Prospective Randomized Double-Blind Controlled Trial of Intrapleural Fibrinolytic Therapy to Enhance Chemical Pleurodesis
Phase: PHASE4
Conditions: Pleural Effusion
Sponsor: Memorial Healthcare System

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CLINICAL TRIAL PROTOCOL
Prospective Randomized Trial of Intrapleural Fibrinolytic Therapy to Enhance Chemical 
Pleurodesis
Principal Investigator:
Mark Block, MD
Chief, Division of Thoracic Surgery
Memorial Healthcare System
1150 N. 35th Ave., Suite 660
Hollywood, FL 33021
954.265.1125
mblock@mhs.net
Research Personnel:
Francisco Tarrazzi, MD
            Thoracic Surgeon
Syed Razi, MD
Thoracic Surgeon
Catherine Tami, APRN
Physician Extender
Krystina Serpa, APRN
Physician Extender
Jenessey Gonzalez, APRN
Physician Extender
Protocol Number:
Current Version Date:
29Nov2022
Study Site(s):
Memorial Regional Hospital
Memorial Hospital West
CONFIDENTIAL
This document is confidential and the property of Memorial Healthcare System (MHS).  No part of it 
may be transmitted, reproduced, published, or used by other persons without prior written authorization 
from the MHS.
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS:____________________________________________________4
1.0 STATEMENT of COMPLIANCE______________________________________________5
2.0 ABSTRACT _______________________________________________________________5
3.0 INTRODUCTION __________________________________________________________6
3.1. Literature Review_________________________________________________________6
3.2. Rationale _______________________________________________________________8
3.3. Research Question ________________________________________________________8
4.0 OBJECTIVES and HYPOTHESES ____________________________________________8
4.1. Primary Objective and Hypothesis ___________________________________________8
4.2. Secondary Objectives and Hypotheses ________________________________________8
5.0. STUDY DESIGN __________________________________________________________9
6.0. POPULATION AND SAMPLE SIZE _________________________________________10
6.1. Sample Size ____________________________________________________________10
6.2. Inclusion and Exclusion Criteria ____________________________________________10
6.3. Randomization __________________________________________________________11
7.0. RECRUITMENT AND CONSENT___________________________________________11
7.1. Recruitment Strategy and Materials__________________________________________11
7.2. Consent Method _________________________________________________________11
7.3. HIPAA Authorization ____________________________________________________12
7.4. Withdrawal_____________________________________________________________12
8. PROCEDURES ____________________________________________________________13
8.1. Study Duration and Timeline_______________________________________________15
8.2. Assessments/Tasks_______________________________________________________16
8.3. Treatments/Interventions __________________________________________________16
8.4. Drugs/Devices __________________________________________________________17
9.0 STATISTICAL Methods ____________________________________________________17
9.1. Primary and Secondary Outcome measures____________________________________17
9.2. Statistical Analysis Plan___________________________________________________18
10.0   STUDY ADMINISTRATION ______________________________________________19
10.1 Confidentiality and Privacy _______________________________________________19
10.2. Quality Control and Quality Assurance______________________________________19
10.3. Records Retention ______________________________________________________20
11.0 ETHICAL CONSIDERATIONS_____________________________________________20
11.1. Potential Risks to Subjects________________________________________________20
11.2 Safeguards to Minimize Risks _____________________________________________21
11.3. Potential Benefits to Subjects _____________________________________________21
11.4. Potential Benefits to Society ______________________________________________21
11.5. Subject Compensation ___________________________________________________21
11.6. Risk/Benefit Assessment _________________________________________________21
12.0   PUBLICATION PLAN ___________________________________________________21
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13.0   CONFLICTS of INTEREST_______________________________________________22
14.0    FUNDING SOURCE ____________________________________________________22
15.0   REFERENCES _________________________________________________________22
16.0  ATTACHMENTS ________________________________________________________24
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LIST OF ABBREVIATIONS:
MHS
Memorial Healthcare System
TSP
Talc slurry pleurodesis
RSP
Radiographically satisfactory pleurodesis
NS
Normal saline
tPA
Tissue plasminogen activator
CxR
Chest x-ray radiography
CT
Computed tomography
MPE
Malignant pleural effusions
PAI-1
Plasminogen activator inhibitor-1
TNF-α
Tumor necrosis factor-alpha
MCP-1
Monocyte chemoattractant protein-1,
TGF-
Transforming growth factor-beta
IL-8
Interleukin- 8
SOB
Shortness of Breath
VA
Visual assessment
REDCap
Research Electronic Data Capture
RSP
Radiographically Satisfactory Pleurodesis
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1.0 STATEMENT OF COMPLIANCE
This document is a protocol for a prospective, randomized, double-blind, controlled trial to 
evaluate the efficacy of supplementing standard talc slurry pleurodesis with intrapleural cathflo 
activase for management of patients with recurrent pleural effusion. The study will be conducted 
in compliance with U.S. and international standards of Good Clinical Practice, applicable Federal 
regulations, International Conference on Harmonization guidelines and all applicable institutional 
research requirements. Collection, recording, and reporting of data will be accurate and will ensure 
the privacy, health, and welfare of research subjects during and after the study.
