Clinical trial NCT04792970
Conditions: Malignant Pleural Effusion
Sponsor: Duke University
Start date: 2021-03-18; Completion date: 2022-10-07
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the experiences of subjects who drain malignant (cancerous) pleural effusions (fluid) from around their lung(s) in a more frequent manner using a talc instilled via tunneled pleural catheter combined with daily drainage and those subjects who drain this fluid in a daily standard manner.

Detailed description:
Study Activities: Patients will be randomized to either the standard daily drainage group or the talc instilled via tunneled pleural catheter combined with standard daily drainage group. Patients will complete questionnaires regarding their health. If you are randomized to the talc group, you will receive talc infused through the tunneled pleural catheter. If you are randomized to the standard daily drainage group, you will not receive any additional therapy. Patients will complete a drainage diary for everyday they drain fluid which will provide information on drainage volume, fluid color, pain, and complications. At 30 days and 90 days post randomization, patients will return to clinic for follow-up, at which time they will have a physical exam, chest x-ray, and complete questionnaires regarding their health.

Risks/Safety Issues: Risks associated with talc include fever and pain. Less likely risks associated with talc include infection, dyspnea, hypoxemia, pneumonia, unilateral pulmonary edema, hemoptysis, pulmonary emboli, and bronchopleural fistula.

Arms: arm 1: This arm consists of eligible participants who are randomized to the Talc arm and would receive Talc therapy instilled into the pleural catheter. arm 2: This arm consists of eligible participants who are randomized to control group and would not receive any intervention.
Interventions: intervention 1: Talc
Intervention descriptions: intervention 1: All patients randomized to the Talc arm will receive Talc therapy through the pleural catheter.

Protocol documents:
Prot_SAP_001.pdf: 
Version 7 
Randomized Controlled Trial of Talc Instillation In Addition To Daily Drainage 
Through a Tunneled Pleural Catheter to Improve Rates of Outpatient 
Pleurodesis in Patients with Malignant Pleural Effusion – The ASAP II Trial 
Participating Sites:  
Duke University Medical Center  
Durham VA Medical Center 
NCT04792970 
Version Date: 01/01/2021


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Purpose of the Study 
To assess the efficacy of talc instilled via tunneled pleural catheter combined with daily drainage 
to induce accelerated pleurodesis in patients with malignant pleural effusion. Our hypothesis is that the 
combination of talc instillation with daily drainage will increase rates of pleurodesis compared with daily 
drainage alone.  
Background and Significance 
Tunneled Pleural Catheters (TPC’s) are an increasingly utilized for the management of malignant 
pleural effusions (MPEs).  TPCs provide rapid relief of dyspnea and improvement in quality-of-life in 
patients with MPEs.1,2 Spontaneous pleurodesis may occur through repetitive drainage of the pleural 
space, however the rates and timing of this event are variable and have been reported to be between 
16% and 65%.1,3,4 Earlier pleurodesis leads to lower supply costs and reduced risk of long term 
complications such as infection, pain or mechanical failure.5,6  This is especially important as malignant 
pleural effusion is associated with a generally poor prognosis and if given limited life expectancy, 
minimizing medical interference and hospitalized days is paramount.7,8
Recent advances in the field of malignant pleural effusion management have prioritized these 
patient centered goals of maximizing quality of life improvements while minimizing time in the hospital.  
Recent research by our own group has shown a 20% improvement in the percentage of patients having 
their TPC removed by 12 weeks with high volume daily drainage of pleural effusions at home.9  Parallel 
research has demonstrated that the addition of talc through a TPC achieves a similar 20% improvement 
in pleurodesis within the first 5 weeks.10 Somewhat surprisingly, the rates of pleurodesis were nearly 
identical between the 2 studies at 48% and 43% respectively9,10. Notably, patients in the talc study 
drained their effusions using an every other day or symptom guided strategy rather than daily drainage. 
We hypothesize that combining both strategies (daily drainage with the addition of talc 
sclerosant) will lead to both earlier, and higher incidence of pleurodesis in the majority of treated 
patients.  We believe that this can be achieved on an outpatient basis without additional interactions 
with the healthcare system. 
Design and Procedures 
To assess if the addition of talc sclerosant to daily outpatient drainage compared with daily 
drainage alone leads to more rapid pleurodesis. 
Study Type: Non-blinded prospective randomized two-arm cohort 
Primary Endpoint: Proportion of cohort able to have TPC removed at 30 days post talc-administration 
(day of randomization will be defined as study day 1) 
Secondary Endpoints: Quality-of-Life Assessment, dyspnea assessment, adverse events 


