for body weight or have a BMI greater than 30. History of post-operative chylothorax following any palliation surgery (except for PLE controls). Known liver dysfunction per medical record review (e.g., defined as ≥ 3X the normal levels of one or both liver transaminases [ALT & AST]) 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 Suspected or active concurrent infectious illness

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 24 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment-inhaled tPA<br>All patients with plastic bronchitis enrolled into the study will receive inhaled tPA. | Drug: Treatment-inhaled tPA<br>* 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.<br>* Other names: Activase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Endpoint: Number of Subjects That Develop New, Active Bleeding | The number of subjects with new systemic and/or pulmonary and/or gross hematuria | Participants will be assessed every 24 hours (daily) for the duration of tPA treatment which was up to 4 days and at hospital discharge which typically occurred within 1 week of treatment initiation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial Oxygen Saturation (%) | Changes in oxygen saturation (%) will be monitored by pulse oximetry (oxygen saturation is the fraction of oxygen-saturated hemoglobin relative to total hemoglobin in the blood). Since this measurement was made at different times for each participant, the mean (SD) oxygen saturation (%) prior to study drug administration (pre-treatment) and at hospital discharge (  1 week post-treatment) was calculated. | Participants will be assessed at screening (if applicable), just prior to treatment and daily for the duration of tPA treatment, up to 4 days, at hospital discharge (  1 week) and again at 30 days. | 
| Forced Expiratory Volume in One Second (FEV1) | The change in FEV1 (L) from pre- to post- tPA treatment will be assessed for each patient. | Participants will be assessed at screening (if applicable), just prior to treatment and then daily for the duration of tPA treatment, up to 4 days, at hospital discharge and again at 30 days. | 
| Forced Expiratory Flow 25-75% (FEF25-75) | The FEF25-75 will be assessed for each patient in the treatment arm prior to study drug, during study drug administration (days 0-4), at hospital discharge (  1 week after treatment) and again at 30 days. | Participants will be assessed at screening (if applicable), just prior to treatment and then daily for the duration of tPA treatment, up to 4 days, at hospital discharge and again at 30 days. | 
| Forced Vital Capacity (FVC) | The FVC (L) from prior to, during and after tPA treatment will be assessed for each patient. | Participants will be assessed at screening (if applicable), just prior to treatment and then daily for the duration of tPA treatment, up to 4 days, at hospital discharge and again at 30 days. | 
| Frequency of Production/Expectoration of Airway Casts | Episodes of the production of airway casts by participants enrolled in the treatment arm will be assessed. | Episodes of cast production will be assessed daily for the duration tPA treatment, up to 4 days and from hospital discharge ( 1 week after treatment) up to 30 days | 
| Changes in the Chest X-ray (CXR) | tPA treatment-induced changes in the CXR will be assessed. The chest x-ray will be scored prior to and after tPA treatment at hospital discharge ( 1 week post treatment). The scores will be derived using the Brasfield scoring system which assesses air trapping, linear markings (bronchial wall thickness), bronchiectasis, lobar involvement and overall severity. A score of 25 represents a normal CXR. Points are deducted from 25 for abnormalities so the lower the score the greater the disease severity. | A CXR will be acquired and assessed two times during the study- once just prior to the initiation of study drug and again at hospital discharge, up to  1 week. | 
| Requirement for Urgent or Emergent Bronchoscopy | Requirement for urgent or emergent bronchoscopy during treatment was assessed. | Participants will be followed for the duration of tPA treatment, up to 4 days. | 
| Requirement for Mechanical Ventilation | Requirement for mechanical ventilation will be assessed in participants enrolled in the treatment arm during the treatment period. | Participants will be followed for the duration of tPA treatment, up to 4 days. | 
| Pathological Assessment (Qualitative) of Fibrin and Mucin Content of Airway Casts | PB cast fibrin and mucin content will be qualitatively assessed in casts that are collected before and after tPA treatment up to hospital discharge ( 1 week) by a co-investigator pathologist. Each cast will be qualitatively assessed for fibrin and mucin content based on standard pathological procedures. | Available (submitted) airway casts will assessed for the duration of the hospital stay, up to hospital discharge ( 1 week). | 
| Detection of Fibrin Degradation Product (FDP) in the Systemic Circulation | Blood samples will be assayed for FDP (mg/L) during the study. This is a measure of fibrin degradation in the blood and is a value that can be altered by tPA treatment. An FDP (or D-dimer) value <0.5 mg/L is considered normal. | FDP will be assessed at screening (if applicable), prior to treatment and then daily during the hospital stay ( 1 week) and again at 30 days | 
| Assessment of Patient Centered Outcomes | We will use a questionnaire to assess how many participants had changes in quality of life related to plastic bronchitis and its treatment during the study in participants enrolled in the treatment arm. For this, the Cystic Fibrosis Questionnaire-Revised (CFQ-R) will be used since there is not a specific plastic bronchitis questionnaire. The CFQ-R is designed to measure impact on overall health, daily life, perceived well-being and symptoms. The CFQ-R uses a Likert scale to rate nine quality of life domains: Physical, role/school, vitality, emotion, social, body image, eating, treatment burden, health perceptions and three symptom scales: Weight, respiratory, and digestion. Each item is summed to generate a domain score. Scores range from 0 to 100, with higher scores indicating better health. | This measurement will be performed prior to tPA treatment, at hospital discharge (  1 week) and again at 30 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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children, congenital heart disease, metabolomics