Inhaled Tissue Plasminogen Activator for Acute Plastic Bronchitis
- Conditions
- HealthyPlastic BronchitisProtein-Losing Enteropathies
- Interventions
- Registration Number
- NCT02315898
- Lead Sponsor
- University of Michigan
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment-inhaled tPA Treatment-inhaled tPA All patients with plastic bronchitis enrolled into the study will receive inhaled tPA.
- Primary Outcome Measures
Name Time Method Primary Endpoint: Number of Subjects That Develop New, Active Bleeding 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. The number of subjects with new systemic and/or pulmonary and/or gross hematuria
- Secondary Outcome Measures
Name Time Method Forced Expiratory Flow 25-75% (FEF25-75) 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. 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.
Requirement for Urgent or Emergent Bronchoscopy Participants will be followed for the duration of tPA treatment, up to 4 days. Requirement for urgent or emergent bronchoscopy during treatment was assessed.
Assessment of Patient Centered Outcomes This measurement will be performed prior to tPA treatment, at hospital discharge (~ 1 week) and again at 30 days. 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.
Arterial Oxygen Saturation (%) 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. 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.
Forced Expiratory Volume in One Second (FEV1) 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. The change in FEV1 (L) from pre- to post- tPA treatment will be assessed for each patient.
Forced Vital Capacity (FVC) 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. The FVC (L) from prior to, during and after tPA treatment will be assessed for each patient.
Frequency of Production/Expectoration of Airway Casts 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 Episodes of the production of airway casts by participants enrolled in the treatment arm will be assessed.
Changes in the Chest X-ray (CXR) 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. 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.
Requirement for Mechanical Ventilation Participants will be followed for the duration of tPA treatment, up to 4 days. Requirement for mechanical ventilation will be assessed in participants enrolled in the treatment arm during the treatment period.
Pathological Assessment (Qualitative) of Fibrin and Mucin Content of Airway Casts Available (submitted) airway casts will assessed for the duration of the hospital stay, up to hospital discharge (~1 week). 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.
Detection of Fibrin Degradation Product (FDP) in the Systemic Circulation 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 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.
Trial Locations
- Locations (6)
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Lucile Packard Children's Hospital, Stanford University
🇺🇸Palo Alto, California, United States
Medical University of South Caroline
🇺🇸Charleston, South Carolina, United States
Cincinnati Children's Hospital
🇺🇸Cincinnati, Ohio, United States
University of Michigan Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States