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Schedule of Events: 
Screening (up to 14 
days prior to 
baseline visit) 
Baseline (Day 0) 
30 day follow-
up visit 
60 day follow-
up visit 
Tunnel Pleural 
Catheter insertion 
(SOC*) 
X 
Chest x-ray (SOC) 
X 
X 
X 
Physical Exam 
(SOC) 
X 
X 
X 
X 
Randomization 
X 
Talc instillation (if 
randomized to 
Talc Arm) (SOC) 
X 
Vital sign 
monitoring for 2 
hours post Talc 
instillation (if 
randomized to 
Talc Arm) (SOC) 
X 
SOB VAS 
questionnaire 
X 
X 
X 
SF-36 
questionnaire 
X 
X 
X 
Daily drainage 
diary review 
X 
X 
X 
AE review 
X 
X 
X 
*Standard of Care (SOC) procedures
Enrollment 
Patients will undergo TPC insertion for malignant pleural effusion as per usual clinical indications 
and protocols in either the inpatient or outpatient setting.  Patients will be eligible for study enrollment 
anytime between catheter insertion and initial clinical follow-up at a maximum of 14 days following TPC 
insertion. Patients will be instructed to drain that catheter daily until initial follow-up. At this 7-14 day 
follow-up appointment for suture removal patients will be asked to drain the morning of the clinic visit 
and a chest x-ray (CXR) will be performed prior to the clinic visit. The catheter may be drained at the 
time of the clinic visit if not done within 8 hours of the visit.  Patients who meet radiographic criteria for 
inclusion (see inclusion/exclusion criteria below) may proceed with randomization via central computer 
generated randomization table. Those who do not meet radiographic criteria will be considered screen 


 
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failures and withdrawn from the study. At the time of randomization, patients will be given baseline 
symptom surveys, a drainage diary, and talc instillation or daily drainage alone based on study arm.  
Tunneled Pleural Catheter Placement 
 
All patients will have undergone placement of a tunneled pleural catheter prior to consideration 
for trial enrollment. These are placed utilizing a standard sterile technique under ultrasound guidance.  
Local Anesthetic will be utilized for placement, which will be performed under sterile conditions on an 
inpatient or outpatient basis at the discretion of the patient’s treatment team. Moderate sedation may 
be utilized during placement at the treating physicians discretion.   
Sclerosant Infusion Procedure 
 
All patients randomized to the Talc arm will receive a slurry composed of 10cc of 1% lidocaine 
and 4g of graded talc suspended in 50cc of 0.9% saline infused through the pleural catheter. The line will 
be flushed with a further 10cc of 0.9% normal saline and then de-accessed and dressed in the usual 
fashion.  Control arm patients will not receive any additional therapy.  The patients receiving talc will be 
monitored on-site for 2 hours for the development of dyspnea, followed by drainage of the catheter. 
Vitals signs will be monitored for stability prior to discharge home.  All patients will be instructed to 
perform drainage daily for the duration of the trial or until catheter removal. 
Drainage 
 
All patients will receive drainage bottles after placement and throughout the study to ensure 
maximum drainage.  Patients and their care givers will be instructed on sterile technique for drainage 
utilizing the tunneled pleural catheters. 
Follow up 
 