2.0 ABSTRACT
Recurrent pleural effusion is a common health problem, affecting approximately 1.5 million 
people each year in the United States. It causes breathlessness, pain and reduced physical capacity 
and can require surgical interventions. A long-standing treatment option is called pleurodesis, in 
which the surface of the lung is induced to adhere to the chest wall, obliterating the pleural space 
to prevent fluid build-up. Talc slurry pleurodesis (TSP) is one of the most common techniques 
used to accomplish this result. With TSP a drain is placed in the pleural space (chest tube), 
followed by instillation of sterile talc in a saline suspension. The talc is a sclerosing agent that 
induces scar formation between the visceral and parietal pleural membranes. Although effective, 
sometimes development of septations and loculations can produce suboptimal results. In patients 
with complex pleural effusion and empyema (infection in the pleural space), intrapleural 
administration of fibrinolytic medication such as cathflo activase (Alteplase®) is used to break 
down pleural loculations and improve pleural fluid drainage. To our knowledge, fibrinolytic 
therapy has never been used to manage loculated collections that develop with TSP. It is currently 
unknown if supplementing TSP with cathflo activase will improve results or impair pleurodesis 
compared to use of TSP alone. 
This protocol describes a prospective, randomized, double-blind controlled trial comparing TSP 
alone to the combination of TSP with cathflo activase for achieving optimal results with 
pleurodesis for recurrent pleural effusion. Patients who sign informed consent will be randomly 
assigned to receive either TSP alone (talc, 5 gm in 50 ml NS) with placebo (50 ml NS) or TSP 
with cathflo activase (4 mg in 50 ml NS) through the chest pleural catheter. Follow-up lasts for 
three months. The primary outcome is achievement of a “Radiographically Satisfactory 
Pleurodesis” (RSP) by day three post-procedure, defined as chest tube drainage of less than 100 
cc over 24 hours and a chest x-ray showing similar or less pleural space opacification than on the 
day TSP was performed (baseline, day 0). Secondary outcomes include the proportion of patients 
who achieve RSP, time needed to achieve RSP, duration of chest tube drainage, length of hospital 
stay after initiation of TSP, proportion of patients requiring repeat TSP, change in serum 
hemoglobin during therapy, objective assessments of pain and dyspnea, and potential 
complications. The incremental cost effectiveness of talc slurry pleurodesis with cathflo activase 
compared to without cathflo activase will be assessed using a static decision tree model, which 
will be constructed using the TreeAge Pro software. This study will recruit 136 patients, with an 
interim analysis for efficacy after 50 patients, and aims to help develop the future standard for 
management of patients requiring pleurodesis for their symptomatic pleural effusion. 
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3.0 INTRODUCTION
A pleural effusion is an accumulation of fluid in the chest around the lung, and is a common clinical 
problem, with an incidence of approximately 1.5 million per year in the United States.(1) Large 
collections compress the underlying lung and contribute to significant morbidity by affecting a 
patient’s ability to breathe easily. A variety of conditions contribute to the development of a pleural 
effusion, such as heart, kidney and liver failure, cancer, and pneumonia. Often, drainage of the 
effusion is sufficient. But if the underlying cause cannot be corrected the effusion will return and 
more definitive management is indicated. Options for definitive management of a recurring pleural 
effusion are either an indwelling catheter to facilitate repeated drainage (e.g. PleurX®) or 
pleurodesis to prevent reaccumulation of fluid by sealing the pleural space.(2–5) Pleurodesis 
occurs in response to inflammation, which can be intentionally induced through either 
mechanical/surgical abrasion or application of a chemical irritant. Chemical pleurodesis is a 
convenient option because it can be done by injection of the chemical in suspension through a 
small drainage tube into the pleural space, rather than requiring surgery. Many agents have been 
used to promote pleurodesis, including sterile talc, tetracycline, doxycycline, bleomycin, silver 
nitrate and povidone iodine.(2)
Chemical pleurodesis is effective but can be incomplete, sometimes leaving the patient with a 
partially sealed pleural space and multiple pockets (“loculations”) of fluid. This is probably the 
result of uneven distribution of the chemical irritant, incomplete contact of the chemical with the 
pleural membranes, and ongoing fluid production that creates pockets, or loculations, that separate 
the pleural membranes and prevent adhesion formation.(6) Fluid in the pleural space is often 
protein rich and partially organized with fibrin “clots”. The Thoracic Surgery Division at the 
Memorial Healthcare System (MHS) has had extensive experience with intrapleural administration 
of cathflo activase (Alteplase®) to improve drainage of complex pleural effusions. This experience 
led to the hypothesis that cathflo activase given along with the chemical pleurodesis agent would 
improve results by 1) improving distribution and contact of the chemical agent with the pleural 
membranes generating a more uniform inflammatory response, and 2) prevent loculations from 
forming and therefore lead to a more complete pleurodesis. The Division started using cathflo 
activase with talc slurry in April 2014 and reviewed results as of December, 2016. 57 patients with 
benign or malignant effusions were treated and pleurodesis was performed 62 times (eight patients 
had bilateral pleurodesis). Because it was not done as part of a formal protocol, there was 
considerable variability in dosing and timing of cathflo activase, but our review suggested that 
results were at least as good as pleurodesis without cathflo activase and that there was no incidence 
of serious complication such as bleeding or respiratory failure. Following this review the protocol 
was modified to specify a cathflo activase dose of 4 mg. Since then, more than 150 additional 
patients with benign and malignant effusions have been treated with the combination of cathflo 
activase and TSP without apparent complication. A prospective randomized evaluation of this 
strategy is indicated to formally evaluate its efficacy.
3.1. Literature Review
Pleurodesis has a long history as the standard of care for palliation of malignant pleural effusions 
(MPE). By sealing the visceral and parietal pleura together there is no residual potential space in 
which fluid can accumulate, thus preventing development of large effusions that compromise 
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breathing. Chemical or physical irritation of the pleural space causes an inflammatory response 
and subsequent fibrin adhesion and fibrotic tissue formation, leading to pleurodesis.(2–4) The 
sclerosing agent is applied either during an operation called thoracoscopy, in which small incisions 
are made and the agent is sprayed directly onto the pleural surfaces (poudrage), or is injected in a 
suspension through an existing drainage tube in the pleural space (slurry). 
