Clinical trial NCT03468933
Conditions: Pleural Infection Empyema Pleural Diseases Parapneumonic Effusion
Sponsor: Tulane University
Start date: 2017-11-01; Completion date: 2019-12-30
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 empyema or complicated parapneumonic effusion (CPPE) in adults.

Detailed description:
Background: Pleural infection (empyema or complex parapneumonic effusion (CPPE)) represents one of the most common clinical diagnoses encountered in clinical practice in the United States (US) It is associated with substantial morbidity and mortality despite advances in medical diagnostic and therapeutic strategies.

Objective: Compare two standard of care treatments: TPA/DNase vs early medical Thoracoscopy

Methods: Investigators will conduct a prospective randomized clinical trial. Plan is to enroll total of 32 patients and randomize those patients to either Medical Thoracoscopy group or Fibrinolytic Therapy group.

Follow-up will be daily until hospital discharge and at 6 and 12 weeks in the outpatient setting

Potential Outcome and Benefit: Determine best strategy for treating patients with pleural infection

Arms: arm 1: Patients randomized to the Fibrinolytic group will receive intrapleural therapy of combined tissue plasminogen activator (tPA) and human recombinant deoxyribonuclease (DNase) via chest tube. arm 2: Patients randomized to the Thoracoscopy group will undergo medical thoracoscopy.
Interventions: intervention 1: tissue plasminogen activator (tPA) and human recombinant deoxyribonuclease (DNase) intervention 2: Medical Thoracoscopy
Intervention descriptions: intervention 1: Patients will receive intrapleural combination of TPA (10 mg) and DNAse (5 mg). Therapy will be given twice daily for a maximum of 6 dose intervention 2: Medical thoracoscopy will be performed as per standard protocols.

Protocol documents:
Prot_002.pdf: 
1 
 
Official Title of the study:  
 
Fibrinolysis Compared to Thoracoscopy for 
Pleural Infection 
 
NCT number: 
 
NCT03468933 
 
Date of the document: 
 
July 1, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
Patient Population 
Subjects (> 18 years of age) with either CPPE or empyema will be screened for inclusion. 
Screening logs recording reasons for non-trial entry will be kept. 
 
CPPE is defined as non-purulent effusions 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/L. 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 26 (Figure 1) with entrapped lung or 2) empyema. 
 
 
Figure 1.Throracic ultrasound showing complex pleural effusion along with septation 
(arrowhead) 
 
Study exclusion criteria are: 1) age <18 years; 2) pregnant women 3) inability to give informed 
written consent; 4) previous thoracic surgery or thrombolytic therapy for pleural infection; 5) 
medical thoracoscopy cannot be performed within 48 hours; 6) inability to tolerate procedure 
due to hemodynamic instability or severe hypoxemia; 7) unable to correct coagulopathy, 8) 
presence of a homogeneously echogenic effusion on pleural US26 (Figure 2) and 9) evidence of 
non-expanadable lung (air in pleural space) after initial thoracentesis or small bore chest tube 
on chest CT imaging. 
Complex septated 


3 
 
 
Figure 2. Thoracic ultrasound showing homogeneously echogenic loculated effusion 
All patients will undergo diagnostic thoracentesis and chest computed tomography as part of 
routine care, prior to the enrollment in the study. Women of childbearing potential will have a 
pregnancy test as part of standard of care and pregnant women will be excluded from the study. 
Intravenous antibiotics will be changed to oral consolidation therapy by the managing consultant 
in light of the clinical response. Antibiotic therapy will be continued between 2 and 6 weeks, as 
required. 
 
Patients who accept to be involved in the trial will sign an informed consent and then will be 
randomized to either Medical Thoracoscopy (Treatment Arm) or Fibrinolytic Therapy (Control 
Arm). (Figure 3) 
 
Chest computed tomography (CT) will be done prior to randomization (day 0),prior to chest tube 
removal and at 12 weeks follow up visit respectively as part of standard of care protocol .On 
chest CT without contrast, pleural effusion will be defined as loculated if it had (1) lobulated 
shape with a convex boarder or (2) compartmentalized, accumulated in a fissure or a non-
dependent portion of the pleura. On chest ultrasound pleural effusion will be defined as fibrin 
strands or septa floating inside the anechoic/hypoechoic pleural effusions along with presence 
of defined multiple pockets in the pleural cavity27 
 
Operative Technique 
I-Medical Thoracoscopy (Thoracoscopy Arm) 
 
Patients will undergo medical thoracoscopy (rigid or semi-rigid) within 48 hours of 
randomization. Under ultrasound guidance, a single port (with a maximum of 2 ports) will be 
placed and thoracoscopy will be performed under moderate sedation in the operating room or 
endoscopy suite with continuous monitoring as per standard protocols, with the patient in a 
lateral decubitus position. The pleura will be carefully inspected through the thoracoscope under 
direct visualization. With the closed biopsy forceps, step by step, fibrinous septate will be 
disrupted with fluid and fibrinopurulent material aspirated and removed from the pleural cavity. A 
suction irrigator device) will be used at the discretion of the operator. Following adhesiolysis , a 
pleural lavage with a liter of  warmed saline will be done. At the end of the procedure, a drain 
homogeneously  
echoegenic 


