Conditions: Advanced Cancers Malignant Pleural Effusions
Keywords: Advanced Cancers Malignant pleural effusions MPE Indwelling pleural catheter IPC Questionnaires Surveys Fentanyl patch Fentanyl by vein Sublimaze Doxycycline Vibramycin Periostat Doryx :Phone calls
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to compare indwelling pleural catheters (IPC) in combination with saline (the current standard of care) versus IPC in combination with doxycycline as treatment for pleural effusions.

Detailed description:
IPC Placement and Placement Follow-Up:

Before the IPC is inserted, you will complete 2 questionnaires about your quality of life and any symptoms you may have. It should take no more than 15-20 minutes to complete. You will also have a chest x-ray and you will rate your pain on a scale of 1-10. These tests are all part of your standard of care and can be explained to you in more detail by your doctor. You will be required to sign a separate consent form in order to have the IPC placed. Your doctor will give you detailed instructions about the IPC placement procedure, including its risks.

After the IPC is placed, the doctor will give you a prescription for a fentanyl patch to help control pain. The study staff will tell you how and when to wear the fentanyl patch and about any side effects that are associated with fentanyl.

About 5 days (+/- 2 days) after the IPC has been placed, you will have a clinic visit where you will be checked up on as part of your standard of care. It is important that you wear your fentanyl patch in the morning before this visit. At this clinic visit, the results of a previously performed chest x-ray will be reviewed, you will be asked to rate your pain on a scale of 1-10, and you will be asked how much fluid has drained from your catheter.

Based on the results of the above Day 5 check-up, if you are found to be ineligible to receive the study drug, the fentanyl patch will be taken off and you will be followed as part of your usual care. However, you will still considered to be on study and you will be followed the same as a participant who receives the study drug.

If you are found to be eligible to receive the study drug, you will receive fentanyl by vein over a few minutes, if needed to help control your pain. The study staff will then begin to drain your catheter and either doxycycline or saline (described below) will be placed in the catheter. The catheter will be capped for 1 hour and then drained again.

To determine if you will receive doxycycline or saline, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. This is done because no one knows if one study group is better, the same, or worse than the other group.

* If you are in Group 1, you will receive doxycycline.
* If you are in Group 2, you will receive saline.

Neither you nor the study doctor will know if you are receiving doxycycline or saline. However, if needed for your safety, the study staff will be able to find out what you are receiving.

Length of Study Participation:

You will receive doxycycline or saline 1 time on this study. Your participation on this study will be over if you withdraw consent or the study closes, whichever takes place first.

Follow-Up:

Between 10-14 days after you have received either doxycycline or saline, you will come to the clinic as part of your usual standard of care so the doctor can check your IPC for possible leaking, infection, to see how much fluid has drained, and to remove any sutures. The catheter may be removed if you have it is leaking or shows signs of infection. You will continue to have this visit 1 time each month as part of your standard of care until the catheter is removed. During each of these visits:

* You will have a chest x-ray to check the status of your lungs.
* You will complete the same 2 questionnaires that you completed before your IPC was placed.

Long-Term Follow-Up:

One (1) time each month after the IPC is removed, you will be called and asked how you are doing, if you are having any side effects, if the disease has come back, and about your overall quality of life. Some of this information may be collected from your medical record. Each phone call should last about 5-10 minutes.

This is an investigational study. Doxycycline is FDA approved and commercially available for the treatment of different types of infections and pleural effusions. It is considered investigational to compare doxycycline to saline to treat pleural effusions.

Up to 250 participants will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Symptom and quality of life questionnaires completed at baseline and at 10 - 14 days after receiving Saline. Participant given a Fentanyl patch which should be worn at follow up visit 5 days after IPC placement. Fentanyl patch then be removed and Fentanyl by vein given prior to catheter draining. Study staff drains the IPC and places Saline in the catheter.

After the IPC is removed, participant is called one time each month by study staff to check on their status. arm 2: Symptom and quality of life questionnaires completed at baseline and at 10 - 14 days after receiving Doxycycline. Participant given a Fentanyl patch which should be worn at follow up visit 5 days after IPC placement. Fentanyl patch then be removed and Fentanyl by vein given prior to catheter draining. Study staff drains the IPC and places Doxycycline in the catheter.

After the IPC is removed, participant is called one time each month by study staff to check on their status

Interventions: intervention 1: Questionnaires intervention 2: Fentanyl Patch intervention 3: Fentanyl (IV) intervention 4: Saline intervention 5: Doxycycline intervention 6: Phone Calls
Intervention descriptions: intervention 1: Symptom and quality of life questionnaires completed at baseline and at 10 - 14 days after receiving Saline or Doxycycline. intervention 2: Participant given a Fentanyl patch, 12 mcg/hour, which should be worn at follow up visit 5 days after IPC placement. intervention 3: Fentanyl 50 mcg given by vein prior to catheter draining. intervention 4: Catheter is drained then Saline placed in the catheter. Catheter is capped for 1 hour and then drained again. intervention 5: Catheter is drained then Doxycycline 500 mg placed in the catheter. Catheter is capped for 1 hour and then drained again. intervention 6: After the IPC is removed, participant is called one time each month by study staff to check on their status.