Study subjects will return for clinic visits at day 30 and 90 after randomization, or a final visit at 
the time of catheter removal (Figure 1). Review of drainage logs, repeat CXR, SOB VAS and 
questionnaire, and quality of life measures will be collected at these timepoints. Day 30 and 90 follow 
up appointments are standard of care for follow up of tunneled pleural catheter management.  
Additional visits will occur as clinically indicated.  
Criteria for Pleurodesis 
Pleurodesis is defined as three consecutive drainage attempts with 50cc or less or less than 
200cc in 1 week.  Patients will be instructed to contact their treatment team who will obtain a CXR to 
evaluate for resolution of effusion. A CXR showing effusion < the size of the effusion at randomization 
will be considered to be successful pleurodesis. Chest x-ray imaging showing an effusion larger than 
what was present at randomization (radiographic score 2-5) will be investigated for dysfunction of the 
pleural catheter. Thoracic ultrasound will be performed at the time of removal of each catheter to 
assess for presence and size of residual pleural fluid, pleural septations, and for the presence or absence 
of lung sliding (appendix 1).  
Management of Dysfunctional Catheters 
Obstructed catheters will be investigated per ASAP I protocol by instillation of 2mg TPA in 8ml 
sterile water and allowed to dwell for 20 minutes followed by drainage. If the output returns to >200cc 


 
5 
after fibrinolytic infusion then patient will return to study protocol.  If fibrinolytic fails to to produce 
immediate drainage and the patient does not have shortness of breath the catheter will be removed and 
the patient will be considered to have undergone partial response. Patients with continued shortness of 
breath will be managed at the discretion of the treating physician and will be considered catheter 
failures.  
Outcome Measures 
Primary Outcome: Percentage of cohort undergoing accelerated pleurodesis.  Patients able to have their 
TPC removed at 30 days post-talc instillation will be considered to have achieved the primary endpoint. 
Pleurodesis is defined as three consecutive drainage attempts with 50cc or less or less than 200cc in 7 
days and lack of respiratory symptoms of cough orshortness of breath previously attributed to pleural 
effusion.  Patients will be considered to have experienced complete (CR) or partial response (PR) 
depending on chest x-ray (CXR) scoring criteria. Patients who experience pleurodesis later than 30 days 
from randomization will be considered to have a delayed CR or PR using the same CXR scoring criteria.  
Chest X-ray scoring (see appendix 1): Chest x-ray scoring will be performed by a blinded pulmonologist 
viewing images identified with study code on a CD supplied by the treating physician. Patients with CR 
will have a CXR score of 0-1, and PR > 2.  
Secondary Outcomes: Dyspnea and Quality-of-Life Measurements. Baseline Dyspnea measurements will 
be performed by Visual Analog Scale (VAS), a validated measure of dyspnea in pleural disease. Quality-
of-Life measurements will be performed using the short form 36 (SF-36) which is a validated survey-
based tool that measures 8 aspects of physical and mental well being.  Both of these survey tools will be 
administered at enrollment, 30, and 90 days after randomization, or at the time of catheter removal if 
prior to the 30 day or 90 day clinical follow-up.  Because patients will be randomized after catheter 
insertion and drainage for 7 to 14 days, we anticipate dyspnea and QOL to be somewhat optimized as 
related to interactions from pleural fluid at randomization. The assessments will be examining stability 
of symptom control over the course of study enrollment.  
Adverse Events 
 