Many chemicals have been tried for inducing pleurodesis. The agents used most often have been 
talc, bleomycin, tetracycline, and doxycycline.(2) A Cochrane review concluded that talc is the 
most effective agent,(7) but recent availability has been limited. In a prospective non-randomized 
study of 109 patients, Stefani and colleagues concluded that talc poudrage was superior to talc 
slurry using chest X-rays after the procedure to examine pleural fluid re-accumulation.(8) A 
presumptive disadvantage with talc slurry is that the talc is distributed unevenly in the pleural 
space. Maneuvers to promote uniform distribution such as frequent patient repositioning while the 
slurry dwells in the pleural space have been recommended, but there is no evidence that this 
improves distribution or results.(9–11) 
Intrapleural fibrinolytic therapy was first described in the late 1940’s. Tillet et al. (12) used a 
partially purified streptococcal concentrate containing streptokinase and streptococcal DNase 
intrapleurally in patients with fibrinous pleurisy and empyema and reported that it breaks down 
fibrin in the pleural space.   Recombinant cathflo activase, or Alteplase®, is a recognized systemic 
treatment for myocardial infarction, pulmonary embolism and thromboembolic stroke.(13) Similar 
to other fibrinolytics, cathflo activase converts plasminogen to the active protease plasmin, which 
degrades fibrin into soluble products. A unique characteristic of cathflo activase is that it is fibrin-
selective and preferentially activates plasminogen at the surface of a clot. Multi-loculated effusions 
are a feature of unsuccessful pleurodesis. An imbalance between activators and inhibitors of the 
fibrinolytic system creates a pro-fibrotic state.(14,15) Elevated levels of plasminogen activator 
inhibitor type 1 (PAI-1) are correlated with those of inflammatory mediators, such as tissue 
necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), transforming growth 
factor β (TGF-), and interleukin-8 (IL-8) within the pleural space.(16) Reduced levels of 
endogenous pleural cathflo activase in this setting are also reported.(16) It has been documented 
that intrapleural cathflo activase prevents ongoing fibrin deposition, lyses pleural adhesion, and 
breaks down fibrinous septations and loculations, resulting in improved drainage of of pleural 
fluid.(17–19) However, to our knowledge, nothing is known about effect of the combined use of 
cathflo activase and Talc on pleurodesis.
The Division of Thoracic Surgery at the Memorial Healthcare System frequently performs 
chemical pleurodesis for recurrent benign and malignant pleural effusions. In our experience, we 
found that lung expansion and extent of effective pleurodesis were better when cathflo activase 
was used to supplement the talc slurry. We hypothesize that cathflo activase given with the 
pleurodesis agent clears fibrin deposits that may coat the mesothelium and inhibit distribution and 
direct contact. In addition, it is our experience that loculations form several days after pleurodesis 
and that another dose of intrapleural cathflo activase given days after TSP may be helpful in 
mitigating this problem. As an outgrowth of our use of cathflo activase to manage loculated 
effusions in other clinical situations, we have used cathflo activase days after the talc slurry to 
break down loculations and improve drainage of retained pleural fluid. Our anecdotal experience 
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suggested that this facilitated a better radiographic result, with more complete pleural apposition 
and pleurodesis, and less loculated effusion. However, given that pleurodesis pathophysiology 
requires fibrin deposition, increasing pleural fibrinolysis could lead to pleurodesis failure. We 
hypothesize that the timing of the cathflo activase is critical to achieving good pleural drainage 
and uniform apposition of the pleural membrane without disturbing the development of fibrosis 
necessary for pleurodesis. Too soon after talc administration may be ineffective in preventing fluid 
loculations, and too late may inhibit pleurodesis. In a review of our experience, three days emerged 
as the best compromise between these two considerations.
3.2. Rationale
Pleurodesis is an option for management of recurrent pleural effusion. But results are often 
incomplete, leading to loculated collections and/or recurrence of the effusion. Intrapleural 
fibrinolytic therapy is safe and effective for management of loculated pleural effusions. We 
hypothesize that giving cathflo activase with Talc will improve distribution of the Talc and contact 
of the Talc with the pleural mesothelium, promoting more rapid and complete pleurodesis with a 
lower incidence of loculations and recurrent effusion.
3.3. Research Question
Does the use of the fibrinolytic agent cathflo activase in conjunction with talc slurry pleurodesis 
increase the rate of successful pleurodesis compared to using the talc slurry alone?
4.0 OBJECTIVES AND HYPOTHESES
4.1. Primary Objective and Hypothesis
Primary objective: To determine if intrapleural administration of Talc slurry with cathflo activase 
will improve successful pleurodesis rates compared to talc slurry alone.  
Null hypothesis: There is no difference in successful pleurodesis rates with intrapleural 
administration of talc with cathflo activase compared to those of Talc alone in the management of 
patients with recurrent pleural effusion.    
4.2. Secondary Objectives and Hypotheses
Secondary hypotheses for this trial are that cathflo activase supplementation for TSP:
1. Is safe
2. Does not inhibit pleurodesis
3. Reduces the incidence of recurrence of pleural effusion
4. Reduces the incidence of incomplete pleurodesis (presence of loculated effusions)
5. Shortens the time to achieve pleurodesis.
6. Does not increase pain associated with TSP
7. Improves the patient’s subjective assessment of dyspnea
8. Does not prolong chest tube drainage or length of hospitalization
9. Is as cost-effective as TSP alone
Secondary objectives for this trial are:
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1. To determine if giving cathflo activase with TSP is associated with a higher incidence of 
complications compared to TSP with placebo.
