Pivotal Multi Center, Randomized, Controlled, Single-Blinded Study Comparing the Silver Nitrate Coated Indwelling Pleural Catheter to the Uncoated PleurX Catheter for the Management of Symptomatic, Recurrent, Malignant Pleural Effusions
Phase: NA
Conditions: Malignant Pleural Effusion
Sponsor: C. R. Bard

Clinical Investigation Plan 
Final v3.0 – 01 June 2017 
A Pivotal Multi-Center, Randomized, Controlled, Single-Blinded Study 
Comparing the Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) to the 
Uncoated PleurX® Pleural Catheter for the Management of Symptomatic, 
Recurrent, Malignant Pleural Effusions 
Study Number: 
 
CS-IP-VH-14-009 
Study Phase:  
 
Pre-market device study 
Investigational Product:  
Silver Nitrate-Coated Indwelling Pleural Catheter 
IDE/Eudamed Number: 
G150146 / CIV-GB-16-07-016364 
Indication:  
Intermittent, long term drainage of symptomatic, recurrent, 
malignant pleural effusion. The device is indicated for 
1) palliation of dyspnea due to pleural effusions and 2) providing 
pleurodesis (resolution of pleural effusion). 
Sponsor:  
 
 
CareFusion 2200, Inc. 
75 North Fairway Drive  
Vernon Hills, Illinois 60061 
 
For this study, the protocol and subsequent amendments were released as follows: 
Original Protocol:   
Final Version 1.0, dated 03JUN2015 
Previous Version: 
 
Final Version 2.0, dated 08OCT2015 
Current Version:  
 
Final Version 3.0, dated 01JUN2017  
 
 
 
 
 
 
 
 
 
Compliance Statement: This study will be conducted in accordance with the Declaration of Helsinki, the 
clinical research guidelines established by the US Code of Federal Regulations (CFR) (Title 21, Parts 50, 
54, 56, and 812; and Title 45 Part 46), the regulations and guidelines of the Therapeutic Goods 
Administration, the International Conference on Harmonisation (ICH) Guidelines for Good Clinical 
Practice (GCP) and International Organization for Standardization (ISO) 14155 (Clinical Investigation of 
Medical Devices for Human Subjects - Part 1: General Requirements and Part 2: Clinical Investigational 
Plans). Study documents will be maintained in accordance with applicable regulations. 
Confidential: The information contained in this protocol is confidential and is intended for the use of 
clinical investigators. It is the property of CareFusion 2200, Inc., or its subsidiaries and should not be copied 
by or distributed to persons not involved in the clinical investigation, unless such persons are bound by a 
confidentiality agreement with CareFusion 2200, Inc., or its subsidiaries. 

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CS-IP-VH-14-009 
 
CareFusion 2200, Inc. 
Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
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Table of Contents 
Table of Contents ..................................................................................................................3 
Protocol Synopsis ..................................................................................................................8 
Glossary of Abbreviations .....................................................................................................18 
1 
Study Administration .....................................................................................................20 
 
Investigators and Study Administrative Structure ............................................20 
 
Institutional Review Board/ Institutional Ethics Committee Approval ...........20 
 
Ethical Conduct of the Study ...............................................................................21 
 
Subject Information and Consent ........................................................................21 
 
Subject Confidentiality .........................................................................................22 
 
Compensation, Insurance, and Indemnity ..........................................................22 
 
Study Monitoring ..................................................................................................22 
 
Case Report Forms and Study Records ..............................................................23 
 
Data Safety Monitoring Board .............................................................................23 
 
Termination of the Study ......................................................................................24 
 
Publication Policy ..................................................................................................24 
 
Financial Disclosure ..............................................................................................24 
 
Personnel Responsibilities ....................................................................................25 
 
Investigator(s) ................................................................................................25 
 
Institutional Review Board/Institutional Ethics Committee ..........................25 
 
Sponsor and/or Designee ...............................................................................25 
2 
Introduction and Study Rationale .................................................................................27 
 
PleurX Indwelling Pleural Catheter System .......................................................28 
 
Silver Nitrate-Coated Indwelling Catheter System ............................................29 
3 
Study Purpose/Objectives ..............................................................................................31 
4 
Investigational Plan .......................................................................................................32 
 
Overall Design and Plan of the Study ..................................................................32 

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Risk/Benefit and Ethical Assessment ...................................................................35 
 
Description of Patient Population ......................................................................35 
 
Justification for Investigation ............................................................................35 
 
Scientific Soundness and Ethical Considerations ..............................................35 
 
Anticipated Benefits to Study Subjects ..............................................................36 
 
Anticipated Risks to Study Subjects ..................................................................36 
4.2.5.1 
Treatment Related Anticipated Adverse Events ........................................36 
4.2.5.2 
Anticipated Adverse Device Effects ..........................................................38 
 
Mitigation Efforts...............................................................................................40 
4.2.6.1 
Changes to the IFU, As Identified In The Risk Analysis Report ...............41 
 
Possible Interactions with Concomitant Medical Treatments ...........................42 
 
Benefit-Risk Analysis Conclusion .....................................................................42 
5 
Selection of Study Population .......................................................................................43 
 
Inclusion Criteria ..................................................................................................43 
 
Exclusion Criteria .................................................................................................43 
 
Withdrawal of Subjects ........................................................................................45 
6 
Device Description .........................................................................................................46 
 
Investigational Device –SNCIPC .........................................................................46 
 
Control Device – PleurX® Pleural Catheter ........................................................47 
 
Devices to be Used .................................................................................................47 
 
Drainage Bottle ..................................................................................................48 
 
Catheter Access Kit............................................................................................49 
 
Catheter Insertion Stylet (Component of Supplemental Insertion Kit) .............50 
 
Packaging and Labeling ........................................................................................50 
 
Device Storage and Accountability ......................................................................50 
 
Investigational Device Proposed Intended Use ...................................................51 
 
Investigational Device Insertion and Removal ...................................................51 

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Method of Assigning Subjects to Treatment Groups .........................................52 
 
Blinding ..................................................................................................................52 
 
Concomitant Medication and Therapy ...............................................................53 
7 
Study Procedures ...........................................................................................................54 
 
Schedule of Events .................................................................................................54 
 
Written Informed Consent and Screening ..........................................................57 
 
Baseline Assessment (Day -3 to Day 0) ................................................................57 
 
Pleural Catheter Insertion (Day 0) ......................................................................58 
 
Post Catheter Insertion (Day 0) ...........................................................................58 
 
Regular Fluid Drainage ........................................................................................59 
 
Subject Diary and Home Measurements ............................................................60 
 
Follow-Up Period ...................................................................................................60 
 
Face-to-Face Follow-Up Visits ..........................................................................60 
 
Telephone Follow-Up Visits ..............................................................................61 
 
Pleurodesis .............................................................................................................62 
 
Collection of Blood Samples .................................................................................63 
 
Silver Testing .........................................................................................................64 
 
Catheter Blockage .................................................................................................64 
 
Quality of Life Measurements ..............................................................................64 
 
Medical Resource Utilization ...............................................................................65 
 
End of Study ..........................................................................................................65 
 
SNCIPC Management Following Study Completion .........................................65 
8 
Efficacy and Safety Assessments ..................................................................................66 
 
Methods of Assessment/Evaluations ....................................................................66 
 
Primary Efficacy Endpoint ................................................................................66 
 
Secondary Efficacy Endpoints ...........................................................................66 
 
Exploratory Efficacy Analysis ...........................................................................67 

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Safety Evaluations .............................................................................................67 
 
Quality of Life and Medical Resource Utilization Analysis ..............................67 
 
Protocol Deviations ...............................................................................................67 
 
Safety Parameters .................................................................................................68 
9 
Data Quality Assurance.................................................................................................73 
 
Data Collection ......................................................................................................73 
 
Database Management and Quality Control ......................................................74 
10 
Statistical Methods .....................................................................................................75 
 
Statistical and Analytical Plans ............................................................................75 
 
Adjustments for Covariates............................................................................75 
 
Stopping Rules and Data Monitoring ............................................................75 
 
Handling of Dropouts and Missing Data .......................................................75 
 
Multi-center Studies and Pooling of Investigational Centers ........................75 
 
Multiple Comparisons/ Multiplicity ..............................................................76 
 
Analysis Populations ......................................................................................76 
 
Demographic and Other Baseline Characteristics .........................................77 
 
Prior and Concomitant Therapy .....................................................................77 
 
Analysis of Efficacy Parameters ....................................................................77 
10.1.9.1 Primary Efficacy Parameter .......................................................................77 
10.1.9.2 Secondary Efficacy Parameter ...................................................................78 
10.1.9.3 Exploratory Efficacy Parameter .................................................................79 
 
Analysis of Safety Parameters ..............................................................................79 
 
Duration of Exposure .....................................................................................79 
 
Incidence of Catheter Occlusion ....................................................................79 
 
Incidence of Infection ....................................................................................79 
 
Serum and Pleural Fluid Silver Levels ..........................................................80 
 
Adverse Events ..............................................................................................80 

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Clinical Laboratory Evaluations ....................................................................80 
 
Other Observations Related to Safety ............................................................80 
 
Quality of Life and Medical Resource Utilization Parameters .........................81 
 
Quality of Life................................................................................................81 
 
Medical Resource Utilization Parameters ......................................................81 
 
Interim Analysis ....................................................................................................81 
 
Subgroup Analyses ................................................................................................82 
 
Determination of Sample Size ..............................................................................82 
11 
References ..................................................................................................................83 
12 
Appendices ..................................................................................................................87 

CS-IP-VH-14-009 
 
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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 8 of 90 
Protocol Synopsis 
Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
Study Title: A Pivotal Multi-Center, Randomized, Controlled, Single-Blinded  Study 
Comparing the Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) to the 
Uncoated PleurX® Pleural Catheter for the Management of Symptomatic, Recurrent, 
Malignant Pleural Effusions 
Study Centers: This study will be conducted at approximately 17 investigational centers 
in the United States (US) and 3 investigational centers in the United Kingdom (UK).  
Principal Investigator:  Joseph B. Shrager, MD 
Study Enrollment and Duration:  
Type of Study:  
Study enrollment will be approximately 12 months, or until 
the last patient is enrolled. Study duration will be 15 months 
(from first patient in to last patient out). Individual subject 
participation will be a total of 90 days: after catheter 
insertion, subjects will be evaluated at 14-day, 30-day, 
60-day, and 90-day follow-up visits plus telephone 
assessments at 7 days, 45 days and 75 days. 
Pre-market device study 
Study objectives: 
The primary objective is to demonstrate that the Silver Nitrate-Coated Indwelling Pleural 
Catheter (SNCIPC) shows superiority compared with the PleurX Pleural Catheter in the 
proportion of subjects achieving pleurodesis without recurrence at 30 days. Recurrence is 
defined as symptomatic pleural effusion confirmed by chest X-ray (CXR) and computed 
tomography (CT) scan with an estimated >300 mL of fluid in the treated hemithorax. 
The secondary objectives of this study are to summarize measures of time to confirmed 
pleurodesis and time to recurrence.   
For the secondary objectives, when non-inferiority is achieved, superiority will 
subsequently be tested to show SNCIPC superiority over the PleurX Catheter. 
Methodology:  
This is a prospective, multicenter, randomized, controlled, single-blinded pivotal study of 
the SNCIPC as compared to the PleurX Pleural Catheter when used as intended to palliate 
dyspnea in subjects with recurrent pleural effusions. Subjects will be recruited during 
consult for their procedure and will return to the study center to be randomized to receive 
either the SNCIPC (treatment group) or the PleurX Pleural Catheter (control group) in a 
2:1 ratio on the day of the procedure. The subjects will be considered enrolled at the time 

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CareFusion 2200, Inc. 
Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 9 of 90 
Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
of randomization. A trained study staff member will insert the catheter in a dedicated 
procedure room or operating suite, using the same technique as for insertion of the PleurX 
catheter. The day of indwelling pleural catheter (IPC) insertion is defined as Day 0. 
Subjects or their caregiver (friend, family member or paid healthcare professional) must be 
able to perform at-home pleural effusion drainage for up to 90 days post-catheter insertion. 
After IPC insertion, subjects will be evaluated at 14-day (±2), 30-day (±2), 60-day, (±3), 
and 90-day (±3) follow-up visits plus a telephone assessment by study center personnel at 
7 (±2) days, 45 (±3) days and 75 (±3) days. In addition, subjects must call the study center 
to make an appointment for an unscheduled visit to assess for pleurodesis and potential IPC 
removal once they measure an output of ≤50 mL of pleural fluid on 3 consecutive drainages 
over a minimum of 5 days. Once pleurodesis is confirmed by CXR, the IPC will be removed 
as soon as feasible. At removal, the SNCIPC will be shipped to the designated analytical 
laboratory to be analyzed for residual silver content. Recurrence is defined as symptomatic 
pleural effusion confirmed by CXR and CT scan with an estimated >300 mL of fluid in the 
treated hemithorax following initially confirmed pleurodesis.     
Follow-up activities:  
Face-to-face follow-up visit assessments to include, as appropriate: 
 Maximal catheter drainage (fluid sample retained for subjects who received 
SNCIPC) and CXR  
 Determination of pleurodesis 
 Determination of previously unidentified trapped lung (as defined in Exclusion 
Criterion #1) 
 Record of AE(s) since last visit 
 Record of further pleural interventions needed 
 Assessment of recurrence post-pleurodesis  
 Record of current oncological treatment 
 Review of subject diary (temperature, drainage volumes, over-the-counter [OTC] 
and prescription medications, oxygen use, chest pain and dyspnea scores, and 
unplanned hospital or emergency department visits) 
 Assessment of analgesia requirements 
 Examination of drain insertion site (with removal of stitches if necessary) 
 Physical examination (including vital signs, oxygen saturations and respiratory 
rate) 
 EQ-5D-5L  health status questionnaire 
 Collection of blood samples (for subjects with SNCIPC, this includes samples for 
serum silver analysis) 
 Serum and/or urine pregnancy test 
 Record of MRU. 

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 10 of 90 
Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
Telephone assessments to include, as appropriate: 
 Record of AEs since last visit 
 Record of further pleural interventions needed 
 Record of current oncological treatment 
 Record of MRU 
 Assessment of analgesia requirements 
 Review of subject diary (temperature, drainage volumes, OTC and prescription 
medications, oxygen use, chest pain and dyspnea scores and unplanned hospital or 
emergency department visits) 
 Assessment of pleurodesis 
 EQ-5D-5L health status questionnaire. 
Subject population: 
Eligible subjects will be ≥ 18 years old, experiencing dyspnea secondary to recurrent 
malignant pleural effusions (MPE) and meet all other inclusion and exclusion criteria. 
Additionally, subjects or their caregiver (friend, family member or paid healthcare 
professional) must be capable of managing at-home pleural effusion drainage. 
Diagnosis and Inclusion Criteria: 
Subjects must meet all of the following inclusion criteria: 
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 
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. 
 
 

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 11 of 90 
Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
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 a pleural drainage. 
Significant trapped lung is deemed present if any 1 of the following criteria is met: 
a) A CXR shows hydropneumothorax.  
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.  
7. Subject has a hypersensitivity to silver, silver nitrate, or silicone. For subjects with 
a self-reported silver hypersensitivity who wish to be considered for enrollment in 
the study, a confirmation test for hypersensitivity to silver nitrate will be performed. 
8. Subject has evidence, in the opinion of the Investigator, of either on-going systemic 
or pleural infection. 
9. Subject has had a lobectomy or pneumonectomy on the side of the effusion. 
10. Subject has undergone a previous attempt at ipsilateral pleurodesis which has failed. 
11. Subject has previously been diagnosed with a serious immunodeficiency disorder.  

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
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Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
12. Subject has bilateral pleural effusions, with both being at least moderate in size 
(greater than one-third of the hemithorax on CXR). 
13. Subject has evidence of fluid loculation such that attempts at pleurodesis are likely 
to be futile. 
14. Subject has a mediastinal shift of ≥2 cm toward the side of the effusion. 
15. Subject is receiving concurrent intrapleural chemotherapy or radiation therapy to 
the ipsilateral chest. 
16. Subject has any clinical condition, diagnosis, or social circumstance that, in the 
opinion of the Investigator, would mean participation in the study would be 
contraindicated. 
17. Subject has no access to a telephone. 
18. Subject has no documented blood values (complete blood count [CBC], coagulation 
tests, urea and electrolytes, and liver function tests [LFTs]) within the last 10 days. 
19. Subject has previously participated in any clinical trial with the investigational 
SNCIPC device. 
20. Subject currently enrolled in any other clinical investigation or who has participated 
in any clinical investigation in the 30 days prior to starting this study. 
Number 
of 
Subjects 
(Planned/total 
for 
each 
treatment 
arm 
with 
an 
estimated/approximate statement): Approximately 119 subjects will be enrolled in the 
study, with subjects randomized 2:1 to receive SNCIPC and PleurX catheters (79 subjects 
and 40 subjects, respectively).   
Test Device: SNCIPC (manufactured by CareFusion 2200, Inc.) 
The SNCIPC is a pleural catheter which is indicated for palliation of dyspnea due to pleural 
effusions and for providing pleurodesis (resolution of the effusion). It can provide 
intermittent, long-term drainage of symptomatic, recurrent pleural effusion. It consists of a 
fenestrated silicone catheter with a proximal valve mechanism, a polyester cuff, and a 
barium sulphate stripe to aid visualization under fluoroscopy, identical to the PleurX 
catheter on which it is based. The fenestrated portion of the SNCIPC is coated with 100 mg 
(+/- 15 mg) of the pleurodesis agent silver nitrate (AgNO3) and inert materials which 
control drug release.  

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Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
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Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
Control/Reference Device:  
PleurX Pleural Catheter (manufactured by CareFusion 2200, Inc.) 
The PleurX Pleural Catheter is a currently marketed device that provides intermittent, long-
term drainage of symptomatic, recurrent pleural effusion. It consists of a fenestrated 
silicone catheter with a proximal valve mechanism, a polyester cuff, and a barium sulphate 
stripe to aid visualization under fluoroscopy.  
Criteria for Evaluation: 
Primary Endpoint 
 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the proportion (%) of subjects achieving pleurodesis 
without recurrence by 30 days after IPC placement, where pleurodesis is defined as: 
 The collection of a minimum of 3 consecutive drainages of ≤ 50 mL of pleural fluid 
over a minimum of 5 days (which begin with the first drainage of ≤ 50 mL) 
  AND 
 CXR, which shows opacification due to pleural fluid occupying less than one 
quarter of the hemithorax (as judged by the investigative study center and the 
blinded third party central radiology service.)  
 