4 
 
(24Fr) will be inserted and connected to underwater seal suction with a negative pressure 
suction of 20 cm H2O. A chest CT without contrast will be performed and if there was no 
evidence of significant residual pleural effusion and chest tube drainage is <75ml/day the chest 
drain will be removed.  The fluid volume will be calculated by measuring the maximum 
perpendicular distance between the surface and the chest wall right above the diaphragm with 
at maximum inspiration in the most dependent position.28  
 
II-Fibrinolytic Therapy (Fibrinolytic Arm) 
 
A chest tube (14-French Seldinger or less) under ultrasonography guidance will be inserted into 
the most dependent area of the pleural effusion or into the largest loculation in patients with 
multiloculated effusions. The dose of DNase (Pulmozyme, Genentech, USA) is 5 mg and the 
dose of tPA (Actilyse, Genentech, USA) is 10 mg, each in 50 ml of 0.9% NaCl. tPA and DNase 
will not be mixed together in one syringe. Concurrent tPA and DNase will be administered 
intrapleurally through the chest tube followed by 60 ml saline flush. The tube will then be 
clamped for 120 minutes before the chest tube will be opened to -20 cmH20 of wall suction. 
Therapy will be given twice daily for a maximum of 6 doses. A  chest CT without contrast will be 
performed and if there was no evidence of significant pleural effusion 28 and chest tube drainage 
is <75 ml/day, the catheter will be removed.  
 
Study Outcome 
Primary outcome measure: 
 Duration of hospital stay after intervention 
 
Secondary outcome measures: 
 
 
Total length of hospital stay 
 
Failure rate of assigned treatment (persistent fever, leukocytosis evidence of loculation 
48 hours post intervention) necessitating intervention defined as any of the following: 
1-Surgical intervention (VATS, open thoracotomy) in the medical thoracoscopy or 
fibrinolytic therapy arm 
2-Need of additional chest tube and/or fibrinolytic therapy in the medical thoracoscopy 
arm due to clinical non-responsiveness 
3-Need of additional chest tube in the fibrinolytic therapy arm due to clinical non-
responsiveness 
 
Adverse events 
o Pleural bleeding defined as drop in serum hematocrit requiring blood transfusion 
or causing hemodynamic instability 
o Significant pain requiring escalation of analgesia  
 
In hospital and 30 day mortality 
 


5 
 
 
Trial Entry  
1. Patients with Pleural Infection  
2. Fulfills Inclusion criteria  
3. Written informed consent  
Randomization  
Medical Thoracoscopy 
Fibrinolytic therapy (TPA/Dnase)  
Follow- up (Post Intervention)  
Inpatient/ Outpatient assessment for data collection 
•
Daily until discharge from hospital  
•
At 6 and 12 weeks (telephone assessment or clinic visit)  
•
Death  
Figure 3. Proposed Study Protocol  

SAP_003.pdf: 
 
 
 
 
 
 
Official Title of the study:  
 
Fibrinolysis Compared to Thoracoscopy for 
Pleural Infection 
 
NCT number: 
 
NCT03468933 
 
Date of the document: 
 
July 1, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis 
We believe that a difference of 2 days in the length of the postintervention hospital 
stay between the two treatment arms would be clinically important. This rationale 
is based on a previous randomized study that compared VATS and streptokinase 
therapy in empyema (1). In that study, the number of chest tube days after VATS 
was 5.8±1.1 days, as compared with 9.8±1.3 days in the streptokinase group. 
Furthermore, a case series from MT trials reported an average postoperative stay of 
7–8 days (2-5), as compared with an average of 10–13 days in IPFT trials (6,7). 
According to a two-sided type I error of 0.05 and 80% power, the sample size was 
16 patients in each group. 
All analyses were performed using GraphPad Prism (version 7.0; GraphPad 
Software). Descriptive statistics were used to summarize the patients’ 
characteristics. The t test was used to examine differences between groups with 
parametric data and the Mann-Whitney U test was used for nonparametric data. 
Fisher’s exact test was used for categorical variables. A P value of <0.05 was 
considered statistically significant. 
 
1-Majid A, Kheir F, Folch A, Fernandez-Bussy S, Chatterji S, Maskey A, 
et al. Concurrent intrapleural instillation of tissue plasminogen activator and 
DNase for pleural infection: a single-center experience. Ann Am Thorac Soc 
2016;13:1512–1518. 
2-BrutscheMH, Tassi GF,Gyo¨ rik S,Go¨ kcimenM, Renard C,MarchettiGP, 
et al. Treatment of sonographically stratified multiloculated thoracic 
empyema by medical thoracoscopy. Chest 2005;128:3303–3309. 
3-Ravaglia C, Gurioli C, Tomassetti S, Casoni GL, Romagnoli M, Gurioli C, 
et al. Is medical thoracoscopy efficient in the management of 
multiloculated and organized thoracic empyema? Respiration 2012; 
84:219–224. 
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make it rupture safely? J Bronchology Interv Pulmonol 2017;24: 
15–20. 
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7- Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, et al. 
Intrapleural use of tissue plasminogen activator and DNase in pleural 
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