2. To determine if giving cathflo activase with TSP improves pleural fluid drainage compared 
to TSP with placebo.
3. To determine if giving cathflo activase with TSP is associated with a greater decline in 
serum Hemoglobin and/or incidence of blood transfusion compared to TSP with placebo.
4. To determine if giving cathflo activase with TSP is associated with an increased incidence 
of repeat pleurodesis compared to TSP with placebo.
5. To determine if giving cathflo activase with TSP is associated with a lower incidence of 
recurrence of pleural effusion compared to TSP with placebo.
6. To determine if giving cathflo activase with TSP is associated with a lower incidence of 
pleural fluid loculations compared to TSP with placebo.
7. To determine if giving cathflo activase with TSP is associated with a shorter time to RSP 
in patients with MPE compared to TSP with placebo.
8. To determine if giving cathflo activase with TSP is associated with a shorter time to RSP 
in patients with benign pleural effusion compared to TSP with placebo.
9. To determine if giving cathflo activase with TSP is associated with any difference in pain 
as measured by a standard visual analog pain scale compared to TSP with placebo.
10. To determine if giving cathflo activase with TSP is associated with any difference in 
scoring on a visual analog scale for measurement of dyspnea compared to TSP with 
placebo.
11. To determine if giving cathflo activase with TSP is associated with shorter duration of 
chest tube drainage compared to TSP with placebo.
12. To determine if giving cathflo activase with TSP is associated with a short length of 
hospital stay after TSP compared to TSP with placebo.
13. To compare hospital costs associated with cathflo activase with TSP compared to TSP 
alone. 
5.0. STUDY DESIGN
The SPIRIT (Standard Protocol Items for Randomized Trials) recommendations were followed in 
preparing this protocol.(20,21) The study is a single center, prospective, randomized, double-blind, 
placebo-controlled trial with two arms to compare the successful pleurodesis rates and potential 
complications after TSP with or without cathflo activase in patients with recurrent pleural effusion.
This study is designed as a single center study at MHS with two study sites, although it may be 
made available to thoracic surgery programs at other institutions to consider opening as a 
collaborative effort to accelerate patient accrual. All patients for whom bedside chemical 
pleurodesis is planned will be considered eligible for the study regardless of effusion etiology. 
Chest X-ray and chest tube insertion will be performed in all consented participants, and the 
drained pleural fluid amounts will be recorded and, if not done before enrollment, sent for 
chemical, bacteriological and cytological evaluation. Then the participants will undergo stratified 
randomization according to effusion etiology (malignant vs. non-malignant) with the use of a 
computer-based system in a 1:1 ratio. TSP with cathflo activase or placebo will be administered 
through the chest tube immediately after randomization. The trial will be conducted on a double-
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blind basis and therefore participants and the clinician will be unaware of each participant’s 
allocated treatment group.      
Additional centers may be invited to participate, in which case the IRB will be notified if other 
programs decide to open the protocol at other sites.  
6.0. POPULATION AND SAMPLE SIZE
Patients will be identified during routine clinical practice at the Division of Thoracic Surgery in 
Memorial Healthcare System. As standard practice patients will be engaged in a discussion of 
appropriate options, including repeated thoracentesis, indwelling pleural catheter, and pleurodesis. 
If the patient and clinical team determine that talc slurry pleurodesis is the most appropriate option, 
then the patient will be considered eligible for the study.
6.1. Sample Size
Based on review of our experience with pleurodesis, TSP can be expected to produce RSP at three 
days in approximately 60% of patients. We anticipate an RSP rate of approximately 80% at three 
days using the combination of talc and cathflo activase. Therefore, in order to detect a 20% 
difference in successful pleurodesis with 80% power, a 5% significance level (1-sided) and 5% 
loss to follow-up, a total of 136 patients (68 in each arm) will be needed in this trial.   
6.2. Inclusion and Exclusion Criteria
All patients for whom bedside chemical pleurodesis is planned will be considered eligible for the 
study regardless of effusion etiology. The experience to date has been that there is no relative or 
absolute contraindication to the use of cathflo activase with pleurodesis, including patients with 
bloody pleural effusion. The principal investigator or a nominated member of the research team 
will approach participants who fulfill the criteria for inclusion in the trial.  
6.2.1. Inclusion Criteria
1. Age > 18 years
2. Symptomatic pleural effusion requiring intervention
3. Expected survival > 3 months
4. Written informed consent to trial participation
6.2.2. Exclusion Criteria
1. Females who are pregnant or lactating
2. Inability to obtain consent from the patient or patient’s designated representative.
3. Inability of the patient to comply with the protocol.
4. Previously documented adverse reaction to talc or cathflo activase.
5. Any oral or intravenous therapy with a steroid medication EXCEPT decadron 
within 72 hours of anticipated pleurodesis procedure. For patients who have 
received decadron, the time period will be increased to within 10 days of anticipated 
pleurodesis procedure.
6. Hospice evaluation ongoing or anticipated within four weeks
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6.3. Randomization
Subjects undergoing pleurodesis as part of their standard of care treatment, and who have signed 
informed consent, will undergo a stratified randomization according to effusion etiology 
(malignant vs. non-malignant) with the use of a computer-based system in a 1:1 ratio. A statistician 
will randomly generate treatment allocation codes (randomization lists for either placebo or cathflo 
activase) according to study design specifications as determined by the statistician and principal 
investigator. The treatment allocations will be given to pharmacy with sealed opaque envelopes. 