Protocol document:
Prot_SAP_000.pdf: 
Protocol 
2015-0142 
October, 26, 2015 
1 
 
 
 
A randomized controlled trial of indwelling pleural catheters versus indwelling pleural 
catheters plus doxycycline pleurodesis for treatment of malignant pleural effusions 
 
Principal Investigator: David Ost, MD, MPH 
Co-investigators: Horiana Grosu MD, George Eapen MD, Liang Li PhD, Saadia Faiz MD, Lara 
Bashoura MD, Vickie Shannon MD, Dave Balachandran MD, Scott Evans MD, Roberto 
Adachi MD, Mona Sarkiss MD, Kent Nouri MD, Roberto Casal MD, Andrew Larson, 
 
Karen Mackenney 
 
 
1.0 Objective 
 
This study is designed to obtain prel
i
minary data comparin
g indwelling pleural catheters 
(IPCs) versus IPCs plus doxycycl
ine for pleurodesis as treatments for mal
i
gnant pleural 
effusions (MPE).  
 The primary outcome is time to pleural catheter removal.  
 Secondary outcomes include assessment of symptom burden, pleurodesis efficacy, 
complications, health care resource util
ization,  need of hospitalization for pain control, 
pain free days and mortality 
 
2.1 Rationale 
 
Malignant Pleural Effusions: 
MPEs occur in 7 to 15% of lung cancer cases and compl
i
cate the course of many other types 
of cancer.1  In the United States, more than 156,000 new cases of MPE occur each year, w
ith 
75% of these being caused by 
lung and breast cancer1,2 Patients usual
l
y present w
ith dyspnea, 
initially on exertion and la
ter at rest. This results in significant functional impairment and 
subsequent decrease 
in qual
i
ty of l
i
fe (QOL). Because MPE occurs in patients w
ith advanced 
cancer, management is pal
liative, w
ith the goal being to allev
iate dyspnea and distress. 
Successful pal
l
i
ation is dependent on long-term re
l
ief of the symptoms that are caused by the 
MPE and prevention of pleural fluid re-accumulation. 
 
Treatment Options: 
Options for the management of MPE incl
ude (1) intermittent thoracentesis; (2) chest tube 
drainage fol
l
owed by pleurodesis; (3) thoracoscopic drainage fol
l
owed by pleurodesis; or (4
) 
pleurodesis using long-term IPCs.  It is useful in th
is context to identify the components of each 
management strategy. 
 
The first component is some method of fluid drainage (i.e. thoracentesis or chest tube or 
catheter). The second component is whether or not a pleurodesis agent is used and if so what 
type. The pleurodesis agent can be talc or doxycycl
i
ne or any of a variety of other agents that 
i
nduce scarring and infla
mmation in the pleura to essential
l
y prevent fluid recurrence.  However, 
pl
eurodesis agents are not always utilized – i.e. in the intermittent thoracentesis and IPC 
strategy no pleurodesis agent is used.  The ev
idence basis for choosing between these 
alternatives has significant gaps and limitati
ons that are clinical
ly 
important, since there are few 
randomized trials and most studies have relatively smal
l sample sizes. 
 
Given these l
i
mitations, meta-analysis3,4 suggested that use of chemical agents for 
pleurodesis was more effective than nothin
g, that talc was the most effective agent, and that talc 
insufflation v
i
a thoracoscopy was more effective than talc slurry v
ia chest tube. However talc as 
a pleurodesis agent is associated w
ith acute respiratory distress syndrome (ARDS) and 
thoracoscopy requires an inpatient stay of several days.  A more recent large phase III 
intergroup trial suggested that talc insufflation v
ia thoracoscopy was similar in efficacy to talc 


Protocol 
2015-0142 
October, 26, 2015 
2 
 
 
slurry v
ia chest tube, but both methods required a prolonged inpatien
ts stay and both had 


Protocol 
2015-0142 
October, 26, 2015 
3 
 
 
 
significant compl
i
cations incl
uding ARDS (8% in the thoracoscopic talc group and 4% in the 
chest talc group).
5 This led to questions regarding talc’s safety, whether del
ivered by chest 
tube or thoracoscopy. In additi
on, the meta-analyses noted above3,4 did not include IPCs, so 
how IPCs compare to thoracoscopic pleurodesis is not as well studied. 
IPCs (IPCs) were pioneered at M
.D. Anderson. They have been shown to be effective in 
rel
i
ev
ing dyspnea and improv
ing QOL.1,6-8   The main compl
i
cation is catheter infection, which is 
fairly uncommon and can usual
l
y be treated w
ith outpatient antibiotics. Typically about two 
thirds of patients w
ith IPCs will eventual
ly 
have decreased drainage, usua
l
ly several weeks to 
months after initial placement. Once drainage is minimal, the IPC i
s typical
ly removed. This is 
done according to a standard management algorithm. Once removed, the fluid usual
ly does not 
recur.  Of note, IPCs management strategies have not typical
ly involved the use of any 
pleurodesis agent, but rather pleurodesis is achieved “spontaneously” after prolonged drainage. 
In addition IPC
’s allow patients to be treated completely in the outpatient setting, which is a 
significant advantage compared to thoracoscopic 
and chest tube pleurodesis techniques. A 
recent randomized control
led trial of IPCs vs. chest tubes w
ith talc slurry found no significant 
difference in terms of dyspnea rel
i
ef at 42 days between the two groups, but dyspnea rel
ief was 
better at 6 months in the IPC group.
9   However, current ev
idence based gui
del
i
nes are not 
definitive as to which approach is best.1 
As a result, based on the l
i
mited cl
i
nical ev
idence avail
able, IPCs a
re now the dominant 
therapeutic option employed for management of MPE at M
D Anderson. However, because of 
the absence of wel
l-designed randomized cl
i
nical trials, l
i
ttl
e consensus ex
ists at the national 
and international level as to the best procedure and as a result there is sign
ificant practice 
variation.
10,11   For example, a survey of physician practice patterns demonstrated that the first- 
choice treatment of MPE in the community was chest tubes 75% of the time, v
ideo-assisted 
thoracoscopy 17% of the time, and medical thoracoscopy 8% of the time.
10 In contrast, at M
.D. 
Anderson, over 90% of outpatients receive IPCs, while inpatients may be treated w
ith either 
thoracoscopy or indwelling catheters. The ex
istence of this w
idespread variation is cause for 
concern because the different techniques probably vary in terms of effectiveness, risk, and cost. 
 
