Bacterial Pleural Effusion Other Than Tuberculosis, Pleural Effusion Associated With Pulmonary Infection
Conditions
Keywords
parapneumonic pleural effusion, empyema, TPA (Activase, Alteplase)
Brief summary
The purpose of this study is to document the efficacy and safety of intrapleural instillation of Activase vs Placebo in the management of complicated pleural effusions and empyemas
Detailed description
The current treatments available for complicated pleural effusions (CPE) include chest tube placement for drainage and IV antibiotics. If this fails and CPE occurs then in most patients thoracotomy is performed. Patients that are not surgical candidates have image guided catheter placement performed, sometimes multiple times. The American College of Chest Physicians (ACCP) formed a CPE panel and published guidelines for treating CPE. Percutaneous image-guided drainage is the most common approach for CPE. The panel recognizes the cumulative data that supports the use of fibrinolytics, VATS, and thoracotomy. The CPE panel acknowledged the lack of randomized clinical trials to determine efficacy and safety of these modalities in CPE and strongly encourages the research to take place. Fibrinolytic therapy is a relatively noninvasive, easy to use, and is relatively inexpensive. If successful, it will prevent sepsis and septic shock, decrease hospital stay, morbidity and mortality and prevent any surgical procedures. Multiple doses of fibrinolytics have been used in CPE with no evidence of systemic anti-fibrinolytic activity. Complications with these medications are also very uncommon and only isolated instances are reported. The benefit from successful pleural drainage using these agents will decrease morbidity, mortality, surgical procedures, and hospital stay.
Interventions
DRUGAlteplase
25 Mg of Alteplase in 100 cc of normal saline was instilled intrapeurally for daily for three days
DRUGPlacebo
Placebo in 100 cc of normal saline was instilled intrapleurally daily for three days
Sponsors
Genentech, Inc.
Midwest Pulmonary and Critical Care
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with complicated pleural effusions * Ability to provide written informed consent and comply with study assessments for the full duration of the study. * Age \> 18 years
Exclusion criteria
* Current use of oral anticoagulants (e.g., warfarin sodium) with an International Normalized Ratio (INR) \>5- Activated partial thromboplastin time (aPPT) \> 80, Platelet count \< 100,000/mm3; * Severe uncontrolled hypertension * Recognized hypersensitivity to Activase; or any component of its formulation; Traumatic pleural effusion * Pregnancy (positive pregnancy test) * In another study for this condition * Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated * Participation in another simultaneous medical investigation * Recent stroke * Intracranial hemorrhage * arteriovenous malformation or aneurysm * Intracranial neoplasm * Acute myocardial infarction * Acute pulmonary embolus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| No Surgical Intervention | patients were followed six weeks per protocol. Most patients treated with Alteplase were also followed for up to six months | CT scans of the chest and Chest X rays (CXR) were used to determine resolution of Pleural effusions/empyema/ pneumonia after 3 days of Alteplase/ Placebo therapy. If no response was noted with the first intervention patients were offered surgery --Decortiation/ Video Assisted Thoracic Surgery (VATS) or to receive the second intervention. Patients that failed the second intervention were offered surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Pneumonia That Responded to Therapy | 6 weeks | patients were followed for 6 weeks and CXR and CT scan were done to document resolution of pneumonia |
| Number of Participants With Pleural Effusion/Empyema That Responded to Therapy | 6 weeks | patients were followed for 6 weeks and CXR and CT scan were done to document resolution of pleural effusion/empyema |
| Number of Participants With Shortness of Breath That Responded to Therapy | 6 weeks | patients were followed for 6 weeks and clinical symptoms of resolution of shortness of breath were documented |
| Number of Participants With Clinical Symptoms of Sepsis That Responded to Therapy | 6 weeks | patients were followed for 6 weeks and resolution of sepsis was documented |
Countries
United States
Participant flow
Recruitment details
Patients with loculated pleural effusions that failed to respond to chest tube placement and standard medical treatment and were considered for surgery were given the option to enter into a double blind cross over trial
Pre-assignment details
108 patients were evaluated but only 100 entered the trial. 2 patients refused, 2 patients admitting physicians opted out of the trial, 3 patients chest tube removed inadvertently, 1 patient for coagulopathy
Participants by arm
| Arm | Count |
|---|---|
| Alteplase; Placebo 25mg of Alteplase in 100 cc of normal saline instilled intrapleurally; 100 cc of normal saline instilled intrapleurally | 100 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | associated prolonged pneumothorax | 1 | 0 |
| First Intervention | bleeding at chest tube site--first dose | 1 | 0 |
| First Intervention | died within 3 weeks | 1 | 0 |
| First Intervention | large lung mass with minimal effusion | 1 | 0 |
| First Intervention | malposition/blocked chest tube tube | 2 | 0 |
| First Intervention | Protocol Violation | 2 | 1 |
| First Intervention | trapped lung | 1 | 0 |
| Second Intervention | discarded for malposition of chest tube | 0 | 2 |
| Second Intervention | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Alteplase; Placebo |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 61 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants |
| Age Continuous | 67 years STANDARD_DEVIATION 15 |
| Region of Enrollment United States | 100 participants |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 42 | 5 / 8 | 8 / 40 |
| serious Total, serious adverse events | 1 / 42 | 0 / 8 | 0 / 40 |
Outcome results
Primary
No Surgical Intervention
CT scans of the chest and Chest X rays (CXR) were used to determine resolution of Pleural effusions/empyema/ pneumonia after 3 days of Alteplase/ Placebo therapy. If no response was noted with the first intervention patients were offered surgery --Decortiation/ Video Assisted Thoracic Surgery (VATS) or to receive the second intervention. Patients that failed the second intervention were offered surgery.
Time frame: patients were followed six weeks per protocol. Most patients treated with Alteplase were also followed for up to six months
Population: intention to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alteplase | No Surgical Intervention | 66 participants |
| Placebo | No Surgical Intervention | 6 participants |
Comparison: A univariate analysis was done to identify possible predictors of successful resolution of symptoms. The chi-square analysis was used to compare the percent successful.p-value: <0.001Chi-squared
Secondary
Number of Participants With Clinical Symptoms of Sepsis That Responded to Therapy
patients were followed for 6 weeks and resolution of sepsis was documented
Time frame: 6 weeks
Population: protocol design prevented assigning symptom resolution to a specific intervention therefore secondary outcome measures in 6 weeks were not analyzed
Secondary
Number of Participants With Pleural Effusion/Empyema That Responded to Therapy
patients were followed for 6 weeks and CXR and CT scan were done to document resolution of pleural effusion/empyema
Time frame: 6 weeks
Population: protocol design prevented assigning symptom resolution to a specific intervention therefore secondary outcome measures in 6 weeks were not analyzed
Secondary
Number of Participants With Pneumonia That Responded to Therapy
patients were followed for 6 weeks and CXR and CT scan were done to document resolution of pneumonia
Time frame: 6 weeks
Population: protocol design prevented assigning symptom resolution to a specific intervention therefore secondary outcome measures in 6 weeks were not analyzed
Secondary
Number of Participants With Shortness of Breath That Responded to Therapy
patients were followed for 6 weeks and clinical symptoms of resolution of shortness of breath were documented
Time frame: 6 weeks
Population: protocol design prevented assigning symptom resolution to a specific intervention therefore secondary outcome measures in 6 weeks were not analyzed