Once a subject has consented to enter the trial and is ready for pleurodesis an envelope will be 
opened and an independent pharmacist (researcher) will prepare the drug or placebo in a syringe 
labeled with “study drug” and the randomization code according to the treatment allocations. 
Syringes containing placebo or cathflo activase (study drug) cannot be distinguished because both 
preparations are clear and colorless and have the same volume. The prepared syringe labeled 
“study drug” will be brought to the bedside by the pharmacist and nurse and the subject will then 
be given the allocated treatment regimen. The subject’s ID, date, time and randomization code will 
be recorded. The doctor/nurse and subject will not know which drug was injected (double blinded). 
The preparer (pharmacist) will retrieve the recorded information, determine if the injection was 
done as planned, and save the documents in a secured place. 
The envelopes should be opened just after the subject has consented to enter the trial and is ready 
for pleurodesis. In case of a broken or lost syringe, the preparer will use the allocation code of the 
envelope and the allocation log to determine whether the syringe should be replaced with placebo 
or study drug.
7.0. RECRUITMENT AND CONSENT
7.1. Recruitment Strategy and Materials
The recruitment process is designed to fit with routine clinical practice. Subjects requiring 
pleurodesis as part of their standard of care for the management of recurrent pleural effusion will 
be recruited directly by the investigators and research staff. The subjects will be given an 
explanation of the study by the investigator and then given the participant information and consent 
form to be read through and ask questions of the investigator. Then the subjects will be asked if 
they wish to participate in this study. If the subject is not able to give consent, then their legally 
designated representative or health care surrogate will be approached. Because cathflo activase 
supplementation of TSP is not an accepted standard of care, if the patient declines participation in 
the study then TSP without cathflo activase will be done.
7.2. Consent Method
Subjects who will take part in the study (or their legally designated representative) will be provided 
a consent form describing the study and providing sufficient information for subjects to make an 
informed decision about their participation in this study. Most subjects will be inpatients, and 
therefore will be able to either provide informed consent at the time of initial contact or be given 
the option to discuss further with family and their legally accepted representative. Because 
inordinate delay in the consent process will have undesirable consequences for delay in therapy 
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and prolongation of hospital stay, patients will be given until approximately noon of the following 
day to either agree or decline to participate. For patients unable to provide consent, their designated 
health surrogate will be approached to discuss study participation and consent. For the occasional 
patient for whom pleurodesis is recommended, the study material and consent form will be 
presented to them in the clinic and they will be given the opportunity to take it home to review 
with family and their legally designated representative. The 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, must be obtained before the subject is submitted to any 
study procedure. The investigator or his qualified designee will then obtain written informed 
consent according to International Conference on Harmonization Good Clinical Practice (ICH 
GCP). This consent form must be signed by the subject, or his/her designated healthcare surrogate, 
and the investigator or the investigator-designated research professional who obtains the consent.  
The completed consent forms will be retained by the Investigator and a copy of the consent form 
will be provided to the study participant.
7.3. HIPAA Authorization
Prior to patient participation in the study, written informed consent will be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of MHS. Each signature must be personally dated by each 
signatory and the informed consent and any additional patient information form retained by the 
investigator as part of the study records. A signed copy of the informed consent and any additional 
patient information must be given to each patient or the patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by the Principal 
Investigator in accordance with the local data protection law. The level of disclosure must also be 
explained to the patient.
The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by appropriate IRB members, and by 
inspectors from regulatory authorities.
7.4. Withdrawal
Patients will have originally consented to trial follow-up procedures, including chest x-ray, CT 
scan, and blood tests where appropriate. Patients have the right to withdraw from the trial at any 
point. A request by a patient to withdraw does not have to be justified and will not affect future or 
ongoing care. In the event of withdrawal, any details available regarding the reason(s) will be 
recorded. Data the patient has previously consented for us to collect and analyses will be retained 
but no further data will be collected. Patients who withdraw before randomization will not be 
included in the final analysis. Because the only investigational intervention in this protocol occurs 
immediately following enrollment, any patient who withdraws from the study, either at their own 
request or at the investigator’s discretion, will be offered all scheduled follow-up care or imaging 
as detailed in the protocol, as this is considered optimal care for a patient after pleurodesis.
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8. PROCEDURES
Figure 1 shows the proposed workflow through the trial. Following the informed consent, each 
participant is assigned a unique study number and baseline data will be collected before 
randomization. At this point the research nurse will briefly explain the procedure and familiarize 
the participant with the Visual Analogue Scale (VAS) system for dyspnea (Appendix I) and pain 
(Appendix II). Trial treatment will be delivered by means of either a pigtail chest tube (size 10-14 
Fr) or PleurX® catheter at bedside after randomization. Outcome measures will be assessed daily 
until the chest tube is removed and at routine follow-up visits at approximately 14 days, 28 days 
and three months after the day of procedure as outpatients if the patient has been discharged. While 
the chest tube is in place, daily symptom assessment will be performed, and daily chest x-ray (PA 
and lateral when possible) and 24-hour drain output will be recorded (Appendix III) to determine 
if RSP has been achieved, or if further intervention is indicated.
RSP is defined as chest tube drainage less than 100 cc over the previous 24 hours and a 
chest x-ray showing similar or decreased pleural space opacification compared to the 
baseline chest x-ray done the day of pleurodesis (day 0).