The date of pleurodesis is defined as the day on which the first of 3 consecutive drainages 
of ≤50 mL was recorded. Recurrence is defined as symptomatic pleural effusion confirmed 
by CXR and CT scan with an estimated >300 mL of fluid in the treated hemithorax. All 3 
drainages and the radiological findings to confirm pleurodesis must occur within the 90-day 
follow-up period.   
Secondary Endpoints  
Secondary Efficacy Endpoints 
 Time to confirmed pleurodesis  
Time to pleurodesis is defined as the duration between the study device insertion 
and the date a subject achieves pleurodesis. 

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Clinical Investigation Plan 
  
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 CONFIDENTIAL  
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Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
 Time to recurrence  
Time to recurrence is calculated for subjects who achieved confirmed pleurodesis. 
It is defined as the duration between successful pleurodesis (the first of a minimum 
of 3 consecutive drainages of ≤50 mL of pleural fluid over a minimum of 5 days) 
and the date subject presents with symptoms of recurrence that is later confirmed 
by CXR and CT scan.   
Exploratory Efficacy Analysis 
The following exploratory analysis will be  performed comparing the two treatment groups: 
 Proportion of surviving subjects without a trapped lung diagnosis following IPC 
placement who have confirmed pleurodesis without recurrence at 14, 30, 60 and 90 
days. 
 Proportion of subjects with confirmed pleurodesis and without recurrence 30 days 
after IPC placement by cancer type (lung, breast and others).  
Safety Evaluations 
The following safety evaluations will be compared between the two treatment groups: 
• Device related safety and adverse events (AEs) 
• Incidence of IPC occlusion 
• Incidence of empyema and cellulitis  
Descriptive statistics for serum and pleural fluid silver levels by time point will be provided 
for subjects who receive SNCIPC.  
Stopping rules for safety will be defined by the Data Safety Monitoring Board (DSMB) 
and outlined in the DSMB charter. The stopping rules are based on safety criteria andthere 
will be no stopping based on efficacy criteria. The DSMB will receive notification of any 
expedited unanticipated adverse device effects (UADEs). 
QoL and MRU Analysis 
 
Pain using 100 mm visual analog scale (VAS) 
 
Dyspnea relief (breathlessness) using Modified Borg dyspnea scale 
 
Health status as measured by the EQ-5D-5L health status questionnaire 
 
MRU data (length of procedure; hospital stay [hours]; unplanned in-hospital 
medical procedures as a result of IPC placement; emergency department visits 
related to IPC placement; length of time IPC in place; drainage schedule and 
frequency; frequency, dose and type [brand name/generic] of prescription and OTC 

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
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Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
medications; frequency and use of oxygen; services required to diagnose, treat, and 
follow up AEs). 
Statistical Methods:  
Analysis of Primary Efficacy Parameter 
The primary analysis will be performed on the Intent-to-Treat (ITT) population.   
The proportion of subjects achieving pleurodesis without recurrence 30 days after IPC 
placement and its 95% confidence interval (CI) by exact binomial method will be 
summarized for each treatment group. Exact unconditional CI for risk difference will be 
used to calculate rate difference and 95% CI. Superiority will be demonstrated when the 
one-sided p-value is less than 0.025.  
A supportive analysis will be done using the Per-protocol (PP) population. 
Analysis of Secondary Efficacy Parameters  
Time to confirmed pleurodesis analysis will be performed using proportional hazards 
model and Kaplan-Meier time-to-event analysis. The analysis will be performed on all 
subjects in the ITT population, and on all subjects in the PP population as a supportive 
analysis. A proportional hazards model will be used to estimate the hazard ratio (HR). Non-
inferiority will be established when HR > 0.7. Time to confirmed pleurodesis will be 
summarized by 25th percentile, median, and 75th percentile, when estimable from the 
Kaplan-Meier estimates for each treatment group. Kaplan-Meier curves for each treatment 
group will be provided. Time to confirmed pleurodesis is defined as the duration between 
the study device insertion and the date of confirmed pleurodesis. For subjects who do not 
have confirmed pleurodesis, censoring rules will be described in the SAP. Incidence 
density for time to confirmed pleurodesis will be evaluated between the two groups by 
summarizing the number of subjects in the ITT population, number of confirmed 
pluerodeses, number of subjects censored in the time to pleurodesis,  and patient-days in 
each treatment group. Patient-days within the treatment group will be calculated as the total 
number of days from study device insertion to confirmed pleurodesis or termination of 
study participation summed for all subjects within the treatment group. 
Time to recurrence analysis will be performed using proportional hazards model and 
Kaplan-Meier time-to-event analysis. The analysis will be performed on all subjects in the 
ITT population who had confirmed pleurodesis, and on all subjects in the PP population 
who had confirmed pleurodesis as a supportive analysis. A proportional hazards model will 
be used to estimate the hazard ratio. Non-inferiority will be established when HR < 1.3. 
Time to recurrence will be summarized by 25th percentile, median, and 75th percentile, 

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Clinical Investigation Plan 
  
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 CONFIDENTIAL  
Page 16 of 90 
Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
when estimable from the Kaplan-Meier estimates for each treatment group. Kaplan-Meier 
curves for each treatment group will be provided. Time to recurrence is defined as the 
duration between confirmed pleurodesis and the date of recurrence. For subjects who do 
not have a recurrence after confirmed pleurodesis, censoring rules  and incidence density 
analysis will be described in the SAP. Incidence density for time to recurrence will be 
evaluated between the two groups by summarizing the number of subjects with confirmed 
pleurodesis, number of recurrences, number of subjects censored in the time to recurrence, 
and patient-days in each treatment group. Patient-days within the treatment group will be 
calculated as the total number of days from confirmed pleurodesis to recurrence or 
termination of study participation summed for all subjects within the treatment group. 
Following the non-inferiority test, superiority will be demonstrated when the one-sided p-
value is less than 0.025 using a proportional hazards model. 
Analysis of Exploratory Efficacy Parameters 
The exploratory efficacy endpoints involving a proportion will be analyzed in the same 
fashion as the primary endpoint. These analyses involve the following endpoints:   
 
Proportion of surviving subjects without a trapped lung diagnosis following 
IPC placement and who have confirmed pleurodesis without recurrence at 14, 30, 
60 and 90 days. 
 
Proportion of subjects achieving pleurodesis without recurrence 30 days after IPC 
placement by cancer type.   
The proportion (%) of  patients achieving pleurodesis without recurrence at 30 days will be 
summarized for each treatment group by cancer type (lung, breast and others). The 
proportions will be compared using a Cochran-Mantel-Haenszel test using the cancer type 
as a stratification factor. The primary analysis will be performed using the ITT population 
and on the PP population as a supportive analysis.  
Analysis of Safety Parameters 
All comparisons between treatment groups for the safety parameters will be descriptive in 
nature. Analyses will include duration of subject exposure to study treatment, incidence of 
IPC occlusion and incidence rate of empyema and cellulitis. For subjects who received 
SNCIPC, serum and pleural fluid silver levels will be measured at regular intervals 
(inductively coupled plasma mass spectrometry [ICP-MS] analysis).   
AEs will be mapped to system organ class and preferred term using the Medical Dictionary 
for Regulatory Activities (MedDRA) dictionary and will include AEs, SAEs, adverse 

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Sponsor: 
Name of Medical Device: 
CareFusion 2200, Inc. 
Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) 
device effects (ADEs), serious adverse device effects (SADEs), unanticipated adverse 
device effects (UADEs), and unanticipated serious adverse device effects (USADEs).  
Results for clinical laboratory tests, vital signs, and physical examination findings and their 
change from baseline will be summarized.   
Analysis of QoL and MRU Parameters 
Pain and dyspnea (breathlessness) will be evaluated using the 100 mm VAS and the 
Modified Borg dyspnea scale, respectively. Patient-reported health status will be evaluated 
using the EQ-5D-5L. Comparison between the two treatment groups involving continuous 
variables will be done using a two-sample t-test. Change from baseline between the two 
treatment groups will be analyzed using a two-sample t-test. Comparison between the two 
treatment groups involving categorical variables will be done using the chi-square test, or 
Fisher’s exact test if more appropriate 
Comparison between the two treatment groups involving continuous variables such as 
length of procedure, length of hospital stay and length of time IPC in place will be done 
using a t-test. All other resource utilization data will be summarized as frequencies and 
counts. 
Subgroup Analysis  
If at least 80% of the total number of US subjects participating in this study are Medicare 
beneficiaries, then no subgroup analysis will be conducted. However, if less than 80% of 
all US subjects enrolled are Medicare beneficiaries, then a subgroup analysis will be 
conducted to evaluate outcomes specifically for the Medicare beneficiaries enrolled in the 
study. All primary and secondary outcomes for the subgroup analyses will be the same as 
for the main analysis. 

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Glossary of Abbreviations 
Abbreviation 
Definition 
AE(s) 
Adverse event(s) 
ADE(s) 
Adverse device effect(s) 
AgNO3 
Silver nitrate 
ATC 
Anatomical Therapeutic Chemical  
C 
Celsius degree 
CBC 
Complete blood count 
CE 
Conformite Europeenne mark 
CFR 
Code of Federal Regulations 
CIP 
Clinical Investigation Plan 
CP 
Conditional power 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CT 
Computed tomography 
CXR 
Chest X-Ray 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOS 
End of study 
F 
Fahrenheit degree 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HR 
Hazard Ratio 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICP-MS 
Inductively coupled plasma mass spectrometry 
IDE 
Investigational Device Exemption 
IEC 
Institutional Ethics Committee 
IFU 
Instructions for Use 
IPC 
Indwelling pleural catheter 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
Intent-to-treat 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LFT 
Liver function tests 

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Abbreviation 
Definition 
LSLV 
Last subject last visit 
m 
Meter 
max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mg/d 
Milligrams per day 
min 
Minimum 
mL 
Milliliter 
mm 
Millimeter 
MPE 
Malignant pleural effusion 
MRU 
Medical resource utilization 
N 
Number of subjects 
NSAID(s) 
Non-steroidal anti-inflammatory drug(s) 
OTC 
Over-the-counter 
PIS 
Patient information sheet 
PP 
Per protocol 
QoL 
Quality of Life 
SADE  
Serious adverse device effect  
SAE(s) 
Serious adverse event(s) 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SD 
Standard deviation 
SNCIPC 
Silver Nitrate-Coated Indwelling Pleural Catheter 
SOP 
Standard operating procedure 
TEAE(s) 
Treatment-emergent adverse event(s) 
UADE(s) 
Unanticipated adverse device effect(s) 
UK 
United Kingdom 
US 
United States 
USADE(s) 
Unanticipated serious adverse device effect(s) 
VAS 
Visual Analog Scale 
WHO  
World Health Organization 

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1 Study Administration 
 
Investigators and Study Administrative Structure 
The Investigator responsible for the conduct of this study, in compliance with this clinical 
investigation plan (CIP), is identified on the Signature page. The Investigator will also sign the 
Investigator Agreement and provide it to the Sponsor or Sponsor’s representative prior to receipt 
of the investigational device and study initiation at that investigational center. 
Sponsor:  
 
 
 
 
 
CareFusion 2200, Inc. 
Clinical Project Manager: 
 
 
 
Lydia Blank 
Contract Research Organization (CRO): 
 
Chiltern International, Ltd 
Project Lead (CRO):   
 
 
 
Neely Bagwell 
Biostatistician (CRO):  
 
 
 
Qin Pan, PhD  
Safety Officer (CRO): 
 
 
 
Riyaz Visram 
Principal Investigator   
 
 
 
Joseph B Shrager, MD 
Clinical laboratory tests will be performed locally. Testing for silver in pleural fluid, serum silver, 
and residual silver nitrate on the removed Silver Nitrate-Coated Indwelling Pleural Catheter 
(SNCIPC) will be performed at a central analytical laboratory. Independent review of chest X-ray 
(CXR) and computed tomography (CT) scans will be performed at a central laboratory. 
 
Institutional Review Board/ Institutional Ethics Committee Approval 
The Investigator agrees that the study will be conducted according to the CIP and the principles of 
Good Clinical Practice (GCP), International Organization for Standardization (ISO), and provided 
in the International Conference on Harmonisation (ICH) guidelines governing clinical study 
conduct. 
The Investigator will conduct all aspects of this study in accordance with all national, state, and 
local laws of the pertinent regulatory authorities. 
The CIP, any CIP amendments, the informed consent form (ICF), and all other forms of subject 
information related to the study and any other necessary documents will be reviewed by an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
It is required that a valid IRB/IEC approves, in writing, the conduct of this clinical study, together 
with the ICF to be used at the respective investigational study center, prior to study initiation. 
The Investigator will submit the protocol and ICF for IRB/IEC review. This will be appropriately 
documented. The IRB/IEC should be asked to give its approval in writing. The names and 
qualifications of the members of the review committee will be recorded and submitted to the 
Sponsor, together with the written approval for the conduct of the study. The members of the 

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IRB/IEC must be independent of the Sponsor and the Investigator. The written approval should 
consist of a completed IRB/IEC approval form or written documentation from the IRB/IEC 
containing the same information. 
Until written approval by the IRB/IEC at an investigational study center has been received by the 
Sponsor, no subject at that study center may undergo any procedures solely for the purpose of 
determining eligibility for this study. 
CIP amendments must also be reviewed and approved by the IRB/IEC and written approval from 
the committee or at least the chairperson (or a designated committee member) must be received 
by the Sponsor before implementation. This written approval will consist of a completed IRB/IEC 
approval form or written documentation from the IRB/IEC containing the same information. Any 
additional requirements imposed by the IRB/IEC or regulatory authority shall be followed, if 
appropriate. 
 
Ethical Conduct of the Study 
The study will be conducted in compliance with the following: 
• the protocol 
• ethical principles of the Declaration of Helsinki and its amendments 
• the principles of the GCP provided in the ICH Harmonised Tripartite Guidelines for GCP, 
1996 
• the latest revision of the ISO guidelines 
• all applicable national laws and regulations including country-specific GCP. 
 
Subject Information and Consent 
The Investigator or his/her representative will explain the nature of the study to each subject, and 
answer all questions regarding this study, prior to obtaining informed consent. Study consent must 
be taken by a medical member of the study team. 
The Investigator will obtain informed consent from each subject prior to being enrolled in the 
study, in accordance with the current version of the GCP guidelines and the laws and regulations 
of the country in which the investigation is being conducted.   
The IRB/IEC must approve the ICF to be used by the Investigator prior to its use. It is the 
responsibility of the Investigator to assure that the subject has signed the ICF before any activity 
or treatment is undertaken. This includes, but is not limited to, the performance of diagnostic or 
therapeutic procedures and the placement of the IPC. The document may be further updated if new 
important information becomes available that may affect subject’s willingness to participate or 
continue in the trial. 

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Subject Confidentiality 
Adequate records must be maintained for the study, including patient medical records, electronic 
case report forms (eCRFs), laboratory reports, worksheets, nursing notes, signed ICFs, product 
forms, SAE forms, and information regarding subject discontinuation and reasons for 
discontinuation. The confidentiality of each record with subject identification is to be guaranteed 
by the clinical Investigator.  Personal medical information may be reviewed by the study monitor, 
properly authorized persons on behalf of the sponsor, or regulatory authorities for the purpose of 
verifying data recorded on the eCRF. Personal medical information will always be treated as 
confidential. 
Anonymous subject identifiers are established within eCRFs and other study documents, including 
image material, that do not disclose protected health information to the Sponsor, CRO or Imaging 
Core Lab. Study information stored electronically is only available to study personnel directly 
involved in the study.  Study information stored in any database must be in a password-protected 
database. Information gathered will not be reused or disclosed to any other person or entity or for 
research other than as detailed within this document. Once the research has been completed, 
subject study information maintained at the study site will be retained for as long as is required by 
law or regulations and at that point will be destroyed. 
This CIP and other study documents contain trade secrets and commercial information that is 
privileged and confidential. Such information is not to be disclosed unless required by laws or 
regulations. The Investigator agrees to use this information only in conducting this study and is 
not allowed to use it for other purposes without written consent from the Sponsor. Results obtained 
from this study as well as any blood, tissue sample, or fluid collected for this study in accordance 
with the protocol, are the property of the Sponsor.  
 
Compensation, Insurance, and Indemnity 
Information regarding compensation, insurance, and indemnity will be provided to the Investigator 
in the Clinical Trial Agreement. Country-specific insurance will be obtained in accordance with 
local regulations. 
 
Study Monitoring 
For protocol monitoring and compliance, an investigational center visit will be held prior to 
initiation of subject enrollment. The CIP, eCRFs, study supplies, and study procedures will be 
explained in detail.  
The purpose of monitoring is to verify the rights and well-being of human subjects are protected; 
that study data are accurate, complete, and verifiable with source data; and that the study is 
conducted in compliance with the protocol, GCP, and the applicable regulatory requirements. 
A monitor assigned by the CRO will conduct regular investigational center visits for the purpose 
of study monitoring per the monitoring plan.  

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The Investigator must agree to allow the study monitor and authorized representatives of Chiltern 
or the Sponsor to inspect all eCRFs and corresponding source documents (e.g., original medical 
records, patient records and laboratory raw data); to allow access to the clinical supplies, 
dispensing, and storage areas; and to agree to assist with their activities, if requested. The 
Investigator should provide adequate time, availability, and space for monitoring visits. 
The monitor will query any missing or spurious data with the Investigator, which should be 
resolved in a timely manner. A monitoring log will be maintained to record each visit, the reason 
for the visit, the monitor’s signature, and the Investigator’s or designee’s confirmation signature. 
 
Case Report Forms and Study Records 
The Investigator agrees to retain copies of the eCRFs with other study documents (e.g., the CIP 
and any amendments, the Summary of Product Characteristics, IRB/IEC approval, signed consent 
forms, and source documents for each subject in the study [e.g., all demographic and medical 
information, including laboratory data, electrocardiograms, medication disposal and subject 
diaries]) in a secure place for a minimum of 2 years after receiving written notification from 
Sponsor that  investigational device has been cleared for marketing. These records must be made 
available for inspection upon reasonable request by a representative of the Sponsor or regulatory 
authorities. 
Subject source documents are the physician’s records maintained at the investigational center. The 
information collected on the eCRF must match the information found on the charts.  
The eCRF data will be collected electronically. Instructions for entering data via internet will be 
provided in the eCRF Completion Guidelines and training will be provided to the investigational 
center staff prior to initiation of the center. 
Periodically, where appropriate, the Monitor or other authorized Sponsor personnel will visit the 
investigational center for the purpose of comparing the data on the eCRF with the source 
documents. The Investigator agrees to make source documents available for this purpose. The 
eCRF should be completed as soon as possible after the data are available. 
In the event the Investigator retires, relocates, or for any other reason withdraws from the 
responsibility for maintaining records for the period of time required, custody of the records will 
be transferred to any other person who accepts responsibility for the records, e.g., the Sponsor, an 
IRB/IEC, or another Investigator. Notice of such transfer will be provided in writing to the 
Sponsor. 
 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will be responsible for recommending 
whether changes to the study may be required and whether to continue or terminate the trial as 
established in its stopping rules. Stopping rules will be defined by the DSMB and outlined in the 
DSMB charter. The stopping rules are based on safety criteria and there will be no stopping based 
on efficacy criteria.   

