Clinical trial NCT03213834
Conditions: Pleural Diseases
Sponsor: University of Florida
Start date: 2017-09-14; Completion date: 2020-02-04
Enrollment: 5 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 complicated pleural infections in adults as defined as complicated parapneumonic effusions or pleural empyema.

Detailed description:
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.

Arms: arm 1: Consisting of chest thoracoscopy arm 2: Consisting of chest fibrinolytic therapy
Interventions: intervention 1: Chest thoracoscopy intervention 2: Chest fibrinolytic therapy intervention 3: tPA intervention 4: DNase
Intervention descriptions: intervention 1: 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 intervention 2: 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. intervention 3: 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. intervention 4: 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.

Protocol documents:
Prot_SAP_003.pdf: 
STUDY TITLE: Fibrinolytic Therapy versus Medical Thoracoscopy for Treatment of Pleural Infection: A 
Randomized Clinical Trial 
NCT03213834 
Date of document: 06-APR-2017 


1 
 
Protocol Document: Fibrinolytic Therapy versus Medical Thoracoscopy for Treatment of Pleural 
Infection: A Randomized Clinical Trial  
 
 
Study Team: 
 
Principal Investigator: Hiren Mehta, MD 
Sub Investigator: Michael Jantz, MD 
Sub Investigator: Tan Lucien Mohammed, M.D. 
Other research staff:  Erin Silverman, Ph.D. CCRC; Jesse West, RN 
 
 
Overall Objective: 
 
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.  
 
Introductory Statement and Background: 
 
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).1 It is associated with substantial 
morbidity and mortality as well as increased hospital costs despite advances in medical 
diagnostic and therapeutic strategies.2-4 The overall mortality of pleural infection approaches 
20% and it is above 30% in elderly patients over 65 years and immunocompromised patients.1,5-
8 
 


2 
 
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.9,10 
 
Rationale: 
 
The intrapleural therapy of combined tissue plasminogen activator (tPA) and human 
recombinant deoxyribonuclease (DNase) in the management of pleural infection has been 
shown to improve the chest radiographic appearance at day 7 in the Multi-center Intra-pleural 
Sepsis Trial (MIST2).9 However, this approach is expensive, with a substantial hospital stay 
(around 12 days), and had a no significant decrease in the rate of surgery referral as compared 
to placebo.9 
 
Although two randomized studies have shown that around 80% of patients with pleural infection 
can be successfully managed medically, early surgical intervention is still considered a first-line 
treatment for pleural infection in some regions around the world 9,10. This approach has been 
justified on the basis of improved clinical outcome and shorter hospital stays for patients 
managed in this way.11-15 
 
Video-assisted thoracoscopic surgery (VATS) has been suggested as a surgical invasive 
approach to clear potentially infected material from the pleural space. In one small randomized 
and another non-randomized prospective trial comparing VATS with intercostal drainage plus 
intrapleural streptokinase, VATS was associated with decreased hospital stays and overall 
costs.16,17 However, there are several limitations that need to be mentioned. First, these two 
trials were under-powered studies without appropriate sample size calculation. Second, VATS 
was compared to intrapleural streptokinase. The intrapleural activity of endogenous 
plasminogen activator inhibitor (PAI-1) in the pathogenesis of pleural infection is important since 
this mediator not only directly inhibits streptokinase but has also been shown to contribute to the 
severity of loculation and poor outcomes with intrapleural fibrinolytic therapy.18-20 Third, large 
case series have shown that VATS is usually performed on a younger and less comorbid 
population (i.e. highly selected patients), compared to the unselected population of patients 
(which are usually sicker, elderly and have multiple comorbidities) with pleural infection seen in 
the fibrinolytic studies.9,10, 11,21 Moreover, failure to respond to medical fibrinolytic therapy might 


3 
 
necessitate invasive surgical intervention, such as VATS, or even open thoracotomy, at a later 
stage of the pleural infection where adequate clearance of the dense septations and thickening 
within and around the pleural cavity is needed to reverse lung restriction and improve 
compliance. However, clinical outcomes are unpredictable, with some patients having no long-
term sequelae but others showing permanent impairment of lung function. 
 
Medical thoracoscopy (MT) is a minimally invasive procedure that can be used to treat pleural 
infection through improving clearance by mechanical adhesiolysis and targeted drain 
placement. MT can also be used in patients who are not fit for general anesthesia by using local 
anesthesia and sedation. MT has shown to be safe and effective in the treatment of pleural 
infection in observational studies.22-25 However, to date, there are no randomized controlled 
trials addressing the potential role of early MT versus fibrinolytic therapy in empyema and 
complicated pleural infection. 
 
Proposal: 
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. 
Methods and Procedures: 
Study Design 
 
This prospective randomized trial will be conducted at UF Health Shands Hospital in 
accordance with Good Clinical Practice Standards and under IRB supervision. A large number 
of patients with pleural infection are treated at our institution, with a multidisciplinary team 
comprised of experienced interventional pulmonologists, chest radiologists and thoracic 
surgeons. We plan to enroll a total of 60 patients with pleural infection that will be randomized 
utilizing a computerized system to either medical thoracoscopy (thoracoscopy group) or 
fibrinolytic therapy (fibrinolytic group). 
 
