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Inhaled Tissue Plasminogen Activator for Acute Plastic Bronchitis (PLATyPuS)

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ClinicalTrials.gov Identifier: NCT02315898
Recruitment Status : Recruiting
First Posted : December 12, 2014
Last Update Posted : September 5, 2019
Sponsor:
Collaborators:
Food and Drug Administration (FDA)
Genentech, Inc.
Information provided by (Responsible Party):
Kathleen A. Stringer, University of Michigan

Tracking Information
First Submitted Date  ICMJE December 8, 2014
First Posted Date  ICMJE December 12, 2014
Last Update Posted Date September 5, 2019
Actual Study Start Date  ICMJE March 19, 2018
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2018)
Primary Endpoint: Number of subjects that develop new, active bleeding [ Time Frame: Participants will be assessed daily for the duration of tPA treatment, up to 4 days and at hospital discharge. ]
The number of subjects with new systemic and/or pulmonary and/or gross hematuria
Original Primary Outcome Measures  ICMJE
 (submitted: December 9, 2014)
Primary Endpoint (safety): development of new, active bleeding that is systemic and/or pulmonary [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 5 days ]
Change History Complete list of historical versions of study NCT02315898 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2018)
  • Arterial oxygen saturation [ Time Frame: Participants will be assessed at screening, just prior to treatment and daily for the duration of tPA treatment, up to 4 days, and again at 30 days. ]
    Changes in oxygen saturation (%) will be monitored by pulse oximetry
  • Forced expiratory volume in one second (FEV1) [ Time Frame: Participants will be assessed at screening, 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) [ Time Frame: Participants will be assessed at screening, 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 FEF25-75 from pre- to post- tPA treatment will be assessed for each patient.
  • Forced vital capacity (FVC) [ Time Frame: Participants will be assessed at screening, 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 FVC (L) from pre- to post- tPA treatment will be assessed for each patient.
  • Frequency of production/expectoration and size of airway casts [ Time Frame: The frequency of cast production will be assessed daily for the duration of hospitalization, up to 5 days and from hospital discharge up to 30 days ]
    The frequency and production and size of airway casts will be assessed.
  • Changes in the chest x-ray (CXR) [ Time Frame: A CXR will be acquired and assessed two times during the study- once before treatment and again at hospital discharge. ]
    tPA treatment-induced changes in the CXR will be assessed. The chest x-ray will be scored prior to and after tPA treatment.
  • Requirement for urgent or emergent bronchoscopy [ Time Frame: Participants will be followed for the duration of tPA treatment, up to 4 days. ]
    Requirement for urgent or emergent bronchoscopy
  • Requirement for mechanical ventilation [ Time Frame: Participants will be followed for the duration of tPA treatment, up to 4 days. ]
    Requirement for mechanical ventilation
  • Fibrin and mucin content of airway casts [ Time Frame: Airway casts will assessed for the duration of the hospital stay, up to 5 days. ]
    PB cast fibrin and mucin content will be assessed for casts collected before and after tPA treatment
  • Detection of fibrin degradation product (FDP) in the systemic circulation [ Time Frame: FDP will be assessed at screening, then daily during the hospital stay, up to 5 days and again at 30 days ]
    Blood samples will be assayed for FDP (mg/L) during the study
  • Assessment of patient centered outcomes [ Time Frame: This measurement will be performed prior to tPA treatment, at hospital discharge (day 5) and again at 30 days. ]
    We will use a questionnaire to assess quality of life related to plastic bronchitis and its treatment
Original Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2014)
  • Efficacy: Frequency of production/expectoration and size of airway casts (weight and length) [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 5 days ]
  • Efficacy: Requirement for urgent or emergent bronchoscopy and/or mechanical ventilation [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 5 days ]
  • Efficacy: Measurement of fibrin and mucin content of airway casts [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 5 days ]
  • Efficacy: Changes in oxygen saturation (as determined by pulse oximetry) [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 5 days ]
  • Efficacy: Changes in respiratory rate [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 5 days ]
  • Efficacy: Changes in the chest x-ray [ Time Frame: In advance of hospitalization and again at the time of hospital admission and again at 30 days ]
  • Efficacy: Detection of fibrin degradation products in the systemic circulation [ Time Frame: Participants will be followed for the duration of the hospital stay, an expected average of 5 days and again at 30 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Inhaled Tissue Plasminogen Activator for Acute Plastic Bronchitis
Official Title  ICMJE Safety and Efficacy of Inhaled Tissue Plasminogen Activator (tPA) for the Acute Treatment of Pediatric Plastic Bronchitis
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 24 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Plastic Bronchitis
  • Protein-Losing Enteropathies
  • Healthy
Intervention  ICMJE Drug: 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.
Other Names:
  • alteplase
  • Activase
Study Arms  ICMJE Experimental: Treatment-inhaled tPA
All patients with plastic bronchitis enrolled into the study will receive inhaled tPA.
Intervention: Drug: Treatment-inhaled tPA
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 9, 2014)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
  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, arteriovenous malformation or aneurysm;
    • known bleeding diathesis;
    • and/or severe uncontrolled hypertension
  2. Body weight >/= 100th percentile or BMI > 30
  3. Known cystic fibrosis
  4. Currently receiving inhaled tPA and/or dornase-alpha and/or inhaled unfractionated or low molecular weight heparin
  5. Protein losing enteropathy
  6. Liver dysfunction (defined as ≥ 3X the normal levels of one or both liver transaminases)
  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.

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 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, Fontan Controls and PLE 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 (Fontan patients).
  3. Known liver dysfunction per medical record review (e.g., liver transaminases of > 3X normal).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 24 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Kathleen A Stringer, PharmD 734-647-4775 stringek@umich.edu
Contact: Kurt R Schumacher, MD 734-615-2369 kurts@umich.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02315898
Other Study ID Numbers  ICMJE UMich Inhaled tPA119678
R01FD005393 ( U.S. FDA Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Study data will be shared in accordance with the NIH's policy on data sharing. The University of Michigan has options for data repository (e.g., ICPSR, http://www.icpsr.umich.edu/icpsrweb/deposit/). All metabolomics data will be deposited in the NIH's Metabolomics Workbench (http://www.metabolomicsworkbench.org/). The study PI will also honor requests made by individual investigators.
Responsible Party Kathleen A. Stringer, University of Michigan
Study Sponsor  ICMJE University of Michigan
Collaborators  ICMJE
  • Food and Drug Administration (FDA)
  • Genentech, Inc.
Investigators  ICMJE
Principal Investigator: Kathleen A Stringer, PharmD University of Michigan
PRS Account University of Michigan
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP