Evaluation of the Surfacer System Approach to Central Venous Access
Phase: NA
Conditions: Venous Occlusion
Sponsor: Merit Medical Systems, Inc.

	  	  
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
pg 1 of 73 
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Clinical	  Investigational	  Protocol	  
	  
Evaluation	  of	  the	  Surfacer®	  System	  Approach	  
to	  Central	  Venous	  Access	  	  
	  
Protocol	  No:	  BVT.Surfacer.17-­‐01	  
	  
Version	  2.0,	  07	  Dec	  2017	  
	  
	  
	  
	  	  	  	  Study	  Sponsor:	  
	  	  	  	  Bluegrass	  Vascular	  Technologies	  Inc.	  (BVT)	  
	  	  	  	  12500	  Network	  Boulevard,	  Suite	  308	  
	  	  	  	  San	  Antonio,	  TX	  78249	  
	  
	  
	  
	  	  	  	  Investigational	  Device:	  
	  	  	  	  Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  
	  
	  
	  
	  
	  
	  
	  
CONFIDENTIAL	  AND	  PROPRIETARY	  
This	  document	  and	  the	  information	  contained	  herein	  may	  not	  be	  reproduced,	  used	  or	  disclosed	  without	  
prior	  written	  permission	  from	  Bluegrass	  Vascular	  Technologies,	  Inc.	  
	  

 
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
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PRINCIPAL	  INVESTIGATOR	  /	  SPONSOR	  SIGNATURE	  PAGE	  
	  
By	  signing	  below,	  I	  confirm	  that	  I	  have	  read	  protocol	  BVT.Surfacer.17-­‐01	  v.	  2.0	  dated	  07Dec17,	  and	  the	  
associated	   study	   documents	   provided	   by	   BVT.	   	   I	   agree	   to	   conduct	   the	   study	   in	   accordance	   with	   the	  
procedures	   outlined	   in	   this	   protocol,	   and	   in	   accordance	   with	   all	   applicable	   laws	   and	   regulations	   and	  
Good	  Clinical	  Practice	  (GCP)	  guidelines.	  
	  
All	  the	  information	  in	  the	  electronic	  case	  report	  forms	  presented	  to	  me	  for	  collection	  by	  BVT	  will	  be	  
entered	  in	  a	  timely	  manner	  ensuring	  completeness,	  legibility	  and	  accuracy.	  	  	  
	  
I	  agree	  to	  actively	  enroll	  subjects	  into	  this	  study	  per	  the	  eligibility	  criteria	  as	  listed	  in	  this	  protocol	  and	  
that	  all	  information	  provided	  to	  me	  by	  BVT,	  including	  pre-­‐clinical	  data,	  protocols,	  electronic	  case	  report	  
forms,	   and	   any	   verbal	   and	   written	   information,	   will	   be	   kept	   strictly	   confidential	   and	   confined	   to	   the	  
study	  staff	  involved	  in	  conducting	  the	  study.	  
In	  addition,	  no	  reports	  or	  information	  about	  the	  study	  or	  its	  progress	  will	  be	  shared	  with	  anyone	  not	  
involved	   in	   the	   study	   other	   than	   BVT	   or	   the	   Institutional	   Review	   Boards	   or	   Independent	   Ethics	  
Committees.	  	  Any	  such	  submission	  will	  indicate	  that	  the	  material	  is	  confidential.	  
	  
The	  Principal	  Investigator	  (PI)	  may	  delegate	  one	  or	  more	  of	  the	  above	  functions	  to	  a	  sub-­‐investigator	  or	  
other	  qualified	  study	  staff.	   The	  PI	  retains	  overall	  responsibility	  for	  proper	  conduct	  of	  the	  study.	  
Principal	  Investigator	  Name:	  	  	  
Title:	  	  
Signature:	  	  	  
Date:	  	  	  
Co-­‐Investigator	  Name:	  
Title:	  	  
Signature:	  	  	  
Date:	  	  	  
Co-­‐Investigator	  Name:	  
Title:	  	  
Signature:	  	  	  
Date:	  	  	  
Sponsor	  Approval	  
Sponsor	  Name:	  
Title:	  
	  	  	  
Signature:	  	  
Date:	  

	  
	  
 
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
pg 3 of 73 
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ABBREVIATIONS	  	  
	  
AE	  
Adverse	  Event	  
BC	  
Brachiocephalic	  
cm	  
Centimeter	  
eCRF	  
Electronic	  Case	  Report	  Form	  
CVC	  
Central	  Venous	  Catheter	  
CVA	  
Central	  Venous	  Access	  
CV	  
Curriculum	  Vitae	  
ECG	  
Electrocardiogram	  
Fr	  
French	  size	  	  
IFU	  
Instructions	  for	  Use	  
IJ	  
Internal	  Jugular	  
IOCVA	  
Inside	  out	  central	  venous	  access	  
IVC	  
Inferior	  Vena	  Cava	  
mg	  
Milligram	  
mm	  
Millimeter	  
MRI	  
Magnetic	  Resonance	  Imaging	  
MI	  
Myocardial	  Infarction	  
SC	  
Subclavian	  	  
SVC	  
Superior	  Vena	  Cava	  	  
TCVO	  
Thoracic	  Central	  Vein	  Obstruction	  
	  
	  
	  

	  
	  
 
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pg 4 of 73 
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CONTENTS	  
1.0	  	  	  	  	  	  	  	  PROTOCOL	  SUMMARY	  ...............................................................	  7	  
1.1	  
Protocol	  Synopsis	  ........................................................................	  7	  
1.2	  
Study	  Flowchart	  	  ........................................................................	  10	  
1.3	  	  
Schedule	  of	  Assessments	  ..........................................................	  11	  
2.0	  	  	  	  	  	  	  INTRODUCTION	  AND	  BACKGROUND	  ........................................	  12	  
2.1	  	  
Background	  ................................................................................	  12	  
2.1.1.	  	   Central	  Venous	  Access	  ..............................................................	  12	  
2.1.2	  
Techniques	  for	  Central	  Venous	  Access	  ......................................	  13	  
2.1.3	  
Conditions	  leading	  to	  CVA	  Occlusion	  ........................................	  16	  
2.1.4	  Complications	  of	  CV	  Catheter	  Occlusion	  .......................................	  18	  
2.2	  	  
Study	  Rationale	  .........................................................................	  20	  
2.3	  
Device	  Development	  .................................................................	  23	  
3.0	  	  	  	  	  	  	  DEVICE	  DESCRIPTION	  ................................................................	  24	  
3.1	  
The	  Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  ..................	  24	  
3.2	  	  
Indication	  for	  Use/Intended	  Use	  ...............................................	  27	  
3.3	  
Principles	  and	  Mode	  of	  Operation	  ............................................	  28	  
3.4	  	  
Contraindications	  ......................................................................	  28	  
3.5	  	  
Device	  Training	  ..........................................................................	  29	  
4.0	  	  	  	  	  	  	  REPORT	  OF	  PRIOR	  INVESTIGATIONS	  .........................................	  29	  
4.1	  	  
Clinical	  Data	  Overview	  ...............................................................	  29	  
4.2	  	  
Anatomical	  Studies	  ....................................................................	  31	  
4.3	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  Proof	  of	  Concept	  Study	  (Elayi	  2011)	  ...................................	  33	  
4.4	  
Investigator	  Experience,	  Gurley	  (2012)	  .....................................	  34	  
4.5.	  
Surfacer®	  System	  FIH	  Evaluation	  (Ebner,	  2013)	  ........................	  37	  
4.6	  
Regulatory	  Status	  ......................................................................	  39	  
5.0	  	  	  	  	  	  	  	  BENEFIT/RISK	  ANALYSIS	  ..........................................................	  39	  
5.	  1	  
Importance	  of	  CVA	  ....................................................................	  39	  
5.2	  	  
Limitations	  of	  Available	  Treatments	  ..........................................	  44	  
5.3	  
Clinical	  Considerations	  ..............................................................	  46	  
5.4	  	  
Surfacer	  System	  Potential	  Benefits	  ...........................................	  47	  
5.5	  
Surfacer	  System	  Potential	  Risks	  ................................................	  48	  
5.6	  	  
Benefit/Benefit	  Statement	  ........................................................	  48	  
6.0	  	  	  	  	  	  	  	  STUDY	  DESIGN	  .........................................................................	  50	  
6.1	  	  
ASA	  Guidelines	  ..........................................................................	  50	  
6.2	  	  
Subject	  Selection	  and	  Participation	  ...........................................	  50	  
6.3	  	  
Study	  Eligibility	  Criteria	  .............................................................	  51	  
6.3.1	  
Inclusion	  Criteria	  .......................................................................	  51	  
6.3.2	  
Exclusion	  Criteria	  .......................................................................	  51	  
6.4	  
Study	  Endpoints	  .........................................................................	  52	  
6.4.1	  
Primary	  Efficacy	  Endpoint	  .........................................................	  52	  

	  
	  
 
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6.4.2	  
Primary	  Safety	  Endpoints	  ..........................................................	  52	  
6.4.3	  
Secondary	  Efficacy	  Endpoint	  .....................................................	  52	  
6.4.4	  
Secondary	  Safety	  Endpoint	  .......................................................	  52	  
7.0	  	  	  	  	  	  	  	  STUDY	  PROCEDURES	  ................................................................	  52	  
7.1	  	  
Informed	  Consent	  ......................................................................	  52	  
7.2	  
Screening	  and	  Baseline	  Assessments	  ........................................	  52	  
7.2.1	  
Screen	  Failures	  ..........................................................................	  53	  
7.3	  	  
Subject	  Enrollment	  ....................................................................	  53	  
7.4	  
Intra-­‐Procedural	  Assessments	  ...................................................	  53	  
7.5	  
Discharge/Post	  Procedure	  Assessments	  ...................................	  54	  
7.6	  	  
Subject	  Withdrawal	  ...................................................................	  55	  
7.7	  
Study	  Completion	  ......................................................................	  55	  
7.8	  	  
Study	  Discontinuation	  ...............................................................	  55	  
8.0	  	  	  	  	  	  	  STATISTICAL	  CONSIDERATIONS	  .................................................	  56	  
8.1	  	  	  	  	  	  	  	  Introduction	  ...............................................................................	  56	  
8.2	  
Study	  Endpoints	  .........................................................................	  56	  
8.2.1	  	  	  	  	  	  Primary	  Endpoints	  .....................................................................	  56	  
8.2.1	  
Secondary	  Endpoints	  .................................................................	  58	  
8.3	  
Statistical	  Analysis	  .....................................................................	  58	  
8.3.1	  
Data	  Reporting	  Convention	  .......................................................	  58	  
8.3.2	  
Assumption	  Verification	  ............................................................	  58	  
8.3.3	  
Pooling	  of	  Study	  Sites	  ................................................................	  58	  
8.3.4	  
Analysis	  Populations	  ..................................................................	  59	  
8.3.5	  
Primary	  Endpoint	  Analysis	  .........................................................	  59	  
8.3.6	  
Secondary	  Endpoints	  Analysis	  ...................................................	  60	  
8.3.7	  
Multiplicity	  ................................................................................	  60	  
8.3.8	  
Safety	  Evaluations	  and	  Analyses	  ...............................................	  60	  
8.3.9	  
Missing,	  Unused	  &	  Spurious	  Data	  .............................................	  60	  
8.3.10	   Interim	  Analysis	  .........................................................................	  61	  
8.3.11	   Subgroup	  Analysis	  .....................................................................	  61	  
9.0	  	  	  	  	  	  	  SAFETY	  .....................................................................................	  61	  
9.1	  
Adverse	  Event	  Classification	  ......................................................	  61	  
9.1.1	  
Adverse	  Event	  ............................................................................	  61	  
9.1.2	  
Anticipated	  Adverse	  Events	  .......................................................	  62	  
9.1.3	  
Serious	  Adverse	  Event/Unanticipated	  Adverse	  Device	  Effect	  ...	  62	  
9.1.4	  	  	  	  	  	  SAE/UADE	  Reporting	  .................................................................	  62	  
9.1.5	  
UADE	  Regulatory	  Requirements	  ................................................	  62	  
10.0	  	  	  	  	  	  STUDY	  MANAGEMENT	  ............................................................	  63	  
10.1	  
Data	  Collection	  ..........................................................................	  63	  

	  
	  
 
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10.2	  
Source	  Documentation	  ..............................................................	  63	  
10.3	  
Data	  Confidentiality	  ...................................................................	  63	  
10.4	  
Record	  Retention	  .......................................................................	  63	  
10.5	  
Study	  Monitoring	  .......................................................................	  64	  
10.6	  
Study	  Oversight	  and	  Compliance	  ..............................................	  64	  
10.6.1	   	  Study	  Non-­‐Compliance	  .............................................................	  64	  
10.7	  	  
	  Investigational	  Device	  Inventory	  ..............................................	  65	  
10.7.1	  	  	  	  Investigational	  Device	  Accountability	  .......................................	  65	  
10.7.2	  	  	  	  Investigational	  Device	  Storage	  ..................................................	  65	  
10.7.3	  	  	  	  Investigational	  Device	  Return	  ...................................................	  65	  
10.8	  	  
	  Protocol	  Deviations	  ..................................................................	  65	  
10.9	  	  
	  Investigator/Site	  Training	  .........................................................	  65	  
10.10	   	  Study	  Changes	  ..........................................................................	  66	  
10.10.1	  	  	  Change	  to	  the	  Protocol	  ............................................................	  66	  
10.10.2	  	  	  IRB/IEC	  Approval	  Withdrawal	  ..................................................	  66	  
10.11	   	  	  Study	  Completion	  ....................................................................	  66	  
10.12	  	  	  	  	  	  Study	  Reports	  ...........................................................................	  66	  
11.0	  	  	  	  	  	  STUDY	  ADMINISTRATION	  ........................................................	  66	  
11.1	  	  
Statement	  of	  Compliance	  ..........................................................	  66	  
11.2	  	  	  	  	  	  ClinicalTrials.gov	  Registration	  ....................................................	  66	  
11.3	  
Investigator	  Responsibilities	  ......................................................	  67	  
12.0	  	  	  	   BVT	  GENERAL	  RESPONSIBILITIES	  ..............................................	  67	  
13.0	  	  	  	  	  PUBLICATION	  POLICY	  ...............................................................	  67	  
14.0	  	  	  	  	  REFERENCES	  .............................................................................	  69	  
15.0	  	  	  	  	  DEFINITION	  OF	  POTENTIAL	  RISKS	  (APPENDIX	  A)	  .......................	  71	  
	  
	  
	  
	  

	  
	  
 
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1.0	  	  	  	  	  	  	  	  PROTOCOL	  SUMMARY	  
1.1	  
Protocol	  Synopsis	  
Study	  Title	  
Surfacer®	  System	  to	  Facilitate	  Access	  in	  Venous	  Occlusions	  	  
Protocol	  Number	    
	  	  BVT.Surfacer.17-­‐01	  
	  	  	  Type	  and	  Phase	  
	  Pre-­‐Market	  Investigational	  Device	  Exemption	  (IDE)	  Study	  
	  	  	  Number	  of	  Sites	  
Three	  sites	  will	  participate	  in	  the	  study	  initially,	  with	  up	  to	  10	  sites	  
overall.	  
Device	  Name	  
Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  
Indication	  for	  Use	    
	  	  The	  Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  is	  	  	    
	  	  intended	  to	  obtain	  central	  venous	  access	  to	  facilitate	  	  	  	  	  	  	    
	  	  catheter	  insertion	  into	  the	  central	  venous	  system	  for	  patients	  	  	  	    
	  	  with	  upper	  body	  venous	  occlusions	  or	  other	  conditions	  that	  	    
	  	  preclude	  central	  venous	  access	  by	  conventional	  methods.	    
Device	  	  
Description	  
	  
The	  Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  (Surfacer®	  
System)	  is	  designed	  to	  facilitate	  entry	  and	  placement	  of	  central	  
venous	  access	  catheters	  within	  the	  peripheral	  vasculature.	  The	  
Surfacer®	  System	  is	  comprised	  of	  four	  components:	  a	  
Workstation	  (Workstation	  Sheath)	  for	  percutaneous	  access	  to	  the	  
femoral	  vein;	  a	  Delivery	  Instrument	  (Surfacer	  Device)	  which	  
contains	  a	  Needle	  Wire	  and	  Needle	  Guide	  which	  is	  advanced	  to	  
the	  supraclavicular	  space;	  an	  Exit	  Target	  which	  provides	  
fluoroscopic	  guidance	  to	  mark	  the	  exit	  point;	  and	  an	  Exit	  
(Peelable)	  Introducer	  which	  is	  introduced	  over	  the	  Needle	  Wire	  to	  
access	  the	  central	  venous	  system.	  The	  Surfacer®	  System	  
facilitates	  the	  entry	  and	  positioning	  of	  standard	  access	  catheters	  
by	  establishing	  a	  transient	  passage	  across	  venous	  occlusions.	  
Once	  the	  access	  is	  obtained	  and	  a	  catheter	  is	  in	  place,	  the	  
Surfacer®	  System	  is	  removed.	  
	  

	  
	  
 
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
pg 8 of 73 
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Study	  Design	  
This	  is	  a	  prospective,	  single-­‐arm,	  multi-­‐center,	  study	  to	  
demonstrate	  the	  safety	  and	  efficacy	  of	  the	  Surfacer®	  System.	  	  
Study	  Objectives	  
	  
This	   goal	   of	   this	   study	   is	   to	   demonstrate	   that	   the	   Surfacer®	  
System,	   once	   in	   place,	   facilitates	   stable	   upper	   body	   central	  
venous	  access	  that	  is	  suitable	  for	  any	  conventional	  catheter.	  
Safety	   will	   be	   evaluated	   based	   on	   the	   overall	   rate	   of	   acute	  
complications	   using	   the	   study	   device	   as	   compared	   to	   historical	  
rates	  
of	  
device/procedure	  
related	  
safety	  
events	  
using	  
conventional	  CVA	  methods.	  	  	  
Efficacy	   will	   be	   evaluated	   by	   the	   rate	   of	   transient	   successful	  
central	  venous	  accesses	  created	  by	  the	  study	  device.	  	  
Planned	  Study	  
Duration	  and	  
Number	  of	  
Subjects	  
Total	  study	  duration	  is	  anticipated	  to	  be	  approximately	  12	  months.	  	  	  
A	  total	  of	  30	  subjects	  is	  planned.	  10	  subjects	  will	  be	  enrolled	  
initially.	  After	  review	  of	  safety	  data,	  enrollment	  is	  expected	  to	  
continue	  to	  30	  subjects	  overall.	  Subjects	  will	  participate	  in	  the	  
study	  as	  follows:	  
• 
Screening/Baseline	  
•	  
Procedure	  (Surfacer	  System	  procedure	  and	  CVA	  catheter	  
insertion)	  
•	  
Hospital	  Discharge	  	  	  
• 
7-­‐days	  (+7)	  Post	  Procedure	  (assessments	  are	  to	  occur	  on	  
Day	  7,	  or	  as	  soon	  as	  possible	  thereafter)	  
	  
Study	  Sites	  
A	  minimum	  of	  three	  (3)	  sites	  in	  the	  United	  States	  and	  Europe	  will	  
participate,	  with	  a	  majority	  of	  the	  subjects	  being	  enrolled	  at	  US	  
sites	  if	  feasible.	  	  	  

	  
	  
 
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
pg 9 of 73 
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Primary	  Study	  
Endpoints	  
	  
	  
	  
	  
	    
Primary	  Efficacy	  Endpoint:	  	  
• Rate	  of	  safe	  insertion	  and	  patency	  of	  CVCs	  created	  across	  
venous	  occlusions.	  
	  
Primary	  Safety	  Endpoints:	  	  
• Acute	  device	  safety,	  defined	  as	  the	  absence	  of	  procedural	  
complications	  (hemopericardium,	  hemothorax,	  
pneumothorax,	  blood	  transfusion,	  resuscitation,	  
emergency	  post-­‐procedural	  intervention,	  transfer	  to	  an	  
intensive	  care	  unit,	  and	  death)	  at	  discharge	  and	  7	  days	  
post-­‐procedure	  
• Overall	  device	  and	  procedure	  related	  anticipated	  adverse	  
events	   compared	   to	   historical	   safety	   data	   from	   CV	  
placement	  procedures.	  
	  	  	  
	  
	  	  Secondary	  Study	  	  
	  	  Endpoints	  
	  
	  
Secondary	  Efficacy	  Endpoint	  
• Surfacer	   System	   clinical	   utility	   use	   from	   insertion	   into	   the	  
femoral	   vein	   to	   sub-­‐clavicular	   exit	   assessed	   by	   the	   ability	   of	  
the	   Surfacer	   System	   to	   facilitate	   central	   venous	   access	  
placement	  	  
Secondary	  Safety	  Endpoint	  
• 
Technique	  conversion	  rate	  
	  

 
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
pg 10 of 73 
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	  	  Inclusion	  Criteria	  
	  
	  
	  
	    
1.	  	  	  	  Subjects	  are	  between	  18-­‐80	  years	  of	  age.	  
2.	   	   Subjects	   have	   been	   referred	   for	   placement	   of	   central	   venous	   access	  
catheter.	  
3.	  	  	   Subjects	   have	   limited	   or	   diminishing	   upper	   body	   venous	   access	   or	  
pathology	  impeding	  standard	  access	  methods.	  
4.	  	   Subjects	  are	  willing	  and	  able	  to	  give	  written	  informed	  consent.	    
Exclusion	  Criteria	  
	  
1.	  	   Subjects	   are	   contraindicated	   for	   Surfacer	   System	   use	   if	   one	   of	   the	  
following	  are	  found	  (per	  the	  IFU):	  
a. Occlusion	  of	  the	  right	  femoral	  vein;	  
b. Occlusion	  of	  the	  iliac	  vein;	  	  
c. Occlusion	  of	  the	  inferior	  vena	  cava.	  	  
2.	  	   Subjects	  are	  contraindicated	  for	  central	  venous	  access	  based	  upon	  the	  
treating	  physician’s	  opinion	  and	  institutional	  standard	  of	  care.	  	  
3.	  	  	   Subject	  has	  acute	  thrombosis	  within	  any	  vessel	  (SVC,	  jugular,	  inferior	  
vena	  cava	  (IVC),	  brachiocephalic	  and	  subclavian)	  planned	  be	  crossed	  
by	  Surfacer	  System.	  	  
4.	   	   Subject	   has	   tortuous	   anatomy	   which	   precludes	   a	   straight	   line	   from	  
femoral	  venous	  entry	  to	  subclavian	  exit.	  
5.	  	  	  Subject	  has	  been	  diagnosed	  with	  active	  pericarditis	  or	  endocarditis.	  
6.	  	  	  Subject	  has	  a	  known	  or	  suspected	  pericardial	  effusion.	  
7.	   	   Subject	   has	   a	   known	   or	   suspected	   aneurysm	   or	   ectasia	   of	   ascending	  
aorta,	  innominate	  artery,	  or	  subclavian	  artery.	  
8.	   	   Subjects	   who	   are	   pregnant	   or	   of	   childbearing	   potential	   not	   taking	  
adequate	  contraceptive	  measures	  or	  nursing	  during	  the	  study.	    

 
 
 
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
pg	  11	  of	  73	  
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1.3	  	  
Schedule	  of	  Assessments	  
STUDY	  ASSESSMENTS	  WILL	  OCCUR	  AS	  FOLLOWS:	  	  
Assessments/Interval	  
Screening	  
Baseline	  
Intra-­‐
Procedural	  
Hospital	  
Discharge	  
7	  Days	  (+7)	  Post	  
Procedure7	  
Informed	  Consent	  
X	  
	  
	  
	  
	  
Study	  Eligibility	  	  
X	  
	  
	  
	  
	  
Medical	  History/Demographics	  
X	  
	  
	  
	  
	  
Physical	  Exam	  including	  Vital	  Signs	  
	  
X	  
	  
X	  
X	  
TCVO	  Lesion	  Type	  Classification	  
	  
X	  
	  
	  
	  
Procedural	  Complication	  Assessment	  
	  
	  
X	  
X	  
X	  
Study	  Device	  Performance	  
	  
	  
X	  
	  
	  
Medications	  	  
(Antithrombotic	  &	  Cardiovascular)	  
	  
X	  
	  
X	  
X	  
Clinical	  Laboratory	  Tests1	  
	  
	  
	  
	  
	  
Pregnancy	  Test2	  
X2	  
	  
	  
	  
	  
Creatinine	  
	  
X	  
	  
	  
	  
Coagulation	  Profile	  (APTT/PT/INR)	  
	  
X	  
	  
X	  
	  
CRP	  
	  
X	  
	  
X	  
	  
LDH/ASAT/ALAT	  
	  
X	  
	  
X	  
	  
Fibrinogen/D-­‐dimer	  
	  
X	  
	  
X	  
	  
Exams	  and	  Tests3	  
	  
	  
	  
	  
	  
AP	  and	  LAT	  Chest	  X-­‐Ray	  or	  cine-­‐
fluoroscopy	  
	  
X4	  
X	  
X5	  
	  
Ultrasound	  or	  Venous	  Duplex	  
Venography	  
	  
X	  
	  
	  
	  
ECG	  12-­‐lead	  
	  
X	  
	  
	  
	  
TTE	  
	  
	  
Only	  If	  Cardiac	  
Events	  
Only	  If	  Cardiac	  
Events	  
	  
Contrast	  Angiography	  
	  
	  
X	  
	  
	  
Fluoroscopy	  
	  
	  
X	  
	  
	  
Cone	  Beam	  CT/cardiac	  echo/advanced	  
imaging	  modalities6	  
	  
	  
X	  
	  
	  
Adverse	  Events	  
	  
	  
X	  
X	  
X	  
Protocol	  Deviations	  
	  
X	  
X	  
X	  
X	  
1	  Laboratory	  tests	  must	  be	  completed	  no	  more	  than	  72	  hours	  prior	  to	  the	  procedure.	  	  
2Pregnancy	  test	  is	  not	  required	  if	  patient	  is	  male	  or	  of	  non	  child	  bearing	  potential.	  
3Ultrasound	   or	   Venous	   Duplex	   Venography	   must	   be	   completed	   no	   more	   than	   7	   days	   prior	   to	   the	   Screening	   Visit.	   Other	  
Screening/Baseline	  tests	  must	  be	  completed	  no	  more	  than	  30	  days	  prior	  to	  the	  Procedure.	  
4AP	  and	  LAT	  chest	  X-­‐ray	  or	  cine	  fluoroscopy	  will	  be	  performed	  prior	  to	  the	  index	  procedure	  to	  define	  the	  pattern	  of	  occlusions,	  to	  rule	  
out	  acute	  thrombosis,	  and	  to	  detect	  pleural	  fluid	  and	  mediastinal	  widening.	  
5	  Post-­‐procedural	  AP	  and	  LAT	  chest	  X-­‐ray	  or	  cine	  fluoroscopy	  will	  be	  performed,	  ideally	  assessed	  immediately	  after	  the	  index	  procedure	  
is	  complete,	  to	  check	  the	  correct	  placement	  and	  position	  of	  the	  CVA	  Catheter	  tip,	  rule	  out	  pleuro-­‐pulmonary	  damage	  (pneumothorax,	  
hemothorax,	   etc.),	   and	   to	   detect	   pleural	   fluid	   and	   mediastinal	   widening.	   	   If	   the	   Investigator	   determines	   that	   additional	   imaging	   is	  
clinically	  indicated	  at	  the	  time	  of	  discharge	  (same	  day	  or	  next	  day	  discharge),	  a	  chest	  x-­‐ray	  may	  be	  obtained.	  

	  
	  
	  
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CONFIDENTIAL	  
	  
2.0	  	  	  	  	  	  	  INTRODUCTION	  AND	  BACKGROUND	  
2.1	  	  
Background	  	  
2.1.1.	  	   Central	  Venous	  Access	  
Central	  venous	  access	  (CVA)	  is	  one	  of	  the	  most	  commonly	  performed	  procedures	  in	  medicine,	  
vital	  to	  many	  patients	  with	  acute	  and	  chronic	  illness.	  Indications	  for	  CVA	  include	  life-­‐sustaining	  
therapies	  such	  as	  hemodialysis,	  chemotherapy	  infusion,	  parenteral	  nutrition,	  hemodynamic	  
monitoring	  and	  fluid	  management.i,	  ii	  
Central	  Venous	  Access	  Devices	  (CVADs)	  have	  become	  a	  mainstay	  for	  patients	  requiring	  
intravenous	  (IV)	  administration	  of	  medications	  and	  other	  therapies.	  In	  fact,	  more	  than	  7	  million	  
CVADs	  are	  implanted	  every	  year	  in	  patients	  in	  the	  United	  States,	  whilst	  in	  Europe	  this	  number	  
is	  reported	  to	  be	  3.5	  million	  constituting	  a	  population	  dependent	  upon	  on	  CVADs	  (Figure	  1).iii,	  iv	  
Obstruction	  or	  occlusion	  of	  CVADs	  due	  to	  venous	  thrombosis,	  with	  a	  reported	  frequency	  of	  up	  
to	  41%,	  is	  a	  serious	  problem	  in	  patients	  requiring	  repeated	  access	  or	  semi-­‐permanent	  access.	  
Chronic	  venous	  occlusions	  occur	  when	  thrombus	  forms	  around	  a	  catheter	  or	  pacing	  lead,	  and	  
organizes	  into	  dense	  thrombus	  or	  fibrous	  tissue	  that	  permanently	  obliterates	  the	  vessel	  lumen.	  
As	  a	  CVA	  is	  vital	  to	  the	  management	  of	  many	  chronic	  medical	  conditions,	  occlusion	  of	  the	  vein	  
hosting	  the	  access	  becomes	  a	  life-­‐threatening	  disease.	  Other	  risks	  include	  infection,	  pain,	  
infiltration	  or	  extravasation.	  
6Cone	  Beam	  CT,	  cardiac	  echo,	  or	  similar	  advanced	  imaging	  modalities	  to	  be	  performed	  in	  subjects	  with	  Type	  IV	  TCVO	  lesions,	  and	  Type	  
III	  TCVO	  lesions	  suspected	  to	  be	  characterized	  by	  unusually	  tortuous	  vessels	  or	  otherwise	  challenging	  anatomy.	  	  
7A	  +7	  day	  visit	  window	  has	  been	  provided	  to	  allow	  for	  outpatient	  clinic	  scheduling.	  	  However	  -­‐	  this	  visit	  is	  to	  occur	  on	  Day	  7,	  or	  as	  soon	  
as	  possible	  thereafter.	  

	  
	  
	  
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CONFIDENTIAL	  
	  	  	  	  	  	  	  	  Figure	  1.	  Conditions	  treated	  with	  Central	  Venous	  Access	  
	  
	  
2.1.2	   Techniques	  for	  Central	  Venous	  Access	  
CVA	  is	  typically	  obtained	  by	  puncturing	  one	  of	  the	  four	  large	  upper	  body	  veins;	  the	  right	  or	  left	  
internal	  jugular	  vein,	  or	  the	  right	  or	  left	  subclavian	  vein	  (Figure	  2).	  A	  guidewire	  is	  introduced	  
through	  the	  puncture	  needle	  and	  advanced	  into	  the	  central	  venous	  circulation.	  A	  plastic	  dilator	  
is	  advanced	  antegrade	  over	  the	  wire	  to	  enlarge	  the	  channel,	  and	  then	  the	  catheter	  is	  advanced	  
to	  the	  superior	  vena	  cava	  or	  right	  atrium.	  The	  tip	  of	  a	  CVAD	  is	  generally	  placed	  in	  either	  the	  
lower	  third	  of	  the	  superior	  vena	  cava	  (SVC)	  or	  the	  caval	  atrial	  junction	  (Figure	  2).	  Due	  to	  a	  
blood-­‐flow	  rate	  of	  approximately	  2	  liters	  per	  minute,	  infusates	  are	  rapidly	  hemodiluted	  and	  
distributed	  in	  the	  central	  venous	  system.	  v,	  vi	  

	  
	  
	  
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Figure	  2.	  Adult	  CVAD	  insertion	  and	  tip	  sitesvii	  
	  
	  
Catheters	  are	  categorized	  into	  (i)	  non-­‐tunneled	  catheters,	  (ii)	  tunneled	  catheters	  with	  
anchoring	  cuff,	  (iii)	  implanted	  ports	  (iv)	  apheresis/dialysis	  catheters	  (tunneled	  and	  non-­‐
tunneled)	  and	  (v)	  PICC	  (peripherally	  inserted	  central	  catheter)	  (Table	  1).vii	  They	  may	  have	  single	  
or	  multiple	  lumens	  and	  can	  be	  open-­‐ended	  or	  valved.	  Multiple	  lumen	  catheters	  are	  
advantageous	  in	  patients	  undergoing	  stem	  cell	  transplantation	  or	  chemotherapy	  whereby	  a	  
number	  of	  agents	  and	  blood	  products	  require	  simultaneous	  infusion.	  Blood	  products	  may	  be	  
administered	  concurrently	  with	  other	  drugs	  infused	  through	  a	  multi-­‐bore	  catheter.	  	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  

	  
	  
	  
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Table	  1:	  Common	  types	  of	  CVADsvii	  
	      
	  
	  
Non-­‐tunneled	  
Catheters	  
Tunneled	  catheters	  
Peripherally	  inserted	  
central	  catheters	  
(PICCs)	  
Implanted	  ports	  
Also	  called	  subclavian,	  
percutaneous,	  acute-­‐
care,	  or	  short-­‐term	  
catheters.	  
Typically	  used	  for	  days	  
or	  weeks,	  for	  all	  types	  
of	  IV	  therapy,	  to	  draw	  
blood,	  and	  to	  monitor	  
central	  venous	  
pressure.	  
May	  be	  placed	  bedside	  
or,	  if	  necessary,	  in	  an	  
emergency	  setting	  
without	  sedation	  
Designed	  for	  long-­‐term	  
use	  and	  frequent	  
venous	  access.	  
Provides	  a	  more	  reliable	  
IV	  access.	  
Used	  for	  extended	  
courses	  of	  antibiotics,	  
chemotherapy,	  and	  
parenteral	  nutrition	  
Surgically	  inserted	  
Often	  used	  when	  a	  
catheter	  will	  be	  needed	  
for	  less	  than	  6	  months	  
or	  when	  access	  to	  the	  
jugular	  or	  subclavian	  
vein	  is	  unavailable	  
Can	  be	  used	  for	  most	  
IV	  therapies	  and	  to	  
obtain	  blood	  samples	  
in	  a	  variety	  of	  care	  
settings	  from	  diverse	  
patient	  populations	  
May	  be	  placed	  bedside	  
or	  in	  an	  outpatient	  
setting	  
Consists	  of	  2	  attached	  
parts:	  
the	  catheter	  and	  portal	  
body	  with	  reservoir	  
Long-­‐term	  dwell	  
capacity,	  requiring	  little	  
maintenance	  when	  not	  
in	  use.	  
Useful	  for	  cyclically	  
infused	  therapies,	  such	  
as	  chemotherapy	  
Blood	  draws	  may	  be	  
done	  through	  the	  port	  
Surgically	  inserted	  
	  
	  
Table	  2	  summarizes	  the	  advantages	  and	  disadvantages	  for	  each	  of	  the	  catheter	  categories.	  An	  
experienced	  member	  of	  the	  Hematology	  Oncology	  team	  should	  make	  the	  decision	  regarding	  which	  
type	  of	  catheter	  is	  most	  appropriate	  at	  the	  outset	  of	  therapy,	  to	  avoid	  multiple	  catheterizations.	  The	  
decision	  made	  is	  based	  on	  diagnosis,	  length	  and	  type	  of	  therapy,	  patient	  preference,	  and	  clinical	  status,	  
availability	  of	  patent	  veins,	  operator	  experience	  and	  previous	  central	  venous	  access	  history.	  For	  
example,	  if	  an	  allogeneic	  transplant	  is	  planned	  a	  double	  or	  triple	  lumen	  skin-­‐tunneled	  catheter	  should	  
be	  inserted	  at	  the	  outset	  to	  ensure	  adequate	  access	  throughout	  chemotherapy	  and	  the	  subsequent	  
transplant.	  
	  
	  

	  
	  
	  
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Table	  2:	  Advantages	  and	  disadvantages	  of	  different	  catheters	  for	  CVAviii	    
2.1.3	   Conditions	  leading	  to	  CVA	  Occlusion	  
Catheter	  occlusion	  is	  the	  most	  common	  non-­‐infectious	  complication	  in	  the	  long-­‐term	  use	  of	  
central	  venous	  access	  devices	  (CVADs).	  In	  fact,	  up	  to	  25%	  of	  catheters	  may	  become	  	  	  	  	  	  
occluded.	  ix,	  x,	  xi	  Occlusions	  may	  occur	  soon	  after	  insertion	  of	  a	  device	  or	  develop	  at	  any	  time	  
during	  the	  course	  of	  intravenous	  (IV)	  therapy.	  
About	  58%	  of	  catheter	  occlusions	  are	  thrombotic,	  resulting	  from	  formation	  of	  a	  thrombus	  
within,	  surrounding,	  or	  at	  the	  tip	  of	  the	  catheter.	  xii,	  xiii	  
About	  42%	  of	  catheter	  occlusions	  are	  due	  to	  non-­‐thrombotic	  causes,	  including	  precipitates,	  
mal-­‐positioning,	  mechanical	  obstructions,	  and	  other	  factors.	  xii	  
Conditions	  leading	  to	  CVA	  catheter	  dysfunction	  are	  outlined	  in	  Figure	  3.	  

	  
	  
	  
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Figure	  3:	  Conditions	  leading	  to	  CVA	  catheter	  dysfunction.	  xiv	  
a) 
intraluminal	  or	  extraluminal	  	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  thrombosis	  
b) 
deposition	  of	  residues	  of	  lipids	  
c) 
precipitation	  (e.g.,	  of	  calcium	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  phosphate)	  by	  simultaneous	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  infusion	  of	  solutions	  with	  low	  and	  	  	  	  	        
	  	  	  	  	  	  	  	  	  	  	  	  	  	  high	  pH	  
d) 
angulation	  or	  folding	  of	  the	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  catheter	  
e) 
pinch-­‐off	  syndrome	  (compression	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  of	  the	  catheter	  between	  the	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  clavicle	  and	  first	  rib,	  mainly	  during	  	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  long-­‐term	  use)	  
f) 
intramural	  migration	  of	  the	  	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  catheter	  tip.	  
	  
	  
Catheter	  obstructions	  can	  be	  thrombotic	  and	  non-­‐thrombotic	  (Figure	  4).	  	  
All	  catheters,	  when	  introduced	  into	  the	  body,	  become	  covered	  with	  plasma	  proteins	  and	  fibrin.	  
This	  is	  the	  body's	  natural	  attempt	  to	  protect	  itself	  against	  a	  foreign	  body.	  The	  fibrin	  starts	  to	  
form	  a	  layer	  around	  the	  outside	  of	  the	  catheter	  within	  minutes	  of	  insertion,	  starting	  at	  either	  
the	  line	  entry	  site	  or	  where	  the	  tip	  contacts	  the	  vein.	  
The	  concentration	  of	  proteins	  on	  the	  catheter	  surface	  equals	  the	  concentration	  in	  the	  
bloodstream	  within	  5	  minutes	  of	  insertion,	  and	  a	  1-­‐mm	  thick	  layer	  of	  platelets	  and	  white	  blood	  
cells	  adhere	  to	  these	  proteins	  within	  24	  hours.	  These	  absorbed	  blood	  components	  can	  allow	  
the	  binding	  and	  colonization	  of	  bacteria,	  which	  can	  increase	  fibrin	  formation	  and	  may	  activate	  
the	  clotting	  mechanism.	  
	  
	  
	  
	  
	  
	  
	  

	  
	  
	  
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Figure	  4:	  Intraluminal	  Thrombus	  &	  Fibrin	  Sheath	  Occlusionsxv,	  xvi	  
	  
	  
	  
Intraluminal	  
Thrombus	  
occurs	  
when	  
blood	  
refluxes	   inside	   the	   catheter	   lumen,	   such	   refluxes	  
may	   result	   from	   patient	   coughing,	   inadequate	  
flushing	   after	   blood	   draws	   or	   checking	   for	   blood	  
return,	  or	  improper	  use	  of	  flush	  syringesxv,	  xvi	  
Fibrin	  sheath	  forms	  when	  fibrin	  adheres	  to	  the	  
external	  catheter	  surface,	  often	  beginning	  at	  the	  
entry	   site,	   and	   may	   encase	   all	   or	   part	   of	   the	  
catheter	  like	  a	  sock	  covering	  the	  entire	  opening	  
of	  the	  catheter	  tip.	  xv,	  xvi	  
	  
2.1.4	  Complications	  of	  CV	  Catheter	  Occlusion	  
Thrombotic	  occlusions	  are	  associated	  with	  several	  complications	  (Figure	  5),	  including:	  
	  
• 
Risk	  of	  infection	  
• 
Pain	  
• 
Infiltration	  or	  extravasation	  
• 
Venous	  thrombosis	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  

	  
	  
	  
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Figure	  5:	  Complications	  associated	  with	  thrombotic	  occlusions.	  
Risk	  of	  infection	  
Formation	   of	   fibrin	   deposits	   and	   biofilm	   is	   a	  
natural	   response	   that	   can	   start	   upon	   catheter	  
insertion.	   Fibrin	   deposits	   and	   thrombi	   provide	   a	  
rich	  culture	  medium	  for	  bacterial	  growth.	  
Thrombus	   formation	   is	   linked	   to	   infection	   risk,	  
caused	   by	   the	   interaction	   of	   fibrin,	   blood	  
components,	   and	   a	   biofilm	   layer	   that	   attracts,	  
encloses,	  
and	  
protects	  
bacteria	  
and	  
microorganisms.	  
Microorganisms	  
can	  
be	  
released	  
into	  
the	  
bloodstream	  as	  a	  result	  of	  aggressive	  flushing	  that	  
shears	  off	  part	  of	  the	  biofilm	  or	  thrombusxvii,	  xviii	  
Venous	  thrombosis	  with	  phlebitis	  (jugular	  
vein)	  /	  Pain	  
	  
Irritation	   to	   the	   vein	   from	   the	   development	   of	   a	  
fibrin	   sheath	   on	   the	   catheter	   can	   result	   in	  
thrombophlebitis	   denoting	   a	   twofold	   injury:	  
thrombosis	  and	  inflammation.	  	  
Venous	  thrombosis	  may	  result	  from	  formation	  of	  a	  
thrombus	   between	   the	   catheter	   and	   the	   vessel	  
wall,	  leading	  to	  complete	  blockage	  of	  the	  vein.	  
Venous	   thrombosis	   is	   frequently	   associated	   with	  
veins	   in	   the	   lower	   extremity	   due	   to	   the	   use	   of	  
hypertonic	  or	  highly	  acidic	  infusion	  solutions.xix	  
Infiltration	  or	  extravasation	  
Infiltration	   is	   the	   leaking	   of	   non-­‐vesicant	   (non-­‐
blistering)	   fluids	   into	   the	   surrounding	   tissue,	   and	  
may	  cause	  pain,	  discoloration,	  and	  swelling.	  
Extravasation	   is	   the	   leaking	   of	   a	   vesicant	  
(blistering)	   medication	   or	   solution	   into	   the	  
surrounding	   tissue,	   resulting	   in	   more	   severe,	  
painful,	  edema,	  and	  tissue	  necrosis	  
Either	  infiltration	  or	  extravasation	  may	  result	  from	  
a	  thrombotic	  occlusion	  or	  physical	  damage	  to	  the	  
linexx,	  xxi	  

 
 
 
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2.2	  	  
Study	  Rationale	  	  
In	  patients	  with	  CV	  occlusions,	  life-­‐saving	  therapies	  such	  as	  (i.e.	  dialysis,	  chemotherapy,	  pacing,	  and	  
nutrition)	  cannot	  be	  administered.	  	  The	  current	  treatment	  for	  central	  venous	  obstruction	  is:	  
to	  re-­‐establish	  access	  in	  the	  current	  vein,	  or	  
to	  “try	  another	  vein”	  
Practice	  guidelines	  have	  been	  published	  by	  several	  scientific	  societies	  to	  address	  problems	  related	  to	  
CV	  access.	  In	  particular,	  Baskin	  et	  al8	  proposed	  an	  algorithm	  for	  management	  of	  occlusion	  and	  
thrombosis	  associated	  with	  long-­‐term	  indwelling	  central	  venous	  catheters	  (Figure	  6).	  	  
After	  ruling	  out	  mechanical	  dysfunction	  and	  medication	  or	  parenteral	  nutrition-­‐related	  etiologies,	  the	  
next	  step	  is	  to	  exclude	  the	  thrombotic	  obstruction.	  A	  contrast	  study	  of	  the	  catheter	  (sometimes	  
referred	  to	  as	  a	  “linogram”)	  can	  be	  used	  to	  detect	  an	  intraluminal	  clot	  or	  fibrin	  sheath.	  	  
Current	  recommendations	  include	  administration	  of	  a	  thrombolytic	  agent	  into	  the	  catheter	  lumen	  with	  
a	  dwell	  time	  of	  at	  least	  30	  minutes	  and	  a	  repeated	  dose	  if	  needed.	  If	  catheter	  patency	  is	  not	  restored,	  a	  
low	  dose	  of	  alteplase,	  a	  tissue	  plasminogen	  activator	  (tPA),	  can	  be	  infused	  over	  6	  to	  8	  hours.	  An	  
ultrasound,	  venogram,	  or	  other	  diagnostic	  study	  is	  warranted	  if	  venous	  thrombosis	  is	  suspected.	  	  
If	  thrombolytic	  therapy	  fails	  to	  clear	  the	  catheter,	  a	  guide	  wire	  can	  be	  inserted	  through	  the	  catheter	  
lumen	  to	  dislodge	  a	  thrombus	  at	  the	  tip	  of	  the	  CVC.	  	  
Fibrin	  sheath	  stripping	  has	  also	  been	  used	  for	  CVC	  occlusion	  that	  is	  resistant	  to	  medical	  management.	  
The	  procedure	  uses	  femoral	  venous	  access	  to	  pass	  a	  vascular	  snare	  device	  to	  dislodge	  and	  remove	  the	  
fibrin	  sheath.	  Although	  effective,	  these	  procedures	  are	  more	  invasive	  and	  are	  only	  used	  as	  a	  last	  resort.	  	  
	  
	  
	  
	  

	  
	  
	  
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Figure	  6:	  Algorithm	  for	  management	  of	  a	  central	  venous	  catheter	  obstruction	  
	  
	  
Due	  to	  the	  lack	  of	  prospective	  studies,	  controversy	  continues	  regarding	  optimal	  management	  of	  a	  
catheter	  related	  thrombosis	  (CRT).	  Recent	  guidelines	  suggest	  dividing	  patients	  with	  CRT	  into	  2	  
categories	  based	  on	  whether	  or	  not	  they	  continue	  to	  need	  central	  venous	  access	  (Figure	  7).	  	  
	  
	  

	  
	  
	  
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Figure	  7:	  Two	  categories,	  for	  patients	  with	  CRT,	  based	  on	  whether	  or	  not	  they	  continue	  to	  need	  central	  venous	  
access	  
	  
	  
For	  patients	  who	  have	  developed	  a	  CRT	  but	  no	  longer	  need	  a	  CVC	  or	  in	  whom	  it	  is	  no	  longer	  
functioning,	  guidelines	  from	  the	  American	  College	  of	  Chest	  Physicians	  (ACCP)	  recommend	  to	  remove	  
the	  catheter	  after	  3–5	  days	  of	  anticoagulation	  therapy.	  However,	  some	  believe	  that	  the	  CVC	  can	  be	  
removed	  once	  a	  patient	  has	  been	  appropriately	  anticoagulated,	  as	  documented	  by	  an	  appropriate	  
partial	  thromboplastin	  time	  (if	  unfractionated	  heparin	  is	  used)	  or	  anti-­‐Xa	  level	  (if	  low	  molecular	  weight	  
heparin	  is	  used).	  	  
The	  length	  of	  time	  a	  patient	  should	  be	  anticoagulated	  following	  removal	  of	  the	  CVC	  is	  controversial.	  
Although	  some	  physicians	  advocate	  anticoagulation	  for	  3	  months	  after	  the	  CVC	  has	  been	  removed,	  
others	  may	  shorten	  the	  course	  depending	  on	  the	  patient	  and	  the	  severity	  of	  the	  clot.	  
For	  the	  majority	  of	  patients	  who	  continue	  to	  require	  central	  venous	  access,	  the	  catheter	  can	  be	  left	  in	  
place	  and	  anticoagulation	  therapy	  initiated.	  	  
Some	  patients	  develop	  a	  thrombosis	  that	  may	  threaten	  life	  or	  limb.	  
Alternatively,	  anticoagulation	  may	  be	  contraindicated,	  in	  which	  case	  the	  CVC	  would	  likely	  require	  

	  
	  
	  
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removal	  regardless	  of	  the	  patient’s	  need	  for	  central	  venous	  access.	  	  
For	  patients	  that	  retain	  their	  catheter,	  current	  recommendations	  include	  initial	  anticoagulation	  for	  
several	  days,	  with	  unfractionated	  heparin	  or	  low	  molecular	  weight	  heparin,	  followed	  by	  at	  least	  3	  
months	  of	  anticoagulation	  with	  a	  vitamin	  K	  antagonist	  or	  low-­‐molecular-­‐weight	  heparin.	  	  
Low-­‐molecular-­‐weight	  heparin	  is	  preferred	  for	  cancer	  patients	  since	  it	  more	  effectively	  prevents	  
recurrent	  thrombosis	  and	  because	  warfarin	  interferes	  with	  some	  chemotherapy	  regimens	  and	  is	  more	  
difficult	  to	  adjust	  when	  thrombocytopenia	  occurs.	  	  
Thrombolytic	  treatment	  for	  an	  upper	  extremity	  DVT	  (deep	  vein	  thrombosis)	  is	  not	  recommended	  for	  
initial	  therapy	  of	  a	  CRT.	  Additionally,	  if	  the	  catheter	  remains	  in	  place	  once	  the	  course	  of	  full-­‐dose	  
anticoagulation	  is	  complete,	  the	  American	  College	  of	  Chest	  Physicians	  recommends	  continued	  
anticoagulation	  therapy	  at	  a	  prophylactic	  dose	  until	  the	  catheter	  is	  removed.	  
Clinicians	  who	  treat	  adults	  should	  refer	  to	  the	  recently	  updated	  ACCP	  guidelines.	  
2.3	  
Device	  Development	  	  
Central	  venous	  access	  (CVA)	  is	  one	  of	  the	  most	  commonly	  performed	  procedures	  in	  medicine	  and	  is	  
vital	  to	  many	  patients	  suffering	  from	  both	  acute	  and	  chronic	  illnesses.	  It	  is	  estimated	  that	  over	  six	  
million	  patients	  worldwide	  require	  central	  venous	  access	  for	  long	  term	  treatment	  or	  chronic	  disease	  
management	  including	  the	  need	  for	  parenteral	  nutrition,	  hemodynamic	  monitoring	  and	  fluid	  
management,	  hemodialysis	  for	  renal	  failure,	  and	  chemotherapy	  infusion.	  	  
The	  Surfacer	  System	  has	  been	  developed	  and	  designed	  to	  satisfy	  an	  unmet	  lifesaving	  clinical	  need:	  
facilitating	  central	  venous	  access	  in	  patients	  for	  whom	  access	  has	  been	  lost	  or	  diminished,	  due	  to	  
obstruction	  of	  central	  veins.	  	  The	  Surfacer	  System	  is	  designed	  to	  safely	  overcome	  chronic,	  total	  
occlusion	  of	  the	  superior	  vena	  cava	  (SVC)	  or	  both	  internal	  jugular	  and	  subclavian	  veins,	  as	  well	  as	  
occlusions	  inaccessible	  by	  conventional	  methods.	  The	  device	  is	  intended	  to	  enable	  access	  using	  the	  
same	  vessel	  that	  would	  not	  be	  accessible,	  or	  would	  prove	  difficult	  to	  access,	  with	  conventional	  
methods,	  and	  therefore	  brings	  potential	  benefits	  that	  cannot	  be	  achieved	  with	  the	  current	  standard	  of	  
care.	  	  
Restoring	  CV	  access	  is	  necessary	  to	  provide	  life-­‐saving	  therapies	  (dialysis,	  chemotherapy,	  pacing,	  

	  
	  
	  
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nutrition),	  but	  it	  is	  also	  important	  to	  avoid	  risks	  such	  as	  post-­‐thrombotic	  syndrome,	  pulmonary	  
embolism,	  and	  catheter	  infections	  that	  are	  known	  to	  be	  associated	  with	  CV	  thrombosis.	  Bluegrass	  
approaches	  this	  problem	  by	  reversing	  the	  standard	  approach	  of	  recanalizing	  or	  bypassing	  occlusions	  by	  
advancing	  a	  catheter	  system	  via	  the	  inferior	  vena	  cava	  to	  the	  superior	  vena	  cava	  and	  to	  the	  location	  of	  
the	  occlusion.	  Once	  tunneled	  through	  the	  occlusion,	  the	  system	  exits	  the	  body	  and	  access	  catheters	  can	  
be	  back-­‐loaded	  into	  the	  body.	  	  
The	  Surfacer	  System	  is	  a	  high-­‐impact	  technology	  for	  clinical	  practice,	  considering	  the	  severity	  of	  the	  
clinical	  condition	  that	  this	  device	  treats	  and	  for	  which	  there	  are	  limited,	  if	  any,	  therapeutic	  options.	  	  
3.0	  	  	  	  	  	  	  DEVICE	  DESCRIPTION	  
3.1	  
The	  Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  
	  
Table	  3:	  Device	  Components	  
	  
	  
A)	  Surfacer	  Workstation	  Sheath:	  
	  
The	  Workstation	  Sheath	  provides	  access	  to	  the	  
peripheral	  venous	  system	  via	  the	  femoral	  vein.	  
The	  Workstation	  Sheath	  provides	  a	  lumen	  for	  the	  
Surfacer	  Device,	  preventing	  injury	  when	  it	  is	  
advanced.	  
The	  Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  (Surfacer®	  System)	  is	  designed	  to	  facilitate	  
entry	  and	  placement	  of	  central	  venous	  access	  catheters	  within	  the	  peripheral	  vasculature.	  The	  
Surfacer®	  System	  is	  comprised	  of	  four	  components:	  a	  Workstation	  (Workstation	  Sheath)	  for	  
percutaneous	  access	  to	  the	  femoral	  vein;	  a	  Delivery	  Instrument	  (Surfacer	  Device)	  which	  contains	  
a	  Needle	  Wire	  and	  Needle	  Guide	  which	  is	  advanced	  to	  the	  supraclavicular	  space;	  an	  Exit	  Target	  
which	  provides	  fluoroscopic	  guidance	  to	  mark	  the	  exit	  point;	  and	  an	  Exit	  (Peelable)	  Introducer	  
which	  is	  introduced	  over	  the	  Needle	  Wire	  to	  access	  the	  central	  venous	  system.	  The	  Surfacer®	  
System	  facilitates	  the	  entry	  and	  positioning	  of	  standard	  access	  catheters	  by	  establishing	  a	  
transient	  passage	  across	  venous	  occlusions.	  Once	  the	  access	  is	  obtained	  and	  a	  catheter	  is	  in	  
place,	  the	  Surfacer®	  System	  is	  removed.	  

	  
	  
	  
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B)	  Surfacer	  Device:	  
	  
The	  Surfacer	  Device	  consists	  of	  a	  Main	  Sheath,	  
Needle	  Guide,	  Needle	  Wire,	  and	  a	  Handle:	  
• 
The	  Main	   Sheath	  is	  8F	  and	  has	  a	  95	  cm	  
effective	  length.	  The	  Main	  Sheath	  provides	  access	  
to	  the	  peripheral	  venous	  system	  via	  the	  femoral	  
vein.	  The	  Main	  Sheath	  has	  a	  lumen	  for	  the	  Needle	  
Guide.	  
• 
The	  Needle	   Guide	  is	  3F	  and	  extends	  10	  
mm	   from	   the	   main	   sheath.	   The	   Needle	   Guide	  
provides	  access	  to	  the	  peripheral	  venous	  system	  
via	   the	   femoral	   vein.	   It	   has	   a	   lumen	   for	   the	  
Needle	   Wire.	   The	   Needle	   Guide	   passes	   though	  
the	  Main	  Sheath.	  
• 
The	  Needle	   Wire	  is	  1F	  and	  180	  cm	  long.	  
The	  Needle	  Wire	  is	  advanced	  through	  the	  Needle	  
Guide	   to	   the	   percutaneous	   exit	   location	   at	   the	  
supraclavicular	  space.	  
• 
The	   Handle	   incorporates	   a	   rotating	  
knob	   to	   position	   the	   Needle	   Guide	   and	   to	   to	  
advance	  and	  retract	  the	  needle	  wire.	  
	    
C)	  Exit	  Target:	  
	  
The	  Exit	  Target	  is	  a	  radiopaque	  marker	  use	  to	  
locate	  the	  desired	  Needle	  Wire	  exit	  location	  on	  
the	  patient’s	  skin	  (the	  supraclavicular	  space)	  
using	  fluoroscopic	  imaging.	  

	  
	  
	  
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D)	  Peelable	  Introducer:	  
	  
The	  Peelable	  Introducer	  provides	  percutaneous	  
access	   to	   the	   venous	   system	   and	   permits	  
insertion	   of	   the	   CVA	   catheter.	   The	   Peelable	  
Introducer	  has	  a	  split	  sheath,	  valve	  and	  dilator.	  
The	  Peelable	  Introducer	  is	  16F	  x	  20	  cm	  long.	  
	  
The	  Surfacer	  System	  catheter	  is	  delivered	  through	  the	  femoral	  vein	  and	  the	  superior	  vena	  cava	  (SVC)	  
into	  the	  peripheral	  venous	  system	  and	  to	  the	  occlusion.	  	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  

	  
	  
	  
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Figure	  8:	  Schematic	  of	  Surfacer	  System	  procedure	  
	  
	  
	  
a)	   The	   Surfacer	   System	   is	   introduced	   via	   a	  
femoral	  
vein	  
approach.	  
The	  
catheter	  
“Workstation	   Sheath”	   component	   is	   navigated	  
along	  the	  illustrated	  path	  to	  the	  desired	  upper	  
body	   veins	   location	   just	   proximal	   to	   the	  
occlusion.	  
b)	  The	  catheter	  “Surfacer	  Device”	  component,	  
is	   passed	   through	   the	   “Workstation	   Sheath”,	  
and	   penetrates	   the	   occlusion.	   The	   Needle	  
Guide	   is	   oriented	   to	   the	   “Exit	   Target”	  
(radiopaque	   ring	   marker)	   by	   fluoroscopy.	   A	  
“Needle	  Wire”	  exists	  the	  Needle	  Guide	  by	  the	  
side	   of	   the	   catheter	   and	   is	   advanced	   toward	  
the	  supraclavicular	  space	  where	  the	  Exit	  Target	  
has	  been	  placed	  and	  perforates	  the	  skin.	  
	    
c)	   The	   “Peelable	   Introducer”	   is	   delivered	   over	  
the	   Needle	   Wire	   and	   advanced	   to	   the	   SVC	   to	  
facilitate	   the	   introduction	   of	   a	   new	   Central	  
Venous	  Catheter	  into	  the	  vein.	  	  
d)	   A	   new	   Central	   Venous	   catheter	   is	   then	  
positioned	  into	  the	  Central	  Venous	  system	  and	  
access	  is	  restored.	  
	  