Objective determination of the chest x-ray finding will be based on the formal Radiology report in 
the medical record. If necessary, the findings will be clarified by personal communication between 
study personnel and the Radiologist reading the film. The algorithm for chest tube and pleural 
space management after TSP is specified in Figure 2. If RSP is not achieved on day 3, then 
management will be determined using the algorithm based on the chest x-ray findings and pleural 
drainage, and may include continued observation, repeat cathflo activase, chest CT, insertion of 
additional pleural drainage tubes, and repeat TSP with or without cathflo activase. At all follow-
up visits after the chest tube has been removed, assessment will include chest x-ray and completion 
of the VAS for pain and dyspnea.
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Figure 1. Proposed Workflow of the Trial
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Figure 2: Chest Tube Management Algorithm
8.1. Study Duration and Timeline
This is an 18-month trial with a minimum of three months of follow-up and subsequent data 
analysis and manuscript production. Enrolment will start in January 2020 and is anticipated to 
continue until July 2021. Patient data will be anonymized with trial number allocations. Data will 
be collected and managed using REDCap electronic data capture tools hosted at Office of Human 
Research of MHS.
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8.2. Assessments/Tasks
Following consent, a baseline assessment will be undertaken pre-randomization by a member of 
the trial team and entered into the REDCap system hosted at Office of Human Research of MHS. 
The following data will be recorded prior to randomization:
1. Patient demographics and physical characteristics
2. Mode of presentation, current diagnosis, cause of effusions (if known).
3. Medical history and current medication.
4. Previous pleural interventions.
5. Symptoms, including pain and SOB according to a visual analog scale (VAS) (Appendix 
I, II).
6. Pleural fluid biochemical and cytological test results
7. Baseline hemoglobin (day of or day before TSP)
8. Baseline (day of or day before TSP) CxR and chest CT (if available) findings.
After randomization and TSP with or without cathflo activase, all patients will have daily follow-
up until the chest tube is removed, and at 14 and 28 days, and three months after TSP. At all visits, 
the following data will be recorded:
1. VAS for chest pain and SOB will be documented (Appendix I, II).
2. CxR (PA and lateral preferred).
3. Drained pleural volumes in 24 hours (if the chest tube is still in place).
4. Serum hemoglobin (only for inpatient visits within three days of the pleurodesis 
procedure).
5. Repeat pleural interventions.
6. Chest CT scan, as justified by the principal investigator.
8.3. Treatments/Interventions
The trial interventions are summarized in Figures 1 and 2 and described in detail below. The 
delivery of each of the treatment and its aftercare will be provided according to its usual practice 
protocols and are not specified in this trial. All patients will have a pigtail chest tube (size 10-14) 
inserted under image guidance, or PleurX® catheter placement. This is current practice for 
management of these patients. Prior to pleurodesis the chest tube will be managed to achieve the 
most complete fluid drainage possible as assessed by CxR and determined by the clinical team. In 
the case of uncertainty, chest CT will be used to confirm the drainage of fluid and adequate 
inflation of the lung.
For all subjects, talc slurry (sterile talc, 5 gm, mixed with lidocaine, 20 mg, diluted in sterile saline 
to a total volume of 100 mL and dispensed into two 60 mL luer lock syringes, prepared by MHS 
Pharmacy Department) will be instilled through the chest tube at bedside. This will be followed 
immediately by instillation of either placebo (arm 1: 50 mL normal saline) or study drug (arm 2: 
cathflo activase, 4 mg, suspended in 50 mL normal saline). This syringe will be prepared by the 
MHS Pharmacy Department based on the randomization results and coded so that neither the 
administering clinical team nor the patient will be able to discern to which arm the patient has been 
assigned. The chest tube will be clamped with orders written to unclamp in 12 hours and insure 
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the tube is connected to a pleural drainage system (e.g. Pleurevac®) set for standard suction of -
20 cm H2O. Daily assessments will be performed until the chest tube is removed. These include 
drainage volume over 24 hours, CxR, and pain and dyspnea scores.
Drainage volume over the prior 24 hours will be recorded daily using the Bedside Pleural Drainage 
Record. If the volume is less than 100 cc/24 hours for day 3 (defined as the third 24-hour period 
following TSP) and the CxR on day 3 shows the pleural space is the same or better than baseline, 
then the chest tube will be removed. If the chest tube is not removed, management will be 
according to the algorithm in Figure 2, and may include: continued monitoring, chest CT to 
evaluate for residual loculated effusion, cathflo activase to evacuate undrained effusion, or repeat 
TSP with or without cathflo activase.
8.4. Drugs/Devices
Sterile talc power, as used in this trial, is a natural, asbestos-free product, supplied sterile in a single 
use 100 ml amber glass vial. It has been used as sclerosing agent to decrease the recurrence of 
malignant pleural effusions in symptomatic patients. The recommended dose is 2 to 5 grams 
administered intrapleurally. Common side effects following pleural administration of talc are 
pleuritic pain and low-grade fever. In this trial, the talc solution mixed with lidocaine will be 
prepared by MHS Pharmacy Department.
Cathflo activase is a naturally occurring protein that splits the inactive zymogen plasminogen into 
the active enzyme plasmin. It is supplied as a sterile power (2 mg) in a single use glass vial 
(Cathflo®, Activase®). Following reconstitution it is stable at room temperature for up to 24 
hours.(22) Given intravenously it is rapidly metabolized by the liver and undergoes biphasic 
elimination with an initial half-life of 3-5 minutes followed by an elimination half-life of 27-46 
minutes.(23) Pharmacodynamics and bioavailability of cathflo activase in the pleural space is not 
known. cathflo activase in the treatment of complex pleural effusion has been evaluated in both 
controlled and non-controlled settings, demonstrating beneficial reductions in effusion volume, 
clinical symptoms, hospital stay, and the need for surgical intervention, without local or systemic 
bleeding. Various intrapleural dosage regimens have been used: 2 to 5 mg diluted in up to 40 mL 
of normal saline or 0.1 mg/kg diluted in 10 to 100 mL of normal saline.(17, 19, 24, 25). In a 
retrospective analysis of 46 patients at MHS treated with cathflo activase for management of 
complex pleural effusion, 131 doses of cathflo activase were given ranging from 2 to 6 mg. No 
difference in efficacy was identified between 4 and 6 mg, and therefore 4 mg was chosen as the 
treatment dose for this protocol (unpublished results).