Patient Population 


4 
 
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 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 27 (Figure 1) or 2) empyema. 
 
 
Figure 1. Throracic ultrasound showing complex pleural effusion along with septation 
(arrowhead) 
 
Prescreening / Study exclusion criteria are as follows:  
1) age <18 years; 
2) pregnancy  
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;  
Complex septated 


5 
 
6) inability to tolerate procedure due to hemodynamic instability or severe 
hypoxemia; 
7) inability to correct coagulopathy;  
8) presence of a homogeneously echogenic effusion on pleural US27 (Figure 2). 
 
Figure 2. Thoracic ultrasound showing homogeneously echogenic loculated effusion 
 
Patients who agree to participate in the trial will sign an informed consent. Next, all patients will 
undergo diagnostic thoracentesis as per standard of care. In addition to standard of care testing 
on pleural fluid, an additional 10 mLs of fluid will be collected to check for markers like 
interleukin-8 and vascular endothelial growth factor. All patients will receive intravenous 
antibiotics according to local hospital guidelines and local microbiology results. Intravenous 
antibiotics will be changed to oral consolidation therapy by the managing consultant in light of 
the clinical response. Antibiotic therapy will be continued for between 2 and 6 weeks, as 
required per standard of care. 
 
Following diagnostic thoracentesis and confirmation of pleural infection, participants will be 
randomly assigned to either receive thoracoscopy (treatment arm) or fibrinolytic therapy (control 
arm). (Figure 3) 
 
Pleural effusion will be defined as loculated if it (1) has a lobulated shape with a convex boarder 
or (2) it is compartmentalized or accumulated in a fissure or a non-dependent portion of the 
pleura. On chest ultrasound the pleural effusion will be defined as loculated if it has fibrin 
homogeneously 
echoegenic 


6 
 
strands or septa floating inside the anechoic/hypoechoic pleural effusion(s) along with the 
presence of defined multiple pockets in the pleural cavity. 28 
Pain scores and general physical status will be assessed using a participant-completed 100-mm 
visual analog scale (VAS) upon randomization, at 6 weeks (via phone call) and 12 weeks follow 
up. 
 
Study Protocol I- Thoracoscopy (Treatment Arm) 
 
Patients will undergo medical thoracoscopy (rigid or semi-rigid) within 48 hours of 
randomization. A single port (with a maximum of 2 ports) will be placed and thoracoscopy will be 
performed under 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.  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. As per standard of care, a chest CT without contrast will be performed when 
chest tube drainage is < 75 mLs and if there was no evidence of significant pleural effusion 
(<200 ml), the catheter will be removed 29 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.29 Any need for 
additional drainage or administration of fibrinolytic or surgery will be considered treatment 
failure.  
 
II-Fibrinolytic Therapy (Control Arm) 
 
A chest tube (14-French or less) 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. 
The dose of DNase (Pulmozyme, Genentech, USA) will be 5 mg and the dose of tPA (Actilyse, 
Genentech, USA) will be 10 mg, each in 50 ml of 0.9% NaCl. The 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 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. As per standard of care, a chest CT without contrast will 
be performed when chest tube drainage is < 75 mLs and if there was no evidence of significant 


7 
 
pleural effusion (<200 ml), the catheter will be removed 29. Any need for additional drainage or 
more doses of fibrinolytic from the existing drainage over and above the 6 doses mentioned or 
surgery will be considered treatment failure.  
 
Study Outcome 
Primary outcome measure: 
• 
Duration of hospital stay after intervention, as defined as thoracoscopy in the 
treatment arm and first dose of fibrinolytic in the control arm 
 
Secondary outcome measures: 
 
• 
Number of days with chest tube drainage 
• 
Total length of hospital stay 
• 
Failure rate of assigned treatment necessitating intervention defined as any of 
the following: 
1-Surgical intervention (VATS, open thoracotomy) in either 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 
• 
Change in pleural fluid volume on chest CT scan from randomization (day 0) to 
prior to chest tube removal measured by radiologist (Mohammed) blinded to treatment 
allocation using image J software. Volume of pleural effusion will be obtained by 
examination of radiographic images obtained during the standard-of-care CT 
examination. 
• 
Infectious biomarker (CRP) from randomization (day 0), at removal of chest tube 
and 12 weeks as per standard of care 
• 
Total costs of each treatment modality in each treatment site 


8 
 
 
Sample Size and Statistical Analysis 
The difference in length of post-intervention hospital stay of 2 days between the two treatment 
arms would be clinically important. 
 
This rationale was based on previous large VATS case series reported by Luh and colleagues30 
in which the mean postoperative stay was 7.2 d ± 3.2 d versus 11.8 d±9.4 d from randomization 
to fibrinolytic therapy until discharge in the MIST2 trial9 and 10 d ± 1.8 d from first intrapleural 
treatment dose until discharge reported by Piccolo and colleagues.31 
 
To demonstrate this difference with 5% significance and 80% power, a minimum of 30 patients 
will be needed in each study group. Baseline characteristics will be compared between the two 
groups using Chi square, t tests, and Mann-Whitney U tests as appropriate. All data will be 
analyzed according to the intention-to-treat principle. A p value of ≤ 0.05 will be considered 
statistically significant. 
 