Rationale and Significance: 
In this context it is useful to quantify what the MDACC current standard of care is and how 
it 
performs, since that w
i
ll be the comparator for this study. In this study the intervention w
i
ll be  
IPC plus pleurodesis agent (doxycycl
i
ne) and the comparator is the current standard of care, 
which is IPC alone. IPC performance has already been studied by our group prev
iously.8 In a 
study of 266 patients undergoin
g IPC placement for MPE at MDACC, using a competing risk 
model, we found the 1-year cumulative incidence of events was: death w
ith IPC in place, 35.7%
; 
IPC removal due to decreased drainage, 51.9%; and IPC removal due to complications, 7.3%. 
Recurrent MPE requiring repeat intervention occurred in 14% of patients whose IPC was 
removed.  Fluid recurrence was more l
i
kely 
if the catheter was removed because of 
compl
ications (e.g. infection) than if it was removed due to decreased drainage (p=0.04). 
 
The proposed study w
il
l be the first randomized trial to eval
uate the combination of IPCs w
ith 
a pleurodesis agent vs. conventional IPC management. This combination strategy offers 
significant potential advantages over ex
isting strategies since it would allow patients w
ith MPE 
to be managed completely as outpatients (something that cannot be done w
ith chest tubes or 
thoracoscopic methods) while sti
ll allow
ing patients the benefits of a pleurodesis agent. The 
pleurodesis agent should shorten the time to pleural space closure, since it will induce more 
inflammation and fibrosis than conventional IPCs alone. Conventional IPCs (i.e. w
ithout any 
pleurodesis agent) rely upon spontaneous pleurodesis after prolon
ged dra
inage but that 
typically takes 2-4 months and it does not always occur. 


Protocol 
2015-0142 
October, 26, 2015 
4 
 
 
 
We hypothesize that addition of a pleurodesis agent w
ill al
low earl
i
er catheter removal. The 
benefit of earl
i
er catheter removal is that it decreases the risk of infectious complications and 
saves money since each pack of drainage bo
ttles costs about $
500. It also 
improves patient 
QOL. 
Our secondary hypothesis is that addition of a pleurodesis agent w
il
l decrease the frequency of 
pleural fluid effusion recurrence requiring intervention in those that have their IPC removed. In 
our prior prospective observational study this occurred in 14% of cases. 
Whi
l
e talc is more effectiv
e than doxycycline for pleurodesis, doxycycline does not have any 
ARDS risk. In addition, s
ince one important goal is to manage patients w
ith MPE completely 
in 
the outpatient setting, the risk of patients developing ARDS at home in an unmonitored setting is 
significant. W hen ARDS has developed in prior st
udies of talc pleurodesis, the patients were 
i
npatients. Outcomes might be significantly worse if ARDS developed rap
idly 
in a tenuous 
cancer patient at home. On balance, since this is a pal
l
iative intervention in patients that often 
have very limited pulmonary reserve, the risks associated w
ith talc due to ARDS therefore 
outweigh the smal
l marginal benefits in terms of fluid recurrence rates as compared to 
doxycycl
i
ne.
3,4   Doxycycline is w
idely av
ail
able and has been used befo
re for pleurodesis, so the 
methods could be easi
l
y repl
i
cated in other institut
ions and would potential
l
y change the 
standard of care. 
 
2.2 Hypothesis 
 
Our hypothesis is that IPCs plus doxycycline will be superior to IPCs alone in terms of 
time to catheter removal. Our secondary hypothesis is that IPC plus doxycycline will be 
superior to IPCs alone in terms of recurrence of effusions requiring drainage after IPC 
removal. 
 
3.1 Type of Subjects to be studied 
 
Inclusi
on Criteria: 
1) Outpatients w
ith MPE undergoing IPC placement; 2) Age 18 or older; 3) Sufficient mental 
capacity to answer SF-6D and Borg score questions. 
 
Exclusi
on Criteria: 
1) Patients undergoing pl
eurodesis for benign disease (e.g., spontaneous pneumothorax); 2) 
Inabi
l
i
ty or unw
i
llingness to give informed consent; 3) Inabi
l
ity to perform phone cal
l and clinical 
fol
l
ow-up at MDACC; 4) Prev
ious intrapl
eural therapy for MPE on the same side; 
5) Chy
lous effusions associated w
ith mal
i
gnant disease; 6) ECOG of 4 and life expectancy < 2 
weeks; 7) Doxycycline allergy 8) Contraindication to placement of an IPC (e.g., uncorrected 
coagulopathy).. 
 
4.1 Research Plan and Methods 
 
Study Design: 
This is a double blind randomized control
l
ed trial of patients w
ith MPE undergoing IPC 
placement as part of their standa
rd of care. The C
l
inical Oncology Research System (CORe) 
w
ill be used to generate randomization. This will be done immediately after the sub
ject has 
consented for the protocol. 
 
