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The purpose of this prospective randomized clinical trial is to compare two currently accepted standard-of-care treatment strategies: medical thoracoscopy as compared to instillation of intrapleural tissue plasminogen activator (TPA) and human recombinant deoxyribonuclease (DNase) for the management of complicated pleural infections in adults as defined as complicated parapneumonic effusions or pleural empyema.
Pleural infection (empyema or complex parapneumonic effusion [CPPE]) represents one of the common clinical diagnoses encountered in clinical practice in the United States (US) and worldwide. The incidence of pleural infection continues to rise with an annual incidence of approximately 65,000 in the US and United Kingdom (UK). It is associated with substantial morbidity and mortality as well as increased hospital costs despite advances in medical diagnostic and therapeutic strategies. The overall mortality of pleural infection approaches 20% and it is above 30% in elderly patients over 65 years and immunocompromised patients.
Treatment of CPPE or empyema requires antibiotics and drainage of the pleural cavity.3 However, in about 30% of cases, it is difficult to remove the fluid due to loculations, septations and increased viscosity of the pleural fluid, and around 20% will need surgical intervention to adequately treat the pleural infection.
Specific Aim 1:
To compare the efficacy of early medical thoracoscopy versus fibrinolytic therapy (tPA/DNase) in patients with complicated parapneumonic effusions or pleural empyema.
CPPE is defined as non-purulent effusion in a patient with clinical evidence of infection such as fever and/or elevated blood leukocyte count and/or elevated CRP, with pleural fluid pH ≤ 7.2 (measured by blood-gas analyzer), or pleural fluid glucose < 60 mg/dl or pleural fluid LDH >1000 IU/L26. Empyema is defined as pus within the pleural space and/or presence of bacteria on pleural fluid Gram stain or culture.
For patients to be considered for the trial they need to fulfill one of the following criteria: 1) CPPE along with evidence of septated pleural effusion on pleural ultrasonography and/or chest CT scan or 2) empyema.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Thoracoscopy Arm | Active Comparator | Consisting of chest thoracoscopy |
|
| Fibrinolytic Therapy Arm | Active Comparator | Consisting of chest fibrinolytic therapy |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Chest thoracoscopy | Procedure | Thoracoscopy will be performed as per standard protocols, with patient lateral decubitus position. Ten mLs of fluid will be collected to check for biomarkers. Adhesiolysis will be attempted and pleural irrigation will be done. At the end of the procedure, a drain will be inserted and connected to an underwater seal with a negative pressure suction |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Hospital Days for Required to Treat Complicated Parapneumonic Effusions or Pleural Empyema. | Time between initiation of treatment and hospital discharge | 30 days starting on day of admission |
| Measure | Description | Time Frame |
|---|---|---|
| Duration of Chest Tube | The number of days, during the hospital admission, where the patient demonstrated chest tube drainage | 30 days starting on day of admission |
| Duration of Entire Hospital Stay for Complete Treatment of Pleural Infection |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hiren Mehta, MD | University of Florida | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida | Gainesville | Florida | 32611 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32421353 | Result | Kheir F, Thakore S, Mehta H, Jantz M, Parikh M, Chee A, Kaphle U, Sisnega C, Fernandez-Bussy S, Majid A. Intrapleural Fibrinolytic Therapy versus Early Medical Thoracoscopy for Treatment of Pleural Infection. Randomized Controlled Clinical Trial. Ann Am Thorac Soc. 2020 Aug;17(8):958-964. doi: 10.1513/AnnalsATS.202001-076OC. |
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After consent, but prior to randomization, all participants underwent diagnostic thoracentesis and confirmation of pleural infection.
The study participants comprised a convenience sample of adults with CPPE or empyema who presented to the UFHealth pulmonary medicine service, met all inclusion / exclusion criteria, and agreed to participate.
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| ID | Title | Description |
|---|---|---|
| FG000 | Thoracoscopy Arm | Consisting of chest thoracoscopy Chest thoracoscopy: Thoracoscopy will be performed as per standard protocols, with patient lateral decubitus position. Ten mLs of fluid will be collected to check for biomarkers. Adhesiolysis will be attempted and pleural irrigation will be done. At the end of the procedure, a drain will be inserted and connected to an underwater seal with a negative pressure suction |
| FG001 | Fibrinolytic Therapy Arm | Consisting of chest fibrinolytic therapy Chest fibrinolytic therapy: A chest tube will be inserted under ultrasonography into the most dependent area of the pleural effusion or into the largest loculation in patients with multi-loculated effusions. A of DNase and tPA will be given. Concurrent tPA and DNase will be administered intrapleurally through the chest tube followed by saline flush. The tube will then be clamped for 120 minutes and after which it will be connected back to wall suction. The intrapleural therapy will be given twice daily for a maximum of 6 doses. tPA: tPA administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses. DNase: DNase administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Thoracoscopy Arm | Consisting of chest thoracoscopy Chest thoracoscopy: Thoracoscopy will be performed as per standard protocols, with patient lateral decubitus position. Ten mLs of fluid will be collected to check for biomarkers. Adhesiolysis will be attempted and pleural irrigation will be done. At the end of the procedure, a drain will be inserted and connected to an underwater seal with a negative pressure suction |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Hospital Days for Required to Treat Complicated Parapneumonic Effusions or Pleural Empyema. | Time between initiation of treatment and hospital discharge | Posted | Median | Full Range | days | 30 days starting on day of admission |
|
Adverse event data was collected starting at consent, and up to 12 weeks post-procedure.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Thoracoscopy Arm | Consisting of chest thoracoscopy Chest thoracoscopy: Thoracoscopy will be performed as per standard protocols, with patient lateral decubitus position. Ten mLs of fluid will be collected to check for biomarkers. Adhesiolysis will be attempted and pleural irrigation will be done. At the end of the procedure, a drain will be inserted and connected to an underwater seal with a negative pressure suction |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Erin Silverman, Research Coordinator | University of Florida | 352-273-5870 | erin.silverman@medicine.ufl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 6, 2017 | Feb 15, 2024 | Prot_SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 14, 2019 | Nov 9, 2021 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D010995 | Pleural Diseases |
| ID | Term |
|---|---|
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D010959 | Tissue Plasminogen Activator |
| D003851 | Deoxyribonucleases |
| C568813 | dornase alfa |
| ID | Term |
|---|---|
| D012697 | Serine Endopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
| D006867 | Hydrolases |
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Subjects will be randomly assigned to receive one of two standard-of-care treatments for severe pleural infection.