3.2	  	  
Indication	  for	  Use/Intended	  Use	  
The	  Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  is	  intended	  to	  obtain	  central	  venous	  access	  to	  
facilitate	  catheter	  insertion	  into	  the	  central	  venous	  system	  for	  patients	  with	  upper	  body	  venous	  
occlusions	  or	  other	  conditions	  that	  preclude	  central	  venous	  access	  by	  conventional	  methods.	  	  

	  
	  
	  
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3.3	  
Principles	  and	  Mode	  of	  Operation	  
The	  Surfacer	  System	  uses	  the	  same	  principle	  technique	  as	  conventional	  CVA	  procedures,	  by	  tunneling	  
through	  or	  bypassing	  the	  occlusion,	  but	  does	  this	  in	  the	  reverse	  direction,	  from	  the	  inside	  to	  the	  
outside.	  With	  the	  Surfacer	  System,	  the	  Surfacer	  Device	  is	  percutaneously	  introduced	  into	  the	  right	  
femoral	  vein.	  It	  is	  advanced	  up	  the	  inferior	  vena	  cava,	  via	  the	  superior	  vena	  cava	  (SVC),	  to	  the	  location	  
of	  the	  occlusion.	  When	  the	  occlusion	  has	  been	  visualized	  under	  fluoroscopy,	  a	  needle	  wire	  is	  oriented	  
to	  advance	  through	  or	  to	  bypass	  the	  occlusion	  and	  to	  exit	  to	  a	  pre-­‐determined	  external	  target.	  A	  new	  
central	  venous	  catheter	  is	  then	  back-­‐loaded	  into	  the	  Peelable	  Introducer	  and	  positioned	  below	  the	  
occlusion.	  Placement	  of	  the	  central	  venous	  catheter	  below	  the	  venous	  occlusion	  restores	  central	  
venous	  access.	  	  
Prepare	  the	  right	  femoral	  and	  right	  sub-­‐clavicular	  area	  for	  sterile	  percutaneous	  access.	  Administer	  
conscious	  sedation	  and	  local	  anesthesia	  according	  to	  hospital	  protocol.	  Follow	  standard	  access	  
procedures	  to	  gain	  access	  into	  the	  femoral	  vein	  using	  .035”	  x	  150-­‐180	  cm	  J-­‐tip	  exchange	  guidewire.	  	  
Advance	  the	  Workstation	  Sheath	  and	  dilator	  over	  the	  exchange	  wire	  to	  the	  venous	  occlusion.	  Once	  the	  
location	  of	  the	  Workstation	  Sheath	  is	  in	  the	  occlusion	  as	  confirmed	  by	  injecting	  a	  small	  bolus	  of	  
contrast,	  place	  an	  Exit	  Target	  to	  the	  exit	  point	  supraclavicular	  and	  proceed	  with	  insertion	  of	  the	  
Surfacer	  Device	  through	  the	  Workstation	  Sheath.	  	  Once	  positioning	  is	  confirmed	  the	  Handle	  can	  be	  
used	  to	  advance	  the	  Needle	  wire	  out	  of	  the	  needle	  guide	  and	  exit	  the	  skin.	  For	  Type	  III	  and	  Type	  IV	  
occlusions,	  inject	  a	  small	  bolus	  of	  5-­‐10cc	  of	  contrast	  through	  Workstation	  sidearm	  to	  exclude	  
extravasation	  of	  contrast	  under	  fluoroscopy	  into	  the	  pleural	  or	  pericardial	  space.	  	  If	  visualization	  cannot	  
be	  confirmed	  a	  4	  or	  5F	  sheath	  could	  be	  back	  loaded	  over	  the	  Needle	  wire	  and	  injection	  of	  contrast	  
could	  be	  performed	  under	  a	  gently	  pull	  back	  to	  opacify	  the	  tract	  of	  exit	  is	  free	  from	  extravasation.	  Once	  
confirmed,	  the	  Peelable	  Introducer	  can	  now	  be	  back	  loaded	  over	  the	  exiting	  wire	  and	  access	  can	  be	  
confirmed	  by	  fluoroscopy.	  Upon	  completion	  of	  the	  procedure,	  a	  desired	  CVA	  catheter	  can	  be	  
exchanged	  or	  introduced	  adjacent	  to	  the	  Peelable	  Introducer.	  	  	  
3.4	  	  
Contraindications	  
The	  Surfacer	  System	  is	  contraindicated	  for	  patients	  with	  an	  occlusion	  of	  the	  right	  femoral	  vein,	  iliac	  vein	  

	  
	  
	  
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or	  inferior	  vena	  cava,	  or	  acute	  thrombosis	  within	  a	  vessel	  to	  be	  crossed	  by	  the	  Surfacer	  System.	  Special	  
precautions	  may	  be	  required	  for	  patients	  with	  coagulation	  disorders	  and	  patients	  on	  anti-­‐coagulation	  
therapy.	  
The	  Surfacer	  System	  is	  not	  intended	  for	  use	  in	  the	  coronary	  or	  cerebral	  vasculature.	  	  
This	  device	  is	  not	  to	  be	  used	  in	  the	  arterial	  system.	  
3.5	  	  
Device	  Training	  	  
BVT	  intends	  to	  implement	  the	  current	  commercial	  device	  training	  program	  under	  way	  in	  Europe,	  and	  
will	  train	  Principal	  Investigators	  and	  study	  staff	  using	  this	  training	  program.	  A	  detailed	  description	  of	  
Surfacer	  System	  preparation	  and	  use	  is	  provided	  in	  the	  Instructions	  for	  Use.	  Principal	  Investigators	  
must	  be	  familiar	  with	  the	  Indications	  for	  Use	  (IFU),	  Contraindications,	  Warnings,	  Precautions,	  and	  
Implantation	  Procedure	  as	  described	  in	  the	  IFU	  prior	  to	  use	  of	  the	  Surfacer	  System.	  Training	  documents	  
and	  the	  IFU	  will	  be	  provided	  with	  the	  study	  manual.	  
	  
4.0	  	  	  	  	  	  	  REPORT	  OF	  PRIOR	  INVESTIGATIONS	  
4.1	  	  
Clinical	  Data	  Overview	  
The	  Inside-­‐Out	  procedure	  (IOCVA)	  using	  modifications	  of	  commercially	  available	  devices	  (Elayi	  2011xxii;	  
Gurley	  2012xxiii)	  has	  been	  reported	  to	  be	  used	  in	  124	  cases	  with	  no	  or	  low	  adverse	  event	  occurrences,	  
and	  life-­‐saving	  benefits	  to	  patients	  with	  few	  therapeutic	  options	  for	  central	  venous	  access	  due	  to	  upper	  
body	  venous	  occlusions.	  	  
The	  Surfacer	  System	  has	  also	  been	  investigated	  in	  an	  approved	  clinical	  study	  of	  12	  patients	  with	  two	  or	  
more	  total	  upper	  body	  venous	  occlusions	  where	  there	  were	  no	  serious	  adverse	  events,	  100%	  technical	  
success	  in	  inserting	  the	  device,	  and	  100%	  success	  in	  achieving	  central	  venous	  access	  in	  all	  patients	  
evaluated.	  
A	  comparison	  of	  the	  successful	  outcomes	  in	  the	  Bluegrass	  Vascular	  clinical	  study	  (N=12),	  with	  the	  
outcomes	  of	  two	  previously	  reported	  studies	  (N=124)	  utilizing	  the	  same	  procedure	  and	  similar	  
technology	  provides	  evidence	  of	  procedural	  safety	  and	  effectiveness	  in	  patients	  with	  chronic	  total	  

	  
	  
	  
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venous	  occlusions.	  See	  Table	  4,	  Clinical	  Outcomes	  of	  IOCVA	  system,	  below.	  	  
	  
Table	  4:	  Summary	  of	  Clinical	  Outcomes	  using	  the	  IOCVA	  Method	  Surfacer	  System	  
	  
Procedure	  
IOCVA	  Method	  
Pacing	  leads	  
placement	  
(Elayi	  2011xxiv)	  
N=8	  
Investigator	  Experience	  
IOCVA	  Methods	  
(Gurley	  2012xxv)	  
N=116	  
BVT	  Surfacer	  System	  
GEN1	  FIH	  Study	  	  
(Ebner	  2013)	  
N=12	  
Fluoroscopy	  
time	  (min)	  
39	  ±	  43	  
2.4	  ±	  1.2	  (type	  I)	  
5.4±7.8	  (type	  II)	  
10.3±11.8	  (type	  III)	  
15.6±2.4	  (type	  IV)	  
7.4	  ±	  2.8	  
Technical	  
success	  
100%	  
100%	  
100%	  
Repeated	  
procedures	  	  
0%	  
1	  procedure	  in	  47	  pts	  (67%)	  
2	  procedures	  in	  12	  pts	  (17%)	  
3	  procedures	  in	  6	  pts	  (9%)	  
4	  or	  more	  procedures	  (7%)	  
2	  procedures	  in	  1	  
patient	  (8.3%)	  
Procedural	  
complications	  
Not	  reported	  
1	  pocket	  hematoma	  	  
due	  to	  excessive	  OAC	  
(0.8%,	  1/116)	  
1	  exit	  site	  hematoma	  
resolved	  with	  manual	  
compression	  
treatment	  	  
(1/12	  patients,	  8.3%,)	  
Overall	  success	  
rate	  
100%	  (136	  out	  of	  136	  patients)	  
Overall	  
complication	  
rate	  
1.47%	  (2	  out	  of	  136	  patients)	  
	  
The	  studies	  presented,	  when	  compared	  with	  the	  success	  and	  safety	  data	  on	  standard	  access	  
procedures	  in	  patients	  with	  obstructed	  central	  veins	  (presented	  in	  section	  2.1	  of	  the	  protocol),	  provides	  
assurance	  that	  the	  overall	  benefits	  of	  the	  Surfacer®	  Inside-­‐Out®	  Access	  Catheter	  System	  potentially	  
exceeds	  the	  potential	  risks	  in	  the	  clinical	  setting.	  Additionally,	  the	  device	  offers	  a	  safe	  and	  effective	  
alternative	  to	  physicians	  and	  patients	  with	  venous	  occlusions,	  for	  whom	  limited	  options	  exist	  to	  deliver	  
life-­‐saving	  therapies.	  	  

	  
	  
	  
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4.2	  	  
Anatomical	  Studies	  	  
All	  current	  methods	  of	  transvenous	  lead	  placement	  require	  puncture	  of	  a	  central	  vein	  from	  outside	  the	  
body.	  IOCVA	  is	  a	  new	  concept	  that	  reverses	  the	  approach	  by	  directing	  a	  needle	  outward	  from	  within	  
the	  body.	  IOCVA	  can	  be	  performed	  safely	  because	  there	  are	  consistent	  anatomic	  relationships	  adjacent	  
to	  the	  thoracic	  central	  veins	  (Figure	  9).	  Soft	  tissues,	  clavicle,	  and	  skin	  bind	  the	  central	  veins	  anteriorly.	  A	  
needle	  directed	  anteriorly	  will	  not	  encounter	  arteries,	  nerves,	  or	  pleura,	  which	  lie	  posterior	  and	  lateral	  
to	  the	  central	  veins.	  Evaluation	  of	  visible	  human	  thorax	  slices	  illustrates	  that	  the	  path	  of	  the	  Inside-­‐Out	  
puncturing	  needle	  is	  free	  from	  critical	  structures	  including	  lungs,	  hilar	  vessels	  and	  arteries,	  as	  showed	  in	  
Figure	  9	  below.	  
	  
	  
	  
	  
	  
	  
	  
	  
	  

	  
	  
	  
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	  	  	  	  Figure	  9:	  Gross	  anatomy	  study	  of	  the	  human	  thorax	  –	  Visible	  Human	  
	  
	  
A:	   Gross	   anatomy	   of	   the	  
human	  
thorax	  
in	  
the	  
horizontal	   plane.	   A	   needle	  
directed	  anteriorly	  from	  the	  
posterior	  
aspect	  
of	  
the	  
clavicle	  
encounters	  
fat,	  
muscle,	  
and	  
skin.	  
This	  
applies	  
to	  
either	  
a	  
subclavian	  or	  supraclavicular	  
exit	  path.	  
	  
B:	   Gross	   anatomy	   of	   the	  
human	  thorax	  in	  the	  sagittal	  
plane.	   Vertical	   line	   marks	  
the	   posterior	   aspect	   of	   the	  
head	   of	   the	   clavicle.	   A	  
needle	   directed	   anteriorly	  
from	   this	   point	   encounters	  
fat,	  muscle,	  and	  skin.	  Critical	  
structures,	   including	   lung,	  
hilar	   vessels,	   and	   arteries,	  
remain	  posterior	  to	  this	  line.	  
	  
C:	  
Sagittal	  
plane	  
view	  
(lateral	   to	   panel	   B)	   showing	  
the	  
positions	  
of	  
the	  
subclavian	  
artery	  
(A),	  
subclavian	   vein	   (V),	   and	  
clavicle	  (CL)	  at	  a	  typical	  point	  
of	  subclavian	  venous	  access.	  
Critical	   structures	   remain	  
behind	   the	   posterior	   aspect	  
of	  the	  clavicle.	  
	  