Anticipated adverse events include pain with drainage, catheter dislodgement, catheter 
malplacement, insertion site cellulitis, and empyema. Catheter obstruction due to fibrin will be 
considered catheter failure, but not an adverse event. There is an extremely small chance of a patient 
developing local anesthetic systemic toxicity from the instillation of lidocaine mixed with the talc slurry. 
Intralipid, used to treat this serious complication will be stored in the outpatient procedure suite pyxis.  
Selection of Subjects and Data Collection 
Diagnosis and Inclusion Criteria: 
Subjects must meet all of the following: 
1. Male or female, at least 18 years of age, inclusive. 
2. Subject has a symptomatic MPE requiring intervention. For an effusion to be 
defined as malignant, at least one of the following must be true: 
a. There is histocytological confirmation of pleural malignancy 
b. The effusion is an exudate (per Light’s criteria) in the context of 
histocytologically proven malignancy elsewhere, with no other clear cause 


 
6 
for fluid identified. 
3. Subject has a history of at least 1 ipsilateral pleural effusion causing dyspnea that 
responded to thoracentesis where the lung expanded and the dyspnea was improved. 
4. Subject is willing and able to provide written informed consent. 
5. Subject is willing and able to meet all study requirements, including follow-up 
visits and receiving study-related telephone calls. 
6. Subject has sufficient pleural fluid to allow safe insertion of an IPC. 
7. Subject has negative pregnancy test if appropriate. 
8. Subject or caregiver is able to perform home drainage of the pleural effusion (a caregiver can be a 
friend, family member, or paid healthcare professional). 
 
Exclusion Criteria: 
Potential study subjects will be excluded if 1 or more of the following exclusion criteria is 
present: 
1. Subject has significant trapped lung, or a proximal bronchial obstruction which is 
likely to lead to trapped lung. For a subject to be eligible for this study, two separate 
study center clinicians must agree that there is no significant trapped lung on the 
same CXR using visual estimation (reference guide). The CXR used to make this 
decision must have been performed ≤30 days preceding the consent form being 
signed, and must have been performed preferably on the same day, but no more 
than 7 calendar days after tunneled pleural catheter insertion. 
Significant trapped lung is deemed present if any 1 of the following criteria is met: 
a) A CXR shows hydropneumothorax other than small (< 1 cm between chest wall and pleural line) apical 
pneumothoraces. 
b) A CXR shows ≥20% of the affected hemithorax to be free of the expected 
lung parenchymal markings and there is no suggestion of pleural fluid. 
c) A CXR shows ≥20% of the affected hemithorax to be occupied with pleural 
fluid AFTER a pleural aspiration which resulted in symptoms suggestive of 
trapped lung (e.g., chest pain or cough). 
2. Subject has a Karnofsky score <50, or a World Health Organization (WHO)/ 
Eastern Cooperative Oncology Group (ECOG) performance status ≥3. Subjects 
who have a performance status of 3 may be considered for the study if the removal 
of their fluid would likely improve their performance score by 1 or more. 
3. Subject is pregnant, planning to become pregnant, or is lactating. 
4. Subject has a history of empyema. 
5. Subject has a history of chylothorax. 
6. Subject has an uncorrected coagulopathy. 
 
 
Randomization and Allocation 
 
Randomization will be performed utilizing a computer system at Duke (the coordinating center) 
with permuted block randomization of random block length.  Allocation will occur at the time of initial 
clinic visit following catheter insertion. 
Data Collection 


 
7 
 
Data will be collected using paper clinical research forms at the clinical sites followed by direct 
entry into a web based, password protected REDCAP database. Duplicate databases will be stored on 
Duke and VA servers to safeguard data security.  
 
 
Initial Data Collection 
 
Data to be collected at the time of enrollment include age, sex, race, ethnicity, effusion side, 
type of maliganancy, date of diagnosis, date of initial thoracentesis, Karnofsky performance score, ECOG 
performance score, comorbidities (anemia, asthma, cerebrovascular accident, chronic kidney disease, 
chronic obstructive pulmonary disease, coagulopathy, congestive heart failure, coronary artery disease, 
diabetes, deep vein thromobosis, pulmonary embolism, hypertension, hypothyroidism, 
hyperthyroidism, interstitial lung disease, nephrotic syndrome, peripheral vascular disease, cirrhosis of 
the liver), pleural fluid characteristics (pH, LDH, Protein, % lymphocytes, glucose, cytology results), prior 
chemotherapy, prior radiotherapy, prior immunomodulatory therapy, VAS dyspnea score, and SF-36 
questionnaire.  Data collected at randomization will be CXR score by treating and blinded physician. 
Follow-up Data Collection 
 