The primary outcome w
i
ll be time to pleural catheter removal. Secondary outcomes will 
incl
ude recurrence of effusion requiring drainage in patients that have their IPC removed. Other 
secondary outcomes w
i
ll be qual
i
ty adjusted surv
ival (calculated using the SF-6D to determine 
utiles and then integrating uti
l
es over time to arrive at qual
i
ty-adjusted surv
ival
), change 
in 


Protocol 
2015-0142 
October, 26, 2015 
5 
 
 
 
dyspnea (usin
g the Borg score), IPC compl
i
cations, procedure associated pain, and need for 
hospital
ization due to pain from pleurodesis.12 
 
Study Procedures: 
The study will prospectively enrol
l patients being treated for MPE as part of their standard 
medical care. Note that all measurements are currently part of the standard of care. This 
includes measurements of QOL, which are captured on the SF-6D for all patients who come  
to pulmonary cl
inic.  A total of 250 patients undergoing IPC treatment for MPE will be enrolled 
and randomized in a 1:1 ratio to either IPC + doxycycline or IPC alone. Fol
lowing enrol
l
ment, 
the schedule of events w
ill be as shown in Figure 1 below. W 
e will obtain informed consent on 
all patients. 
 
The study will be blinded to the patient and the long term cl
i
nical care management team. 
After initial consent at the time of IPC placement, research coordinators w
ill arrange for a 
single extra v
isit to be made at day 5 +/- 2 for all patients. The reason for the 5 +/- 2 days is to 
allow patients to co
me during regular cl
inic hours rather than on weekends. During this 
additional v
isit a different physician team, cal
l
ed the pleurodesis team, w
ill give patients either 
doxycycline or sal
i
ne control v
ia the IPC. This team is different than the team that will be 
making all cl
i
nical management decisions. The pleurodesis team will only be giv
ing the drugs 
on day 5 and managing perioperative pain. In this way all management decisions as to 
catheter removal, compl
ications, and other aspects of pleural effusion care w
ill be made by  
the standard cl
inical care team who w
ill be blinded as to the patient’s study status. Patients 
that receive intrapleural pleurodesis agents, w
hether it is talc or doxycycline or other agents, 
sometimes have significant pa
in during the procedure.  The standard of care is to control this 
w
ith short acting narcotics. But we need to keep the management team bl
inded as to the use 
of these narcotics since that might bias their decision making. 
 
A standardized pain control algorithm, developed in con
junction w
ith the pain clinic, w
ill be 
used. This is shown in figure 2 and this will be used by the pleurodesis team in conjunction 
w
ith the pain management cl
i
nic in the perioperative period to control pain. W e will assess 
pain using a VAS as well. 
Subsequent v
isits w
ill fol
l
ow the current standard of care algorithms. This dictates how 
often the catheter is drained and when the catheter is removed and how infections and 
complications are dealt w
ith. These are all in our current care pathways and w
ill be carried out 
by the usual clinical team. These are shown in figures 3-5 and cover routine drainage (figure 
3), malfunctions (figure 4), and infections (figure 5).  Research coordinators w
ill capture this 
data and do phone cal
l follow-up after the catheters are removed in order to determine if fluid 
recurs. Patients will be followed for at l
east 1 year after IPC placement. 
 
Data Collection and Confidentiality Procedures: 
The data will be kept in a database on a password-protected computer in a secure office. 
This information w
ill only be accessible to the study investigators and staff. 
 
Statistical Considerations: 
All statistical analyses w
ill be performed in coll
aboration w
ith Dr. Liang Li from the Department of 
Biostatistics. Our system of analysis will be to build a composite picture of patients w
ith MPE in 
order to examine how the intervention affects outcome. W e w
ill look at 1) time to catheter 
removal; 2) time to symptomatic fluid recurrence fol
l
owing IPC removal; 3) qual
i
ty adjusted 
surv
ival; 4) dyspnea; and 5) pain free days, the need of hospitalization for pain control and 
mortality. 
 


Protocol 
2015-0142 
October, 26, 2015 
6 
 
 
 
The primary outcomes of interest w
ill be time to catheter removal. In our prior study, 148 of 
the 266 patients undergo
ing IPC eventually had their catheter removed (56%, 95% CI 49%- 
62%).8 This outcome w
ill be analyzed by cause-specific hazard Cox model w
ith treatment 
group as a covariate. Whenever a catheter is removed the cause for removal w
ill be 
documented. For the analysis causes will include removal due to decreased drainage (i.e. as 
per plan) as well as removal due to complications (e.g. infection, empyema, refractory pain) or 
other reasons (e.g. catheter plugged but no complication to the patient, patient preference 
w
ithout a compl
i
cation). We know from our prior study that most removals are due to 
decreased drainage (86%), compl
i
cations (10%), or other (4%).8   Death w
ill be a censored 
event for the primary analysis.  For cause specific removal, other causes of removal w
ill be 
considered as censored event. W 
e will also analyze time to catheter removal for any cause. 
For the primary outcome we will also conduct pre-specified secondary analyses to eval
uate 
the effect of pre-installation fluid drainage amount (i.e. how much was being put out from the 
IPC the day of the procedure) and size of residua
l effusion as assessed by CXR on time to 
catheter removal. W e w
ill also assess for an interaction between these variables and the  
effect of doxycycline on the outcome of time to catheter removal. 
 
We hypothesize that for patients w
ith very little drainage (defined as < 150 ml the day of 
randomization) that also have small effusions, that doxycycline will have less effect on time to 
catheter removal while in patients w
ith larger amounts of fluid drainage doxycycline w
ill have 
more effect. 
For the primary outcome, assuming a Hazard ratio of 2.0 for time to removal of doxycycline 
vs. conventional treatment and a 1:1 ratio of IPC + doxycycline: conventional IPC patients, 
then to have 90% power to detect a difference w
ith a two-sided alpha set at 0.05 will require 
48 events in each arm (total events=96). The lower border of the 95% CI for catheter removal 
from our prior study of IPCs was 49%. So if only 49% of patients have the
ir catheter removed 
for decreased drainage then this w
ill require 196 patients to be enrol
led. If 10% of patients 
drop out then a total of 218 patients will need to be enrolled to generate the 196 patients that 
w
ill generate 96 events (i.e. catheter removals). We expect dropout rates to be low based on 
our prior observational study and because the only difference in the intervention arm is a 
single v
isit at day 5. Everything else is standard of care. W e will be conservative and enroll 
250 patients. 
 