Significance 
To our knowledge, there are no randomized clinical trials evaluating the efficacy of early medical 
thoracoscopy versus fibrinolytic therapy in patients with pleural infection. This study should 
clarify the role of early medical thoracoscopy in patients with complicated parapneumonic 
effusions or pleural empyema. Currently, many centers worldwide primarily treat patients with 
pleural infection by placing a chest tube with pleural fibrinolysis. In case of failure of such an 
approach, which means that several treatment days are lost, a more invasive procedure is 
needed. By this time, significant pleural septae have formed, and often a surgical VATS or 
thoracotomy under general anesthesia becomes necessary. Therefore, this pivotal study could 
lead to changes in the management of patients with pleural empyema/CPPE. 
Human Subjects Will Be Used 
The research team will explain the details about the study to the patient. This discussion will 
also serve to answer any questions that the subject may have. Potential risks will be minimized 
by providing adequate time and opportunity for the subjects to review and ask questions about 
the study prior to consenting to participate. The subject will have an option to opt out of the 


9 
 
study at any point of time without any obligations or loss of treatments through UF Health 
Shands Hospital or other treatment centers.  
All collected data will be de-identified and linked to the subject by a unique identifying number. 
The data will be secured by the research team and will not affect patient care in any manner. 
The investigators will not use or disclose the means of record identification for any other 
purpose. The protected health information (PHI) will not be reused or disclosed to any other 
person or entity except for other research for which the use of the PHI would be permitted under 
the Privacy Rule.  
After enrollment, a number will be assigned to the subject. This number will be used for all study 
documents to maintain the privacy of the subject. The subjects will have the phone numbers of 
the study team members for any questions or concerns that might arise throughout the study 
period. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, will be 
obtained before that subject is submitted to any study procedure. 
 
No Animals or Biohazardous Materials Will Be Used. 
Risks and Benefits 
If successful, this study may improve standard of care treatment for pleural infection by 
clarifying which of two standard-of-care procedures produces superior clinical outcomes 
including decreased length of stay and decreased need for adjuvant / subsequent treatments 
following initial treatment for pleural infection. 
Risk associated with thoracentesis: 
a. 
Pain during placement (minor and controlled with anesthesia) 
b. 
Bleeding. During insertion of the needle, a blood vessel in the skin or chest wall 
may be accidentally nicked. Bleeding is usually minor and stops on its own. Sometimes, 


10 
 
bleeding can cause a bruise on the chest wall. Rarely, bleeding can occur into or around 
the lung and may require a chest tube or surgery. 
 
Collapsed lung. When the needle is being placed, it may puncture the lung. This 
hole may seal quickly on its own. If the hole does not seal over, air can leak out and 
build up around the lung. This build-up of air can cause part or all of the lung on that side 
to collapse (pneumothorax). If this happens, the doctor can place a chest tube between 
the ribs into the chest to remove the air that is leaking from the lung  
 
Risks associated with sedation: 
a. Drowsiness, slurred speech, tremor, fatigue, and low blood pressure, increase 
carbon dioxide in your blood, slowing of the heart rate, anxiety, confusion, dizziness 
and shivering 
b. .Respiratory depression. Trained medical professionals with extensive 
experience and expertise will administer these medications and will be responsible 
for monitoring the participant during the course of the procedure. 
 
Risks associated with thoracoscopy: 
a. 
Chest pain (5%). The nerves between the ribs are bruised after the procedure, 
which can cause some persistent pain. 
b. 
Air leak from lung (1-5%). A small hole develops in the lung. This means the 
chest tube has to stay in longer.  
c. 
Bleeding (< 1%). Usually it is minor and settles quickly. Bleeding is more 
common if you have been taking blood thinning drugs. 
d. 
Heart problems (< 1%). A brief minor strain may be put on the heart. This can 
cause abnormal beating of the heart, fluid to accumulate in the lungs, a heart attack, or 
the heart may stop beating.  
e. 
Low oxygen levels (< 1%). Participants will be administered oxygen if needed.  
f. 
Death(< 1%) as a result of this procedure is  uncommon.  
 
Risks associated with chest tubes: 


11 
 
a. 
Pain during placement—Discomfort often occurs as the chest tube is inserted. 
Doctors try to lessen any pain or discomfort by giving a local numbing medicine. The 
discomfort usually decreases once the tube is in place. 
b. 
Bleeding (<5%)—During insertion of the tube, a blood vessel in the skin or chest 
wall may be accidentally nicked. Bleeding is usually minor and stops on its own. Rarely, 
bleeding can occur into or around the lung and may require surgery. Usually bleeding 
can just be watched with the chest tube in place. 
c. 
Infection (< 5%)—Bacteria can enter around the tube and cause an infection 
around the lung. The longer the chest tube stays in the chest, the greater the risk for 
infection. The risk of infection is decreased by special care in bandaging the skin at the 
point where the tube goes into the chest. 
 
Risks associated with fibrinolytic therapy: 
a. 
Pain (15%)-While the medications are in the pleural space, participants may feel 
some discomfort. Usually such pain can be relieved by analgesics. 
b. 
Bleeding (5%)-While medications are in the pleural space, participants may 
experience bleeding inside the pleural space. Usually, it resolves with stopping 
medications. Rarely, blood transfusion might be need or require surgery. 
 