	  
	  

	  
	  
	  
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4.3	  	  	  Proof	  of	  Concept	  Study	  (Elayi	  2011)	  
Elayi	  CS,	  Allen	  CL,	  Leung	  S,	  Lusher	  S,	  Morales	  GX,	  Wiisanen	  M,	  Aikat	  S,	  Kakavand	  
B,	  Shah	  JS,	  Moliterno	  DJ,	  Gurley	  JC.	  
Inside-­‐out	  access:	  a	  new	  method	  of	  lead	  placement	  for	  patients	  with	  central	  
venous	  occlusions.	  
Heart	  Rhythm.	  2011	  Jun;8(6):851-­‐7	  
This	  study	  described	  the	  experience	  of	  using	  the	  Inside-­‐Out	  central	  venous	  access	  method	  to	  place	  
pacemaker	  and	  defibrillator	  leads	  in	  8	  patients	  with	  upper	  body	  central	  venous	  occlusions	  that	  could	  
not	  be	  crossed	  with	  conventional	  methods.	  IOCVA	  can	  be	  performed	  safely	  because	  there	  are	  
consistent	  anatomic	  relationships	  adjacent	  to	  the	  thoracic	  central	  vein.	  
This	  study	  demonstrates	  that	  the	  inside-­‐out	  central	  venous	  access	  can	  be	  successfully	  and	  safely	  
applied	  to	  establish	  central	  venous	  access	  in	  patients	  with	  chronic,	  total	  SVC	  and	  subclavian	  vein	  
occlusions	  that	  cannot	  be	  recanalized	  with	  currently	  available	  technology.	  
Eight	  patients	  were	  treated	  using	  off-­‐the-­‐shelf	  devices,	  physician	  modified	  for	  use	  in	  an	  IOCVA	  
approach.	  All	  patients	  were	  referred	  for	  clinically	  indicated	  permanent	  pacemaker	  or	  defibrillator	  
implantation	  in	  accordance	  with	  practice	  guidelinesxxvi.	  Additionally,	  all	  patients	  had	  chronic	  SVC,	  
brachiocephalic,	  and/or	  subclavian	  vein	  occlusions	  that	  prevented	  a	  standard	  prepectoral	  transvenous	  
approach	  to	  device	  implantation.	  The	  occlusions	  consisted	  of	  long	  segments	  of	  densely	  fibrotic	  lumen	  
obliteration	  that	  could	  not	  be	  recanalized	  by	  conventional	  interventional	  techniques	  using	  a	  variety	  of	  
guidewires,	  catheters,	  and	  dilators.	  
Occlusions	  were	  resistant	  to	  aggressive	  probing	  with	  0.035-­‐inch,	  stiff-­‐shaft	  hydrophilic	  wires	  and	  
supporting	  catheters.	  Probing	  was	  attempted	  from	  at	  least	  one	  direction	  and,	  in	  some	  cases,	  from	  both	  
sides	  of	  the	  occlusion.	  None	  of	  the	  patients	  had	  collateral	  venous	  channels	  suitable	  for	  lead	  placement.	  	  
An	  attempt	  at	  inside-­‐out	  central	  venous	  access	  was	  offered	  after	  explanation	  of	  potential	  risks,	  
including	  the	  possibility	  of	  risks	  not	  yet	  known	  for	  the	  procedure.	  
	  

	  
	  
	  
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Figure	  10:	  Images	  from	  pacing	  leads	  using	  IOCVA	  insertion	  methodology	  
	      
	  
All	  procedures	  were	  performed	  in	  a	  setting	  that	  was	  capable	  of	  managing	  major	  complications.	  
No	  clinical	  complications	  occurred	  except	  a	  for	  a	  small	  pocket	  hematoma	  that	  resolved	  without	  
intervention.	  
	  
4.4	   Investigator	  Experience,	  Gurley	  (2012)	  
John	  C	  Gurley,	  MD	  
Inside-­‐out	  Central	  Venous	  Access	  -­‐	  Presentation	  (University	  of	  Kentucky	  May	  
9,	  2012)	  
Heart	  Rhythm	  Society	  2012,	  May	  9-­‐12,	  Boston	  MA	  
	  
Dr.	  John	  C.	  Gurley,	  MD	  presented	  the	  results	  of	  116	  procedures	  utilizing	  the	  Inside-­‐Out®	  technique	  for	  a	  
variety	  of	  procedures	  involving	  upper	  body	  venous	  obstructions.	  Gurley	  used	  off-­‐the-­‐shelf	  devices	  
(modified)	  to	  provide	  central	  venous	  access	  for	  patients	  with	  Type	  1	  to	  Type	  4	  venous	  occlusions	  
(Figure	  11).	  

	  
	  
	  
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Figure	  11:	  Type	  and	  Distribution	  of	  Treated	  Occlusions	  
	  
	  
	  
	  
Dr.	  Gurley	  reported	  successful	  results	  with	  this	  approach	  over	  multiple	  subsequent	  inside-­‐out	  
procedures	  as	  follows:	  
• 
One	  procedure	  in	  47	  patients	  (67%	  procedures)	  
• 
Two	  procedures	  in	  12	  patients	  (17%	  procedures)	  
• 
Three	  procedures	  in	  6	  patients	  (9%	  procedures)	  	  
• 
Four	  or	  more	  procedures	  (8%	  procedures)	  
The	  rates	  of	  procedural	  entry	  sites	  used	  prior	  to	  attempting	  the	  IOCVA	  procedure	  are	  summarized	  in	  
Figure	  12	  below.	  
	  
Figure	  12:	  Entry	  Sites	  

	  
	  
	  
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The	  technological	  differences	  of	  the	  Surfacer®	  System	  (a	  device	  designed	  specifically	  for	  this	  procedure)	  
are	  such	  that	  a	  minimal	  clinical	  impact	  may	  be	  expected	  as	  compared	  with	  the	  Gurley	  procedure.	  These	  
differences	  were	  addressed	  in	  a	  clinical	  study	  (protocol	  ID	  CR-­‐4001)	  conducted	  by	  Bluegrass	  Vascular	  
Technologies,	  Inc.	  The	  interim	  results	  of	  this	  study	  have	  been	  published	  (Ebner	  2013).xxvii	  
In	  total,	  116	  IOCVA	  procedures	  were	  successfully	  completed	  by	  Dr.	  Gurley,	  with	  no	  complications	  or	  
technical	  failures,	  and	  with	  one	  adverse	  event	  due	  to	  a	  delayed	  pocket	  hematoma	  associated	  with	  
excessive	  anticoagulation.	  The	  IOCVA	  mean	  fluoroscopy	  time	  by	  type	  of	  occlusion	  is	  shown	  in	  Figure	  13.	  	  
Of	  these	  116	  procedures,	  83.6%	  (97	  procedures)	  were	  associated	  with	  successful	  right	  supraclavicular	  
exits	  utilizing	  the	  equivalent	  technology,	  in	  the	  same	  anatomy	  and	  for	  the	  same	  clinical	  effect	  as	  
Surfacer	  Inside-­‐Out	  Access	  Catheter	  System.	  	  
	  
Figure	  13:	  IOVCA	  Fluoroscopy	  Time	  by	  Occlusion	  Type	  
	  
	  
	  
Results	  from	  Dr.	  Gurley’s	  investigations	  provided	  evidence	  of	  the	  feasibility	  and	  safety	  of	  the	  inside-­‐out	  
approach	  using	  modified	  commercially	  available	  components	  and	  procedural	  steps	  that	  are	  equivalent	  
to	  those	  utilized	  by	  the	  Surfacer®	  System.	  

	  
	  
	  
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4.5.	   Surfacer®	  System	  FIH	  Evaluation	  (Ebner,	  2013)	  
Adrian	  Ebner,	  MD;	  Santiago	  Gallo,	  MD;	  Carlos	  Cetraro,	  RT(R);	  John	  Gurley,	  MD;	  and	  
Laura	  Minarsch,	  CVT,	  RT(R)	  
Inside-­‐Out	  Upper	  Body	  Venous	  Access:	  The	  first-­‐in-­‐human	  experiences	  with	  a	  
novel	  approach	  using	  the	  Surfacer	  Inside-­‐out	  Access	  Catheter	  System	  
Endovascular	  Today	  June	  2013	  
	  
The	  study	  published	  by	  Ebner	  et.	  al.	  represents	  the	  final	  report	  of	  a	  clinical	  investigation	  performed	  by	  
Bluegrass	  Vascular,	  study	  CR4001,	  using	  the	  Surfacer	  System	  GEN1.	  More	  details	  on	  study	  CR4001	  are	  
provided	  in	  the	  next	  paragraph.	  
Severe	  renal	  dysfunction	  and	  venous	  occlusive	  disease	  are	  major	  causes	  of	  morbidity,	  mortality,	  and	  
increased	  medical	  costs,	  especially	  within	  the	  dialysis	  population.	  The	  long-­‐term	  risks	  of	  central	  venous	  
access	  include	  occlusion,	  which	  can	  occur	  within	  days	  of	  catheter	  placement	  and	  is	  a	  common	  problem	  
in	  patients	  requiring	  repeated	  access	  or	  semi-­‐permanent	  access.	  Central	  venous	  occlusion	  can	  deprive	  
patients	  of	  vital	  therapies	  such	  as	  hemodialysis,	  cardiac	  pacing,	  chemotherapy,	  and	  drug	  infusion.	  
Because	  simple	  central	  venous	  occlusions	  force	  providers	  to	  sacrifice	  secondary	  veins,	  patients	  often	  
endure	  the	  morbidity	  of	  venous	  hypertension	  and	  the	  mortality	  risk	  of	  an	  access	  crisis.	  Central	  venous	  
occlusive	  disease	  is	  entirely	  iatrogenic,	  highly	  destructive,	  and	  vastly	  underappreciated	  by	  the	  general	  
medical	  community.	  
As	  part	  of	  a	  safety	  and	  feasibility	  study,	  12	  patients	  (ranging	  from	  27-­‐63	  years	  of	  age)	  consented	  and	  
were	  treated	  with	  the	  Surfacer	  IOCVA	  System.	  All	  patients	  presented	  with	  severe	  renal	  dysfunction	  and	  
compromised	  upper	  venous	  occlusive	  disease.	  They	  also	  required	  hemodialysis	  and	  had	  two	  or	  more	  
occluded	  upper	  body	  venous	  access	  points;	  one	  patient	  was	  diabetic.	  The	  study	  was	  performed	  at	  the	  
Italian	  Hospital	  in	  Asuncion,	  Paraguay.	  Patients	  underwent	  the	  following	  tests:	  
• 
routine	  chest	  radiography	  and	  electrocardiography	  (ECG)	  
• 
venous	  duplex	  venography	  
Patients	  were	  sedated	  with	  intravenous	  midazolam	  plus	  fentanyl.	  	  All	  patients	  had	  creatinine	  levels	  
averaging	  10.0.	  	  

	  
	  
	  
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Average	  procedure	  time	  was	  32.8	  ±	  16.9	  minutes	  (Table	  5)	  and	  decreased	  with	  increased	  operator	  
experience	  (Figure	  14).	  
Average	  amount	  of	  contrast	  used	  was	  approximately	  16	  ml.	  
All	  twelve	  patients	  received	  a	  central	  venous	  access	  catheter,	  which	  remained	  in	  place	  and	  was	  
confirmed	  to	  be	  functional	  and	  patent	  at	  14-­‐days	  post-­‐procedure.	  
Table	  5:	  Procedural	  Results	  
	  
	  
	  
	  

	  
	  
	  
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Figure	  14:	  	  Surfacer	  Inside-­‐Out	  Access	  Catheter	  FIH	  Procedure	  Times
	  
	  
Results	  show	  that	  this	  novel	  approach	  provides	  safe	  and	  effective	  percutaneous	  central	  venous	  access,	  
despite	  chronic	  occlusion	  of	  the	  SVC.	  Inside-­‐out	  central	  venous	  access	  should	  be	  explored	  further	  as	  a	  
new	  option	  for	  patients	  with	  upper	  body	  venous	  occlusive	  disease.	  
Clinical	  relevance:	  The	  patients	  in	  the	  clinical	  trial	  of	  the	  Bluegrass	  Inside-­‐out	  System	  were	  treated	  in	  
accordance	  with	  the	  standard	  of	  care	  at	  the	  hospital,	  international	  guidelines	  and	  recommendations.	  
The	  procedures	  are	  consistent	  with	  those	  described	  in	  the	  published	  guidelines	  and	  articles	  discussed	  
in	  this	  LRR.	  The	  absence	  of	  complications	  in	  this	  consecutive	  series	  of	  hemodialysis	  patients	  with	  
compromised	  upper	  venous	  occlusive	  disease,	  demonstrates	  the	  safety	  and	  efficacy	  of	  the	  Surfacer	  
System	  technology.	  
4.6	  
Regulatory	  Status	  
The	  Surfacer	  System	  has	  been	  CE	  Marked	  and	  is	  commercially	  available	  in	  Europe.	  	  The	  Surfacer	  System	  
is	  an	  investigational	  device	  in	  the	  United	  States.	  
5.0	  	  	  	  	  	  	  	  BENEFIT/RISK	  ANALYSIS	  
5.	  1	  
Importance	  of	  CVA	  
Central	  venous	  access	  is	  vital	  to	  many	  patients	  with	  acute	  and	  chronic	  illness,	  being	  one	  of	  the	  most	  
commonly	  performed	  procedures	  in	  medicine.	  Hemodialysis,	  fluid	  management,	  chemotherapy	  
infusion	  and	  parenteral	  nutrition	  are	  examples	  of	  life-­‐sustaining	  therapies	  that	  would	  not	  be	  possible	  

	  
	  
	  
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without	  CVA.	  
The	  indications	  for	  long-­‐term	  venous	  access	  are	  widening	  and	  include	  the	  following:	  
• 
Cancer	  chemotherapy	  
• 
Long-­‐term	  antibiotic	  therapy	  (e.g.	  infected	  prosthetic	  joints,	  bacterial	  endocarditis,	  cystic	  
fibrosis)	  
• 
Parenteral	  nutrition	  (e.g.,	  short	  bowel	  syndrome)	  hemodialysis	  
• 
Repeated	  blood	  transfusions	  	  
• 
Repeated	  venesection	  
The	  aim	  of	  CVA	  therapy	  is	  to	  position	  the	  catheter	  in	  a	  large	  vein	  to	  allow	  adequate	  dilution	  of	  infused	  
products;	  reduced	  pain	  on	  injection;	  delay	  in	  the	  development	  of	  thrombosis;	  and	  aspirate	  blood.	  
There	  is	  increasing	  use	  of	  long-­‐term	  central	  venous	  access	  devices,	  both	  in	  and	  out	  of	  hospital.	  Despite	  
the	  apparent	  similarity	  between	  short	  and	  long-­‐term	  access	  devices,	  there	  are	  important	  differences	  in	  
design,	  usage	  and	  patterns	  of	  complication	  that	  are	  relatively	  specific	  to	  longer-­‐term	  venous	  access.	  
Central	  venous	  catheters	  or	  CVCs	  are	  commonly	  inserted	  via	  the	  internal	  jugular,	  external	  jugular,	  
subclavian,	  or	  femoral	  veins	  (Table	  8).	  
	  