Secondary outcomes for pleural fluid recurrence and qual
ity adjusted surv
ival are really 
exploratory, since the number of events and the magnitude of the effect are likely to be smal
l
. 
For pleural fluid recurrence fol
l
owing catheter removal, we only expect 14% of patients to 
develop recurrence requiring drainage. Since we have powered the study to have 96 catheter 
removals, we expect only 14 patients to have fluid recurrence requiring additional intervention. 
For the secondary outcome of qual
ity-adjusted surv
iv
al (measured as QALYs), we expect 
basel
ine utility to be approx
imately 0.6 based on our prior study.
8   In prior multivariate analysis 
the factors impacting change in utility were chemotherapy or radiation after IPC and severity  
of baseline dy
spnea.  Patients w
ith more dyspnea experienced greater improvement in qual
ity 
adjusted surv
ival since the procedure improved their condition more dramatically. W e w
ill use 
the Kaplan-Meier product-limit method to estimate median QALYs fol
l
owing IPC placement. 
We w
ill use paired t-test to compare baseline and 1-month Borg scores and utilities. A 
general
ized linear model w
ill be used to evaluate whether other variables have any impact on 
the pairw
ise differences between baseline and 1 month. 


Protocol 
2015-0142 
October, 26, 2015 
7 
 
 
 
Data Safety Monitoring Board 
 
The data safety monitoring board w
ill monitor complications in both arms. Based on prior 
studies conducted at MDACC, 26 of 266 patients (9.8%, 95% CI 6.5% - 14.0%) had one or  
more complications related to IPC at so
me point after placement.
8   Compl
ications included 
wound site infections (4%), empyema (1%), trapped lung (2%), clo
gged IPC (3%), dislodgement 
of the IPC (1%), leakage (0.4%), pain and 
discomfort (0.4%), kinked IPC (0.4%), and decreased 
drainage due to sub-pulmonic location (0.4%). We w
i
l
l monitor compl
i
cations in both arms 
fol
l
ow
ing randomization (i.e. day 5 onward) to ensure the compl
i
cations in each arm are not 
higher than 14% (the upper l
i
mit of the 95% CI). It is important to recognize that doxycycline and 
talc pleurodesis are the two most commonly used sclerosin
g agents in the United States, so 
there 
is a large b
ody of data on doxycycline administered v
ia chest tubes indicating that it is 
safe. Talc, w
hil
e more effective, has more risk in terms of ARDS. 
 
In terms of efficacy or futi
l
ity interim analysis, if efficacy 
is demonstrated earl
ier, we w
il
l still 
want to enrol
l the entire cohort, since the secondary outcomes such as time to fluid recurrence, 
are exploratory but important, since we w
ill base future power calculations off the exploratory 
data col
l
ected in this study, so it will be worthwhile to col
l
ect data on the entire cohort. 
Wi
th regard to futi
l
i
ty, while it is possible the study w
ill not achieve the goal H
R of 2.0 for time 
to removal, a competing risk analysis at MDACC of 266 patients demonstrated the 1-year 
cumulative inci
dence of death w
ithout catheter removal was 35.7% (95% CI : 29.5% - 42.0%); 
the 1-year cumulative inc
idence of catheter removal due to decreased drainage was 51.9% 
(95%CI: 45.4% - 58.3%); and the 1-year cumulative incidence of catheter removal due to 
compl
i
cations or other reason was 7.3% (95% CI: 4.2% - 10.5%).8  The median time for catheter 
removal when it was removed due to decreased drainage was 2 months. Typically after chest 
tube doxycycline installation on i
npatients the chest tube is removed w
ithin 1 week. W e estimate 
that since we w
ill be giv
ing the doxycycline at day 5 +/-2 after IPC placement, and the next 
fol
l
ow up is at day 14 and then routine fol
l
ow up at day 28, that 65-87% of patients w
i
ll have 
pleurodesis in the intervention arm. The 65-87% success rate 
is the estimated rate for 
doxycycl
i
ne chest tube pleurodesis (not IPC which has not been done but they should be 
simi
l
ar).  So our chances of demonstrating cl
i
nical success are high. 
However, even if we fail to achieve statistical significance, measurement of the H
R w
ill be 
useful in determining future avenues of work, prov
ided the sample size is large enough. If we 
were to demonstrate early futi
l
ity, it would not be the same as prov
ing that doxycycline does not 
work, and the observed sample size at that time point would be too low and the confidence 
intervals too w
ide to draw useful conclusi
ons other than that it was unl
i
kely that the study woul
d 
succeed. If we complete the study to n=250, we should have a more precise representation of 
the HR which w
ill al
low us to evaluate whether we should a) change the sclerosing agent to 
something more potent (e.g. talc); b) redo the study as a multicenter study using our new 
estimated HR from this study; or c) a combination of the above. In addition, it may be that a 
subset of patients (e.g. those that have persistent fluid drainage on day of randomization>150 
ml) w
ill have a benefit, but this w
il
l require a larger cohort to look at these subsets. 
 
Budget 
 
We wi
l
l seek Research-related patient care clinical charges funding (RPCCC) for the 2 
patient v
isits that are not currently part of our standard of care. Pleurodesis for MPE is covered 
by al
l carriers and is part of the standard of care, the only part that is not part of the standard of 
care is the additional v
isit which is unnecessary for the control arm if this was the standard of 
care. All drugs and other aspects would be standard of care. The CPT code would be 99212. 