Privacy risks: As with any study, there is a risk that personal health information, collected 
during the course of research, may be disclosed. The research team will to everything within 
their power to mitigate and minimize this risk. The data collected both written and electronic will 
be held securely in a locked cabinet and secure server behind the UF Health firewall 
respectively. Only the study individual will be contacted and the questionaries’ administered in 
the privacy of a secluded clinic room. The data collected will be restricted to only the minimum 
amount necessary to accomplish the aim of the study.  
 
Risks associated with psychological stress: Participants may feel embarrassed or 
uncomfortable responded to questions. Participants will be informed that they may refuse to 
answer any of the questions and may take a break at any time during the study. Participants are 
also free to withdraw from the study at any time. 


12 
 
 
Conflict of Interest 
All research personnel associated with this protocol report no actual or perceived conflicts of 
interest. 


13 
 
 
Trial Entry / Prescreening 
1. Patients with pleural infection  
2. Fulfills inclusion criteria and does not meet exclusion criteria 
3. Written informed consent is obtained 
Randomization  
Thoracentesis  
Medical Thoracoscopy 
Fibrinolytic therapy (TPA/Dnase)  
Follow- up (Post Intervention)  
Inpatient/ Outpatient assessment for data collection as standard of care 
•
General physical status and pain scale scores at 6 and 12 weeks (telephone 
assessment or clinic visit)  
•
Death  
Figure 3. Proposed Study Protocol  
Screening  


14 
 
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Marks DJ, Fisk MD, Koo CY, et al. Thoracic empyema: a 12-year study from a 
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Lim TK, Chin NK. Empirical treatment with fibrinolysis and early surgery reduces 
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Komissarov AA, Florova G, Azghani A, Karandashova S, Kurdowska AK, Idell S. 
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Karandashova S, Florova G, Azghani AO, et al. Intrapleural adenoviral delivery of 
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Ann Am Thorac Soc 2014; 11:1419-25 
 