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Change in pleural fluid volume on chest CT scan from randomization (day 0) to prior to chest tube removal will be measured by a radiologist blinded to treatment allocation using image J software
|
| Chest fibrinolytic therapy | Procedure | A chest tube will be inserted under ultrasonography into the most dependent area of the pleural effusion or into the largest loculation in patients with multi-loculated effusions. A of DNase and tPA will be given. Concurrent tPA and DNase will be administered intrapleurally through the chest tube followed by saline flush. The tube will then be clamped for 120 minutes and after which it will be connected back to wall suction. The intrapleural therapy will be given twice daily for a maximum of 6 doses. |
|
| tPA | Drug | tPA administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses. |
|
|
| DNase | Drug | DNase administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses. |
|
|
Number of days patient registered as in-house for treatment of pleural infection
| 30 days starting on day of admission |
| Treatment Failure | Following intervention, if patient requires (1) surgical intervention (VATS, open thoracotomy), (2) an additional chest tube, or (3) a repeat procedure | 30 days starting on day of admission |
| Number of Participants With Adverse Events | Number of participants who experienced documented adverse events during their hospital stays | 30 days starting on day of admission |
| Mortality | In hospital and 30 day mortality measures | 30 days starting on day of admission |
| BG001 | Fibrinolytic Therapy Arm | Consisting of chest fibrinolytic therapy Chest fibrinolytic therapy: A chest tube will be inserted under ultrasonography into the most dependent area of the pleural effusion or into the largest loculation in patients with multi-loculated effusions. A of DNase and tPA will be given. Concurrent tPA and DNase will be administered intrapleurally through the chest tube followed by saline flush. The tube will then be clamped for 120 minutes and after which it will be connected back to wall suction. The intrapleural therapy will be given twice daily for a maximum of 6 doses. tPA: tPA administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses. DNase: DNase administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses. |
| BG002 | Total | Total of all reporting groups |
| Participants |
| No |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Consisting of chest fibrinolytic therapy
Chest fibrinolytic therapy: A chest tube will be inserted under ultrasonography into the most dependent area of the pleural effusion or into the largest loculation in patients with multi-loculated effusions. A of DNase and tPA will be given. Concurrent tPA and DNase will be administered intrapleurally through the chest tube followed by saline flush. The tube will then be clamped for 120 minutes and after which it will be connected back to wall suction. The intrapleural therapy will be given twice daily for a maximum of 6 doses.
tPA: tPA administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses.
DNase: DNase administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses.
|
|
| Secondary | Duration of Chest Tube | The number of days, during the hospital admission, where the patient demonstrated chest tube drainage | Posted | Median | Full Range | days | 30 days starting on day of admission |
|
|
|
| Secondary | Duration of Entire Hospital Stay for Complete Treatment of Pleural Infection | Number of days patient registered as in-house for treatment of pleural infection | Posted | Median | Full Range | days | 30 days starting on day of admission |
|
|
|
| Secondary | Treatment Failure | Following intervention, if patient requires (1) surgical intervention (VATS, open thoracotomy), (2) an additional chest tube, or (3) a repeat procedure | Posted | Count of Participants | Participants | 30 days starting on day of admission |
|
|
|
| Secondary | Number of Participants With Adverse Events | Number of participants who experienced documented adverse events during their hospital stays | Posted | Count of Participants | Participants | 30 days starting on day of admission |
|
|
|
| Secondary | Mortality | In hospital and 30 day mortality measures | Posted | Count of Participants | Participants | 30 days starting on day of admission |
|
|
|
| 0 |
| 3 |
| 0 |
| 3 |
| 0 |
| 3 |
| EG001 | Fibrinolytic Therapy Arm | Consisting of chest fibrinolytic therapy Chest fibrinolytic therapy: A chest tube will be inserted under ultrasonography into the most dependent area of the pleural effusion or into the largest loculation in patients with multi-loculated effusions. A of DNase and tPA will be given. Concurrent tPA and DNase will be administered intrapleurally through the chest tube followed by saline flush. The tube will then be clamped for 120 minutes and after which it will be connected back to wall suction. The intrapleural therapy will be given twice daily for a maximum of 6 doses. tPA: tPA administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses. DNase: DNase administered intrapleurally through the chest tube followed by saline flush. The intrapleural therapy will be given twice daily for a maximum of 6 doses. | 0 | 2 | 0 | 2 | 0 | 2 |
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| D004798 |
| Enzymes |
| D045762 | Enzymes and Coenzymes |
| D057057 | Serine Proteases |
| D010960 | Plasminogen Activators |
| D001779 | Blood Coagulation Factors |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001685 | Biological Factors |
| D004950 | Esterases |