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The DSMB will receive notification of any expedited unanticipated adverse device effects 
(UADEs). A consideration for holding a review meeting or stopping further enrollment to the trial 
may be made if there is: 
• an unanticipated patient death definitely or probably related to the device, or 
• there is a pattern of serious toxicity clearly related to the device as assessed by the DSMB 
members based on the severity of disease of the enrolled population. Such a toxicity pattern 
must be different from what might be expected from those events associated with 
progression of the patient's disease.   
 
The DSMB may provide additional considerations as outlined in the DSMB charter. In order to 
ensure that the DSMB will be fully informed while reviewing UADEs, serious toxicity or any 
other safety concerns related to the device, the DSMB will be unblinded in its assessment of this 
safety data. The DSMB will develop a consensus on its list of recommendations, including that 
relating to whether the trial should continue. 
In the absence of notifications of UADEs or serious safety related concerns, DSMB will schedule 
regular meetings at a frequency outlined in the DSMB charter.  
The Sponsor will be responsible for deciding whether to amend the protocol, to continue or to stop 
the trial based on the DSMB recommendations. 
 Termination of the Study 
The Sponsor reserves the right to terminate this study prematurely, either in its entirety or at a 
specific study center, for reasonable cause provided that written notice is submitted a reasonable 
time in advance of the intended termination. The Investigator may also terminate the study at their 
study center for reasonable cause, after providing written notice to the Sponsor a reasonable time 
in advance of the intended termination. Neither party requires advance notice if the study is stopped 
due to safety concerns. If the Sponsor chooses to terminate the study for safety reasons, it will 
immediately notify the Investigator and subsequently provide written instructions for study 
termination. Subjects who have not completed treatment in the study at the time of termination 
will be advised and offered alternative treatment, as medically appropriate.    
 Publication Policy 
Study information is considered confidential and may not be published or otherwise disclosed 
without permission from the Sponsor. At a minimum, study results will be published on 
www.clinicaltrials.gov on all primary and secondary outcomes, no later than 1 year after 
completion of the trial (including completion of the trial if it has been terminated early).   
 Financial Disclosure  
Consistent with Title 21 CFR Part 54, all Investigators will complete a Financial Disclosure Form 
that permits the Sponsor to demonstrate that an Investigator has no personal or professional 

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financial incentive regarding study outcome or the future approval or disapproval of an 
investigational device such that the Investigator’s research might be biased by such incentive. 
 Personnel Responsibilities 
 Investigator(s)  
The following are the responsibilities of the Investigator(s): 
1. Permit Sponsor representatives to inspect facilities and records. 
2. Submit CIP and ICF to the IRB/IEC and await approval. 
3. Submit proposed amendments to the CIP and ICF to the IRB/IEC and await approval, 
unless the change reduces the risk to subjects. 
4. Obtain signed ICF from each subject prior to subject enrollment. 
5. Maintain subject blinding regarding the randomization arm to which they are assigned, 
throughout the study. 
6. Enroll subjects, execute study, transcribe data from source documents to case report 
forms. 
7. Address questions and/or inconsistencies reported on the eCRFs. 
8. Submit annual progress reports, final reports and AE reports to IRB/IEC and to Sponsor. 
9. Maintain device accountability throughout the study, including recording their receipt, 
use, disposition and return of all devices at the end of the study. 
10. Conduct study in accordance with the CIP and in compliance with GCP. 
11. Maintain medical histories of subjects. 
12. Retain study records for a minimum of 2 years after receiving written notification from 
Sponsor that the investigational device has been cleared for marketing. 
 Institutional Review Board/Institutional Ethics Committee 
The following are the responsibilities as defined by IRB/IEC policies: 
1. Review and approve, modify or disapprove the study CIP. 
2. Receive annual and final reports on study progress. 
3. Review and approve, modify or disapprove the ICF. 
 Sponsor and/or Designee 
1. Submit and obtain an approved Investigational Device Exemption (IDE) from Food and 
Drug Administration (FDA) prior to initiating this study. 
2. Ensure study is conducted in accordance with the CIP and GCP. 

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3. Assure IRB/IEC approval of the CIP and ICF is obtained. 
4. Select Investigators. 
5. Review prospective Investigator curriculum vitae (CVs) and qualify Investigators for the 
study. 
6. Obtain investigator agreement and financial disclosure for all study personnel for which it 
is required. 
7. Provide the devices to the study centers as needed. 
8. Conduct day-to-day administration of study. 
9. Investigate unanticipated AEs. 
10. Document CIP deviations. 
11. Submit required reports to FDA and other regulatory agencies as applicable. 
 

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2 Introduction and Study Rationale 
Pleural effusions, or excess fluid build-up between the pleural linings of the lung, affect over 
1 million people in the United States annually.1 While some effusions are asymptomatic, most 
result in significant breathlessness for patients. Of these, over 150,000 effusions are secondary to 
a malignancy,1,2 and most of those are recurrent and unresponsive to traditional medical 
management. The prognosis for patients with malignant pleural effusion (MPE) is nearly always 
poor, with average life expectancy following diagnosis of 4-6 months.1 
Treatment for MPE has traditionally focused on three approaches: repeat thoracentesis, chemical 
pleurodesis, or placement of an IPC. Although a single thoracentesis procedure is the least invasive 
and least expensive option, relief is usually short lived. Repeated thoracentesis is possible, but 
requires the subject to visit the clinic frequently in order to manage their symptoms. This approach 
does not lead to consistent symptom control, increases risks of infection, and is particularly time 
consuming for patients with a short life expectancy. 
The most commonly used alternative, chemical pleurodesis, is intended to fully resolve the 
effusions but requires a typical in-patient hospital stay of 4 to 9 days2,3 and may result in significant 
pain and fever following the introduction of the pleurodesis agent. The agent is usually introduced 
via a chest tube (inserted under local anesthetic) or insufflated during thoracoscopy (which may 
be performed under sedation or general anesthetic). The most commonly used agent for 
pleurodesis worldwide is talc.1,2,4  Although talc is effective, it still fails to achieve pleurodesis in 
a significant proportion of patients. Additionally, even for those talc patients who initially achieve 
pleurodesis, up to 30% have recurrence after 30 days.1,4  Silver nitrate has also been used and 
studied extensively for pleurodesis, both in animals and in humans. From 1932 to 1983, silver 
nitrate was one of the primary agents to initiate pleurodesis for pneumothorax and other conditions, 
including pleural effusions.5-10 
More recently, a clinical study in 2005 showed silver nitrate to be effective in achieving 
pleurodesis with minimal side effects.11  
In 2007, a clinical study of over 600 subjects showed silver nitrate to be effective in achieving 
pleurodesis.12 By contrast, an IPC is typically placed on an out-patient basis using local anesthesia, 
and can be used to drain a recurrent pleural effusion at home by the patient or caregiver using 
vacuum bottles. The market-leading IPC is the PleurX Pleural Catheter, manufactured by 
CareFusion, Inc. It is currently indicated for both the palliation of dyspnea due to pleural effusion 
and for providing pleurodesis. 
The ideal approach to managing MPE, therefore would be to reliably and permanently resolve 
effusions (i.e., achieve pleurodesis), in a short period of time and in an out-patient setting, with 
lower levels of pain and lower costs. This is particularly true if the outpatient management of MPE 
can provide equivalent or even favorable quality of life (QoL) results compared to other (inpatient) 
treatment options without negatively impacting mortality.13  

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In addition to the cost-savings, outpatient treatment, when possible, is important because patients 
with MPE are older, on average (between 60 to 67 years old)13-16 with a relatively a short life 
expectancy. Although the PleurX catheter is currently indicated for pleurodesis, its rate of 
achieving pleurodesis is typically lower than that of talc (46% in a median of 26.5 days and mean 
of 56 days14 for PleurX vs 78% talc insufflation pleurodesis success at 30 days).4  Furthermore, the 
average time required to achieve pleurodesis using PleurX (around 2 months)14 is less than optimal 
for clinicians and patients who desire both a timely and definitive resolution of the pleural effusion 
symptoms. The SNCIPC has been designed with the aim of enhancing the PleurX pleural catheter’s 
pleurodesis performance by the addition of an established pleurodesis agent, silver nitrate. A 
secondary benefit to this approach for the relatively small proportion of patients who potentially 
may not achieve pleurodesis even with the addition of silver nitrate is the ability for those patients 
to still drain the pleural effusions through the same catheter, without the need for an additional 
invasive procedure. 
 
PleurX Indwelling Pleural Catheter System 
The PleurX pleural catheter first received FDA clearance and Conformite Europeenne (CE) 
marking in 1997 through 510(k) K971753 and TUV certificate G1 11 06 70837 016, respectively. 
The safety and effectiveness of the PleurX product line was originally established following a 
clinical study (IDE G930085) performed by Putnam et al. from 1994 to 1997 and since this time, 
physicians around the world have gained considerable experience using pleural catheters in both 
in-patient and out-patient settings.14 The Putnam study was also able to support the literature which 
suggested that pleurodesis could be achieved more readily if the pleural space was well drained, 
keeping the pleura in close apposition. In that study, 42 of 91 (46%) subjects treated with an IPC 
achieved pleurodesis within 8 to 223 days (median = 26.5, mean = 56 days). Four subsequent 
studies of the PleurX pleural catheter yielded pleurodesis rates of 41 to 59% within median times 
of 39 to 90 days17-20, leading to the conclusion that although an uncoated PleurX pleural catheter 
can achieve pleurodesis, it is likely to do so in a timeframe and at rate of occurrence that is variable 
and less than optimal for some subjects.  
The primary PleurX pleural catheter material is silicone, which includes a stripe of barium sulphate 
to aid visualization under fluoroscopy. The indwelling portion of the catheter includes multiple 
fenestrations to help collect the excess pleural fluid to be drained, as well as a polyester cuff that 
allows tissue in-growth near the skin to help reduce infection. The external portion of the catheter 
includes a valve at the proximal end, which is used to seal the catheter when not in use and allow 
controlled access during drainage (Figure 2-1; for the purposes of this document, distal is defined 
as furthest away from the clinician and proximal is defined as closest to the clinician). 

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Figure 2-1.  The PleurX indwelling pleural catheter 
 
As noted above, the PleurX pleural catheter is FDA cleared and CE marked for both palliation of 
dyspnea associated with pleural effusions and for pleurodesis. In clinical practice, the current 
PleurX product is most commonly used to palliate symptoms associated with recurrent pleural 
effusions in terminal cancer patients. 
 
Silver Nitrate-Coated Indwelling Catheter System 
Silver nitrate has been used and studied extensively for pleurodesis, both in animals and in humans. 
5-12, 21-33 The addition of a silver nitrate coating to the PleurX pleural catheter is expected to create 
a more consistent pleural layer inflammatory response, and thereby reduce the variability and 
overall timeframe in which the PleurX pleural catheter achieves pleurodesis. From 1932 to 1983, 
silver nitrate was one of the primary agents to initiate pleurodesis for pneumothorax and other 
conditions, including pleural effusions. 5-10 
More recently, a clinical study in 2005 showed silver nitrate to be effective in achieving 
pleurodesis with minimal side effects, utilizing half the dose typically used in earlier studies (i.e. 
100 mg vs. 200 mg).11  
A clinical study of over 600 subjects in 2007 showed silver nitrate to be effective in achieving 
pleurodesis, utilizing a relatively high dose of 1000 to 1500 mg.12 Beginning in the early 1990s, 
new research was conducted to see if lower concentrations (doses) of silver nitrate could still be 
effective, with the intention of reducing past side-effects associated with the agent which often 
included pain. The research showed that lower doses could indeed still produce pleurodesis, while 
reducing the side effects.24, 27, 28 Several animal studies since 1995 have also confirmed the safety 
and efficacy of lower-dose silver nitrate for pleurodesis when compared with other pleurodesis 
agents that are more commonly used today.24-32 
Silver nitrate has also been used as an antimicrobial, a cautery agent, and to treat warts.34 
A pilot clinical trial was also conducted to evaluate the investigational SNCIPC device. The SEAL-
MPE Trial was a Pilot Study Evaluating the Initial Safety and Efficacy of the Silver Nitrate-Coated 

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Indwelling Pleural Catheter for the Medical Management of Symptomatic, Recurrent, Malignant 
Pleural Effusions. This single study center, single-arm investigation was the first use of this device 
with enrollment of 10 patients and was conducted at Southmead Hospital, in Bristol, UK.   
The purpose of the pilot study was primarily to provide data regarding the safety of the SNCIPC 
in patients suffering with recurrent, symptomatic MPE. However, clinical effectiveness and 
performance characteristics of the SNCIPC were also assessed. The primary endpoint was to 
evaluate device-related safety and AEs. Secondary endpoints included breathlessness and chest 
pain (as measured by visual analog scale [VAS]); pleurodesis success at 14, 28 and 60 days; time 
to pleurodesis; QoL as measured by the EQ-5D-5L health status questionnaire; serum and pleural 
fluid silver levels; and to assess the need for further pleural intervention post-IPC removal. Overall, 
the results indicated that there were no safety concerns that would prevent the device from moving 
onto the larger, multi-center, pivotal clinical trial being proposed. There were no unanticipated 
serious adverse device effects (USADEs) reported during the 60-day follow-up period. The pilot 
study findings and observations were used to inform the design of the proposed pivotal trial. 
Further details on results of this study are discussed in the Report of Prior Investigations.      
In summary, published data and preliminary results of the unpublished pilot study suggest that 
silver nitrate is effective in achieving pleurodesis and that lower doses than those used historically 
are likely to improve its safety profile for this indication. This clinical investigation will evaluate 
the safety and performance of SNCIPC, a modified PleurX catheter which contains a silver nitrate 
coating on the indwelling portion of the catheter to enhance pleurodesis. 
An overall image and detailed description of the device is provided in Section 6. 

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3 Study Purpose/Objectives 
The primary objective is to demonstrate that the SNCIPC Pleural Catheter shows superiority 
compared with the PleurX Pleural Catheter in the proportion of subjects achieving pleurodesis 
without recurrence at 30 days. Recurrence is defined as symptomatic pleural effusion confirmed 
by CXR and computed tomography (CT) scan with an estimated >300 mL of fluid in the treated 
hemithorax.  
The secondary objectives of this study are to summarize measures of time to confirmed pleurodesis 
and time to recurrence. 
For the secondary objectives, when non-inferiority is achieved, superiority will subsequently be 
tested to show SNCIPC superiority over the PleurX Catheter. 
The following exploratory objectives will be evaluated including device safety, device 
performance, quality of life (QoL) and medical resource utilization (MRU). 

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4 Investigational Plan 
 
Overall Design and Plan of the Study 
This is a prospective, multicenter, randomized, controlled, single-blinded pivotal study of the 
SNCIPC as compared to the PleurX Pleural Catheter when used as intended to palliate dyspnea in 
subjects with recurrent pleural effusions. The study is designed to provide powered evidence that 
the SNCIPC shows superiority compared to PleurX Pleural Catheter in the proportion of subjects 
achieving pleurodesis without recurrence at 30 days.  
The SNCIPC is equivalent to the predicate device (PleurX Pleural Catheter) in design, materials, 
manufacturing, intended use, and preclinical test results, with the exception of the added silver 
nitrate coating. The silver nitrate coating is intended to enhance the pleurodesis-inducing 
properties of the IPC.   
Eligible subjects will have undergone at least 1 successful lung expansion after thoracentesis and 
are experiencing a reoccurrence of pleural effusions that are causing dyspnea. Subjects or their 
caregiver (friend, family member or paid healthcare professional) must be able to perform at-home 
pleural effusion drainage for up to 90 days post-IPC insertion. Clinicians, caregivers and patients 
will be adequately trained to ensure that the drainage procedure and measurement of drainage 
volumes will be consistent.  
Subjects will be recruited during consult for their procedure and will return to the study center to 
be randomized to receive either the SNCIPC (treatment group) or the PleurX Pleural Catheter 
(control group) in a 2:1 ratio on the day of the procedure. Subjects will be considered enrolled at 
the time of randomization. A trained study staff member will insert the IPC in a dedicated 
procedure room or operating suite using the same technique as for insertion of the PleurX catheter. 
At the time of insertion, the pleural cavity should be maximally drained (as limited by subject signs 
or symptoms). The day of IPC insertion is defined as Day 0. Subjects should have a post-insertion 
CXR (posterior-anterior and lateral) within 6 hours of the procedure concluding, but after they 
have been maximally drained. Assessments for trapped lung should be done at Day 14 and Day 30 
post insertion.   
After IPC insertion, subjects will be evaluated at 14-day (± 2), 30-day (±2), 60-day (±3), and 
90-day (±3) follow-up visits plus telephone assessments by study center personnel at 7 (±2) days, 
45 (±3) days and 75 (±3) days.   
In addition, subjects must call the study center to make an appointment for an unscheduled visit to 
assess for pleurodesis and potential IPC removal once they measure an output of ≤50 mL of pleural 
fluid on 3 consecutive drainages over a minimum of 5 days. Once pleurodesis is confirmed every 
effort should be made to schedule IPC removal as soon as feasible. At the time of SNCIPC 
removal, the SNCIPC should be shipped to the designated central analytical laboratory for residual 
silver testing. 

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Safety and efficacy assessments will be performed as noted in the Schedule of Procedures and 
Assessments (Section 7.1). 
End of study (EOS) is defined as the date the last subject completes the last visit of the study 
(LSLV).   
 

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Figure 4-1.  Study Flow Diagram 
 
 
 
 
 
 
Eligible subjects who provided written informed consent 
Baseline assessment within 14 days of consent. 
To include: Medical history, Medication history, Physical/respiratory examination,  QoL 
(chest pain, dyspnea, EQ-5D-5L health status questionnaire), Chest X-ray, Blood 
samples, Pregnancy test (if applicable), Temperature, AE monitoring  
Catheter insertion within 72 hours of baseline assessment. (Note: procedure 
performed on an out-patient basis, unless otherwise directed by the physician.)   
Maximal drainage at time of catheter placement. Pleural fluid sample retained and serum 
samples collected from SNCIPC subjects only for silver analysis.  Medical resource 
utilization data collected.
Face-to-Face Follow-up visits at days 14 (±2), 30 (±2), 60 (±3), and 90 (±3).  
Telephone assessments on days 7 (±2), 45 (±3) and 75 (±3)  
Assessments may include: Drainage and chest X-ray, Determination of pleurodesis, 
Determination of previously unidentified Trapped Lung, Record of AEs, Record of 
further pleural interventions, Assessment of recurrence post-pleurodesis, Record of 
current oncological treatment, Review of subject diary, Assessment of analgesia 
requirements, Examination of drain insertion site, Physical/respiratory examination, 
EQ-5D-5L health status questionnaire, Blood and fluid samples, Pregnancy test, Record 
of medical resource utilization.  
Drainage daily from placement until 14-day follow up visit, then at least 3 per week 
until 30-day follow up visit, then as needed.  
Subject diary to include: chest pain and dyspnea scores; drainage volumes; OTC and 
prescription medications; frequency and use of oxygen; temperature; unplanned hospital 
or emergency department visits. 
Assessment of Pleurodesis and Recurrence 
Unscheduled visits to determine pleurodesis success and recurrence. 