ICF_001.pdf: 
IRB Project #: IRB201700012
Page 1 of 14
IRB Version: 10/01/2018
PI Version: 5/10/2019
INFORMED CONSENT FORM
to Participate in Research, and
AUTHORIZATION 
to Collect, Use, and Disclose Protected Health Information (PHI)
INTRODUCTION
Name of person seeking your consent:
Place of employment & position: 
GENERAL INFORMATION ABOUT THIS STUDY
1. Name of Participant ("Study Subject")
___________________________________________________________________ 
2. What is the Title of this research study (this “Research Study”)?
Fibrinolytic Therapy versus Medical Thoracoscopy for Treatment of Severe Pleural 
Infection: A Randomized Clinical Trial
3. Whom do you call if you have questions about this Research Study (the “Study 
Team”)?
Principal Investigator: Hiren Mehta, M.D.
(352) 273-8737 (business hours)
(352) 265-0111 (24 hour)
Other research staff:  Erin Silverman, Ph.D. 
(352) 273-5870 (business hours)
4.  Who is paying for this Research Study?
The sponsor of this study is the University of Florida, Gatorade Fund
5.  In general, what do you need to know about this Research Study?
Agreeing to become involved in any research is always voluntary.  By signing this 
form, you are not waiving any of your legal rights.  If you decide not to participate in 
this research, you will not be penalized in any way and you will not lose any benefits 
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to which you are entitled. If you have questions about your rights as a research 
subject, please call the University of Florida Institutional Review Board (IRB) office at 
(352) 273-9600.    
a) In general, what is the purpose of the research, how long will you be 
involved?  
The purpose of this research study is to compare two currently accepted 
standard-of-care adjuvant treatment strategies for the management of severe 
infections of the space surrounding the lungs. We will compare two standard of 
care procedures: 
Procedure 1: Medical thoracoscopy, and 
Procedure 2: Fibrinolytic therapy 
These procedures are described later. This study will help us determine if one 
procedure is superior to the other for treating severe infection of the areas 
surrounding the lungs. Specifically: 
   Comparing the length of hospital stay for patients who receive Procedure 1, 
with those of patients who receive Procedure 2. 
   Comparing the need for later, more invasive procedures to treat pleural 
infections for patients who receive Procedure 1, with those of patients who 
receive Procedure 2. 
   Comparing the number of days of chest tube drainage following Procedure 1 
versus the Procedure 2. 
You are being asked to be in this research study because you have been 
diagnosed with a severe infection of the areas surrounding the lungs. This is 
called a pleural infection. The pleura is thin tissue covered by a layer of cells 
(mesothelial cells). This tissue surrounds the lungs and lines the inside of the 
chest wall. The pleural space is the area between the lungs and the chest wall. 
This space helps keep the lungs inflated by allowing them to “stick” to the chest 
wall. It also contains a small amount of liquid, which helps lubricate the surface 
of the lungs, helping them slide along the inner chest wall during breathing. 
Sometimes, fluid, air, or particles can move into the pleural space from other 
areas of the body. When this happens, the liquid in the plural space can become 
infected and lead to severe compromises in health, including death if left 
untreated. In addition, infections within the pleural space may result in an 
unwanted compression of the lung, resulting in shortness of breath and difficulty 
performing normal day-to-day physical activities. 
A description of this clinical trial is available on www.ClinicalTrials.gov as 
required by U.S. law. This Web site will not include information that can identify 
you. At most, the Web site will include a summary of the results. You can search 
this Web site at any time. The ClinicalTrials.gov number for this study is 
NCT03213834.
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b) What is involved with your participation, and what are the procedures to be 
followed in the research? All participants will have a complete medical evaluation 
and chest tube placement. Depending on which group you are assigned to, you 
may undergo medical thoracoscopy or fibrinolytic therapy.
c) What are the likely risks or discomforts to you? Potential risks include pain 
during chest tube placement, bleeding, collapsed lung, anesthesia-related 
drowsiness or depressed breathing, heart problems, air leak from the lungs, low 
oxygen levels, infections, and death.
d) What are the likely benefits to you or to others from the research? Medical 
thoracoscopy or fibrinolytic therapy are both acceptable options for treatment of 
pleural infection. We do not know whether one treatment is superior to another. It 
is not possible to predict whether you will benefit directly from participation in this 
study. Your participation may help others in the future as a result of knowledge 
gained from the research that might help other people with lung infections.
e) What are the appropriate alternative procedures or courses of treatment, if 
any, that might be helpful to you? If you do not want to be in this study, you may 
choose to have a medical thoracoscopy, or fibrinolytic therapy, as part of your 
normal clinical care.
Additional and more detailed information is provided within the remainder of this 
Informed Consent form, please read before deciding if you wish to participate in this 
study.
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY?
6. What will be done as part of your normal clinical care (even if you did not 
participate in this Research Study)? 
This study compares two standard-of-care procedures for treating severe infection in 
the areas surrounding the lungs. As part of your normal clinical care, you will undergo 
either Procedure 1 (Medical thoracoscopy) or Procedure 2 (Fibrinolytic therapy) as 
treatment for this infection. The decision to undergo, or not undergo, treatment for your 
infection is one you make with your doctor, just as with normal clinical care.
7.  What will be done only because you are in this Research Study? 
If you choose to participate in this study you will be randomly assigned (much like the 
flip of a coin) to receive either Procedure 1 or Procedure 2 as treatment for your 
infection. You will not be able to choose which procedure you have, and your doctor 
will not be able to choose the procedure for you either. Rather, your treatment will be 
determined by chance. In a “randomized” study, you procedures you will receive. From 
that point forward your treatment will proceed just as it would during normal clinical 
care. 
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If you choose to participate in this study we will also take a small amount of fluid from 
the pleural space to test for various biomarkers that give us information about the 
body’s responses to infection. This fluid will be sampled when performing procedure 1 
or procedure 2 as a part of which procedure you get randomized to.
We will also make measurements of how much fluid is in the area around your lungs, 
both before and after treatment. This measure will be made by looking at the images 
are produced when you receive your standard-of-care CT scan once treatment ends.
You will meet with the principal investigator, Dr. Hiren Mehta, M.D./ Dr Michael Jantz,  
MD (Co-PI) throughout the course of this study. They will evaluate the results of your 
tests before scheduling the study procedure. Dr. Hiren Mehta and/or Dr Michael Jantz 
will perform the procedure and will monitor your health until you are discharged, and 
for all follow-up visits.
Baseline Procedures (these are measures that will be collected before you 
receive get randomized to one of the procedures for your infection):
We will obtain a medical history from you, as well as from your medical chart. You 
will have a general physical examination. This will include measuring your height, 
weight, heart rate, blood pressure, respiratory rate, and how much oxygen is 
contained in your blood.
Examination of your lung function
You will undergo an ultrasound examination of the pleural space to measure how 
much pleural fluid there is and find the best location for the doctor to take a sample 
of this fluid via needle. An ultrasound is a non-invasive test that makes pictures with 
sound waves. During the ultrasound examination, the medical team will check your 
pleural cavity (the thin fluid-filled space between the two pulmonary pleurae (visceral 
and parietal) of each lung) to look for the pleural fluid and localize a safe pocket to 
insert a small needle for fluid sampling.
Thoracentesis involves placing a thin needle or tube into the pleural space to 
remove some of the fluid. The needle or tube is inserted through the skin, between 
the ribs and into the chest. This procedure is done to remove fluid for testing. The 
needle or tube is removed when the procedure is completed.
If you meet criteria for inclusion in the study, you will complete informed consent
which involves reading, discussing, and signing this document. During informed
consent all your questions about this study and all study-related procedures will be
answered.
Randomization Procedures
Once you consent to participate in this study, and meet all of the eligibility criteria you 
will be randomly assigned to receive either Procedure 1 (Medical thoracoscopy) or 
Procedure 2 (Fibrinolytic therapy).  This assignment will be completed using a 
computer-generated spreadsheet. You have a 1 in 2 (50%) chance of being assigned 
to Procedure 1 and a 1 in 2 (50%) chance of being assigned to Procedure 2. You will 
not be able to choose which procedure you receive.
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Procedures
If you qualify to take part in this research study, you will undergo these procedures:
If you are assigned to receive Procedure 1 (Medical thoracoscopy) the following 
will be completed. 
Before and during the medical thoracoscopy: 
 You will report to the bronchoscopy suite and sign a separate (standard of care) 
consent form in order to undergo thoracoscopy. This procedure will occur in the 
bronchoscopy suite. 
 A sedative drug may be injected into your vein to relax you. Sometimes you will 
not remember having the procedure because of the sedative. 
 The doctor will make a small incision with a scalpel and will then insert a 
telescopic device through the hollow tube. The doctor will use this instrument to 
look around the pleural space. 
 The doctor will clean the pleural space and may break any existing adhesions to 
help your lung expand. 
 The doctor will then place chest tube, commonly referred to as “putting in a chest 
tube.” This is a procedure that is done to drain fluid, blood, or air from the space 
around the lungs. 
Monitoring after the medical thoracoscopy: 
 You will be transferred to an observation area after the study procedure 
 You should gradually become more alert as the sedation/ anesthesia wears off 
 You will remain in the hospital until infection is improved and your chest tube is 
removed 
 At discharge, you will be given instructions for your medications and follow-up 
appointments by your treating team. 
If you are assigned to receive Procedure 2 (Fibrinolytic therapy), the following 
will be completed: 
Before and during fibrinolytic therapy:
 You will report to the bronchoscopy suite and sign a separate (standard of 
care) consent form in order to undergo fibrinolytic therapy. This procedure will 
occurin the bronchoscopy suite. 
 A sedative drug may be injected into your vein to relax you. Sometimes you will 
not remember having the procedure because of the sedative. The skin will be 
thoroughly cleaned and you will be given an injection of local anesthetic into 
the skin and then into the muscle between your ribs. 
 The doctor will use a scalpel to make a cut, from ¾ inch to 1½ inches long, 
between the ribs (the exact location depends on what is being drained and its 
location in the lungs). Then the doctor will guide the tube into the chest. The 
tube is usually a little thinner than a pinky finger, although there are different 
sizes that can be used. The doctor will collect 10 mL of fluid from the placed 
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drain, in order to check for substances that are produced, by the body, in 
response to infection 
 It will be stitched into place to prevent it from slipping out. A sterile dressing 
bandage is placed over the insertion site. The doctor will use an ultrasound, a 
non-invasive device that makes pictures out of sound waves, to help guide the 
placement of the chest tube. 
 The doctor will inject medicines through the chest tube and into the pleural 
space up to 6 times. These medicines will thin the fluid that is in the area 
surrounding your lungs, helping the fluid to drain and the infection to be 
removed. This may take one to two days, to a week or more depending on the 
severity of your infection.
Monitoring after fibrinolytic therapy:
 You will be transferred to an observation area after the study procedure 
 You should gradually become more alert as the sedation/ anesthesia wears off 
 You will be asked to rate your pain using a simple pain measurement scale 
 You will remain in the hospital until infection is improved and your chest tube is 
removed. This can be anywhere from a day or two to a week, depending on 
how severe the infection. 
 You will have a standard-of-care CT scan to determine if your infection is 
resolved. 
 At discharge, your treating team will give you instructions for your medications 
and follow-up appointments.
Patients in both groups will participate in routine follow-up clinic visits at 
approximately 6 and 12 weeks after discharge from the hospital.
Table 1 summarizes the tests and procedures.
Table 1. Summary of tests and procedures
Medical thoracoscopy 
group
Fibrinolytic therapy group
Evaluation
X
X
Medical thoracoscopy
X
Fibrinolytic therapy
X
Chest tube
X
X
Once this research study is completed, any information that could identify you might 
be removed from any identifiable private information or identifiable biospecimens 
collected and that, after such removal, the information or biospecimens could be used 
for future research studies or distributed to another investigator for future research 
studies without additional informed consent from you or your legally authorized 
representative.
If you have any questions now or at any time during this Research Study, please 
contact one of the Research Team members listed on the front page of this form.
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8. What identifiable health information will be collected about you and how will it be 
used?
The Research Team will collect:

Medical and research records

Hospital cost and billing records

Records about your study visits

Records of physical exams

Laboratory, X-ray, and other test results

Questionnaires

Records about any study
The Research Team may collect this information from other healthcare providers, 
such as laboratories, which are a part of this research, as well as healthcare providers 
that are not part of this research (other doctors, hospitals or clinics). Other 
professionals at the University of Florida or Shands Hospital who provide study-
related care, and the University of Florida Institutional Review Board (IRB), may also 
collect your health information. 
The Research Team listed in question 3 above will use or share your health 
information as described below to carry out this research study. 
9. With whom will this health information be shared?
This health information may be shared with:

the study sponsor (listed in Question 4 of this form);

United States governmental agencies which are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health 
and Human Services, and the Office of Human Research Protections;

Government agencies which are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state and local 
health departments.

Hospital and Clinical Research Accrediting Agencies

Data and Safety Monitoring boards that oversee this study

The IRB that reviewed this Research Study and ensures your rights as a Study 
Subject are protected 
Otherwise, your identifiable health information will not be shared without your 
permission unless required by law or a court order. Once your health information is 
shared with those listed above, it is possible that they could share it without your 
permission because it would no longer be protected by the federal privacy law. 
10. How long will you be in this Research Study?
You will be in this research study for up to 12 weeks after getting discharged from the 
hospital.
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This Authorization to use and share your health information expires at the end of the 
study, unless you revoke it (take it back) sooner.
11.How many people are expected to take part in this Research Study?
At least 60 patients are expected to take part in this study.
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND 
WHAT ARE YOUR OPTIONS?
12.What are the possible discomforts and risks from taking part in this Research 
Study?
As a result of your participation in this study, you are at risk for possible complications 
listed in this section. You should discuss these with the investigator and with your 
regular doctor if you choose. 
Thoracentesis: 
You will sign a separate consent form for the thoracentesis. The thoracentesis consent 
form will also include possible complications. 