9.0 STATISTICAL METHODS
9.1. Primary and Secondary Outcome measures
The primary outcome measure is the proportion of patients with successful pleurodesis at day 3 
after administration of TSP. Successful pleurodesis is defined as “radiographically satisfactory 
pleurodesis” (RSP), as evidenced by 1) chest x-ray demonstrating similar or decreased amount 
of pleural fluid/opacification compared to day 0 (day pleurodesis is performed) and 2) drainage 
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of less than 100 ml of fluid over the preceding 24 hours. Chest x-ray results will be scored on a 
three-point scale (-1, 0, +1) based on comparison of pleural space opacification on the side of the 
TSP to baseline:
1. Worse (-1): Pleural space opacification is worse, suggesting residual undrained fluid 
or reaccumulation of loculated fluid.
2. Same (0): Pleural space opacification similar to baseline.
3. Better (+1): Pleural space opacification is better, suggesting less pleural fluid than at 
baseline.
The secondary outcome measures will include the following:
1. Proportion of patients with RSP at any time after TSP
2. Duration of chest tube drainage
3. Days to achieve RSP
4. Pain and dyspnea scores as assessed by a visual-analogue scale (on a scale from 0 
to 100 mm, with a score of 0 indicating a complete absence of symptoms and a score 
of 100 maximum symptoms).
5. Proportion of patients requiring repeat pleurodesis
6. Proportion of patients requiring additional chest tube
7. Change in serum hemoglobin levels within three days of cathflo activase
8. Length of hospital stay (in days) after TSP.
9. All hospital costs associated with both treatment arms. 
9.2. Statistical Analysis Plan
Statistical summaries and analyses of data will be performed at MHS. Descriptive analysis will be 
performed for all data including means and standard derivation or medians for continuous variables 
and proportions for categorical variables. Comparison of outcomes between the two arms will be 
performed using t-test for numerical variables and Pearson 2-test or Fisher’s exact for categorical 
variables, and a one-sided p-value of 0.05 will be considered to be statistically significant.
The main analysis for primary outcome will be performed as per the intention-to-treat principle, 
and will include all the randomized participants with an observed outcome.(26) The primary 
outcome of the success rate of pleurodesis at day 3 will be analyzed using 2-test. Time to 
symptomatic fluid recurrence following initial successful pleurodesis within 3 months follow-up 
period will be analyzed using a log-rank test. An interim analysis will be performed by the 
Memorial Healthcare System Quality and Safety Steering committee under Dr. Tom Macaluso 
(currently officially the DSMB for MHS) after 50 patients are randomized in order to test for 
efficacy. The O’Brien-Fleming stopping rule will be used, which requires a P value of < 0.0088 
(1-sided) for the primary outcome in order to stop at the interim analysis. The O’Brien-Fleming 
rule requires a P value of < 0.05 (1-sided) at the final analysis in order to declare a statistically 
significant difference in the primary outcome.(27) Analyses will be performed with the use of 
Prism 7.0 or SPSS 26 software.
Costs will be those related to study medications, initial hospital stay, and subsequent 
hospitalizations. All costs will be reported in US dollars and in 2020 prices. Cost data for both 
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arms will be obtained from MHS Strategic Financial Support Services.  Outcomes will be 
measured in terms of probability of treatment success and/or complication, and utility of health 
states, which will be transformed to quality-adjusted life years (QALYs), calculated as the success 
rate of pleurodesis from each patient at day 3 after administration of TSP combined with pain and 
dyspnea scores.
10.0   STUDY ADMINISTRATION
10.1 Confidentiality and Privacy
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
This protocol and any amendments will be submitted to a properly constituted IRB, in agreement 
with local legal prescriptions, for formal approval of the study conduct. The IRB will be requested 
to grant approval of an authorization to collect the Protected Health Information with consent from 
subjects for research purposes. Prior to patient participation in the study, written informed consent 
will be obtained from each patient according to ICH GCP and to relevant MHS SOPs. Subjects 
may voluntarily withdraw from the program or revoke their authorization to share information 
related to the research. If a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. 
Study data will be recorded and managed using REDCap (Research Electronic Data Capture) 
system hosted at Office of Human Research of MHS. No identifying information will be present 
on the REDCap. Instead, the data will be labeled by a unique study ID that will be linked to a 
separate master-code document that will be stored on a secure password-protected server. REDCap 
is a secure, web-based application designed to support data capture for research studies, providing 
1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and 
export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; and 4) procedures for importing data from external sources. The key linking 
data to PHIs will be destroyed by deleting the document five years after completion of the study.
10.2. Quality Control and Quality Assurance
The study will be conducted according to the principles of Good Clinical Practice (GCP) and local 
standard operating procedures (SOPs). After data have been entered into the REDCap, a system of 
data validation checks will be implemented and applied to the subject. The accuracy of the data 
will be verified by comparing study data to source documents. Medical records and progress notes 
will be kept accurate and up to date and available at all times for inspection in the event of audit. 