Pleurodesis success: collection of a minimum of 3 consecutive drainages of ≤50 mL of 
pleural fluid over a minimum of 5 days (which begin with the first drainage of ≤ 50 mL) 
AND chest X-ray which shows opacification due to pleural fluid occupying less than 
one quarter of the heimthorax (as judged by the investigative site and third party 
radiology service). 

Recurrence: symptomatic pleural effusion confirmed by chest X-ray and CT scan 
with an estimated >300 mL of fluid in the treated hemithorax. 
Post day 90, subjects will revert to standard clinical follow-up. 

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Risk/Benefit and Ethical Assessment 
 Description of Patient Population 
The patients likely to be considered for eligibility in this study typically have end-stage cancer, are 
on average between 60 to 67 years old, and may have additional significant health issues that could 
be secondary to the malignancy. Eligible subjects will be ≥ 18 years old (male or female), 
experiencing dyspnea secondary to recurrent MPE, who are capable of managing at-home pleural 
infusion drainage and meet all other inclusion and exclusion criteria as defined in the study 
protocol (Section 5). A targeted total of 119 subjects will be enrolled in the investigation. 
Information regarding sample size justification is described in Section 10.6. 
 Justification for Investigation  
The proposed clinical investigation presented in this IDE application involves the use of the 
SNCIPC investigational medical device. The SNCIPC investigational device is a modification to 
the PleurX catheter (a previously FDA cleared IPC). 
The use of IPCs to manage MPE is well established in clinical practice. They have two purposes: 
to provide a means of draining large volumes of pleural effusion in the patient’s home or outpatient 
setting, thereby reducing dyspnea, and to induce pleurodesis in some patients. This pleurodesis is 
thought to be induced by the presence of the catheter through mechanical irritation of the pleural 
surfaces and keeping the pleural space dry through repeated drainages. It results in a closure of the 
pleural space which eliminates the effusion and related symptoms. There are a number of IPCs 
available in the US market as FDA cleared devices for this use. The proposed investigation is 
designed to provide evidence of safety and efficacy of a modified FDA cleared IPC (510 [k] 
K121849), the PleurX catheter (CareFusion 2200, Inc.). 
The modification associated with the SNCIPC investigational device involves the application of 
the silver nitrate coating that enhances the pleurodesis-inducing properties of the catheter. The 
device description (Section 6.1) provides further details on the silver nitrate coating.  
The intention is that the SNCIPC investigational device will increase clinical utility by providing 
clinically significant improvements in time to pleurodesis, as well as the likelihood of pleurodesis 
in the patient.  
 Scientific Soundness and Ethical Considerations  
This study is designed to provide scientifically sound data to support conclusions about the safety 
and effectiveness of the SNCIPC in subjects with symptomatic, recurrent MPE. Measures taken to 
ensure that the study provides scientifically valid data and to minimize potential bias are as 
follows: 
1. Subject selection, study procedures and endpoints are prospectively defined in a detailed 
clinical investigational plan.  

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2. To address issues of potential bias, subjects are randomly assigned to treatment with 
either the SNCIPC or PleurX control device and subjects remain blinded to the treatment 
assignment throughout the study duration. 
3. Standardization of the primary outcome measure. The primary study effectiveness 
endpoint, pleurodesis, is an objective measurement obtained independently by trained 
research personnel using drainage volumes and CXR. 
4. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and other anti-
inflammatory agents are tracked during the study, as well as other medications and 
supplements. 
5. Subject blinding will be maintained through the study duration. 
6. Standardized eCRFs will be used for all subjects to ensure uniform data collection.  
 Anticipated Benefits to Study Subjects 
The use of the SNCIPC device is expected to both increase the proportion of patients who achieve 
pleurodesis and to reduce the time in which pleurodesis occurs, when compared to a standard IPC. 
The clinical benefits anticipated from the SNCIPC and its potential early removal once pleurodesis 
is attained are as follows: 
 Improved patient QoL 
 Reduced risk of pleural infection  
 Reduced risk of procedure site infection 
 Reduced risk of IPC-related pain. 
 Anticipated Risks to Study Subjects 
4.2.5.1 Treatment Related Anticipated Adverse Events 
Anticipated AEs are those AEs which are anticipated to occur during this clinical trial and are 
believed to be consistent with those associated with the study population, the IPC insertion 
procedure or pleural effusion drainage, or those which have been identified by CareFusion as part 
of their risk assessment. These risks are well understood for any IPC placement, and are not 
necessarily unique to the SNCIPC. 
The following are anticipated AEs and should be recorded. This list is not exhaustive; any other 
AE which is considered by the Investigator to be relevant should also be recorded. If an expected 
AE meets the criteria for a serious AE (SAE) then it should also be recorded and reported to the 
designated CRO and to the ethics committee as described in Section 8.3. 

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Associated with IPC insertion procedure (including initial drainage), and removal 
procedure: 
 Catheter site bleeding after skin closure following placement, requiring treatment beyond 
redressing or application of pressure 
 Chest pain/ discomfort related to the insertion (and initial drainage) procedure, requiring 
treatment beyond oral analgesia 
 Hypersensitivity reaction to either local anesthetic, conscious sedation (if used), or general 
anesthetic  
 Accidental or non-accidental damage to catheter due to placement technique 
 Catheter dislodgement after insertion which results in cuff migration through the skin 
incision 
 Damage to underlying lung or other viscera during placement  
 Surgical emphysema which either causes patient symptoms or requires treatment 
 Pleural fluid leakage or ooze from insertion site requiring intervention 
 Wound dehiscence requiring intervention 
 Persistent hemodynamic compromise unresolved after basic measures 
 Pneumothorax/ hydropneumothorax on post-insertion CXR, requiring intervention 
 Need to remain in hospital after insertion for reasons related to trial participation 
 Re-expansion pulmonary edema requiring treatment 
 Hemothorax, as defined by a pleural fluid hematocrit ≥50% of the blood hematocrit 
 Catheter site bleeding after skin closure following removal, requiring treatment beyond 
redressing or application of pressure 
 Catheter removal site infection (as defined by the presence of either erythema or discharge 
in association with the removal site) requiring treatment 
 Chest pain/ discomfort related to the catheter removal procedure, requiring treatment 
beyond oral analgesia 
 Inability to remove catheter without causing undue distress. 
 
Associated with the on-going placement and drainage of the IPC: 
 Catheter site bleeding after skin closure, requiring treatment beyond redressing or 
application of pressure 
 Catheter site infection (as defined by the presence of either erythema or discharge in 
association with the insertion site) requiring treatment 

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 Pleural infection (as defined by the presence of any of the following: positive pleural fluid 
culture; purulent pleural fluid; clinical signs and test results consistent with pleural 
infection) 
 Chest pain/ discomfort related to the insertion procedure, requiring treatment beyond oral 
analgesia 
 Other pain associated with position or repeated drainage of the catheter, requiring treatment 
beyond simple analgesia (paracetamol, NSAIDs, weak opiates) 
 Accidental or non-accidental damage to catheter during use 
 Catheter dislodgement which results in cuff migration through the skin incision 
 Hypersensitivity reaction to associated dressings, requiring treatment 
 Surgical emphysema which either causes patient symptoms or requires treatment 
 Pleural fluid leakage or ooze from insertion site requiring intervention 
 Wound dehiscence requiring intervention 
 Persistent hemodynamic compromise unresolved after basic measures 
 Pneumothorax/ hydropneumothorax on post-insertion CXR, requiring intervention 
 Procedure tract metastasis, as defined as a new subcutaneous nodule >1 cm in diameter 
(that is not considered to be granulation tissue) within 5 cm of a relevant incision site 
 Hemithorax, as defined by a pleural fluid hematocrit ≥50% of the blood hematocrit 
 Re-expansion pulmonary edema requiring treatment 
 Pleural fluid loculation, as seen on thoracic ultrasound or CXR, resulting in either: 
a) an increase in symptoms or 
b) a reduction in drainage output not considered to be due to pleurodesis or drain 
blockage to such an extent such that the Investigator would consider device removal 
or the administration of intrapleural fibrinolytics. 
Associated with trial participants’ underlying malignancy: 
 Death or hospital admission due to disease progression or complication(s) of said disease 
 Symptoms attributable to side effects of medications used for control of underlying 
malignancy, or symptoms caused by it, leading to hospital admission or death. 
4.2.5.2 Anticipated Adverse Device Effects 
 Allergic reaction 
 Transient pain 
 Increased production of pleural fluids shortly after catheter placement leading to increased 
dyspnea and/ or pain 

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 Coated portion of catheter placed in the tunnel resulting in pain/ irritation 
 Catheter/ valve malfunction resulting in fluid leakage or pneumothorax and leading to 
catheter removal 
 Coating damage during placement resulting in difficulty feeding through peel-away sheath, 
change in the drug elution profile, or some top-coat being left in the body after catheter 
removal 
 Catheter cut by physician during catheter placement resulting in a lower dose of silver 
nitrate, a change in elution profile, or cause the coating to be left in the body when the 
catheter is removed 
 Occlusions of the drainage system (drainage bottle or drainage line) resulting in the need 
for another drainage bottle or line to be used 
 Catheter occlusion resulting in the physician needing to perform a flushing procedure or 
removing the catheter   
 Silver nitrate left in tunnel from placement procedure resulting in limited tissue ingrowth 
to the cuff 
 Encasement of catheter/ loculation of pleural space resulting in the inability to fully drain 
the space and requiring another intervention 
 Failures related to drug content and elution  
o Wrong dosage (outside specified range) resulting in pain if too high or lower 
pleurodesis effect if too small 
o Non-homogenous silver nitrate coating resulting in highly concentrated silver 
nitrate causing tissue damage or bleeding in the pleural space 
o Wrong elution curve resulting in pain if too fast or lower pleurodesis effect if too 
slow 
o Effects of silver nitrate on the pleural space including increased pleural effusion 
leading to increased dyspnea and pain associated with the therapeutic effect of the 
device 
 Effects of the coating on catheter mechanical properties including a reduction in catheter 
strength causing tears or rips during removal, a reduction in valve sealing properties 
causing fluid leakage or pneumothorax 
 Premature catheter removal when pleurodesis is incorrectly assumed leading to dyspnea 
and need for further intervention 
 Effect of unblocking the catheter on pleurodesis when a fibrinolytic agent used to unblock 
the catheter decreases the pleurodesis effect 
 Silver nitrate coating affected by light exposure causing degradation that reduces the 
pleurodesis effect 
 Biocompatibility including leachables/ extractables leading to a patient reaction to the 
device. 

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 Mitigation Efforts 
The following features of the design and manufacturing/ quality control are intended to minimize 
the occurrence and/or impact of the anticipated adverse device effects (ADEs) noted above should 
they occur. 
Coated portion of catheter placed in the tunnel:  The coated portion of the device has been limited 
in length to just beyond the most proximal fenestration in order to reduce the likelihood of leaving 
the coated portion of the catheter in the tunnel tract. 
Catheter/ valve malfunction:  The catheter and valve have undergone stringent design testing, and 
are manufactured under Good Manufacturing Practice (GMP) to ensure the highest quality 
standards. 
Coating damage during placement: The choice of the top-coat polymer material is intended to 
simultaneously control the release of the silver nitrate and ensure durability for the typical forces 
and stresses applied during the placement procedure. The coated catheter has undergone design 
testing to ensure the coating is not damaged during placement. 
Catheter cut by physician:  Physicians are trained and instructed (per instructions for use [IFU]) 
not to cut the tip of the catheter during tunneling. In addition, this protocol specifically calls out 
the placement procedure (which does not include cutting of the catheter tip).  
Occlusions of the drainage system (drainage bottle or drainage line):  Occlusions of the drainage 
system, including the bottle or drainage line are easily managed by use of additional bottles or 
replacement of the drainage line. This can be performed at home without the need to return to the 
hospital. Patient follow-up occurs at regular intervals, and will assist in mitigation of this risk. 
Proper instruction is given to all patients when an IPC is placed to ensure they are capable of 
managing the effusion at home. 
Catheter occlusion:  Catheter occlusion may occur due to patient physiology. The Catheter Access 
Kit is intended to assist in clearing blockages or obstructions within the catheter without the need 
to remove the catheter. 
Silver nitrate in tunnel:  The choice of the top-coat polymer material is intended to simultaneously 
control the release of the silver nitrate and ensure durability for the typical forces and stresses 
applied during the placement procedure. The coated catheter has undergone design testing to 
ensure the coating is not damaged during placement resulting in being left in the tunnel. 
Encasement of catheter/ loculation of pleural space:  Loculation may occur due to patient 
physiology and clinical state. However, frequent follow-ups reviewing the drainage output, 
symptoms and CXR will determine if this has occurred and adjust treatment accordingly.  
Failures related to drug content and elution:  The catheter is designed to contain 100 mg of silver 
nitrate which will elute over time. The manufacturing process applies a spray coat of the silver 
nitrate. This process limits the amount of total silver on the catheter based on tightly controlled 
parameters and multiple tests to confirm the amount of silver nitrate applied.  

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The spray technology also creates a homogeneous coating of silver nitrate along the coated length. 
This is confirmed through design testing. 
The design of the coating is intended to limit the silver nitrate from releasing as a bolus. The 
coating is applied in a dip process. Dip parameters are tightly controlled and tested to confirm the 
elution rate of the catheter. 
Effects of the coating on catheter mechanical properties:  The choice of the top-coat polymer 
material is intended to simultaneously control the release of the silver nitrate and ensure durability 
for the typical forces and stresses applied during the placement procedure. The coated catheter has 
undergone design testing to ensure the coating is not damaged during placement. 
Premature catheter removal:  Premature catheter removal is not anticipated based on the design 
of the protocol and mandatory checks in place to confirm pleurodesis. Catheter removal due to 
patient health concerns will be documented per AE reporting requirements. 
Effect of unblocking the catheter on pleurodesis:  Unblocking the catheter using a declotting agent 
is not anticipated to effect pleurodesis. The Catheter Access Kit IFU provides information on the 
internal volume of the catheter so that the declotting agent will be limited to the catheter and not 
significantly enter the pleural space.   
Silver nitrate coating affected by light exposure:  The SNCIPC is protected from ultra-violet light 
during manufacturing by the addition of UV filters in the coating area. In addition, the catheters 
are protected from light by the packaging, including a foil pouch. Light should not affect the 
catheter during the length of a typical catheter placement procedure. 
Biocompatibility including leachables/ extractables:  The catheter is considered biocompatible per 
applicable ISO 10993 testing. Leachables/ Extractables testing has been performed and has shown 
no increased toxicological risk over the PleurX catheter. 
4.2.6.1 Changes to the IFU, As Identified In The Risk Analysis Report 
The following risk items are to be included in the SNCIPC IFU due to the residual risks associated 
with the silver nitrate coating. They were not, therefore, previously included in the standard PleurX 
Catheter IFU. 
 A new contraindication was added: “Use of the Coated Pleural Catheter is contraindicated 
when there is a known silver hypersensitivity.” 
 Two new cautions were added: “To preserve coating integrity, avoid excessive handling of 
the coated portion of the catheter.” and “Potential complications of a silver nitrate coated 
catheter may include loculations or catheter occlusions.” 
 The following note is given when attaching the fenestrated end of the catheter to the 
tunneler:  “Note: Hold the catheter by the distal tip when assembling to the tunneler.”    

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 The following note is given when detaching the catheter from the tunneler: “Disconnect 
the tunneler from the catheter by pulling it. Note: Do not cut the catheter.” 
 An incise patch will be used to cover the fenestration in the sterile drape, to protect the 
patient’s skin from exposure to silver nitrate during the procedure. 
 Possible Interactions with Concomitant Medical Treatments 
There are not expected to be any reactions with subject’s concomitant medications. 
 Benefit-Risk Analysis Conclusion 
The potential benefits for patients in the trial are centered on the potential for a more rapid 
achievement of pleurodesis. These clinical benefits are a reduction in dyspnea and reduction in 
effusion volume. The risks associated with the trial are largely in relation to administration of 
silver nitrate in conjunction with the well-established PleurX IPC. The toxicity of silver is well 
documented, and the use of silver nitrate in pleurodesis has been extensively reported in numerous 
publications as recently as 2013. Silver nitrate is an appropriate pleurodesing agent with 
established efficacy, and the risks (pain, increased effusion) are documented as being mitigated by 
a lower dose of silver nitrate administered over time rather than as a bolus. Care has been taken in 
the design and manufacture of the silver nitrate coating. The coating has been designed and 
manufactured to minimize risks as far as possible, while maintaining the incremental benefits over 
the current standards of care for MPE. The majority of the potential AEs that could be anticipated 
in the study (Section 4.2.5) are related to the procedures involved in management of MPE with a 
standard IPC and are well known and easily managed by the treating physician. Potential events 
related to the silver nitrate (hypersensitivity, transient pain, increased effusion volume) are 
mitigated by the patient follow-up schedules, clinician training, and the protocol design. These 
risks are clinically comparatively insignificant when set against the potential benefits afforded to 
a patient population of the type to be included in this investigation. 

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5 Selection of Study Population 
Eligible subjects will be ≥18 years old, experiencing dyspnea secondary to recurrent MPE and 
meet all other inclusion and exclusion criteria. Additionally, subjects or their caregiver (friend, 
family member or paid healthcare professional) must be capable of managing at-home pleural 
effusion drainage. 
Investigators must keep a record of subjects who were considered for enrollment but were never 
enrolled (e.g., subject screening log so as to address concerns over selection bias). 
 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria: 
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 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 a pleural 
drainage. 
Significant trapped lung is deemed present if any 1 of the following criteria is met:  
a) A CXR shows hydropneumothorax.  