Pain during placement—Discomfort can result from the needle at the time it is 
inserted. Doctors try to lessen any pain or discomfort by giving a local numbing 
medicine (topical anesthetic). The discomfort is usually mild and goes away 
once the needle or tube is removed.

Bleeding—During insertion of the needle, a blood vessel in the skin or chest wall 
may be accidentally nicked. Bleeding is usually minor and stops on its own. 
Sometimes, bleeding can cause a bruise on the chest wall. Rarely, bleeding can 
occur into or around the lung and may require a chest tube or surgery. 

Collapsed lung—When the needle is being placed, it may puncture the lung. 
This hole may seal quickly on its own. If the hole does not seal over, air can leak 
out and build up around the lung. This build-up of air can cause part or all of the 
lung on that side to collapse (pneumothorax). If this happens, the doctor can 
place a chest tube between the ribs into the chest to remove the air that is 
leaking from the lung 
Moderate sedation may cause these risks/possible complications: 

Drowsiness, slurred speech, tremor, fatigue, and low blood pressure, increase 
carbon dioxide in your blood, slowing of the heart rate, anxiety, confusion, 
dizziness and shivering.

Respiratory depression. Trained medical professionals with extensive 
experience and expertise will administer these medications and will be 
responsible for you care during the course of the procedure. 
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Thoracoscopy: 
You will sign a separate consent form for the thoracoscopy. The thoracoscopy consent 
form will also include possible complications.

Chest pain (5%). The nerves between the ribs are bruised after the procedure, 
which can cause some persistent pain.

Air leak from lung (1-5%). A small hole develops in the lung. This means the 
chest tube has to stay in longer. 

Bleeding (< 1%). Usually it is minor and settles quickly. Bleeding is more 
common if you have been taking blood-thinning drugs. 

Heart problems (< 1%). A brief minor strain may be put on the heart. This can 
cause abnormal beating of the heart, fluid to accumulate in the lungs, a heart 
attack, or the heart may stop beating. 

Low oxygen levels (< 1%). You will be given oxygen. 

Death(< 1%) as a result of this procedure is uncommon.
Chest tube: 
You will sign a separate consent form for the chest tube. The chest tube consent form 
will also include possible complications.

Pain during placement—Discomfort often occurs as the chest tube is inserted. 
Doctors try to lessen any pain or discomfort by giving a local numbing medicine. 
The discomfort usually decreases once the tube is in place.

Bleeding (<5%) — During insertion of the tube, a blood vessel in the skin or 
chest wall may be accidently nicked. Bleeding is usually minor and stops on its 
own. Rarely, bleeding can occur into or around the lung and may require 
surgery. Usually bleeding can just be watched with the chest tube in place.

Infection (< 5%)—Bacteria can enter around the tube and cause an infection 
around the lung. The longer the chest tube stays in the chest, the greater the 
risk for infection. The risk of infection is decreased by special care in bandaging 
the skin at the point where the tube goes into the chest.
Fibrinolytic Therapy: 
The fibrinolytic therapy includes possible complications.

Pain (15%)-While the medications are in the pleural space, you might feel some 
discomfort. Usually such pain can be relieved by analgesics.

Bleeding (5%)-While medications are in the pleural space, you might experience 
bleeding inside the pleural space. Usually, it resolves with stopping medications. 
Rarely, blood transfusion might be need or require surgery. 
Reproductive Risks: 
If you are pregnant, you will not be able to participate in this study. Females who have 
the potential to become pregnant will require a negative urine pregnancy test prior to 
starting study procedures. 
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Privacy: 
The data collected both written and electronic will be held securely in a locked cabinet 
and secure server behind the UF Health firewall respectively. Only the study individual 
will be contacted and the questionaries’ administered in the privacy of a secluded clinic 
room. The data collected will be restricted to only the minimum amount necessary to 
accomplish the aim of the study.
Psychological Stress: 
You may refuse to answer any of the questions and you may take a break at any time 
during the study. You may stop your participation in the study at any time. 
Researchers will take appropriate steps to protect any information they collect about 
you. However, there is a slight risk that information about you could be revealed 
inappropriately or accidentally. Depending on the nature of the information, such a 
release could upset or embarrass you, or possibly affect your insurability or 
employability. Questions 17-21 in this form discuss what information about you will be 
collected, used, protected, and shared.
This Research Study may also include risks that are unknown at this time.
Please note, participating in more than one research study or project may further 
increase the risks to you.  If you are already enrolled in a research study, please inform 
one of the Research Team members listed in question 3 of this form or the person 
reviewing this consent with you before enrolling in this or any other research study or 
project.
During the study, the Research Team will notify you of new information that may 
become available and might affect your decision to remain in the study. 
The University of Florida is required by law to protect your health information. Your 
health information will be stored in locked filing cabinets or on computer servers with 
secure passwords, or encrypted electronic storage devices, as required by University 
policy. However, there is a slight risk that information about you could be released 
inappropriately or accidentally. Depending on the type of information, a release could 
upset or embarrass you, or possibly affect your ability to get insurance or a job. 
If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the Research Team members listed in question 
3 in this form.
13a. What are the potential benefits to you for taking part in this Research Study?
So far medical thoracoscopy or fibrinolytic therapy are both acceptable options for 
treatment of pleural infection. We do not know whether one treatment is superior to 
another. It is not possible to predict whether you will benefit directly from participation 
in this study.
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13b. How could others possibly benefit from this Research Study?
Your participation may help others in the future as a result of knowledge gained from 
the research that could help other people with similar disease.
13c. How could the Research Team members benefit from this Research Study?
In general, presenting research results helps the career of a researcher. Therefore, the 
Research Team listed in question 3 of this form may benefit if the results of this 
Research Study are presented at scientific meetings or in scientific journals.
14.What other choices do you have if you do not want to be in this study? 
Taking part in this study is voluntary. Instead of being in this study, you have the 
following options: 