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The study Radiologist (JD) will review chest x-rays from a random sampling of at least 30% of 
study subjects to independently assess the findings after TSP compared to before (i.e. worse, better, 
or the same). These findings will be used in both the interim analysis and the final analysis to 
validate the clinical decision-making during patient management. The interim analysis will be 
performed by the MHS Quality and Safety Committee. The completed case report forms will 
undergo quality control assessment once the patient has completed or withdrawn from the trial by 
the trial coordinator and manager before transcription onto a password-protected database on a 
secure computer network. This will be performed by two members of the trial team to ensure 
quality control and data reliability. In addition, the study will be monitored by the Office of Human 
Research’s Monitoring and Compliance Officer for regulatory as well as data accuracy purposes.
10.3. Records Retention
Study data will be recorded into the REDCap system hosted at Office of Human Research of MHS, 
and the trial database will be transferred securely to the principal investigator. All CxR and CT 
images relating to trial participation will be securely stored on MHS systems in line with routine 
clinical practice. Representative CxR and CT images will be stored on an encrypted trial hard 
drive. The study site will retain all records related to the study in accordance with MHS and ICH 
GCP guidelines in order to comply with applicable regulatory requirements. 
11.0 ETHICAL CONSIDERATIONS
11.1. Potential Risks to Subjects
From the limited published data and our experience on clinical use of Talc and cathflo activase for 
pleurodesis, the treatment appears safe.  The following are expected risks associated with the 
proposed interventions for this trial:

Pain at drain site

Bleeding

Fever

Allergic reaction to cathflo activase
Pain and fever are well-acknowledged risks of TSP and are not specific to the experimental 
intervention in this trial. Subjects may or may not have some or all of these risks from treatment 
with either one of the reagents used in this study. The risks for the use of talc with cathflo activase 
are the same as for standard of care with Talc alone except for an increased risk of bleeding and 
the possibility of an allergic reaction. Neither an allergic reaction nor clinically significant bleeding 
has been encountered with more than 300 doses so far administered in routine clinical practice at 
MHS.
Any adverse event that results in hospitalization or prolonged hospitalization will be documented 
and reported as a serious adverse event unless specifically instructed otherwise in this protocol. 
Details of any adverse events or serious adverse events will be collected during routine and trial 
follow-up visits. The clinical course of each event will be followed until resolution, stabilization, 
or until it has been determined that the study treatment or participation is not the cause.  Serious 
adverse events that are still ongoing at the end of the study period must be followed up to determine 
the final outcome. All AEs and SAEs will be recorded in the patient’s medical records and reported 
to the IRB.
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In the event of a serious adverse event such as anaphylaxis, exsanguinating hemorrhage or death, 
the study code will be broken to determine if the subject received the study drug.
11.2 Safeguards to Minimize Risks
This study will be conducted in compliance with the standards of good clinical practice. Participant 
safety will be ensured through regular review and follow-up. During the procedures, vital signs 
including blood pressure and oxygen saturation measurements will be used to ensure patient well-
being. Hemodynamic measurements and serum hematocrit will be used to monitor for clinically 
significant pleural bleeding. Chest X-ray will be used to verify tube position.
11.3. Potential Benefits to Subjects
There may be an immediate potential benefit to patients. The combination of talc with cathflo 
activase may increase successful pleurodesis rates and may also shorten the time of pleurodesis 
compared to talc alone, thus potentially improving patient symptoms and reducing the need for 
additional pleural interventions and hospital stay. Patient discomfort may also be reduced by 
earlier chest tube removal and shorter pleurodesis times.
11.4. Potential Benefits to Society
If this trial is positive, it will directly improve future care for patients requiring pleurodesis for 
their symptomatic recurrent pleural effusion.
 
11.5. Subject Compensation
There is no compensation for subjects participating in this study.
11.6. Risk/Benefit Assessment
This study is to determine if intrapleural administration of cathflo activase improves the successful 
rates of TSP. The procedures used in the trial are the same as for standard care of pleurodesis with 
talc. The risks to patients participating in this trial are potential for loss of privacy, and that there 
may be an increased risk of bleeding with cathflo activase compared to talc alone. However, 
participants may benefit from the research if cathflo activase improves the efficacy of the TSP 
and/or the result. Based on our previous findings that intrapleural administration of cathflo activase 
improved drainage of these complex pleural effusions with no significant complications noted 
(Block M, et al. unpublished data), it is possible that participants will benefit from this trial without 
increase in pleurodesis-related complications.  
12.0   PUBLICATION PLAN
The principal investigator and co-investigators of this study will be responsible for ensuring the 
results obtained from this study, regardless of the outcomes, will be reported to MHS’s IRB within 
a reasonable timeframe after conclusion of the study. Results will be published in international and 
peer-reviewed scientific journals and presented at international conferences.
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13.0   CONFLICTS OF INTEREST
 There are no conflicts of interest by any investigator in this study.
14.0    FUNDING SOURCE
Genentech has agreed to support this trial through provision of the study drug (cathflo activase) 
at no cost and financial support for administrative expenses.
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20. Chan A-W, Tetzlaff JM, Altman DG, Dickersin K, Moher D. SPIRIT 2013: new guidance for 
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21. Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 
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saline solution. J Vasc Interv Radiol JVIR. 2003 Jan;14(1):99–102. 
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16.0  ATTACHMENTS
1. Appendix I-Visual assessment scale for dyspnea
2. Appendix II-Visual assessment scale for pain
3. Appendix III-Bedside pleural drainage record
4. Appendix IV–Study Datasheet
5. Appendix V-Genentech Investigator Initiated Study Safety Information 
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