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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.  
7. Subject has a hypersensitivity to silver, silver nitrate, or silicone. For subjects with a 
self-reported silver hypersensitivity who wish to be considered for enrollment in the study, 
a confirmation test for hypersensitivity to silver nitrate will be performed. 
8. Subject has evidence, in the opinion of the Investigator, of either on-going systemic or 
pleural infection. 
9. Subject has had a lobectomy or pneumonectomy on the side of the effusion. 
10. Subject has undergone a previous attempt at ipsilateral pleurodesis which has failed. 
11. Subject has previously been diagnosed with a serious immunodeficiency disorder.  
12. Subject has bilateral pleural effusions, with both being at least moderate in size (greater 
than one-third of the hemithorax on CXR). 
13. Subject has evidence of fluid loculation such that attempts at pleurodesis are likely to be 
futile. 
14. Subject has a mediastinal shift of ≥ 2 cm toward the side of the effusion. 
15. Subject is receiving concurrent intrapleural chemotherapy or radiation therapy to the 
ipsilateral chest. 
16. Subject has any clinical condition, diagnosis, or social circumstance that, in the opinion of 
the Investigator, would mean participation in the study would be contraindicated. 
17. Subject has no access to a telephone. 
18. Subject has no documented blood values (complete blood count [CBC], coagulation tests, 
urea and electrolytes, and liver function tests [LFTs]) within the last 10 days. 
19. Subject has previously participated in any clinical trial with the investigational SNCIPC 
device. 
20. Subject currently enrolled in any other clinical investigation or who has participated in any 
clinical investigation in the 30 days prior to starting this study. 

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 45 of 90 
 
Withdrawal of Subjects 
Subjects may be discontinued from study treatment and assessments at any time. Subjects are 
also free to discontinue their participation in the study at any time, without prejudice to further 
treatment. 
Wherever possible, subjects should be seen and assessed by the Investigator(s) at withdrawal.   
In the eCRF, study completion or discontinuation will be documented with the reason for any 
discontinuation. Possible reasons for a subject discontinuing participation in the study are: 
 AE(s) that endanger the health of subjects, making it ethically unacceptable to continue 
 deterioration of the subject’s clinical condition(s) that requires appropriate 
therapy/treatment during the study period 
 withdrawal of consent 
 lost to follow up 
 death. 
In case of an AE, the subject is to be followed up until resolution of the AE.  
 
 

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 46 of 90 
6 Device Description 
 
Investigational Device –SNCIPC  
The investigational device is manufactured by the Sponsor, CareFusion 2200, Inc., and is termed 
the Silver Nitrate-Coated Indwelling Pleural Catheter, or SNCIPC.  
The SNCIPC consists of a fenestrated silicone catheter with a proximal valve mechanism and a 
polyester cuff, identical to the PleurX catheter on which it is based. The fenestrated portion of the 
catheter is coated with 100 mg (+/- 15 mg) of the pleurodesis agent silver nitrate (AgNO3) and 
inert materials which control the drug release. The inert coating materials cover the entire 
fenestrated portion of the catheter, while the silver nitrate begins approximately 3 cm from the 
distal tip. The coating ends before the subcutaneously tunneled portion of the catheter. The entire 
coated region is visually detectable (Figure 6-1).  
A barium sulphate stripe runs the entire length of the catheter to aid visualization under 
fluoroscopy. The valve is designed to prevent the passage of air or fluid in either direction unless 
it is accessed with the specifically matched drainage line or vacuum bottles, also manufactured 
and provided by CareFusion (Section 6.2).  
Manufacturing will be carried out in accordance with the requirements of Annex 13 of the GMP 
guidelines, ICH GCP requirements, Sponsor approved SOPs and all applicable US/EU laws as 
well as the local and applicable regulatory requirements.  
Mode of Action 
Like the uncoated IPC on which it is based, the primary mode of action of the SNCIPC is to provide 
intermittent drainage of fluid accumulation from around the lungs, which in turn provides 
palliative care and pleurodesis for recurrent symptomatic pleural effusions that do not respond to 
treatment of the underlying disease. Secondary to its primary mode of action, the catheter is coated 
with silver nitrate that elutes into the pleural space over time to increase the rate and proportion of 
pleurodesis events. Pleurodesis provides for catheter removal with long-lasting reduction in 
effusion volume and dyspnea without ongoing pleural drainage, catheter management, and 
catheter-associated complications.   

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 47 of 90 
 
Figure 6-1.  Silver Nitrate-Coated Indwelling Pleural Catheter 
 
 
Control Device – PleurX® Pleural Catheter 
The control device in this study is the currently marketed, FDA-approved PleurX Pleural Catheter 
system which is provided in a kit as described in Section 6.3.   
The PleurX pleural catheter consists of a fenestrated silicone catheter with a proximal valve 
mechanism, a polyester cuff, and a barium sulphate stripe to aid visualization under fluoroscopy. 
When the catheter has been placed in the pleural space, the fenestrations allow the excess pleural 
fluid to be removed by drainage through the outer end of the catheter. The valve is designed to 
prevent the passage of air or fluid in either direction unless it is accessed with the specifically 
matched drainage line or vacuum bottles, also manufactured and provided by CareFusion.     
 
Devices to be Used  
The SNCIPC will be provided in two different kits (catalog codes) for the clinical investigation:  
catalog code 50-4999 will be used for the US Clinical Trial study centers and catalog code 50-2999 
will be used for the UK Clinical Trial study centers. The SNCIPC will be exactly the same in both 
kits. The only difference between the two kits are the placement components that accompany the 
device.   
The control device will also be provided in two different kits (catalog codes). Catalog code 
50-7000B will be used for the US control device and code 50-7050 will be used for the UK control 
device. The kits contain preparation, placement, closing, drainage and dressing components as 
described in the manufacturer’s IFU. 

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
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During the clinical investigation, the SNCIPC will be used with certain non-investigational devices 
for placement, drainage and management of occlusions (if needed) as described below. The 
non-investigational devices are FDA cleared and CE marked and will be used in the clinical 
investigation in accordance with the manufacturer’s intended uses. 
 Drainage Bottle 
The SNCIPC will be intended for use with the existing FDA cleared PleurX Drainage Kit 
(50-7500B). This comprises a 500 mL vacuum bottle with drainage line. The intended uses of the 
PleurX drainage kit components are consistent with their 510K and CE-marked intended purpose 
and they are not, therefore, regarded as investigational devices. 
The SNCIPC or control device can be attached to the PleurX Vacuum Bottle (500 mL; Figure 6-2) 
for suction and drainage collection. The PleurX Vacuum Bottle is a pre-evacuated single use 
plastic vacuum bottle. The bottle is fitted with a pre-attached drainage line with an access tip that 
is unique to the PleurX pleural catheter and SNCIPC. The pinch clamp on the drainage line is 
closed before the access tip is connected to the catheter valve. Once the access tip is securely mated 
to the catheter valve, the support clip is removed from the bottle and discarded. Without the support 
clip, the flexible bottle cap and white T-plunger can be depressed, driving the spike into the foil 
covering, piercing the seal and releasing the vacuum. The pinch clamp is released and drainage 
begins.  
The materials intended for the drainage of the PleurX and SNCIPC catheters are designed to be 
used by anyone who has undergone a short training session (e.g., patients, caregivers, nurses, or 
other health professionals).  

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
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Figure 6-2.  PleurX Vacuum Drainage Bottle (500 mL) 
 
 Catheter Access Kit  
The PleurX Catheter Access Kit (50-7280; Figure 6-3) will be used to provide access to the PleurX 
Catheter for any necessary flushing to unblock the catheter. To access the SNCIPC or control 
device, the access tip is connected to the valve and a syringe with flushing agent is connected to 
the Needleless Access Valve. The intended uses of the PleurX Catheter Access Kit components 
are consistent with their 510(k) cleared and CE-marked intended purpose and they are not, 
therefore, regarded as investigational devices.   
 
Figure 6-3. Catheter Access Kit 
 
Access Tip 
Needleless Access Valve 

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CareFusion 2200, Inc. 
Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 50 of 90 
 Catheter Insertion Stylet (Component of Supplemental Insertion Kit) 
The PleurX Supplemental Insertion Kit (50-7262) contains a Catheter Insertion Stylet (Figure 6-4) 
which can be used to aid in insertion of the SNCIPC or control device by stiffening the catheter 
during insertion through the peel-away sheath. The US kit 50-4999 Coated Indwelling Pleural 
Catheter System contains the Catheter Insertion Stylet, but the UK kit 50-2999 Catheter Placement 
Mini-Kit does not. It is an optional component which the physician may choose to use if desired. 
UK physicians may pull a Catheter Insertion Stylet from the Supplemental Insertion Kit. The 
intended uses of the Catheter Insertion Stylet components are consistent with their 510(k) cleared 
and CE-marked intended purpose and they are not, therefore, regarded as investigational devices. 
The Kit also contains a valved peel-away sheath which should not be used as a part of this trial.   
Figure 6-4.  Catheter Insertion Stylet 
 
 
Packaging and Labeling 
Packaging and labeling will be carried out in accordance with the requirements of Annex 13 of the 
GMP guidelines, ICH GCP requirements, Sponsor approved SOPs and all applicable US/EU laws 
as well as the local and applicable regulations.  
Final labeling and packaging of the products will be performed by CareFusion 2200, Inc. in 
accordance with their SOPs, FDA and international regulation. Product labels comply with US and 
EU regulatory requirements including the statements “USA: CAUTION—Investigational device. 
Limited by Federal (or United States) law to investigational use” and/or “EU: CAUTION: 
Investigational device exclusively for use in a clinical investigation”.  
 
Device Storage and Accountability 
All investigational devices supplied to the study center will be fully catalogued and traceable from 
manufacture to subject insertion, and, if removed or returned, from subject to disposal, back to the 
Sponsor, or to the central analytical lab for the SNCIPC residual silver testing.  
All devices will be stored in a Sponsor-approved environment at the study center prior to insertion 
(Table 6-1); 50-7050 (UK Control Device), 50-7500B (Drainage Bottles), 50-7280 (Catheter 
Access Kit), and 50-7262 (Supplemental Insertion Kit) do not have specific storage requirements.  
Batches of the SNCIPC will be identified by unique batch number. The Principal Investigator, or 
an authorized designee, will maintain adequate records of the receipt and, when appropriate return 
or disposal of all investigational devices.  
The Principal Investigator will return to the study Sponsor any unused devices and a copy of 
the completed device inventory. 

CS-IP-VH-14-009 
 
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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 51 of 90 
Table 6-1.  Device Storage Conditions 
US Control Device 
US Test Device 
UK Test Device 
50-7000B  
50-4999 
50-2999  
Store at controlled room 
temperature (68°F to 77°F/20°C to 
25°C). Avoid freezing and 
excessive heat above 104°F (40°C). 
Caution: Contains Alcohol and 
gives off flammable vapors. Keep 
away from heat, sparks, and open 
flame. 
Store at controlled room 
temperature (68°F to 77°F/20°C to 
25°C). Avoid freezing and 
excessive heat above 104°F 
(40°C). 
Caution: Contains Alcohol and 
gives off flammable vapors. Keep 
away from heat, sparks, and open 
flame. 
 
 
Store at controlled room temperature 
(59°F to 77°F/15°C to 25°C). Avoid 
freezing and excessive heat above 
104°F (40°C). 
Note:  UK test device does not 
include Lidocaine or 
Chloroprep,therefore the approved 
temperature range is wider than the 
US devices.  
Note:  50-7050 (UK Control Device), 50-7500B (Drainage Bottles), 50-7280 (Catheter Access Kit), and 50-
7262 (Supplemental Insertion Kit) do not have specific storage requirements. 
 
Investigational Device Proposed Intended Use 
The proposed investigational device, SNCIPC, is anticipated to have the identical indications for 
use as the originally cleared PleurX pleural catheter:  
Indicated for intermittent, long term drainage of symptomatic, recurrent, malignant pleural 
effusion. The device is indicated for 1) the palliation of dyspnea due to pleural effusion and 2) 
providing pleurodesis (resolution of the pleural effusion). 
The current PleurX device has been primarily used in patients diagnosed with terminal 
malignancies.  
The PleurX pleural catheter allows a patient to periodically drain excess pleural fluid into a vacuum 
bottle in the comfort of their own home and it also leads to pleurodesis. The investigational 
SNCIPC product will be used in the same manner, but with added irritation coming from a 
sclerosing agent (silver nitrate) within the catheter coating. Since it is well established that silver 
nitrate can be used as a pleurodesis agent, it is believed that adding a silver nitrate coating to the 
currently cleared IPC will create a more consistent pleural layer inflammatory response, and will 
therefore reduce the overall timeframe in which the PleurX pleural catheter achieves pleurodesis 
and increase the frequency of pleurodesis occurrence. 
 
Investigational Device Insertion and Removal 
The SNCIPC investigational device is inserted in a procedure virtually identical to that of the 
PleurX catheter on which it is based; the only difference in procedure is that the SNCIPC insertion 
will utilize an incise patch over the fenestration of the sterile drape to protect the patient’s skin 

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CareFusion 2200, Inc. 
Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 52 of 90 
against potential exposure to silver nitrate. Full details of this procedure can be found in the 
SNCIPC IFU. One IPC will be placed per patient. Briefly, a subject is positioned so as to allow 
easy access to their fluid collection and to ensure comfort during insertion. The IPC may be 
inserted under general anesthetic or small amounts of conscious sedation, although it is typically 
performed using only local anesthetic which is infiltrated after an appropriate sterile field has been 
created. Two small skin incisions are made, between which the catheter is tunneled using a tunneler 
attached to the distal end. The fenestrated portion of the tube is then inserted into the pleural space 
using a break-away introducer and a standard Seldinger technique. The skin incisions are sutured 
closed and the catheter dressed. A typical insertion procedure may take 15 to 30 minutes.   
If removal of an SNCIPC is required, the procedure is once again identical to that of the PleurX 
catheter removal. The method is undertaken using aseptic technique and local anesthesia. A small 
incision is made adjacent to the area where the tube enters the subcutaneous tissues, before the 
cuff is freed using blunt forceps dissection. Once loose, the catheter is withdrawn in a single 
smooth motion. A typical removal procedure may take 5 to 15 minutes, although this may be 
extended if more fibrous adhesion than normal has developed. 
For the purposes of this study, all investigational device removals and insertions will be performed 
by a medical professionals trained and experienced in the use of the PleurX device.   
 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomly allocated to treatment groups on the day of IPC placement. The 
randomization will be stratified by site. The randomization codes will be generated within the 
Biometrics Department of the designated contract research organization (CRO) by a statistician 
not involved in the study. The randomization algorithm will be based on the PROC PLAN 
procedure of SAS®, Version 9.2 or higher.  
The Investigators will randomize the subjects in ascending order of the site-specific randomization 
lists. 
The randomization codes and the complete generation procedure will be filed in a secure location 
by the designated CRO until the study database is opened. A copy of the list will be sent to 
CareFusion 2200, Inc., for the purpose of assigning the kits to the subjects. 
 
Blinding 
Study subjects will be blinded since the external components for either study device are the same; 
however, the Principal Investigators will remain unblinded since the two study devices can be 
readily distinguished by outward appearance prior to placement. The independent radiologist(s) 
who will evaluate the scans will be blinded to the identity of the investigational product given to 
the subject.  
The blind will be broken at the end of the study, after every subject has completed the study, been 
entered in the database, and the database is locked.   

CS-IP-VH-14-009 
 
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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
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The DSMB or other regulatory bodies (i.e., FDA, IRB/IEC) will have access to the unblinded data 
when necessary for reviewing, evaluating and/or reporting on subject safety issues or concerns 
during the conduct of the clinical research trial. Details of this process will be explained in the 
DSMB Charter. 
This is a single-blinded study; a dummy randomization scheme will be followed when 
programming summary outputs so as not to program with bias on safety and efficacy outputs 
prepared for the DSMB. However, actual treatment codes will be used to validate programs for 
production of the displays. Details of the process are explained in the SAP. 
 Concomitant Medication and Therapy 
Medication required for treatment of symptoms/diseases is permitted during the study and has to 
be documented in the eCRF as described in Section 10.1.8 (including name of the medication, date 
of administration and its duration, dose, and indication for use). Concomitant pleurodesis 
procedures (i.e. talc pleurodesis) will not be allowed.  
 

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Clinical Investigation Plan 
  
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 54 of 90 
7 Study Procedures 
 
Schedule of Events 
The schedule of events is provided in Table 7-1 and detailed in the sections below. 

CS-IP-VH-14-009 
  
 
 
CareFusion 2200, Inc 
Study Protocol 
 
 
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 55 of 90 
Table 7-1.  Schedule of Events 
 
 
 
Study Visit 
 
 
Procedure 
Pre-Screeninga 
 Screening  (Day -14 
to Day -1) 
 Baseline Assessmentb   
(Day  -3 to Day 0) 
Insertion  (Day 0) 
Follow-Up Visits 
Study Day (+/- Days) 
Follow-Up to Confirm 
Pleurodesisd 
Pleural Catheter  
Removal 
Confirm Recurrencee 
Between Follow-Up 
Visits 
7c 
(+/-
2) 
14 
(+/-
2) 
30 
(+/-
2) 
45c 
(+/-
3) 
60 
(+/-
3) 
75c 
(+/-
3) 
90 
(+/-
3) 
I/E criteria and PIS 
X   
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Sign consent form(s) 
 
  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medicationsf 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Physical examinationg 
 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
Assessment of analgesia requirements 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum (S) or urine (U) pregnancy testh 
 
S 
(U) 
 
 
 
 
 
 
 
S 
 
 
 
 
Silver nitrate hypersensitivity testi 
 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-rayj 
 
(X) 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
CT Scan 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Randomization (within 24 hours prior to 
IPC insertion) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Collect blood samples for clinical safety 
testsk 
 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Collect blood samples for serum silver 
testing (SNCIPC only)l 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Maximal pleural drainagem 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
X 
Pleural fluid samples for silver testing 
(SNCIPC only)n 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
Medical resource utilizationo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Diary completionp 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
QoL measurements (pain and 
dyspnea)p,q 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
QoL measurements (EQ-5D-5L health 
status questionnaire)q 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
AE monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Previously unidentified trapped lungr 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Residual silver testing (SNCIPC only)s 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 

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CareFusion 2200, Inc 
Study Protocol 
 
 
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
Page 56 of 90 
Abbreviations: CBC = complete blood count; eCRF = electronic case report form; CRP = C-reactive protein; CXR = chest X-ray; EQ-5D-5L = 
European Quality of Life-5 Dimensions; I/E = inclusion/exclusion; IPC = indwelling pleural catheter; LFT = liver function tests; OTC = over-the-
counter; PIS = patient information sheet; SNCIPC = Silver Nitrate-Coated Indwelling Pleural Catheter; PA = poster-anterior; VAS = visual analog scale 
a. Review of existing CXR and laboratory data will be performed during pre-screening I/E criteria review. 
b. The Baseline Assessment must take place by the end of the 14th day after consent is obtained, and ≤72 hours prior to placement of IPC.  
c. Follow-up on Days 7, 45, and 75 will be by telephone. 
d. Subjects must call the site to make an appointment for an unscheduled visit to assess for pleurodesis and potential IPC removal once they measure an 
output of ≤50 mL of pleural fluid on 3 consecutive drainages over a minimum of 5 days. IPC removal may or may not occur on the same day as the 
follow-up visit to confirm pleurodesis.   
e. An unscheduled CXR and CT scan may be performed on subjects who present with signs and symptoms consistent with potential recurrence as 
described in the protocol. 
f.  Including current oncological treatment and analgesia requirements. 
g. A complete physical examination including vital signs (blood pressure, temperature and heart rate), blood oxygen saturations and respiratory rate. 
h. For subjects who have a screening and baseline visit on the same day, only the serum (S) pregnancy test will be required. For subjects who have 
screening and baseline visits on different days, both pregnancy tests will need to be conducted as indicated.  
i. For subjects with a self-reported silver hypersensitivity and who wish to be considered for enrollment in this study, a patch test will be performed to 
confirm silver nitrate hypersensitivity. 
j. Subjects require a baseline CXR only if they have not had one in the previous 5 days. CXR to include 3 views (single decubitus, PA and lateral) for 
insertion day (post-placement) and pleurodesis assessment and two views (PA and lateral) for baseline and all other follow-up visits. 
k. Clinical blood tests to include CBC, CRP, coagulation tests, urea and electrolytes and LFTs.   
l. For patients who receive SNCIPC, clinical blood tests will include serum silver testing. 
m. Pleural drainage is to take place daily until the day 14 follow up visit, and no less than 3 times per week between the day 14 follow up visit and the 
day 30 follow up visit. The frequency of drainage from the day 30 visit onwards is according to clinical need. All drainages are to occur in the 
subject’s home or in a suitable clinical area. 
n. For subjects with SNCIPC, pleural fluid samples will be collected for silver testing until the point of catheter removal.  
o. Information regarding but not limited to length of procedure for IPC insertion; hospital stay (hours); length of time IPC in place; drainage schedule/ 
frequency; frequency/dose/type of prescription/OTC medications; frequency/use of oxygen should be recorded in the notes and appropriate eCRF. 
p. The following should be documented in the appropriate page of the diary: all drainages, chest pain measurements (VAS), dyspnea scores (Modified 
Borg dyspnea scale), self-measured temperature as well as the frequency and use of oxygen, OTC and prescription medications, and unplanned 
hospital or emergency department visits. Chest pain, dyspnea and temperature measurements should take place after day’s drainage, if appropriate.     
q. QoL measurements include chest pain and dyspnea scores (baseline assessment and insertion day [post placement and drainage] will be on the 
appropriate eCRF; all other time points will be captured in the subject diary) and EQ-5D-5L health status questionnaire (on the appropriate eCRF). 
r.  Significant trapped lung is deemed present if any 1 of the following criteria is met: (1) CXR shows hydropneumothorax, (2) CXR shows ≥20% of the 
affected hemithorax to be free of the expected lung parenchymal markings and there is no suggestion of pleural fluid, or (3) 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.   
s. Upon removal, SNCIPC should shipped to the designated central analytical lab for residual silver testing. 