7 
 
 
Protocol2015-0142 
August 17, 
2015 
 
Figure 1. Study flow chart 
 
Outpatients with MPE eligible for IPC, consents to trial at time of IPC. There must be no evidence of extensive loculation or 
hydropneumothorax or other contraindication to pleurodesis or narcotics. IPC placed by “long term” team and a f/u with the 
pleurodesis team for day 5 +/- 2 is arranged by 
the research coordinator (Clinic visit with MLP and procedure) 
 
 
 
Patient comes in on day 5 + 2 and is seen and treated by “pleurodesis team” 
 Fentanyl patch 12 mcg/hr in AM. Comes in and gets CXR 
 If ECOG <= 2 
AND patient is now an outpatient AND if patient is eligible for pleurodesis – 
defined as not tremendous
ly 
loculated 
by ultrasound and no hydropneumothorax or severe pain after drainage of the effusion (defined as >2 points more than the pain 
experienced on first day of drainage) or small amount of fluid output despite large am
ount of fluid being present on CXR with 
estimated residual volume based on CXR and drainage volume being >= 500 ml or other contraindication to pleurodesis AND if 
there are no contraindications to narcotics then random
ize. 
 If patient is ineligible for random
ization due to above items then take fentanyl patch off and managed as per usual standard of care. 
 
 
 
 
 
Rando mized to Rx arm (visit is not standard of care) 
 Managed by pleurodesis 
team 
 Fentanyl patch 12 mcg/hr placed if not already on, 
Fentanyl 50 mcg IV given, drain maximally
, Pleurodesis 
agent 
instilled, 1 hr dwell time, re-drain 
 Pain control algorithm with d/c home and pain managed 
by pleurodesis 
team 
Rando mized to placebo arm 
(visit not 
standard of care) 
 Managed by pleurodesis 
team 
 Fentanyl patch 12 mcg/hr placed if not already on, 
Fentanyl 50 mcg IV given, drain maximally
, saline 
instilled, 1 hr dwell time, re-drain 
 Pain control algorithm with d/c home and pain managed 
by pleurodesis 
team 
 
 
 
 
Patient comes in on day 10-14 as per usual standard of care 
 Suture removal 
 Management 
is now by 
the “long-term” team
, which is blinded 
to the status of pleurodesis agent used for the patient 
 Standard of care follow-up monthly 
until removal criteria met 
 
 
 
 
Protocol criteria for removal of IPC are m
et (standard of care) 
 CXR (standard of care) 
 Remove IPC as appropriate per protocol. 
 Monthly follow-up afterward by research coordinator 
documents 
o Recurrence 
status defined 
as recurrent effusion on 
the 
same side requiring 
intervention and 
o Dyspnea and QOL 
 Outcomes 
o Time 
to catheter removal 
o Time 
to recurrent pleural effusion requiring 
intervention 
o Dyspnea (Borg score) 
o Pain 
intensity and pain free days 
o Complications 


8 
Protocol2015-0142 
August 
17, 
2015 
 
 
 
Figure 2. Pain Control A
lgorithm for IPC 
Indwelling pleural catheter pleurodesis Pain Control A
lgorithm. 
 
1. Identify patient for IPC w
ith pleurodesis and consent patient. Obtain basel
ine measures 
for Borg, SF6D, and pain instrument, as per usual standard. Consent patient for trial i
f 
pleurodesis is feasible (i.e. not tremendously loculated effusion and no 
hydropneumothorax or trapped lung or other contraindication to pleurodesis). 
2. If patient consents schedule f/u appointment for day 5 +/- 2 at the time of IPC placement 
w
ith pleurodesis team. This is a f/u v
isit w
ith MLP w
ith a procedure slot booked as well 
for same day (can be booked as IPC) 
3. Give them a fentanyl patch 12 mcg/hour to take home. This is to be placed on day 5 +/- 
2 ideal
l
y in the morning u
pon waking up prior to f/u appoint since it takes time to have 
effect 
4. Patient comes in for schedul
ed v
isit on day 5 +/- 2 for CXR and then to CPC cl
i
nic and is 
assessed by MLP.  Basel
i
ne SF6D, pain instrument, Borg as per usual standard. 
Assuming no dramatic change or infection then goes to procedure area. Nurse places 
IV. 
5. Give pain control w
ith Fentany
l 50 mcg at start of IPC procedure 
6. Drain pleural fluid as per usual standard of care until pain or cough. 
7. Reassess patient and pa
in control and give one additi
onal dose of fentany
l 25 mcg if 
pai
n VAS 5-7 or fentany
l 50 mcg if VAS is 8-10. If pai
n level on VAS is 0 – 4 no 
additi
onal fentany
l is needed. 
8. Instill pleurodesis agent (e.g. Doxycycl
ine 500 mg dissolved in 50 ml of normal sal
i
ne + 
25 ml of 1% l
i
docaine (250 mg)) 
9. Cap for 1 hour, giv
ing additional doses of fentany
l 25 mcg if pain VAS 5-7 or fentany
l 50 
mcg if VAS is 8-10. If pain level on VAS is 0 – 4 no additi
onal fentany
l is needed. 
10. If pain control is not ade
quate, defined as a VAS of 7-10, whi
l
e in the cl
i
nic fol
l
ow
ing IPC 
after fentanyl total dose is 150 mcg or if there is doubt about maintenance of control then 
patient goes to pain clinic on the 4
th floor for walk in appointment prior to discharge. 
Pulmonary a
ttending or MLP places consult to pa
in clinic in orders. Pulmonary recovery 
area nurse is to put in an onl
i
ne consult and cal
l
s the pai
n clinic at 2-1430 to notify them 
patient is coming gives hand/off sign out.  If there are problems regardin
g availabi
lity  
then nurse can speak to pain clinic superv
isor, Angela Jacob. If there is no availability i
n 
pain clinic for walk i
n then the back-up is to send them to EC and have the 
inpatient pain 
serv
ice come to see as a consult. If this occurs, please place typed note in cl
i
nic station 
using IPC template, del
i
neating need for pain control. 
11. If pain control is good, defined as a 
VAS of 0-4, patient and fami
l
y receive instruction on 
pain control algorithm and patient goes home on Hydrocodone 5 mg w
ith 
acetominophen 325 mg tablets every 4 hou
rs PRN, dispense 28 tablets (7 days) in 
addition to the fentany
l patch placed prev
iously. Fentanyl patch should be taken off in 3 
days. Fol
l
ow-up care is as per usual IPC protocol. 
12. If pain control is inadequate at home, defi
ned as persistent pain (VAS >= 
5) despite use 
of hydrocodone on more than four occasi
ons in a 24 hour period, patient cal
l
s in to 
pul
monary cl
i
nic, speaks to cl
i
nic nurse.  If pain is the issue, she contacts MLP who 
assesses patient. If pain management does not requi
re pain clinic (i.e. relatively minor), 