	  
	  
	  
	  
	  

	  
	  
	  
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Table	  8:	  CVA	  Access	  Sites	  
	    
Subclavian	  Access	  
Jugular	  Access	  
	  
	  
Femoral	  Access	  
Peripheral	  Inserted	  Central	  
Catheter	  (PICC)	  
	  
Catheter-­‐related	  vein	  thrombosis	  is	  a	  recurrent	  problem	  with	  longer-­‐term	  venous	  access	  devices.	  It	  is	  
thought	  that	  thrombus	  starts	  at	  the	  site	  of	  the	  venipuncture	  and	  then	  migrates	  along	  the	  catheter	  to	  
eventually	  occlude	  the	  tip.	  Such	  thrombus	  can	  be	  seen	  on	  ultrasound	  floating	  around	  the	  catheter	  
within	  the	  vessel	  lumen,	  or	  as	  a	  ghost	  after	  catheter	  removal.	  Thrombus	  creates	  an	  obstruction	  to	  
infusion	  of	  fluids	  and	  withdrawal	  of	  blood,	  and	  there	  is	  a	  strong	  link	  between	  thrombus	  and	  infection.	  
In	  a	  literature	  review	  conducted	  by	  Bluegrass	  Vascular	  Technologies,	  Acute	  Risks	  of	  mechanical	  
complications	  during	  the	  CVA	  insertion	  procedure	  include	  arterial	  puncture,	  malposition,	  local	  
hematoma,	  pneumothorax,	  hemothorax,	  air	  embolism,	  arrhythmias,	  accidental	  removal	  and	  failure	  of	  
catheterization.	  Similarly,	  other	  mechanical	  complications	  are	  vessel	  perforation,	  atrial	  perforation	  and	  
catheter	  malfunctions	  (Karkee,	  2010)xxviii.	  Table	  9	  displays	  safety	  rates	  for	  CVA	  insertion	  procedures	  via	  

	  
	  
	  
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subclavian	  and	  femoral	  routes.	  
Reported	  rates	  of	  arterial	  puncture	  are	  in	  the	  range	  of	  1.3%	  -­‐	  4.2%	  for	  subclavian	  access,	  2.2%	  -­‐7.5%	  for	  
jugular	  access,	  and	  2.4%	  -­‐	  4.3%	  for	  femoral	  access.	  The	  percentage	  of	  misplacement	  is	  between	  0%	  -­‐	  
3%	  in	  subclavian	  access,	  between	  0%	  -­‐	  2.2%	  in	  jugular	  access,	  0%	  in	  femoral	  access.	  In	  the	  articles	  
analyzed	  the	  percentage	  of	  pneumothorax	  and	  hemothorax	  are	  reported	  respectively	  in	  a	  range	  of	  0%	  -­‐	  
3%	  and	  0.04%	  in	  subclavian	  approach,	  0%	  for	  both	  pneumothorax	  and	  hemothorax	  for	  the	  jugular	  and	  
femoral	  access,	  33%	  for	  both	  pneumothorax	  and	  hemothorax	  for	  the	  translumbar	  access.	  Mechanical	  
complications	  are	  common	  in	  venous	  catheter	  insertion.	  The	  values	  reported	  are	  6.5%	  for	  subclavian	  
access,	  5.8%	  for	  jugular	  access,	  between	  3.6%	  and	  14.3%	  for	  femoral	  access	  and	  between	  8%	  and	  21%	  
for	  Translumbar	  access.	  The	  risk	  of	  Hematoma	  with	  the	  subclavian	  approach	  is	  7.5%;	  jugular	  approach	  
is	  between	  1.0%	  -­‐	  12%;	  femoral	  approach	  is	  between	  0%	  -­‐	  7.2%;	  and	  translumbar	  or	  transhepatic	  is	  
between	  0%	  -­‐	  4.5%	  (Table	  9).	  	  
Long	  Term	  Risks	  after	  the	  placement	  of	  the	  CVA	  catheter	  include	  complications	  related	  to	  the	  
permanence	  of	  the	  catheter	  such	  as	  infections,	  deep	  venous	  thrombosis,	  catheter	  colonization,	  and	  
thrombotic	  complications.	  These	  complications	  are	  common	  for	  all	  types	  of	  Central	  Venous	  Access.	  
Typical	  rates	  of	  infection	  are	  reported	  in	  a	  range	  of	  0.4%	  -­‐	  29.3%	  for	  the	  subclavian	  access,	  0.76	  -­‐	  40%	  
for	  the	  jugular	  access,	  0.6%	  -­‐	  40.5%	  for	  the	  femoral	  access	  and	  9.5%	  -­‐	  28%	  for	  the	  translumbar	  access.	  
Thrombotic	  complications	  are	  reported	  for	  each	  access	  site	  examined,	  with	  values	  between	  0.8%	  -­‐	  4.5%	  
for	  the	  subclavian	  access,	  4.3%	  -­‐	  22.7%	  for	  the	  jugular	  access,	  2.4%	  -­‐	  12.7%	  for	  the	  femoral	  access	  and	  
3.2%	  -­‐	  33%	  for	  the	  translumbar	  access.	  	  Deep	  venous	  thrombosis	  values	  are	  reported	  in	  a	  range	  of	  5.8%	  
-­‐	  6.5%	  for	  the	  subclavian	  access,	  0.5%	  -­‐	  12.8%	  for	  the	  jugular	  access,	  0.5%	  -­‐	  8.9%	  for	  the	  femoral	  access	  
and	  16.7%	  for	  the	  translumbar	  access.	  Typical	  rates	  of	  catheter	  colonization	  are	  reported	  in	  a	  range	  of	  
1.4%	  -­‐	  4.9%	  for	  the	  subclavian	  access,	  4.6%	  -­‐	  25.2%	  for	  the	  jugular	  access,	  7.2%	  -­‐	  40.5%	  for	  the	  femoral	  
access	  and	  8%	  –	  33.3%	  for	  the	  translumbar	  access.	  
In	  summary,	  although	  femoral	  vein	  cannulation	  has	  been	  reported	  as	  easier	  than	  subclavian	  or	  jugular,	  
this	  vascular	  access	  type	  is	  associated	  with	  higher	  risk	  of	  mechanical	  complications	  and	  catheter	  
colonization/infection	  compared	  to	  jugular	  and	  subclavian	  access.	  	  

	  
	  
	  
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Translumbar	  access	  sites	  are	  associated	  with	  the	  highest	  risk	  of	  complications	  compared	  to	  jugular,	  
subclavian	  and	  transfemoral	  accesses.	  Indeed,	  the	  inferior	  vena	  cava	  access	  is	  preferred	  only	  when	  
other	  accesses	  are	  occluded.	  Immediate	  hazards	  of	  translumbar	  access	  include	  retroperitoneal	  
bleeding	  and	  inadvertent	  puncture	  of	  the	  right	  renal	  artery.	  Delayed	  complications	  include	  catheter	  
migration	  and	  dislodgment,	  spontaneous	  retroperitoneal	  hemorrhage,	  and	  IVC	  stenosis	  progressing	  to	  
chronic	  occlusion.	  Catheter	  erosion	  into	  the	  right	  ureter	  (ureteral	  fistula)	  has	  also	  been	  reported.	  
Translumbar	  central	  venous	  catheters	  should	  be	  used	  only	  for	  patients	  with	  no	  other	  option.	  
	  
Table	  9.	  	  Safety	  rates	  for	  Standard	  CVA	  Insertion	  Procedures	  
**Mechanical	  complications	  include	  arterial	  puncture,	  malposition,	  local	  haematoma,	  pneumothorax,	  
haemothorax,	  air	  embolism,	  arrhythmias,	  accidental	  removal	  and	  failure	  of	  catheterization.	  Similarly,	  other	  
mechanical	  complications	  are	  vessel	  perforation,	  atrial	  perforation	  and	  catheter	  malfunctions	  (Karkee,	  2010).	  
Note:	  complication	  or	  data	  not	  analysed/mentioned	  in	  the	  articles	  are	  indicated	  with	  a	  dash	  (-­‐).	  
	  
	  
	  
	  
	  
	  
	  
SUBCLAVIAN	  
Arterial	  
Puncture	  
Misplacement	  
Pneumo-­‐
thorax	  
Hematoma	  
Hemothorax	  
Mechanical	  
complications**	  
Author	  
Year	  
Pts	  
%	  
Pts	  
%	  
Pts	  
%	  
Pts	  
%	  
Pts	  
%	  
Pts	  
%	  
Alexandrou	  E.	  
2014	  
2383	  
1.3%	  
2383	  
2.4%	  
238
3	  
0.4%	  
	  
-­‐	  
238
3	  
0.04%	  
	  
-­‐	  
Karkee	  D.V.	  
2010	  
203	  
3%	  
203	  
3%	  
203	  
0.5%	  
	  
-­‐	  
	  
-­‐	  
203	  
6.5%	  
Biffi	  R.	  
2009	  
-­‐	  
-­‐	  
136	  
0%	  
136	  
0%	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
Bertogli	  S	  
1996	  
424	  
4.2%	  
	  
-­‐	  
424	  
1.4%	  
424	  
7.5%	  
	  
-­‐	  
	  
-­‐	  
Smith	  H.O.	  
1995	  
133	  
3.8%	  
	  
-­‐	  
133	  
3%	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
	  
FEMORAL	  
Arterial	  
Puncture	  
Misplacement	  
Pneumo-­‐
thorax	  
Hematoma	  
Hemothorax	  
Mechanical	  
complications**	  
Author	  
Year	  
Pts	  
%	  
Pts	  
%	  
Pts	  
%	  
Pts	  
%	  
Pts	  
%	  
Pts	  
%	  
Hingwala	  J.	  
2014	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
Alexandrou	  E.	  
2014	  
163	  
4.3%	  
163	  
0%	  
163	  
0%	  
	  
-­‐	  
163	  
0	  
	  
-­‐	  
Yeral	  M.	  
2013	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
45	  
0%	  
	  
-­‐	  
	  
-­‐	  
Parienti	  J.J.	  
2008	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
370	  
1.1%	  
	  
-­‐	  
	  
-­‐	  
Lorente	  L.	  
2008	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
184	  
7.61%	  
Al-­‐Hwiesh,	  A.K.	  
2007	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
14	  
14.3%	  
Montagnac	  R.	  
1997	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
	  
-­‐	  
55	  
3.63%	  
Bertoglio	  S.	  
1996	  
41	  
2.4%	  
	  
-­‐	  
41	  
0%	  
41	  
7.2%	  
	  
-­‐	  
	  
-­‐	  

	  
	  
	  
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5.2	  	  
Limitations	  of	  Available	  Treatments	  
Usually,	  when	  venous	  occlusion	  or	  thrombus	  fibrin	  formation	  occurs,	  the	  occluded	  vessel	  is	  difficult	  to	  
access	  or	  deemed	  no	  longer	  patent	  or	  usable	  for	  long-­‐term	  central	  venous	  access.	  Consequently,	  
another	  access	  is	  required.	  Conventional	  methods	  for	  CVA	  in	  the	  presence	  of	  central	  venous	  occlusion	  
have	  significant	  limitations,	  as	  described	  in	  Table	  10.	  
	  
Table	  10:	  Conventional	  methods	  for	  central	  venous	  occlusion	  
	  
Options	  
Therapeutic	  approach	  for	  CVA	  
Issues	  
Other	  upper	  
body	  veins	  
	  
When	   confronted	   with	   occlusion	   of	   a	  
central	   vein,	   physicians	   usually	   utilize	  
one	  of	  the	  remaining	  upper	  body	  veins	  
(jugular	   and	   subclavian).	   The	   process	  
can	  continue	  until	  all	  four	  central	  veins	  
have	  been	  obliterated.	  
Loss	   of	   all	   four	   upper	   body	   central	   veins	  
creates	   an	   access	   crisis	   leaving	   the	   patient	  
without	   a	   central	   venous	   lifeline.	   When	   all	  
four	   upper	   body	   central	   veins	   become	  
occluded;	   physicians	   are	   forced	   to	   utilize	  
alternative	   approaches	   that	   are	   much	   less	  
desirable.	  
Femoral	  Veins	  
Access	  	  
The	  femoral	  veins	  are	  utilized	  for	  long-­‐
term	   CVA	   when	   upper	   body	   sites	   are	  
no	  longer	  available.	  Femoral	  veins	  are	  
attractive	   secondary	   targets	   because	  
they	  are	  relatively	  easy	  to	  access	  and,	  
in	  most	  communities,	  the	  only	  option	  
for	  central	  venous	  access	  when	  upper	  
body	  sites	  have	  been	  exhausted.	  
Femoral	  venous	  catheters	  have	  poor	  stability	  
due	  to	  leg	  movement,	  as	  well	  as	  high	  rates	  of	  
infectious	   and	   thrombotic	   complications.	  
Catheter	  migration,	  kinking	  and	  retraction	  are	  
unique	   and	   common	   problems	   that	   result	  
from	   leg	   movement.	   It	   is	   clear	   that	   the	  
femoral	  veins	  are	  poorly	  suited	  to	  long-­‐term	  
central	  venous	  access.	  
The	  use	  of	  femoral	  veins	  for	  long-­‐term	  access	  
can	  quickly	  lead	  to	  occlusions	  that	  eliminate	  a	  
future	   route	   of	   temporary	   central	   venous	  
access,	  further	  compounding	  the	  problem	  of	  
lost	  central	  venous	  access.	  
Inferior	  Vena	  
Cava	  access	  
Translumbar	   puncture	   of	   the	   inferior	  
vena	   cava	   (IVC)	   is	   available	   in	   some	  
tertiary	  
care	  
centers,	  
but	  
this	  
procedure	   is	   technically	   challenging	  
and	  carries	  significant	  risks.	  
Translumbar	   central	   venous	   catheters	  
should	  be	  used	  only	  for	  patients	  with	  
no	  other	  option	  
Immediate	   hazards	   of	   translumbar	   access	  
include	  
retroperitoneal	  
bleeding	  
and	  
inadvertent	  puncture	  of	  the	  right	  renal	  artery.	  
Delayed	  
complications	  
include	  
catheter	  
migration	   and	   dislodgment,	   spontaneous	  
retroperitoneal	  hemorrhage,	  and	  IVC	  stenosis	  
progressing	   to	   chronic	   occlusion.	   Catheter	  
erosion	  into	  the	  right	  ureter	  (ureteral	  fistula)	  
has	  been	  reported.	  
Transhepatic	  
access	  
Direct	   puncture	   of	   the	   liver	   can	  
provide	   access	   to	   the	   inferior	   vena	  
cava	   and	   right	   atrium	   via	   a	   hepatic	  
vein.	  
Due	  to	  poor	  catheter	  performance	  and	  
Transhepatic	  
access	  
is	  
associated	  
with	  
substantial	   risks,	   and	   experience	   with	   the	  
procedure	  
is	  
still	  
limited.	  
Serious	  
complications	   include	   liver	   laceration,	   intra-­‐
peritoneal	   bleeding,	   and	   procedure-­‐related	  
death.	  Catheter	  instability	  due	  to	  respiratory	  

	  
	  