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     CareFusion 2200, Inc. 
Study Protocol 
 
Final v3.0, 01 June 2017 
 
 CONFIDENTIAL  
     Page 57 of 90 
 
 
Written Informed Consent and Screening  
All subjects who present with a recurrent, symptomatic MPE will be considered for study entry. 
Subjects will be selected based upon the study inclusion and exclusion criteria (Section 5). 
Potential participants who are amenable to study entry will be provided with a patient information 
sheet (PIS). Following this, subjects will be allowed sufficient time, in their own opinion, to 
consider study entry, and will be offered the opportunity to ask any further questions and complete 
an ICF and consent for placement of the IPC.  
The subject is to be informed verbally and in writing about the nature, risks, benefits, and 
expectations of participating in the clinical study and a copy of the subject ICF is to be given to 
the subject in the appropriate language (Section 1.4).  
The ICF is to be signed by the subject and countersigned by the attending Investigator prior to 
proceeding with the visit. All subjects who were provided a PIS and who signed the ICF will be 
defined as having been screened. At this point, a subject screening number will be assigned and 
all screened subjects will be recorded on a dedicated screening log. A subject will be defined as 
having been enrolled from the date of their randomization. Subjects who are unable to provide 
written informed consent will not be enrolled and no study-related procedures will be performed. 
The following observations/procedures are to be performed and checked at the screening visit: 
• Check of inclusion/exclusion criteria 
• CXR if they have not had one in the previous 5 days 
• Patch testing if the subject has a self-identified silver hypersensitivity and consents to silver 
nitrate hypersensitivity testing in order to determine eligibility. 
• Blood samples will be collected for clinical tests including: CBC, coagulation tests, urea 
and electrolytes, LFTs, C-reactive protein (CRP), and serum pregnancy test (if applicable). 
 
Baseline Assessment (Day -3 to Day 0) 
The study baseline assessment must take place by the end of the 14th day after study consent is 
obtained, and within 72 hours prior to placement of the IPC. The assessment may be performed 
by any appropriately trained member of the study team, and should include: 
• Review of inclusion/exclusion criteria  
• Complete physical examination including vital signs (blood pressure and heart rate),  
blood oxygen saturations and respiratory rate 
• Complete medical history with a specific focus on dyspnea symptoms, previous 
procedures and cancer treatments  
• Review of the use of previous/concomitant treatments or medications or any other 
clinical condition(s)  

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Study Protocol 
 
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• Gender, age, race, body weight and body height 
• QoL by subjective VAS score for chest pain, Modified Borg dyspnea scale, and EQ-5D-5L 
health status questionnaire (see Appendices, Section 12) 
• CXR (posterior-anterior view and lateral view), unless performed within the previous 
5 days 
• Urine pregnancy test (for subjects who have a screening and baseline visit on the same 
day, only the serum pregnancy test will be required.) 
• Collection of blood samples, as detailed in Section 7.10 below. 
 
Subjects should have their IPC inserted within 72 hours of the baseline assessment taking place. 
If insertion is not possible within 72 hours, the subject should be withdrawn from the study. In this 
circumstance, should the subject become eligible for study entry at a later date they may be re-
consented using a new unique identifier. 
 
Pleural Catheter Insertion (Day 0) 
A description of the insertion technique for the SNCIPC is summarized in Section 6.7 and detailed 
in the IFU. Catheters must be placed by a member of the study team who is trained and adequately 
experienced in the insertion of the standard PleurX catheter. The procedure should take place in a 
dedicated procedure room or operating suite, and should be performed under local anesthetic with 
or without conscious sedation or under general anesthesia. The IPC should be inserted and fixed 
in place using the same positioning and technique as for a PleurX catheter. At the time of insertion 
the pleural cavity should be maximally drained (as limited by subject signs or symptoms). For 
SNCIPC subjects, a sample of this fluid should be reserved and processed for silver analysis. 
Drainage volume, details of procedural complications and drug doses should be recorded in the 
notes as well as on the appropriate eCRF. The day of IPC insertion is defined as study Day 0. 
 
Post Catheter Insertion (Day 0) 
Subjects should have a post-insertion CXR (single decubitus, PA and lateral views) within 6 hours 
of the procedure concluding, but after they have been maximally drained.  
After insertion, subjects should be admitted to an appropriate clinical area or ward and should have 
physiological observations (pulse, blood pressure, temperature, blood oxygen saturations and 
respiratory rate) checked and recorded at least every 30 minutes for 2 hours, beginning with the 
end of the procedure. Subjects may be discharged home after 2 hours, as long as they are stable 
and meet local post-procedure discharge criteria. Appropriate analgesia should be available to 
subjects post-procedure. 
Before discharge, subjects should be provided with the necessary study documentation, including: 

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• A participant diary (Section 7.7)  
• Emergency contact card 
• Pre-paid envelopes addressed to the study team 
• Instructions for draining and the drainage schedule 
• Instructions for properly measuring drainage volumes 
• Instructions on obtaining drainage bottles  
• Instruction to call clinical site once the subject has drained ≤50 mL on 3 consecutive 
drainages over a minimum of 5 days (i.e., meet pleurodesis requirement). 
IPC insertion in this study should be completed as an outpatient procedure (or per hospital standard 
of practice) unless the Principal Investigator determines there is a clinical need for the subject to 
remain in-patient, in which case the reason for the delay should be documented in the notes and 
on the appropriate eCRF. Subjects requiring hospital admission post-procedure may need to have 
this event recorded as an SAE (Section 8.3). Subjects who remain in hospital for more than 24 
hours should have drainage volumes, observations and symptoms recorded in their diary in the 
same manner as those who are discharged.  
MRU information including but not limited to procedure start and end times (length of procedure), 
hospital stay [hours], and unplanned in-hospital medical procedures as a result of IPC placement 
should be recorded in the notes as well as on the appropriate eCRF. Further details regarding MRU 
information to be collected is provided in Section 7.14. 
 
Regular Fluid Drainage 
Drainage may take place either in the subject’s home or in a suitable clinical area. All drainages 
after discharge should be performed using standard aseptic technique and, unless taking place in a 
hospital setting, should be done using PleurX vacuum drainage bottles. All drainage volumes must 
be recorded in the subject’s diary. Subject must contact the clinical site once he/she has drained 
≤50 mL on 3 consecutive drainages over a minimum of 5 days (i.e., met pleurodesis requirement). 
Drainage schedule 
• Study Day 1 to Day 14 follow up visit (Day 14 ±2 days): subjects should be drained at 
least once daily. 
• Study Day 15 (or after 14-day follow up visit, whichever comes later) to Day 30 follow 
up visit (Day 30 ±2 days): subjects should be drained ≥ 3 times per week, with the actual 
frequency determined by the clinician according to clinical need. 
• Study Day 31 (or after 30 day follow up visit, whichever comes later) to EOS/Day 90: 
subjects may be drained as often as is necessary, with the actual frequency determined by 
the clinician according to clinical need. 

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Subjects will continue to drain according to the schedule above until the time that pleurodesis is 
confirmed by CXR. Following pleurodesis confirmation, the patient does not need to drain from 
that time until IPC removal, unless there is a clinical need. 
 
Subject Diary and Home Measurements 
Prior to discharge, subjects should be issued with a calibrated in-ear or oral thermometer and a 
study-specific diary record. The diary will allow for the charting of fluid drainage volumes; 
frequency, dose and type (generic or brand name) of over-the-counter (OTC) and prescription 
medications; frequency and use of oxygen; QoL measures for chest pain and dyspnea 
(Section 7.13); and the daily recording of the subject’s self-measured temperature. The diary will 
also include the question(s) if any unplanned hospital visits or emergency department visits 
occurred due to IPC placement. 
The diary and thermometer should be brought to each face-to-face follow-up visit (study Days 14, 
30, 60, 90/EOS) where they will be reviewed by the study team; during telephone consults, diary 
entries will be reviewed over the phone (Section 7.8). 
All measurements should take place on the same days as drainage (i.e. daily for study Days 1 to 
14 days, then ≥3 times per week until Day 30; then as often as necessary according to clinical 
need). Chest pain, dyspnea and temperature measurements should take place after the day’s 
drainage, if appropriate.   
If a subject is no longer able to complete follow-up visits, the diary should be returned to the study 
team in the prepaid envelope provided by the study site. 
 
Follow-Up Period  
The per-subject follow-up period for this study is 90 days post IPC insertion. Follow-up will be 
face-to-face (Days 14, 30, 60, and 90) and by telephone (Days 7, 45, and 75). 
 Face-to-Face Follow-Up Visits 
Subjects should attend the study site for face-to-face study follow-up visits on study Days 14 and 
30. If possible, subjects should attend the site for face-to-face visits on study Days 60 and 90 as 
well. If an appointment cannot be arranged for the designated day, the follow-up visit may take 
place within the designated allowable range. If the subject is unable to attend the study site due to 
illness or incapacity the follow-up visit may be performed either over the telephone (with 
necessary documentation sent by post); alternatively, a member of the study team may visit the 
subject at home. If a follow-up visit is still not possible, or takes place outside of the allotted 
window (±2 days for Study Days 14 and 30; ±3 days for Study Days 60 and 90), then a protocol 
deviation should be recorded. In the event of a subject’s death during the follow-up period, any 
information which can be obtained by examination of standard health records may be used to 
complete the appropriate eCRF, and any study-related data collected by the subject prior to their 
death should be mailed to the study team. 

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Face-to-face follow-up visits may be performed by any appropriately trained member of the study 
team, and should be preceded by both a maximal catheter drainage (with fluid sample storage for 
patients who received SNCIPC) and CXR (PA and lateral views).  
Each face-to-face visit should include the following: 
 Determination of pleurodesis 
 Determination of previously unidentified Trapped Lung (as defined in Exclusion Criterion 
#1; Day 14 and Day 30) 
 Record of AE(s) since last visit 
 Record of further pleural interventions needed 
 Assessment of recurrence post-pleurodesis (as defined in Section 7.9) 
 Record of current oncological treatment  
 Review of subject diary (temperature, drainage volumes, OTC and prescription 
medications, oxygen use, chest pain and dyspnea scores, and unplanned hospital or 
emergency department visits) 
 Assessment of analgesia requirements 
 Examination of drain insertion site (with removal of stitches if necessary) 
 Physical examination (including vital signs, oxygen saturations and respiratory rate) 
 EQ-5D-5L health status questionnaire 
 Collection of blood samples (for subjects with SNCIPC, this includes samples for serum 
silver analysis) 
 Serum pregnancy test (Day 90) 
 Record of MRU. 
Data obtained at the follow-up visit should be entered onto the appropriate eCRF. Subjects should 
be given an appointment for their next visit or telephone follow-up before the end of the 
consultation. 
 Telephone Follow-Up Visits 
On study Days 7, 45 and 75, subjects should be contacted by a member of the study team to 
undergo a telephone follow-up consultation. If subjects are unavailable on the allocated day then 
the call may take place either 2 days before or 2 days after. If a face-to-face or home visit is 
clinically indicated, then the follow-up may take place as a face-to-face visit instead. If neither a 
face-to-face nor a telephone follow-up can be completed, or if either takes place outside of the 
allocated window, then a protocol deviation should be recorded. 
Subjects should be contacted at home, ideally after that day’s drainage has taken place (if 
scheduled). They should be reminded to complete their VAS and Modified Borg measurements 

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for chest pain and dyspnea for that day and the EQ-5D-5L health status questionnaire, which can 
be conducted via phone or on paper. These should be either mailed to the study team or brought to 
the next face-to-face appointment. The telephone consultation should involve: 
 Record of AE(s) since last visit 
 Record of further pleural interventions needed 
 Record of current oncological treatment 
 Assessment of pleurodesis 
 Assessment of analgesia requirements 
 Review of subject diary (temperature, drainage volumes, OTC and prescription 
medications, oxygen use, chest pain and dyspnea scores, and unplanned hospital or 
emergency department visits) 
 Assessment of pleurodesis 
 EQ-5D-5L health status questionnaire 
 Record of MRU. 
Data obtained during the telephone follow-up should be entered onto the appropriate eCRF. 
Subjects should be given an appointment for their next visit or telephone follow-up before the end 
of the consultation. 
 
Pleurodesis  
Pleurodesis will be defined as:  
 the collection of at least 3 consecutive drainages of ≤50 mL of pleural fluid over a minimum 
of 5 days (which begin with the first drainage of ≤50 mL) 
• CXR (minimally PA, lateral, and single decubitus views), which shows opacification due 
to pleural fluid occupying less than one quarter of the hemithorax (as judged by the 
investigative site and the blinded third party central radiology service).   
 
Determination of response for clinical management of subjects will be assessed at the clinical sites 
per criteria outlined in the protocol. Scans (CXR and CT) will be submitted to the imaging core 
laboratory for assessment. Details of how assessments will be performed will be included within 
the Imaging Charter which is specific and only used for the independent review.   
Detailed information regarding the acquisition and submission of images to the imaging core 
laboratory is found in the Imaging Manual, which is specific to the clinical sites. 
Subjects must call the site to make an appointment for an unscheduled visit to assess for 
pleurodesis and potential IPC removal once they measure an output of ≤50 mL of pleural fluid on 
3 consecutive drainages over a minimum of 5 days.   

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The date of pleurodesis is defined as the day on which the first of 3 consecutive drainages of 
≤50 mL was recorded. All 3 drainages and the radiological findings to confirm pleurodesis must 
occur within the 90 day follow-up period. 
Subjects should be assessed for pleurodesis at each face-to-face and telephone follow-up 
assessment by the review of their participant diary. Those in whom pleurodesis is confirmed to 
have occurred should be scheduled for IPC removal as soon as feasible.  
If more than one drainage of >50 mL occurs during the period between pleurodesis being 
confirmed and the planned IPC removal date, then the removal should be cancelled until the 
conditions for pleurodesis are met once more. If this occurs then new dates for pleurodesis and 
IPC removal should be recorded and planned based on the second set of 3 consecutive drainages.  
Recurrence is defined as symptomatic pleural effusion confirmed by CXR and CT scan with an 
estimated >300 mL of fluid in the treated hemithorax. Post-pleurodesis recurrence is evaluated by 
the physician using the following criteria: 
1. Is the subject experiencing increasing dyspnea compared with the time of 
pleurodesis?  If yes order a CXR. If no, there is no recurrence.  
2. Does the CXR show evidence of increasing opacification compared with the CXR at 
the time of pleurodesis (confirmed by two clinicians)?  If yes, order a CT scan. If no, 
there is no recurrence. 
3. Does the CT scan show an effusion estimated at least 300 mL (either unloculated, 
loculated or multi-loculated)? If yes, there is a recurrence. If no, there is no recurrence. 
Note:  If it is possible to do a thoracentesis and drain the fluid, then the volume removed should 
be recorded, as well as whether the subject experienced symptom relief. However, this information 
does not affect the determination of recurrence. 
 Collection of Blood Samples 
To be eligible for study participation, subjects must have had blood taken for CBC, coagulation 
tests, urea and electrolytes and LFTs within 10 days of study consent. 
Methods for blood sample collection, processing, and shipment are described in instructional 
materials provided to investigational sites. Samples for clinical blood tests will be processed in the 
local laboratory for analysis; samples for serum silver analysis will be processed at the specified 
central laboratory. 
During their baseline assessment, at each face-to-face follow-up visit and on the first post-insertion 
in-patient day, subjects should have blood taken for the assessment of CBC, coagulation tests, urea 
and electrolytes, LFTs, and CRP, with the results entered into the eCRF as soon as available. For 
patients who received SNCIPC, a blood sample will also be taken for serum silver analysis 
(Section 7.11). 