Choose to have medical thoracoscopy or fibrinolytic therapy without being 
involved on the study 
This research study is not meant to diagnose or treat medical problems. Participation 
in this research study does not take the place of routine physical examinations or visits 
to your regular doctor. We recommend that you discuss these and other options with 
the investigator and your regular doctor so that you can make a well-informed decision 
about participating in this study.
You may also refuse to authorize the use of your health information, but if you refuse, 
you may not be allowed to be in this research study or receive any research-related 
treatment that is only available in this research study. However, your decision not to 
sign this Authorization will not affect any other treatment you may be eligible to receive.
15a. Can you withdraw from this study?
You may withdraw your consent and stop participating in this Research Study at any 
time.  If you do withdraw your consent, there will be no penalty to you, and you will not 
lose any benefits to which you are otherwise entitled. If you decide to withdraw your 
consent to participate in this Research Study for any reason, please contact the 
Research Team listed in question 3 of this form. They will tell you how to safely stop 
your participation.
You can also change your mind and take back this Authorization at any time by sending 
a written notice to the Research Team listed in question 3 of this form to let them know 
your decision. If you take back this Authorization, the Research Team may only use 
and disclose your health information already collected for this research study. No 
additional health information about you will be collected or disclosed to the Research 
Team. However, if you take back this Authorization, you may not be able to continue in 
this study. Please discuss this with a member of the Research Team listed in question 
#3.
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15b.Can the Principal Investigator withdraw you from this Research Study? 
You may be withdrawn from this Research Study without your consent for the following 
reasons:

The study doctor thinks it necessary for your health or safety

You have not followed study instructions 

Administrative reasons require your withdrawal
WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE?
16. If you choose to take part in this Research Study, will it cost you anything?
Study Services 
The Sponsor will pay for or provide the following study-required services/activities at no 
cost to you: 

Study questionnaires

Lab analysis of pleural fluid for study purposes only 
If you receive a bill for these services, please contact Hiren Mehta at 352-273-8737 
Items/Services Not Paid for by the Sponsor 
Any other medical services you receive would have been provided to you even if you 
were not in this study. These services will be billed to you or your insurance company 
in the usual manner. You will be responsible for paying any deductible, co-insurance, 
co-payments, for those services, and for any non-covered or out-of-network services. 
Some insurance companies may not cover costs associated with studies. Please 
contact your insurance company for additional information.
17.Will you be paid for taking part in this Research Study?
You will not receive any payment for taking part in this study.
18.What if you are injured while in this Research Study? 
If you are injured as a direct result of your participation in this study, only the 
professional services that you receive from any University of Florida Health Science 
Center healthcare provider will be provided without charge. These healthcare providers 
include physicians, physician assistants, nurse practitioners, dentists or psychologists. 
Any other expenses, including Shands hospital expenses, will be billed to you or your 
insurance provider. 
You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with research studies or 
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research-related injuries. Please contact your insurance company for additional 
information. 
The Principal Investigator will determine whether your injury is related to your 
participation in this study. 
No additional compensation is routinely offered. The Principal Investigator and others 
involved in this study may be University of Florida employees. As employees of the 
University, they are protected under state law, which limits financial recovery for 
negligence.
Please contact one of the Research Team members listed in question 3 of this form if 
you experience an injury or have questions about any discomforts that you experience 
while participating in this Research Study.
 
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SIGNATURES
As an investigator or the investigator’s representative, I have explained to the participant 
the purpose, the procedures, the possible benefits, and the risks of this Research Study; 
the alternative to being in the study; and how the participant’s protected health information 
will be collected, used, and shared with others: 
Signature of Person Obtaining Consent and 
Authorization
Date
You have been informed about this study’s purpose, procedures, possible benefits, and 
risks; the alternatives to being in the study; and how your protected health information will 
be collected, used and shared with others. You have received a copy of this Form. You 
have been given the opportunity to ask questions before you sign, and you have been told 
that you can ask questions at any time.  
You voluntarily agree to participate in this study. You hereby authorize the collection, use 
and sharing of your protected health information as described above. By signing this form, 
you are not waiving any of your legal rights.
Signature of Person Consenting and Authorizing
Date
 
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