Safety and Efficacy of Inhaled Tissue Plasminogen Activator (tPA) for the Acute Treatment of Pediatric Plastic Bronchitis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 6
- 主要终点
- Primary Endpoint: Number of Subjects That Develop New, Active Bleeding
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 5 Years 至 24 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Treatment-inhaled tPA
All patients with plastic bronchitis enrolled into the study will receive inhaled tPA.
干预措施: Treatment-inhaled tPA (Drug)
结局指标
主要结局
Primary Endpoint: Number of Subjects That Develop New, Active Bleeding
时间窗: 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
次要结局
- 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.)
- Requirement for Urgent or Emergent Bronchoscopy(Participants will be followed for the duration of tPA treatment, up to 4 days.)
- Assessment of Patient Centered Outcomes(This measurement will be performed prior to tPA treatment, at hospital discharge (~ 1 week) and again at 30 days.)
- 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.)
- 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.)
- 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.)
- 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)
- 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.)
- Requirement for Mechanical Ventilation(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(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(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)
研究者
Kathleen A. Stringer
Professor
University of Michigan