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 Silver Testing 
For subjects who received the SNCIPC, the following samples will be collected for silver testing: 
 Blood samples will be collected at SNCIPC insertion day and at each face-to-face follow-
up visit for serum silver testing. 
 On the day of SNCIPC insertion and at each face-to-face follow-up visit, a sample of 
pleural fluid is to be collected from the applicable drainage container after the fluid 
volume has been measured and recorded. Samples will be sent to the central laboratory 
for silver level analysis.   
 At the time of SNCIPC removal (at Pleurodesis, end of study (EOS) or Early Termination 
as applicable), the SNCIPC should be inspected for structural integrity then the SNCIPC 
should be shipped to the designated analytical laboratory for residual silver testing.  
Methods for blood and pleural fluid sample collection, processing, and shipment are described in 
instructional materials provided to investigational sites. Samples for clinical blood tests will be 
processed in the local laboratory for analysis. Pleural fluid and blood samples for silver analysis 
will be processed at the specified central laboratory.    
 Catheter Blockage 
Catheters should be suspected of being blocked if pleural fluid is not consistently being drained in 
the context of radiological findings suggestive of an increasing effusion, or if a piece of debris is 
visible within the exterior portion of the drainage tube.  
In the first instance, an attempt should be made to unblock the catheter using simple methods such 
as flushing or agitating with a small amount of sterile 0.9% saline solution. The Catheter Access 
Kit (50-7280) is provided for this purpose. Should these attempts fail, the Investigator may 
consider the use of a fibrinolytic agent in line with local policy. Such an agent, if used for the 
purposes of catheter unblocking, should only be instilled into the catheter itself, with as little as 
possible being injected into the pleural space. 
 Quality of Life Measurements 
QoL measurements include VAS score for chest pain, Modified Borg scale for dyspnea, and 
EQ-5D-5L health status questionnaire (see Appendix, Section 12).   
Chest pain and dyspnea scores will be collected for each subject, beginning at their baseline 
assessment and ending when their follow-up is completed or is terminated due to death or 
withdrawal.  
All subjects will provide a score for thoracic pain and dyspnea during their baseline assessment. 
Beginning on study Day 1 (the day after IPC insertion), subjects should repeat these measurements 
using the participant diary provided. Scores for pain and dyspnea should be recorded on a daily 
basis for the first 14 days after insertion, with subsequent recordings on each day that drainage 
takes place. The score should be noted after that day’s drainage takes place.  

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All subjects will complete the EQ-5D-5L health status questionnaire during their baseline 
assessment and at each follow-up visit through EOS. 
If a subject dies before their diary can be collected, this should be sent via mail to the study site. 
 Medical Resource Utilization  
Select face-to-face and telephone visits also will include collection of MRU information. To 
evaluate MRU, information will be collected within the following categories: hospitalizations, 
emergency department visits, provider visits, medications, other treatments, procedures. Within 
these categories, information will include planned and unplanned treatments procedures and 
provider visits, duration/frequency of treatment, medication name(s) dose, frequency, and overall 
duration, use of medical equipment, treatment of AEs as well as OTC and prescription treatments. 
In addition, insurance information, including both primary and secondary, if applicable, will be 
collected. Specific information will include, but may not be limited to: length of procedure; 
hospital stay (hours); unplanned in-hospital medical procedures as a result of IPC placement; 
emergency department visits related to IPC placement; length of time IPC in place; drainage 
schedule and frequency; frequency, dose and type of prescription and OTC medications; frequency 
and use of oxygen; and services required to diagnose, treat, and follow up AEs. 
 End of Study 
The study will cease recruitment once the last subject has been randomized and treated (ITT) after 
any sample size readjustments have been taken into consideration. However, as subjects may be 
followed up to day 90 post IPC insertion, the provisional EOS date will be 90 days after the 
insertion of the last study subject’s IPC. At the end of each subject’s follow-up period they will be 
stratified as ‘alive or ‘dead,’ and survival data collated.  
  SNCIPC Management Following Study Completion 
For all subjects who continue to have an SNCIPC in situ at EOS/ Day 90, the subject’s physician 
will be responsible for administering patient care. If clinically appropriate in the opinion of the 
Principal Investigator, subjects will be offered the choice of having their catheter removed or, if 
regular drainage with symptomatic benefit continues, having the catheter left in place. Subjects 
who choose to have their catheter removed will be made aware that they may require insertion of 
a standard PleurX catheter, or an alternative procedure (or procedures) for the purposes of pleural 
fluid management.   

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8 Efficacy and Safety Assessments 
 
Methods of Assessment/Evaluations 
 Primary Efficacy Endpoint 
The primary objective is to demonstrate that the SNCIPC Pleural Catheter shows superiority 
compared to the PleurX Pleural Catheter in the proportion of subjects achieving pleurodesis 
without recurrence at 30 days.   
Ho: pT – pC ≤ 0     versus    Ha: pT - pC > 0  
where pT is the rate of pleurodesis without recurrence at 30 days for the study device, pC is the 
rate for the control device.  Rejecting the null hypothesis will establish superiority of the study 
device over the control device. 
Exact unconditional CI for risk difference will be used to calculate rate difference and 95% CI.35 
The primary efficacy endpoint is the proportion (%) of subjects achieving pleurodesis without 
recurrence by 30 days, where pleurodesis is defined as: 
• The collection of a minimum of 3 consecutive drainages of ≤ 50 mL of pleural fluid over 
a minimum of 5 days (which begin with the first drainage of ≤ 50 mL) 
AND 
 CXR, which shows opacification due to pleural fluid occupying less than one-quarter of 
the hemithorax (as judged by the investigative site and the blinded third party central 
radiology service).  
The date of pleurodesis is defined as the day on which the first of 3 consecutive drainages of 
≤50 mL was recorded. 
Radiologic endpoint data will be based on scans (CXR and CT) submitted to the third party 
imaging core laboratory for assessment. Clinical endpoint data will be based on data collected 
from the clinical study centers. The primary efficacy endpoint will be based on a combination of 
radiologic and clinical data. 
 Secondary Efficacy Endpoints 
• Time to confirmed pleurodesis 
Time to confirmed pleurodesis is defined as the duration between the study device insertion 
and the date a subject achieves pleurodesis.  
 Time to recurrence  
Time to recurrence is calculated for subjects who achieved confirmed pleurodesis. It is 
defined as the duration between successful pleurodesis (the first of a minimum of 
3 consecutive drainages of ≤50 mL of pleural fluid over a minimum of 5 days) and the date 

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the subject presents with symptoms of recurrence that is later confirmed by CXR and CT 
scan. 
 Exploratory Efficacy Analysis 
The following exploratory analysis will be performed comparing the two treatment groups: 
• Proportion of surviving subjects without a trapped lung diagnosis following IPC placement 
who have confirmed pleurodesis without recurrence  at 14, 30, 60, and 90 days 
• Proportion of subjects with confirmed pleurodesis and without recurrence by 30 days after 
IPC placement by cancer type (lung, breast and others).  
 Safety Evaluations 
The following safety evaluations will be performed comparing the two treatment groups:  
 Device related safety and AEs 
 Incidence of IPC occlusion 
 
Incidence of empyema and cellulitis (as coded by Medical Dictionary for Regulatory 
Activities [MedDRA] and described in the data management plan). 
Descriptive statistics for serum and pleural fluid silver levels by time point will be provided for 
subjects who receive SNCIPC. 
 Quality of Life and Medical Resource Utilization Analysis 
 Pain using 100 mm VAS scale 
 Dyspnea relief (breathlessness) using Modified Borg dyspnea scale 
 Health status as measured by the EQ-5D-5L health status questionnaire 
 MRU data (length of procedure; hospital stay [hours]; unplanned in-hospital medical 
procedures as a result of IPC placement; emergency department visits related to IPC 
placement; length of time IPC in place; drainage schedule and frequency; frequency, dose 
and type [brand name/generic] of prescription and OTC medications; frequency and use of 
oxygen; services required to diagnose, treat, and follow up AEs). 
 
Protocol Deviations 
A protocol deviation is defined as an instance of failure to follow, intentionally or unintentionally, 
the requirements of the protocol. 
After signing the ICF, all care pertaining to a subject’s involvement in the study or their SNCIPC 
should be completed as defined in this CIP, without deviation. However, at the medical discretion 
of the Investigator or other healthcare teams, or under emergency circumstances, deviations from 
the protocol to protect the rights, safety and well-being of study participants may proceed without 
prior approval of the Sponsor and the regulatory body/bodies. Such deviations should be 
documented and reported to the Sponsor and regulatory body/bodies (as necessary) as soon as 

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possible (ideally within 48 hours of knowledge of the deviation occurring), using the study 
deviation page of the eCRF.  
All deviations from the CIP will be monitored by the Sponsor or appropriate designee. Protocol 
deviations will not be granted, but, if they occur, sites will be required to report them. 
The Sponsor retains the right to suspend the study or disqualify the Principal Investigator if deemed 
necessary based upon the nature of reported protocol deviations. CIP deviations which may result 
in suspension include not complying with the signed tripartite agreement, the investigational plan, 
FDA regulations, or any conditions of approval imposed by the reviewing regulatory agency. 
 
Safety Parameters 
AEs that occur during the study after the subject has signed the ICF are to be collected and reported 
on the eCRF, regardless of whether they are reported by the subject, elicited by Investigator 
questioning, detected through physical examination, or by other means. 
As far as possible, each AE is described by: 
• duration (start and end dates) 
• start/end of study medication 
• severity grade (mild, moderate, severe) 
• Investigator causality (relationship to the study product) 
• action(s) taken (concomitant medication, change of study medication etc.) including 
start and end of respective action 
• concomitant diseases and respective medication in general 
• start, end and dosage of rescue medication 
• outcome. 
AE 
An AE is any untoward medical occurrence (change in anatomical, physiological, or metabolic 
function) in a subject, which does not necessarily have any causal relationship with the product 
under investigation.  
TEAE 
Treatment-emergent AEs (TEAEs) are those AEs occurring from time point of device insertion 
until last visit. 
Device Deficiency 
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or 
performance, such as malfunction, misuse or use error and inadequate labeling.  

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ADE 
An ADE is an AE related to the use of an investigational medical device. This definition includes 
AEs resulting from insufficient or inadequate IFU, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device. The definition also includes 
any event resulting from use error or from intentional misuse of the investigational medical 
device. Further details regarding anticipated ADEs are provided in Section 4.2. 
UADE 
A UADE is any serious AE on health or safety, any life-threatening problem or death caused by, 
or associated with a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the application; or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects. 
SAE 
A serious adverse event (SAE) is defined in the ISO 14155 standard as an AE that led to death 
or to a serious deterioration in the health of the subject that either resulted in: 
 a life threatening illness or injury, or, 
 a permanent impairment of a body structure or a body function, or, 
 in-patient or prolonged hospitalization, or, 
 medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 
An SADE is an ADE that has resulted in any of the consequences characteristic of an SAE. 
A USADE is an SADE which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. NOTE: ‘Anticipated’ means an effect 
which by its nature, incidence, severity or outcome has been previously identified in the risk 
analysis report. 
Events that require intervention to prevent one or more of the outcomes listed in the definition 
above are also to be considered as serious. Examples of such events are intensive treatment in 
an emergency department or at home for allergic bronchospasm, blood dyscrasias or convulsion 
that does not result in hospitalization, or development of drug dependency or drug abuse.  
However, medical judgment will be exercised in deciding whether an event is serious in any 
other situations considered medically relevant. 
The evaluation of the AE as serious or not-serious is made independently of any attribution of 
causality. 
Events NOT considered to be SAEs are those that require: 
 treatment, which is elective or pre-planned, for a pre-existing condition that is unrelated 
to the indication under study and does not worsen 

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 treatment on an emergency, out-patient basis for an event NOT fulfilling any of the 
definitions of serious given above and NOT resulting in hospital admission for the 
purpose of this study, a hospitalization is defined as a hospital stay of at least 8 hours 
and/or an overnight stay. 
AE Intensity 
AE intensity determined by the clinical Investigator on the basis of his/her direct observations 
or the subject’s reporting: 
 Mild: causes no limitation of usual activities; the subject may experience slight 
discomfort 
 Moderate: causes some limitation of usual activities; the subject may experience 
annoying discomfort 
 Severe: causes inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
AE Causality (relationship guide) 
Any AE has to be judged for causality (relationship to study device and relationship to study 
procedure).   
The relationship of an AE to the study product is to be graded on the basis of the following: 
 Probable: a reaction that follows a reasonable temporal sequence from 
administration of the product; that follows a known response pattern to 
the suspected product; that is confirmed by an improvement on stopping 
the product; and that cannot be reasonably explained by the subject’s 
clinical state 
 Possible: 
a reaction that follows a reasonable temporal sequence from 
administration of the product; that follows a known response pattern to 
the suspected device; but that may have been produced by the subject’s 
clinical state or other therapeutic interventions on him/her 
 Unlikely: 
a reaction that occurs with an improbable temporal sequence from 
administration of the product; that can be explained by the clinical state 
of the subject/participant or by other therapeutic interventions or other 
drugs or underlying disease providing plausible explanations.  
 Unrelated: a reaction that occurs without a reasonable temporal sequence from 
administration of the product; that can be explained by the clinical state 
of the subject or by other therapeutic interventions on him/her and that 
does not improve or disappear following interruption of the product. 
Handling of AEs 
If an AE occurs, appropriate diagnostic and therapeutic measures are to be taken and the study 
product has to be discontinued if appropriate. Follow-up evaluations of the subject are to be 

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performed until the subject recovers or until the clinical Investigator considers the situation to be 
no longer clinically significant. 
If clinically significant laboratory abnormalities appear at the final visit, appropriate additional 
tests may to be performed to clarify the nature of any clinically significant laboratory abnormalities 
that occur. 
AEs are monitored and registered on the AE form of the eCRF at each visit. In absence of a specific 
diagnosis, an individual AE form has to be filled in for each sign or symptom. 
Persistent AEs will be entered once in the eCRF until they are resolved or if a new event has to be 
documented due to deterioration. These AEs will be carefully monitored; further details of 
monitoring of persistent AEs will be provided in the monitoring plan. If an AE is still not resolved 
at the end of the study, this will documented as ongoing. 
For recurrent AEs, i.e., AEs of the same nature, but with a different date of onset, an individual 
AE form has to be completed for each of them. 
AEs occurring after the termination of the study individually and/or of the study in total are to be 
reported to CareFusion even after the clinical study has been finished if, in the judgment of the 
Investigator, there is an association between the event and the previous use of the product under 
investigation. 
If the AE is classified as serious, the clinical Investigator also must complete the SAE report form. 
It is the responsibility of the Investigator to send the SAE report form by fax or email to the Global 
Safety Department of Chiltern within 1 working day and to retain the original copy of the form 
(keeping a photocopy in the Investigator Site File). At the earliest possible date, the SAE report 
form must be followed by a detailed report and any documentation that may be available, e.g., 
hospital case records, autopsy reports, and/or other pertinent documents. 
If the AE is classified as UADE, the clinical Investigator must report the UADE to Chiltern within 
1 working day. 
The Investigator will be responsible for reporting the SAE to ethics committees. Chiltern will be 
responsible for initial reporting of SAEs/ UADEs to Sponsor with narratives and follow-up reports. 
The safety team will also be responsible for reporting expedited safety reports to international sites 
and regulatory authorities and Central Ethics Committees, distributing periodic line listings to 
international sites and regulatory authorities and Central Ethics Committees as required per local 
regulations. 
Contact information for Chiltern’s Global Safety Department: 
US Fax: (866) 869-1551 
UK Fax: 00-800-6664-2277 
Email: globalsafetyadvantage@chiltern.com 
 

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Pregnancy 
While not considered an SAE unless a serious criterion is met, pregnancies occurring in subjects 
enrolled on the study or in their partners must be reported and followed to outcome. The 
Investigator should complete the pregnancy report form and submit within 1 business day of 
knowledge of the pregnancy. Following delivery or termination of pregnancy, the follow-up 
pregnancy report form should be completed and submitted via fax to the Global Safety Department 
of Chiltern. Spontaneous abortions should always be reported as SAEs. 
The safety officer will forward pregnancy reports to CareFusion the next business day.  
Pregnancies occurring up to 30 days after the last follow-up should be reported. In the event the 
pregnancy outcome occurs following EOS, the Investigator will report the pregnancy outcome 
directly to CareFusion. 
 
 
 

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9 Data Quality Assurance 
Detailed procedures will be separately provided in the data management, monitoring, and quality 
plans. 
 
Data Collection 
All subject data must be reported on the eCRFs in an anonymous fashion. Subjects are identified 
only by screening number.  
The Investigator and staff will be responsible for the completeness, accuracy, and legibility of the 
information in the eCRF and other study documents. In line with Good Documentation Practices, 
the source data should be attributable, original, and contemporaneous. For documents other than 
eCRFs, only ballpoint pen is to be used and any change of data is to be done by striking out the 
incorrect data with a single line and dating and initialing the changes made. 
The study monitors will check the eCRFs against the source documents for accuracy and validity 
as per the monitoring schedule, as applicable, which includes any data recorded directly on the 
eCRF (for example, no prior written or electronic record of data). Also, any step in creation of 
source data is to be identified such as a computerized system used to create, modify, maintain, 
archive, retrieve, or transmit source data. The subject diary will remain as source documentation 
at the investigational site and will only be source data verified by the monitors but not collected. 
Source data verification will include the diary data, eCRF data, and accountability of devices. 
Upon completion of the eCRF, each site is to ensure quality of data and subject safety. Once eCRFs 
are completed, they will be available for review by the monitor and the designated CRO Clinical 
Data Management department. Completed eCRFs will be reviewed remotely for logical 
discrepancies. The monitor will ensure that all data queries and subsequent amendments in the 
eCRF documentation are made according to GCP guidelines.  
A copy of the eCRF is to be archived by the Investigator together with the study documents, source 
data, and laboratory records for the time required by the national regulation.  
Site Audits 
The Sponsor or its designee may carry out an audit at any time. Investigators will be given adequate 
notice before the audit occurs. The purpose of an audit is to confirm that the study is conducted as 
per protocol, GCP/ISO and applicable regulatory requirements, that the rights and well-being of 
the subjects enrolled have been protected, and that the data relevant for the evaluation of the 
investigational product have been captured, processed and reported in compliance with the planned 
arrangements. The Investigator will permit direct access to all study documents, device 
accountability records, medical records, and source data.  
Regulatory authorities may perform an inspection of the study, even up to several years after its 
completion. If an inspection is announced, the Investigator or the site must inform the Sponsor 
immediately. 

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Database Management and Quality Control 
The CRO will be responsible for the activities associated with the data management of this study, 
including the production of an eCRF, setting up a relevant database, along with appropriate 
validation of data and resolution of queries. All data will be entered into an eCRF. Automated and 
manual checks will be made against the data entered into eCRF to ensure completeness and 
consistency. Resolution of queries will be implemented in the database. 
AEs will be standardized for terminology and classification, using MedDRA. Concomitant 
medications will be classified by site of action and therapeutic and clinical characteristics using 
the World Health Organization (WHO) DRUG dictionary. Versions of the dictionaries to be used 
will be documented in the Data Management Plan and the Statistical Analysis Plan (SAP). 