9 
Protocol2015-0142 
August 
17, 
2015 
 
 
 
MLP and pulmonary attendi
ng modify regimen, ad
just pain meds, and MLP then fol
l
ows- 
up by phone at 24 hours after intervention to verify 
pain is control
l
ed. If pain is sti
l
l not 
control
l
ed patient needs to go to pain clinic.  Alternatively if pain is too severe at first 
contact then patient goes straight to pain clinic at MLP/pulmonary attending discretion. 
MLP notifies attending pu
lmonary physician and puts in consult for pain cl
inic at same 
time. MLP cal
l
s pai
n clinic at 2-1430 to notify them pati
ent is comin
g and gives hand/off 
sign out. If there are problems regarding avai
l
ability then MLP can speak to pain cl
i
nic 
superv
isor, Angela Jacob. If there is no avai
l
abi
lity in pain clinic for walk in then the 
back-up is to send them to EC and have the inpatient pai
n serv
ice come to see as a 
consult. If this occurs, please place typed note in cl
i
nic station using IPC template, 
del
i
neating need for pain control so that hand-offs are good. Either way, MLP should 
document in clinic station w
ith typed or dictated note patient phone encounter, includi
ng 
level of pain (1-10 or VAS), duration, what old pain regimen was (e.g. fentanyl patch 12 
mcg/hour and hydrocodone-acetominophen 5-375 one PO QID PRN) and what the 
change was (e.g. increase hydrocodone-acetominophen to 10-375 one PO QID PRN), 
and plan for f/u. 
13. If patient is overly sedated, patient takes off patch early and does not take hydrocodone 
and calls pulmona
ry cl
i
nic and speaks to MLP. MLP modifies and rev
iews w
ith attending. 
MLP does phone call fol
low-up at 24 hours to verify that modification of regimen works 
(i.e. pain control
l
ed and not overly sedated). 
 
 
Pai
n Cl
i
nic info: 
4th Floor 
Phone 2-1430 
Angela Jacob, superv
isor 


1
0 
Protocol2015-0142 
August 
17, 
2015 
 
 
 
Figure 3. Drainage A
lgorithm 
of Pleural Fluid after 
IPC 
Insertion 
 
 
 
After IPC 
insertion 
 Keeps daily drainage log 
 Remove as much flu
id as possible until drainage 
stops, there 
is pain, or persistent cough 
 
 
 
 
 
Daily drainage < 150 m
l for 3 consecutive days and 
steady decline in 
the amount of drainage 
 
 
 
 
 
 
Drain fluid every other day 
Possible IPC malfunction or complications 
if: 
 Drainage decreases sudden
ly in 24 
hour period. 
 Worsening shortness of breath 
 Worsening chest pain or discomfort 
 Fever 
 Erythema or drainage or evidence of 
wound infection 
 
 
 
Drainage every other day < 150 ml on 3 occasions and 
steady decline in 
the amount of drainage 
 
Clinic visit for possible IPC 
malfunction or 
infections 
 
 
 Stop drainage 
 CXR with clinic visit in 3 days 
 Assess for pleurodesis and possible IPC removal 


1
1 
Protocol2015-0142 
August 
17, 
2015 
Figure 
4. 
Management 
algorithm 
of 
IPC 
malfunctions 
 
 
<80% lung re-expansion on CXR 
and 
Moderate or large amount of fl
uid on 
ultrasound 
  
 
 
 
 
Possible IPC M
alfunction C
linic Visit for 
Decreased Drainage 
 
 CXR PA and Latera
l 
 Ultrasound of hemithorax 
 Review drainage logs and symptoms 
 Attempt pleura
l fluid drainage w
ith IPC 
 
 
 
 
 
 
>80% lung re-ex
pansion on CXR 
and 
Respiratory symptoms unchanged or 
improved 
and 
No evidence of infection 
<80% lung re-expansion on CXR 
and 
Absent or small amount of fluid 
on ultrasound 
 
 
 
Possible pleurodesis 
  Remove IPC once drainage 
criteria met for durati
on 
 
 
Stable or improv
ed symptoms 
  Remove IPC once drainage 
criteria met for duration
 
 
 
Worsening symptoms 
  rTPA 4mg/20cc via IPC 
  Drain fluid after one hour 
Possible pleurodesis 
  Remove IPC once 
drainage criteria 
met for duration 
 