Karnofsky score, ECOG score, VAS dyspnea score, SF-36 questionnaire, and CXR scoring will be 
collected at the 30 day and 90 day clinic visits, or at the time of catheter removal. Thoracic ultrasound 
examination will be performed at time of catheter removal.  
Subject Recruitment and Compensation 
Consent Process- Consent form and material subject to IRB approval 
Risk/benefit assessment- There are two primary risks to patients associated with this study.  The first is 
the risk of respiratory failure associated with talc pleurodesis.  Respiratory failure is a rare but well 
documented risk associated with the use of talc for pleurodesis.  This event is rarely fatal and occurs 
roughly 1 in every 10,000 patients when utilizing graded talc.  The second concern is obstruction of the 
tunneled pleural catheter by talc.  This happens spontaneously in about 10% of patients and can be 
managed in >90% of these patients with the instillation of tissue plasminogen activator through the 
catheter.  Previous trials of talc instillation through tunneled pleural catheters have not noted a higher 
than baseline rate of TPC blockage with this treatment regimen.  Expected side effects of talc instillation 
include pain and fever which are temporary and can be treated with over the counter analgesics and 
anti-pyretics. 
Potential benefits of participation in this study include less long-term fluid collection and potential 
earlier removal of the catheter. 
Cost to the Subject- There will be no increased cost of care to the patients as the instillation will occur 
during routine follow up visit after TPC placement. Talc will be supplied as part of clinical care. Clinic 
visits are occurring as part of our routine clinical care for malignant pleural effusion treated with 
tunneled pleural catheters. Drainage bottles will be obtained through usual care pathways.  
Data Analysis and Statistics 


 
8 
Power Calculation 
 
Assuming a 45% rate of TPC removal in the control arm, and a 65% rate of TPC removal in the 
experimental arm (a 20% improvement) and a margin of error of 5% we calculate we would need to 
enroll 92 patients per group to have 90% power to detect a significant difference with p<0.05  using a 
one sided superiority test.  Given a 10% dropout rate seen in the other two major studies within this 
field, we assume we would need 101 patient’s per treatment arm.  We anticipate including 2 centers in 
this study and we estimate that accrural will be reached within 36 months.  Study will be completed at 
40 months to allow for complete follow up of all patients enrolled. 
 
Statistics will be performed by a statistician blinded to which treatment group allocation 
Planned Interim Analysis 
 
An interim analysis will be conducted once 100 subjects have been recruited and 90 day data 
collected. Analysis will be for the primary outcome only. Statistically significant difference in pleurodesis 
rates as measured by Fisher’s Exact Test with p < 0.05 will trigger early termination of the study.  
Data and Safety Monitoring 
 
All study records will be kept securely by in the study coordinators or local site investigators 
office.  Digital records will utilize secured Redcap database software on the Duke or VA networks.  Only 
the study personnel will have access to the records.  Subject data will be coded with a study number 
after recruitment.  The code crosswalk key will be kept in a separate location from the study data. 
 
 
 
References 
Tunneled Pleural Catheter placed
Days (-14 to 0) patient's 
screened for possible 
inclusion into study. 
Consent performed at 
time of insertion up to 
day of initial clinic visit.
Follow up appointment
Day 1 - randomization 
(with talc instillation if 
appropriate) of eligible 
patient's during clinic 
visit.
Clinical Follow up 
Day 30 and 90 if not yet 
pleurodesed, or until 
catheter removed by 
treatment team for 
succesfull pleurodesis, 
or withdrawal from 
study 


 
9 
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2.   
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