Healthy, Plastic Bronchitis, Protein-Losing Enteropathies
Conditions
Keywords
children, congenital heart disease, metabolomics
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.
Interventions
DRUGTreatment-inhaled tPA
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.
Sponsors
Genentech, Inc.
University of Michigan
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 24 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment-inhaled tPA All patients with plastic bronchitis enrolled into the study will receive inhaled tPA.
Treatment-inhaled tPA: 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. | 8 |
| PLE Controls Participants with congenital heart disease and protein losing enteropathy but with no history of plastic bronchitis | 8 |
| Fontan Controls Participants with Fontan physiology with no history of plastic bronchitis or PLE | 9 |
| Healthy Controls Participants without congenital heart disease and no history of pulmonary disease (including plastic bronchitis) or protein losing enteropathy | 12 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | 2 in the treatment arm did not meet treatment eligibility; a healthy control screen failed | 2 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Treatment-inhaled tPA | Total | Healthy Controls | Fontan Controls | PLE Controls |
|---|---|---|---|---|---|
| Age, Continuous | 12.1 years STANDARD_DEVIATION 4.1 | 12.6 years STANDARD_DEVIATION 3.3 | 11.7 years STANDARD_DEVIATION 2.5 | 14 years STANDARD_DEVIATION 3.2 | 13 years STANDARD_DEVIATION 2.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 6 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 28 Participants | 7 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 28 Participants | 11 Participants | 8 Participants | 4 Participants |
| Region of Enrollment United States | 8 participants | 37 participants | 12 participants | 9 participants | 8 participants |
| Sex: Female, Male sex Female | 4 Participants | 13 Participants | 4 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male sex Male | 4 Participants | 24 Participants | 8 Participants | 5 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 9 | 0 / 12 |
| other Total, other adverse events | 8 / 8 | 0 / 8 | 0 / 9 | 1 / 12 |
| serious Total, serious adverse events | 1 / 8 | 0 / 8 | 0 / 9 | 0 / 12 |
Outcome results
Primary
Primary Endpoint: Number of Subjects That Develop New, Active Bleeding
The number of subjects with new systemic and/or pulmonary and/or gross hematuria
Time frame: 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.
Population: The number of new, active systemic bleeding events were assessed for participants enrolled in the treatment arm only. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment-inhaled tPA | Primary Endpoint: Number of Subjects That Develop New, Active Bleeding | 0 Participants |
Secondary
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.
Time frame: 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.
Population: Oxygen saturation was assessed at screening (if applicable), prior to treatment and daily for the duration of tPA treatment, at hospital discharged and at 30 days. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study.~Because pulse oximetry was measured at different times during hospitalization across patients, we report the mean pre-treatment and the hospital discharge (\~1 week post-treatment) mean (SD) values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment-inhaled tPA | Arterial Oxygen Saturation (%) | Pre-treatment | 90.6 percent | Standard Deviation 4.7 |
| Treatment-inhaled tPA | Arterial Oxygen Saturation (%) | Post-treatment (hospital discharge) | 90.6 percent | Standard Deviation 4.2 |
Secondary
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.
Time frame: This measurement will be performed prior to tPA treatment, at hospital discharge (~ 1 week) and again at 30 days.
Population: The number of participants enrolled in the treatment arm who had a relevant change in CTQ-R questionnaire domain scores from pre-treatment to hospital discharge were not able to be assessed because there were no participants who completed questionnaires at these two time points. No data are available for this secondary outcome.
Secondary
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.
Time frame: 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.
Population: All patients that received tPA. CXRs were scored by a pediatric pulmonologist using the Brasfield scoring system. 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. This outcome was pre-specified for the treatment arm of the study only; CXRs were not obtained in the control arms.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment-inhaled tPA | Changes in the Chest X-ray (CXR) | Pre-treatment | 20.6 score on a scale (0-25 normal) | Standard Deviation 0.74 |
| Treatment-inhaled tPA | Changes in the Chest X-ray (CXR) | Post-treatment | 20.9 score on a scale (0-25 normal) | Standard Deviation 0.9 |
Secondary
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.
Time frame: 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
Population: Blood levels of FDP were assessed from participants in the treatment arm of the study. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study. The pre-treatment average of participants and the post-treatment average (at hospital discharge, \~ 1 week from the start of treatment) are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment-inhaled tPA | Detection of Fibrin Degradation Product (FDP) in the Systemic Circulation | Pre-treatment | 0.32 mg/L | Standard Deviation 0.08 |
| Treatment-inhaled tPA | Detection of Fibrin Degradation Product (FDP) in the Systemic Circulation | Hospital discharge (~1 week) | 4.14 mg/L | Standard Deviation 4.11 |
Secondary
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.