 
 
 
<150 cc of fluid drained 
  Repeat rTPA v
ia IPC 
  Drain after overnight wait 
>150 cc of flu
id drained 
  CXR PA and lateral 
  Monitor symptoms 
  Resume drainage 
schedule 
 
 
 
<150 cc of fluid drained 
  Remove IPC 
  CT chest 
  Consider alternativ
e 
interv
entions 
>150 cc of flu
id drained 
  CXR PA and latera
l 
  Monitor symptoms 
  Resume drainage 
schedul
e 


1
2 
Protocol2015-0142 
August 
17, 
2015 
 
 
 
Figure 5. Management algorithm of 
possible 
IPC 
related 
infections 
 
 
 
Possible IPC Infect
ion 
 
  History and physica
l 
  Examine tunnel and ex
it site 
  Gram stain and cu
lture any exudate 
  Drain IPC and send for microb
iology, 
chemistr
ies, cell count, differential 
  CXR PA and Latera
l 
  Ultrasound 
  CBC and serum chemistries 
 
 
 
 
 
 
 
 
Local infection 
  Temperature < 38 degrees C 
  No rigors 
  No purulent p
leural flu
id 
 No evidence of systemic infect
ion 
 
 
 
 
 
 
 
 
Tunnel infection 
  Erythema, tenderness, indurat
ion 
over tunnel tract more 
than 2 cm 
from ex
it site 
  Remove IPC 
  Oral antibiotics w
ith MRSA 
coverage for 10 days 
  Adjust antib
iot
ics based on 
culture results 
  Consider intervent
ions for 
palliation of symptoms from 
residual pleural f
luid 
  Follow-up in one week. 
IPC fluid suggests infect
ion but no 
evidence of systemic tox
icity 
  Temperature < 38 degrees C 
  No purulent pleura
l fluid 
  Diagnostic thoracentesis and 
manage based on results 
 
 
 
 
 
 
 
 
 
Ex
it site infection 
  Erythema, tenderness, indurat
ion 
only at ex
it site 
  Remove IPC if no pleural flu
id, 
>80% re-ex
pansion, and minimal 
draina
ge otherw
ise continue IPC 
drainage 
  Oral antibiot
ics w
ith MRSA 
coverage for 10-15 days 
  Adjust ant
ibio
tics based on 
culture results 
  If IPC in p
lace, follow up tw
ice for 
a week, then weekly for a month. 
  If IPC out, fol
low-up in two weeks. 
 
 
Empyema or systemic infect
ion 
 Fever > 38 degrees C 
  Purulent fluid 
  Evidence of systemic infect
ion 
  Admit for treatment 
  Chest CT and ultrasound to 
assess residual f
luid 
  Empiric antib
iot
ics including 
MRSA coverage 
  Adjust ant
ibio
tics based on 
cultures 
  Thoracic surgery consu
ltatio
n if 
residua
l fluid persists 


1
3 
Protocol2015-0142 
August 
17, 
2015 
 
 
 
 
 
5.0 Informed Consent/Authorization 
 
We do plan to consent patients for this randomized control
l
ed study. 
 
6.0 References 
 
1. 
Kvale PA
, Selecky PA
, Prakash UB. Palliative care 
in 
lung cancer: ACCP evidence-based clinical practice 
guidelines (2nd edition). Chest 
2007; 
132:368S-403S 
2. 
Sahn SA
. Malignant pleural effusions. Semin Respir Crit Care Med 2001; 
22:607-616 
3. 
Tan C, Sedrakyan A
, Browne J, 
et al. The evidence on the effectiveness of management for malignant 
pleural effusion: a systematic review
. Eur J Cardiothorac Surg 2006; 
29:829-838 
4. 
Shaw P, Agarwal R. Pleurodesis for malignant pleural effusions. Cochrane Database Syst Rev 
2004:CD002916 
5. 
Dresler CM, Olak J, Herndon JE, 2nd, 
et al. Phase III intergroup study of 
talc poudrage vs talc slurry 
sclerosis for malignant pleural effusion. Chest 2005; 127:909-915 
6. 
Tremblay A
, Michaud G. Single-center experience with 
250 tunnelled pleural catheter 
insertions for 
malignant pleural effusion. Chest 2006; 129:362-368 
7. 
Warren WH, 
Kalimi R, Khodadadian LM, 
et al. Management of malignant pleural effusions using 
the 
Pleur(x) catheter. Ann Thorac Surg 
2008; 85:1049-1055 
8. 
Ost DE, Jimenez CA
, Lei 
X, 
et al. Quality-adjusted survival follow
ing 
treatment of malignant pleural 
effusions with 
indwelling pleural 
catheters. Chest 
2014; 145:1347-1356 
9. 
Davies HE, Mishra EK, Kahan BC, 
et al. Effect of an indwelling pleural catheter vs chest tube and talc 
pleurodesis for relieving dyspnea 
in patients w
ith malignant pleural effusion: 
the TIME2 random
ized 
controlled 
trial. JAMA 2012; 307:2383-2389 
10. 
Lee YC, Baumann MH, Maskell NA
, 
et al. Pleurodesis practice for malignant pleural effusions 
in five 
English-speaking countries: survey of pulmonologists. Chest 2003; 124:2229-2238 
11. 
Heffner JE, Klein JS. Recent advances 
in 
the diagnosis and management of malignant pleural effusions. 
Mayo Clin Proc 2008; 83:235-250 
12. 
Brazier J, Roberts J, Deverill M. The estimation of a preference-based measure of health from 
the SF-36. J 
Health Econ 2002; 
21:271-292