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10 Statistical Methods 
 Statistical and Analytical Plans 
Standard statistical methods will be employed to analyze all data. Assumptions of normality and 
homogeneity of variance will be tested and if distributional assumptions are violated, 
non-parametric techniques will be employed.  
Data collected in this study will be reported using summary tables and patient data listings. Tables 
will display results for each group as well as all patients combined. For categorical variables, 
frequencies and percentages will be presented. For continuous variables, the number of subjects, 
mean, standard deviation, median, minimum, and maximum will be presented. Continuous data 
subject to censoring (i.e., time to event data) will be summarized by the 25th percentile, median, 
and 75th percentile, when estimable from the Kaplan-Meier estimates. 
The SAP formally defines the analysis populations, describes any data handling conventions, and 
specifies all statistical methods to be used in analysis of the data.  
A 30% non-inferiority margin was established for secondary objectives, based on clinical 
relevance.  Justification of the non-inferiority margin for the secondary endpoints is included in 
the SAP.  
 Adjustments for Covariates 
The primary efficacy analysis does not have any adjustment for covariates.  
 Stopping Rules and Data Monitoring 
Stopping rules will be defined by the DSMB and outlined in the DSMB charter as described in 
Section 1.9. The stopping rules are based on safety criteria and there will be no stopping based on 
efficacy criteria. 
 Handling of Dropouts and Missing Data 
In the primary efficacy endpoint, if a patient discontinues the study prior to 30 days, the subject 
will be counted as not achieving pleurodesis (considered a “failure”). Missing data will not be 
imputed. For time to event variables, subjects who discontinue the study will be censored at the 
time of discontinuation. Subjects who do not experience the event and did not discontinue the 
study will be censored at the subject’s last visit. 
 Multi-center Studies and Pooling of Investigational Centers 
No single site will enroll more than 40 subjects without prior approval from the Sponsor. In the 
event that there are small sample sizes at some sites, sites may be grouped using the following 
procedure to create “analysis-sites” for analysis purposes. These analysis sites will be created for 
US and UK independently to preserve the ability to differentiate between countries. Analysis-sites 
are based on a target size of at least 5 subjects per treatment group at each site. If investigative 

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sites have at least 5 ITT subjects per treatment group, they will retain their identities in the 
analyses. All investigative sites with fewer than 5 ITT subjects per treatment group will be rank 
ordered by size and sorted secondarily by site identification number to break ties. Starting with the 
smallest investigative site, subjects will be combined site by site by treatment group, until the first 
time the resulting analysis site has at least 5 ITT subjects in each treatment group. The process 
continues until all sites are accounted for. If the last analysis-site has fewer than 5 ITT subjects per 
treatment group, it will be combined with the most recently created analysis-site.   
Although a site effect is not anticipated, the homogeneity of treatment effect across analysis-sites 
will be tested using a Breslow-Day test at a two-sided 15% alpha level. If the Breslow-Day test is 
significant at 15% level, a meta-analysis will be performed to investigate treatment differences 
across analysis-sites.  
The proportion (and 95% CIs) of patients achieving pleurodesis without recurrence at 30 days will 
be presented for each treatment group by analysis-site for descriptive purposes. 
 Multiple Comparisons/ Multiplicity 
Serial gatekeeping procedures will be used to preserve the overall alpha of the study at the 
one-sided 2.5% level.36 
The endpoints will be tested sequentially in the following order with no adjustments for 
multiplicity:  
1) Superiority test on the primary endpoint  
2) Non-inferiority on the first secondary endpoint (time to pleurodesis) 
3) Superiority on the first secondary endpoint (time to pleurodesis) 
4) Non-inferiority test on the second secondary endpoint (time to recurrence)  
5) Superiority on second secondary endpoint (time to recurrence). 
 
Each of the above endpoints will be tested for superiority using a one-sided alpha of 2.5% for 
superiority. 
Exploratory, safety, QOL and MRU analysis will not be considered for alpha spending since 
they will be evaluated for investigative purposes only. Any results obtained from these 
analyses will not be considered as a basis for any claims. 
 Analysis Populations 
Analyses will be based on the Safety, All Randomized, Intent-to-Treat, and the Per-Protocol 
populations. The definitions of the analysis sets follow those given in the ICH E9 guideline.  
• All Randomized Population:  All subjects randomized to either the study device or 
the control device will be included in the All Randomized Population. The All 
Randomized Population will be analyzed according to the treatment group to which 
the subjects were randomized. 

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• Safety Population:  Subjects in the All Randomized population who received either 
the study device or the control device will be included in the Safety population. The 
Safety Population will be analyzed according to the treatment subjects received.  
• Intent-to-Treat Population: All subjects randomized to either the study device or 
the control device and received one of the treatments will be included in the ITT 
population. The ITT population will be analyzed according to the treatment group to 
which subjects were randomized.  
• Per-protocol Population: Subjects in the ITT population who do not have major 
protocol deviations will be included in the Per-protocol (PP) population. 
The major protocol deviations will be defined at the time of evaluability evaluation to occur 
in the blinded manner and finalized before database lock and unmasking. 
 Demographic and Other Baseline Characteristics 
All baseline summaries will be based on the All Randomized and ITT populations. 
Gender and race will be summarized using counts and percentages. Age, height (cm), and weight 
(kg) will be summarized with descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum [min], and maximum [max]). Age may be summarized by 
decades using n and %. Other baseline characteristics may be summarized as necessary. 
Similar summary statistics for background and demographic characteristics for only the ITT 
population will also be done by center.   
 Prior and Concomitant Therapy  
The World Health Organization (WHO) Drug Dictionary will be used to classify medications by 
preferred term and WHO Anatomical Therapeutic Chemical (ATC) classification of ingredients. 
Medications will be summarized using counts and percentages by WHO ATC classification of 
ingredients and by preferred term. Anticoagulants will be summarized separately for the ITT 
population. 
Medications with start date and stop date prior to insertion of study device will be included in the 
prior medication summary. Medications taken during the study, including those started prior to 
insertion of study device, will be included in the concomitant medication summary. 
 Analysis of Efficacy Parameters 
10.1.9.1 Primary Efficacy Parameter 
The primary analysis will be performed on the ITT Population. 
The proportion of subjects achieving pleurodesis without recurrence 30 days after IPC placement 
and its 95% confidence interval (CI) by exact binomial method will be summarized for each 

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treatment group. Exact unconditional CI for risk difference will be used to calculate rate difference 
and 95% CI.35  
Superiority will be demonstrated when the one-sided p-value is less than 0.025.  
A supportive analysis will be performed in the exact same manner as described above but utilizing 
the PP Population. 
10.1.9.2 Secondary Efficacy Parameter 
Time to confirmed pleurodesis analysis will be performed using a proportional hazards model and 
Kaplan-Meier time-to-event analysis. The analysis will be performed on all subjects in the ITT 
population, and on all subjects in the PP population as a supportive analysis. A proportional 
hazards model will be used to estimate the hazard ratio. Non-inferiority will be established when 
HR >0.7.  
Time to confirmed pleurodesis will be summarized by 25th percentile, median, and 75th percentile, 
when estimable from the Kaplan-Meier estimates for each treatment group. Kaplan-Meier curves 
for each treatment group will be provided. Time to confirmed pleurodesis is defined as the duration 
between the study device insertion and the date of confirmed pleurodesis. For subjects who do not 
have confirmed pleurodesis, censoring rules will be described in the SAP.  
Incidence density for time to confirmed pleurodesis will be evaluated between the two groups by 
summarizing the number of subjects in the ITT population, number of confirmed pluerodeses, 
number of subjects censored in the time to pleurodesis, and patient-days in each treatment group. 
Patient-days within the treatment group will be calculated as the total number of days from study 
device insertion to confirmed pleurodesis or termination of study participation summed for all 
subjects within the treatment group. 
Time to recurrence analysis will be performed using proportional hazards model and Kaplan-Meier 
time-to-event analysis. The analysis will be performed on all subjects in the ITT population who 
had confirmed pleurodesis, and on all subjects in the PP population who had confirmed pleurodesis 
as a supportive analysis. A proportional hazards model will be used to estimate the hazard ratio. 
Non-inferiority will be established when HR <1.3.  
Time to recurrence will be summarized by 25th percentile, median, and 75th percentile, when 
estimable from the Kaplan-Meier estimates for each treatment group. Kaplan-Meier curves for 
each treatment group will be provided. Time to recurrence is defined as the duration between 
confirmed pleurodesis and the date of recurrence. For subjects who do not have a recurrence after 
confirmed pleurodesis, censoring rules  and incidence density analysis will be described in the 
SAP.  
Incidence density for time to recurrence will be evaluated between the two groups by summarizing 
the number of subjects with confirmed pleurodesis, number of recurrences, number of subjects 
censored in the time to recurrence, and patient-days in each treatment group. Patient-days within 

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the treatment group will be calculated as the total number of days from confirmed pleurodesis to 
recurrence or termination of study participation summed for all subjects within the treatment 
group. 
Superiority will be demonstrated when the one-sided p-value is less than 0.025 using a proportional 
hazards model. 
10.1.9.3 Exploratory Efficacy Parameter 
The exploratory efficacy endpoints involving a proportion will be analyzed in the same fashion as 
the primary endpoint. These analyses involve the following endpoints:   
 Proportion of surviving subjects without a trapped lung diagnosis following IPC 
placement and who have confirmed pleurodesis without recurrence at 14, 30, 60 and 
90 days.  
 Proportion of subjects achieving pleurodesis without recurrence by 30 days by cancer 
type.  
The proportion (%) of subjects achieving pleurodesis without recurrence at 30 days will be 
summarized for each treatment group by cancer type (lung, breast and others). The proportions 
will be compared using a Cochran-Mantel-Haenszel test using the cancer type as a stratification 
factor. The primary analysis will be performed on the ITT population and a supportive analysis 
will use the PP population. 
 Analysis of Safety Parameters 
All comparisons between treatment groups for the safety parameters will be descriptive in nature. 
Further details will be provided in the SAP. 
 Duration of Exposure 
The duration of subject exposure to study treatment will be quantified as the number of days 
between IPC insertion and removal. It will be listed and summarized for all subjects in the Safety 
Population by treatment group.  
 Incidence of Catheter Occlusion 
Incidence rate of IPC occlusion is defined as proportion of subjects who experienced IPC occlusion 
while on study. It will be summarized for all subjects in the Safety Population by treatment group. 
Fisher exact test will be used to compare between treatment groups.  
 Incidence of Infection 
Incidence rate of empyema and cellulitis while on study, as coded by MedDRA and described in 
the data management plan, will be summarized for all subjects in the Safety population by 
treatment group. The Fisher exact test will be used to compare between treatment groups.  

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 Serum and Pleural Fluid Silver Levels 
Serum and pleural fluid silver levels will be measured at regular intervals for the SNCIPC subjects 
using the gold-standard inductively coupled plasma mass spectrometry (ICP-MS) analysis. It will 
be summarized for all subjects who received SNCIPC by summary statistics (N, mean, median, 
standard deviation, minimum and maximum values). 
 Adverse Events 
The Investigator’s verbatim term of each AE will be mapped to system organ class and preferred 
term using the MedDRA dictionary. 
AEs will be summarized by system organ class and preferred term; a subject will only be counted 
once per system organ class and once per preferred term within a treatment. Subject counts and 
percentages and event counts will be presented for each treatment group and totaled for all 
treatment groups for the following: 
• All AEs 
• All AEs by severity 
• All SAEs 
• All ADEs 
• All SADEs 
• All UADEs and USADEs 
 
Comparison between the two treatment groups for frequency of any AEs, and frequency of any 
ADEs will be done using a Fisher exact test. 
Listings will be presented by subject for all AEs, SAEs, deaths, and AEs leading to discontinuation 
from the study. 
 Clinical Laboratory Evaluations 
Clinical laboratory results at each time point and for change from baseline will be displayed using 
summary statistics (n, mean, median, standard deviation, minimum and maximum values). 
All clinical laboratory data will be presented in listings. Within each listing, laboratory values 
outside the normal ranges will be flagged as either high (H) or low (L). In addition, shift tables 
will be presented to display the shift in the normal range categories (L, normal [N], H) from 
baseline to specified time point. Baseline is defined as the latest result obtained prior to the 
insertion of study device.  
 Other Observations Related to Safety 
Vital Sign Measurements  
Pre-implantation values, post-implantation values, and the change from baseline in vital sign 
measurements (blood pressure, heart rate, respiratory rate and temperature) will be summarized 

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with descriptive statistics (n, mean, SD, median, min and max) at each time point by treatment. 
The baseline value will be the latest value obtained prior to the insertion of the study device.  
Physical Examination Findings 
The number and percentage of subjects with abnormal findings on physical examination will be 
summarized by organ system.   
  Quality of Life and Medical Resource Utilization Parameters 
 Quality of Life 
Pain and dyspnea (breathlessness) will be evaluated using the 100 mm VAS and the Modified 
Borg dyspnea scale, respectively. Patient-reported health status will be evaluated using the 
EQ-5D-5L health status questionnaire. Comparison between the two treatment groups involving 
continuous variables will be done using a two-sample t-test. Change from baseline between the 
two treatment groups will be analyzed using a two-sample t-test. Comparison between the two 
treatment groups involving categorical variables will be done using the chi-square test, or Fisher’s 
exact test if more appropriate. 
 Medical Resource Utilization Parameters 
Comparison between the two treatment groups involving continuous variables such as length of 
procedure, length of hospital stay and length of time IPC in place will be done using a t-test. All 
other resource utilization data will be summarized as frequencies and counts and compared using 
Fisher’s Exact test as appropriate. 
 Interim Analysis 
There will be an unblinded sample size evaluation to see if the assumption used for current sample 
size is reasonable. The sample size adjustment will be based on the promising zone approach as 
detailed in Mehta and Pocock (2011).37  
The interim analysis will be conducted at 2/3 of the information rate, when 80 subjects are 
evaluable for the primary endpoint under the superiority hypothesis with the  purpose of 
determining if the sample size needs to be increased to provide sufficient power for testing at the 
final analysis. Sample size will not be reduced under any circumstances. The study will not be 
stopped prematurely for efficacy prior to the 119 subjects being enrolled. Through simulation 
based on the methods outlined in Wang et al38, it was determined that Type I error is controlled 
under 0.025 (details in SAP). The below rules will be followed, where conditional power (CP) is 
CP at interim. 
 Unfavorable Zone:  CP < 0.395   
→ Study size will remain the same at 119 
 Promising Zone:  0.395  ≤ CP < 0.8  → Study size will be increased to 179 
 Favorable Zone:  CP ≥  0.8                 → Study size will remain the same at 119 

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0.395 is the minimum CP derived from conservative extrapolation from Table 1 in Mehta and 
Pocock (2011)37 to determine the unfavorable zone. 
Interim analysis procedures and control of access to the unblinded interim data are described in 
the SAP. 
 Subgroup Analyses 
If at least 80% of the total number of US subjects participating in this study are Medicare 
beneficiaries, then no subgroup analysis will be conducted. However, if less than 80% of all US 
subjects enrolled are Medicare beneficiaries, then a subgroup analysis will be conducted to 
evaluate outcomes specifically for the Medicare beneficiaries enrolled in the study. All primary 
and secondary outcomes for the subgroup analyses will be the same as for the main analysis. 
For this analysis, the Medicare population will be defined as any subject recruited in the US, who 
is:  
 is at least 65 years old (even if he/she did not indicate Medicare as primary insurance), 
 or under 65 years old, and receives Medicare health insurance (due to a disability). 
 
 Determination of Sample Size 
The sample size was calculated based on the primary efficacy endpoint: rate of pleurodesis at 
30 days. A sample size of 79 subjects in the study device group and 40 subjects in the control study 
device group is planned for the study based on 80% power to demonstrate superiority of the study 
device group over the control group with a one-sided type I error 2.5%.  
The unadjusted rates of pleurodesis are assumed to be 75% for the study device group, and 35% 
for the control device. Assuming 20% subjects will have trapped lung who cannot achieve 
pleurodesis, and 20% of the remaining subjects will drop out before reaching the 30 days follow 
up, and will be considered as failures for the primary endpoint, the adjusted pleurodesis rates 
[calculated as: expected rate *(1-drop-out rate)*(1-trapped lung rate)] are 48% for the study device 
group and 22% for the control device. Subjects who are discontinued/withdrawn after entering the 
randomized treatment phase will not be replaced. When 80 subjects reach the primary endpoint, 
an unblinded sample size reassessment will be performed as detailed in Section 10.4. 
Details of sample size estimation are included in the SAP. 
 

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12 Appendices 
 
APPENDIX 1 | KARNOFSKY SCORING39 
 
Level of function 
Score 
Symptoms 
Able to carry on normal activity and 
to work; no special care needed. 
100 
Normal no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
Unable to work; able to live at home 
and care for most personal needs; 
varying 
amount 
of 
assistance 
needed. 
70 
Cares for self; unable to carry on normal activity or to do active 
work. 
60 
Requires occasional assistance, but is able to care for most of his 
personal needs. 
50 
Requires considerable assistance and frequent medical care. 
Unable to care for self; requires 
equivalent 
of 
institutional 
or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although death 
not imminent. 
20 
Very sick; hospital admission necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 
 
APPENDIX 2 | WHO SCORING40 
 
Grade 
Explanation of activity 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
  
 
APPENDIX 3 | LIGHT’S CRITERIA FOR DETERMINING EXUDATIVE EFFUSIONS41 
 
An effusion is likely to be an exudate if at least one of the following is present: 
• The ratio of pleural fluid protein to serum protein is greater than 0.5 
• The ratio of pleural fluid lactate dehydrogenase (LDH) and serum LDH is greater 
than 0.6 
• Pleural fluid LDH is greater than 0.6 (or ⅔) times the normal upper limit for serum. 

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APPENDIX 4 | MODIFIED BORG DYSPNEA SCALE42 
Instructions for Borg Dyspnea Scale 
 
• Use this scale to rate the difficulty of your breathing. 
 
• It starts at number 0 where your breathing is causing you no difficulty at 
all and progresses through to number 10 where your breathing difficulty 
is maximal. 
 
• How much difficulty is your breathing causing you right now? 
 
 
 
0 
Nothing at all 
0.5 
Very, very slight (just noticeable 
1 
Very slight 
2 
Slight 
3 
Moderate 
4 
Somewhat severe 
5 
Severe 
6 
7 
Very severe 
8 
9 
Very, very severe (almost maximal) 
10 
Maximal 

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APPENDIX 5 | SAMPLE EQ-5D-5L HEALTH STATUS QUESTIONNAIRE (UK 
VERSION)43, 44 
A sample page of the EQ-5D-5L health status questionnaire is provided below. Currently there 
are 123 language versions of the EQ-5D-5L self-complete health status questionnaire, including 
UK and US English. 

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APPENDIX 6 | VISUAL ANALOG SCALE45 
The VAS is a horizontal line, 100 mm in length, anchored by word descriptors at each end for each 
symptom extreme, as illustrated below. The patient places a mark on the line the point which 
represents his/her current perception of his/her pain. The VAS score is determined by measuring 
in millimetres from the left hand end of the line to the point that the patient marks.