Time frame: 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.
Population: The FEF25-75 will be assessed for each patient in the treatment arm. This is because the outcome measures were per-specified to collect data only from the treatment-inhaled tPA arm of the study.~Many treatment arm participants did not have values at all time points.The outcome measure is the pre-treatment average, the overall average during treatment (days 0-4) and the average at hospital discharge (\~ 1 week) after treatment initiation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment-inhaled tPA | Forced Expiratory Flow 25-75% (FEF25-75) | Pre-treatment | 1.23 Liters/second | Standard Deviation 0.2 |
| Treatment-inhaled tPA | Forced Expiratory Flow 25-75% (FEF25-75) | Treatment (days 0-4) | 1.76 Liters/second | Standard Deviation 0.94 |
| Treatment-inhaled tPA | Forced Expiratory Flow 25-75% (FEF25-75) | Hospital discharge (~1 week) | 1.14 Liters/second | Standard Deviation 0.09 |
Secondary
Forced Expiratory Volume in One Second (FEV1)
The change in FEV1 (L) from pre- to post- tPA treatment will be assessed for each patient.
Time frame: 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.
Population: The FEV1 (L) was assessed prior to and during inhaled tPA treatment, at hospital discharge and at the 30 d follow up visit. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study.~Many treatment arm participants did not have values at all time points.The outcome measure is the pre-treatment average, the overall average during treatment (days 0-4) and the average at hospital discharge (\~ 1 week) after treatment initiation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment-inhaled tPA | Forced Expiratory Volume in One Second (FEV1) | Pre-treatment | 1.7 Liters | Standard Deviation 0.95 |
| Treatment-inhaled tPA | Forced Expiratory Volume in One Second (FEV1) | Treatment (days 0-4) | 1.60 Liters | Standard Deviation 0.62 |
| Treatment-inhaled tPA | Forced Expiratory Volume in One Second (FEV1) | Hospital Discharge (~1 week) | 1.42 Liters | Standard Deviation 0.66 |
Secondary
Forced Vital Capacity (FVC)
The FVC (L) from prior to, during and after tPA treatment will be assessed for each patient.
Time frame: 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.
Population: The FVC (L) before, during and after tPA treatment will be assessed. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study.~Many treatment arm participants did not have values at all time points.The outcome measure is the pre-treatment average, the overall average during treatment (days 0-4) and the average at hospital discharge (\~ 1 week) after treatment initiation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment-inhaled tPA | Forced Vital Capacity (FVC) | Pre-treatment | 2.0 Liters | Standard Deviation 1.14 |
| Treatment-inhaled tPA | Forced Vital Capacity (FVC) | Treatment (days 0-4) | 1.91 Liters | Standard Deviation 0.66 |
| Treatment-inhaled tPA | Forced Vital Capacity (FVC) | Hospital discharge (~1 week) | 1.80 Liters | Standard Deviation 0.65 |
Secondary
Frequency of Production/Expectoration of Airway Casts
Episodes of the production of airway casts by participants enrolled in the treatment arm will be assessed.
Time frame: 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
Population: Assessment of cast production during the study period was made in the PB treatment arm only. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study. This was based on self report. Cast sizes were not assessed or reported.~The cumulative number of episodes of cast production reported at 30 days is reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment-inhaled tPA | Frequency of Production/Expectoration of Airway Casts | 9 episodes of cast production (30d) |
Secondary
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.
Time frame: Available (submitted) airway casts will assessed for the duration of the hospital stay, up to hospital discharge (~1 week).
Population: Any PB casts that were expectorated by treatment participants were sent for pathological analysis of casts by UM pathology. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study.~None of the PB-tPA treated study participants produced and submitted airway casts for pathological assessment. Therefore, no data are available for this outcome measure.
Secondary
Requirement for Mechanical Ventilation
Requirement for mechanical ventilation will be assessed in participants enrolled in the treatment arm during the treatment period.
Time frame: Participants will be followed for the duration of tPA treatment, up to 4 days.
Population: The number of participants in the treatment arm who required mechanical ventilation was recorded. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment-inhaled tPA | Requirement for Mechanical Ventilation | 0 Participants |
Secondary
Requirement for Urgent or Emergent Bronchoscopy
Requirement for urgent or emergent bronchoscopy during treatment was assessed.
Time frame: Participants will be followed for the duration of tPA treatment, up to 4 days.
Population: The number of treatment arm participants who required urgent or emergent bronchoscopy was recorded. This is because the outcome measures were pre-specified to collect data only from the treatment-inhaled tPA arm of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment-inhaled tPA | Requirement for Urgent or Emergent Bronchoscopy | 0 Participants |