	  
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CONFIDENTIAL	  
Options	  
Therapeutic	  approach	  for	  CVA	  
Issues	  
very	   substantial	   hazards,	   transhepatic	  
puncture	  for	  long-­‐term	  central	  venous	  
access	  should	  only	  be	  considered	  as	  a	  
last	  resort	  
movement	   is	   a	   major	   problem.	   Catheter	  
mobility	  also	  causes	  kinking,	  perforation,	  and	  
related	   malfunctions	   that	   require	   catheter	  
removal.	  Early	  thrombosis	  occurs	  much	  more	  
frequently	  with	  transhepatic	  than	  with	  upper	  
body	  catheters	  
Atrial	  access	  
Atrial	   access	   or	   surgical	   placement	   of	  
catheters	  directly	  into	  the	  right	  atrium,	  
has	   been	   described	   in	   a	   few	   patients	  
who	  
required	  
life-­‐sustaining	  
nutritional	  
support	  
and	  
had	  
no	  
alternative	  
for	  
vascular	  
access.	  
Isolated	   case	   reports	   describe	   right	  
thoracotomy,	  median	  sternotomy,	  and	  
video-­‐assisted	   thoracic	   surgery	   to	  
place	   catheters	   in	   the	   right	   atrium	   or	  
the	  right	  atrial	  appendage.	  
Delayed	   complications	   of	   surgically-­‐placed	  
central	   venous	   catheters	   include	   catheter	  
migration,	   dislodgment,	   infection,	   bleeding	  
and	  pleural	  effusion.	  
Thoracic	   surgery	   for	   placement	   central	  
venous	   catheters	   is	   highly	   invasive	   and	   not	  
easily	  repeated.	  
Occluded	  vessel	  
recanalization	  
Recanalization	  of	  the	  occluded	  vessel,	  
with	   placement	   of	   a	   new	   Central	  
Venous	   Catheter,	   may	   allow	   recovery	  
of	   the	   lost	   central	   venous	   access	  
without	  involvement	  of	  other	  veins.	  
Scientific	  
literature	  
describes	  
this	  
method	  as	  “sharp	  recanalization”:	  the	  
distal	  sharp	  tip	  of	  a	  catheter	  is	  forced	  
to	   cross	   the	   occluding	   thrombus.	   A	  
fluoroscopic	   target	   is	   placed	   on	   the	  
other	  side	  of	  the	  occlusion,	  requiring	  a	  
second	   skin	   entry	   point.	   After	   the	  
thrombus	   is	   crossed,	   a	   loop	   is	  
introduced	   to	   catch	   and	   pull	   a	   new	  
Central	   Venous	   Catheter	   inside	   the	  
vessel.	  	  
The	  
sharp	  
recanalization	  
procedure	  
is	  
complex	  and	  not	  standardized.	  
It	  
often	  
requires	  
new	  
transcutaneous	  
accesses	  both	  from	  the	  femoral	  vein	  and	  from	  
the	   occluded	   vein,	   more	   distally	   than	   the	  
previous	  access	  location.	  
There	   is	   no	   single	   device	   that	   has	   been	  
developed	  
to	  
perform	  
this	  
procedure,	  
although	   the	   Outback	   and	   Rosh-­‐Uchida	  
catheters	   have	   been	   used	   “off	   label”	   to	  
perform	  the	  procedure.	  

 
 
 
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5.3	  
Clinical	  Considerations	  
Upper	  body	  veins	  are	  always	  preferred	  for	  long-­‐term	  central	  venous	  access.	  Devices	  placed	  via	  upper	  
body	  veins	  provide	  the	  best	  combination	  of	  patient	  comfort	  and	  mobility,	  device	  stability,	  accessibility,	  
and	  infection	  risk.	  When	  the	  upper	  body	  central	  veins	  are	  lost,	  the	  remaining	  alternatives	  are	  
undesirable	  for	  anything	  but	  emergency,	  temporary	  access.	  Central	  venous	  catheterization	  can	  be	  
obtained	  with	  access	  from	  sites	  other	  than	  the	  jugular	  or	  subclavian	  veins,	  but	  with	  major	  short	  and	  
long-­‐term	  complication	  rates.	  Advantages	  and	  disadvantages	  of	  the	  available	  access	  routes	  are	  
summarized	  in	  Table	  11.	  
	  
Table	  11:	  Advantages	  and	  disadvantages	  of	  different	  routes	  for	  CVA	  
	  
CV	  Catheter	  
Insertion	  Route	  
Advantages	  
Disadvantages	  
Arm	  veins	  (cephalic,	  
basilic)	  
Simple	  to	  access,	  veins	  visible	  
and	  palpable	  
No	  vital	  organs	  close	  
Patient	  comfort	  
Failure	  to	  achieve	  central	  position	  
High	  incidence	  of	  thrombosis	  
Low	  maximum	  infusion	  rates	  
Internal	  jugular	  
Simple	  to	  insert	  
Direct	  route	  to	  central	  veins	  
High	  flow	  rate,	  low	  risk	  of	  
thrombosis	  
Lower	  risk	  of	  pneumothorax	  
Patient	  discomfort	  
Higher	  rate	  of	  late	  complications,	  
especially	  infection	  
Tunnelling	  more	  difficult	  to	  chest	  wall	  
Subclavian	  axillary	  
Less	  patient	  discomfort	  
Lower	  risk	  of	  long-­‐term	  
complications	  
Curved	  insertion	  route	  
Difficult	  to	  access	  
Acute	  complications	  -­‐	  pneumothorax,	  
haemothorax,	  nerve	  damage	  
Femoral	  
High	  flow,	  good	  for	  dialysis	  
Easy	  insertion	  
Higher	  rate	  of	  infection	  and	  
thrombosis	  
Poor	  stability:	  migration,	  kinking,	  
retraction	  
Patient	  discomfort	  
Difficult	  in	  obese	  patients	  
Inferior	  Vena	  Cava	  
(Translumbar)	  
Last	  option	  procedure	  
Technically	  challenging	  
Procedural	  risks:	  retroperitoneal	  
bleeding,	  renal	  artery	  puncture	  
Migration,	  Dislodgement,	  Occlusion	  

 
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5.4	  	  
Surfacer	  System	  Potential	  Benefits	  
As	  described	  in	  Table	  11,	  the	  innovative	  approach	  of	  the	  Surfacer	  System	  brings	  advantages	  to	  patients	  
that	  no	  longer	  have	  adequate	  access	  or	  who	  cannot	  achieve	  CVC	  using	  conventional	  approaches	  to	  
central	  venous	  catheterization.	  
The	  potential	  benefits	  of	  the	  Surfacer	  System	  IOCVA	  approach	  include	  but	  are	  not	  limited	  to	  the	  
following:	  	  
• Reduction	  of	  Insertion	  Risk	  
Reversing	  the	  path	  to	  venous	  access	  is	  intended	  to	  avoid	  or	  reduce	  risks	  of	  damage	  or	  
involvement	  of	  other	  anatomical	  structures,	  such	  as	  arterial	  puncture	  (with	  edema	  or	  
serious	  bleeding),	  lung	  injury	  (i.e.	  pneumothorax	  or	  hemothorax)	  or	  nerve	  damage.	  	  
	  
• 
Ease	  of	  Procedure	  
The	  aiming	  features	  using	  the	  Exit	  Target,	  specifically	  developed	  for	  fluoroscopy,	  allow	  
precise	  needle	  positioning	  and	  accurate	  delivery	  to	  the	  skin	  surface.	  The	  simplicity	  of	  
the	  procedure,	  which	  requires	  placing	  the	  ring	  at	  planned	  CVC	  exit,	  makes	  it	  attractive	  
and	  suitable	  for	  clinical	  application	  in	  the	  larger	  treatment	  population.	  
	  
• 
Ability	  to	  Cross	  Occlusions	  
The	  Surfacer	  System	  may	  be	  able	  to	  create	  central	  venous	  access	  in	  subjects	  with	  prior	  
multiple	  occlusions	  or	  who	  have	  no	  other	  options.	  	  
	  
• 
Ability	  to	  Spare	  Other	  Vessels	  
The	  Surfacer	  System	  may	  be	  able	  to	  utilize	  a	  previously	  occluded	  vessel	  and	  spares	  
/salvages	  other	  vessels	  for	  physiological	  circulation	  and	  other	  access	  requirements.	  	  In	  
emergent	  situations,	  this	  could	  be	  a	  lifesaving	  benefit	  to	  patients	  who	  have	  few	  or	  no	  
other	  options	  for	  venous	  access.	  
	  
THE	  SURFACER	  SYSTEM	  APPROACH	  HAS	  DEMONSTRATED	  THE	  FOLLOWING	  BENEFITS:	  
• 
low	  patient	  risk	  
• 
quick	  and	  safe	  procedure	  
• 
solution	  for	  Central	  Thoracic	  Veno-­‐Occlusive	  Diseases	  in	  no	  option	  cases,	  with	  the	  
potential	  to	  achieve	  repeated	  access	  from	  a	  single	  point	  
• 
success	  in	  patients	  with	  no	  upper	  body	  access	  
• 
preserve	  jugular	  vein	  access	  

	  
	  
	  
	  
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5.5	  
Surfacer	  System	  Potential	  Risks	  
Potential	  risks	  associated	  with	  using	  the	  Surfacer	  System	  are	  considered	  to	  be	  similar	  those	  associated	  
with	  routine	  interventional	  procedures	  and	  with	  the	  patient’s	  underlying	  condition.	  	  List	  of	  Potential	  
Risks	  and	  Definitions	  can	  be	  found	  in	  Appendix	  A.	  	  
These	  potential	  risks	  include,	  but	  are	  not	  limited	  to:	  
	  
• 
Pain	  
• 
Infection	  
• 
Bleeding	  
• 
Adverse	  tissue	  reaction;	  allergic	  reaction	  
• 
Cardiovascular	  sequelae	  including:	  	  perforation,	  tamponade,	  spasm	  or	  effusion	  
• 
Lymphatic	  system	  sequelae	  	  
• 
Pulmonary	  sequelae	  including:	  pneumothorax,	  pulmonary	  embolism	  
• 
Vascular	  sequelae	  including	  vasospasm,	  vessel	  perforation,	  dissection,	  or	  aneurysm	  
• 
Unintended	  embolization	  or	  thrombosis	  
• 
Arrhythmias	  
• 
Neurologic	  sequelae	  including	  stroke;	  transient	  ischemic	  attack;	  nerve	  injury	  
• 
Arteriovenous	  Fistula	  	  
• 
Death	  
• 
Surfacer	  System	  component	  failure	  or	  malfunction	  
	  
5.6	  	  
Benefit/Risk	  Statement	  	  
The	  Surfacer	  System	  is	  intended	  to	  provide	  a	  solution	  in	  patients	  with	  an	  upper	  body	  venous	  occlusion	  
or	  other	  thrombotic	  fibrin	  occlusive	  pathology	  impeding	  standard	  access	  methods,	  including	  
contraindication	  to	  use	  of	  remaining	  veins.	  	  
The	  Surfacer	  System	  is	  designed	  to	  allow	  Central	  Venous	  Catheterization	  utilizing	  an	  inside-­‐out	  
approach.	  This	  approach	  brings	  benefits	  to	  patients	  with	  CV	  occlusion,	  in	  whom	  alternate	  access	  options	  
(conventional	  access	  methods)	  are	  not	  feasible	  or	  are	  associated	  with	  high	  risk	  and	  morbidity.	  
This	  new	  reversed	  approach	  brings	  expected	  benefits	  to	  patients	  in	  whom	  alternate	  access	  options	  are	  
not	  feasible	  or	  associated	  with	  high	  risks.	  Expected	  benefits	  include:	  reduction	  of	  insertion	  risk;	  ease	  of	  

	  
	  
	  
	  
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procedure	  thanks	  to	  the	  use	  of	  a	  visible	  exit	  target,	  enabling	  precise	  aiming	  of	  the	  needle;	  ability	  to	  
overcome	  occlusions	  in	  subjects	  with	  limited	  or	  no	  other	  options;	  and	  ability	  to	  spare	  other	  vessels.	  	  
The	  Surfacer	  System	  approach	  to	  CVA	  catheterization	  provides	  visual	  and	  placement	  (steering)	  benefits	  
that	  cannot	  be	  achieved	  with	  conventional	  approaches	  in	  patients	  with	  central	  vein	  occlusions.	  	  
Additionally,	  the	  Surfacer	  System	  device	  provides	  access	  to	  occluded	  veins,	  using	  the	  same	  vessel	  that	  
was	  lost	  for	  CVA.	  Preclinical	  verification	  and	  validation	  of	  the	  Surfacer	  System	  and	  clinical	  experiences	  
demonstrate	  safety	  and	  effectiveness	  of	  the	  Surfacer	  System	  procedure.	  	  
The	  Surfacer	  System	  is	  not	  associated	  with	  long-­‐term	  risks,	  because	  the	  device	  is	  for	  temporary	  use.	  
However,	  the	  Surfacer	  System	  allows	  CVA	  catheters	  to	  be	  successfully	  placed	  for	  short-­‐term	  and	  long-­‐
term	  use.	  Therefore,	  it	  is	  important	  to	  analyze	  and	  compare	  the	  immediate	  procedural	  risks	  of	  other	  
conventional	  approaches	  in	  patients	  with	  central	  vein	  occlusions	  in	  order	  to	  determine	  the	  risk	  
reduction	  that	  is	  achieved	  with	  the	  Surfacer	  System	  approach.	  
The	  Inside-­‐Out	  approach,	  based	  on	  reversing	  the	  path	  to	  venous	  access,	  has	  shown	  the	  capability	  to	  
avoid	  or	  reduce	  the	  reported	  clinical	  risks	  of	  damage	  or	  involvement	  of	  other	  anatomical	  structures,	  
such	  as	  arterial	  puncture	  (with	  edema	  or	  even	  serious	  bleeding),	  lung	  injury	  (i.e.	  pneumothorax	  or	  
hemothorax)	  or	  nerve	  damage.	  No	  such	  events	  were	  observed	  in	  a	  large	  series	  of	  over	  124	  patients	  who	  
underwent	  this	  procedure	  as	  well	  as	  the	  12	  patients	  in	  the	  first	  in	  human	  study.	  
The	  scientific	  literature	  and	  human	  clinical	  experience	  finds	  that	  the	  Surfacer	  System	  provides	  stable,	  
upper	  body	  central	  venous	  access	  that	  is	  suitable	  for	  any	  conventional	  catheter.	  	  Therefore,	  based	  on	  
the	  current	  evidence	  and	  testing,	  the	  benefits	  of	  use	  of	  the	  Surfacer	  System	  outweigh	  the	  risks	  in	  the	  
defined	  patient	  populations.	  	  

	  
	  
	  
	  
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Central	  venous	  occlusions	  place	  patients	  at	  significant	  clinical	  risks,	  including:	  
• 
Cerebral	  edema,	  which	  puts	  patients	  at	  risk	  for	  chronic	  memory	  loss,	  learning	  deficiency,	  
and	  possible	  MS	  linkage	  
• 
Current	  standard	  of	  care	  “outside-­‐in”	  approach	  increases	  the	  risk	  of	  significant	  puncture,	  
rips	  and	  tears	  to	  arteries,	  lungs,	  and	  other	  critical	  systems	  
• 
Increased	  infection	  risk	  once	  jugular	  veins	  are	  obliterated	  and	  access	  is	  shifted	  to	  the	  use	  
subclavian	  and	  femoral	  access	  sites	  
	  
6.0	  	  	  	  	  	  	  	  STUDY	  DESIGN	  	  
This	  study	  has	  been	  designed	  as	  a	  prospectively	  enrolled,	  single-­‐arm,	  multicenter	  study	  to	  demonstrate	  
the	  safety	  and	  efficacy	  of	  the	  BVT	  Surfacer	  System	  in	  patients	  who	  require	  central	  venous	  access.	  	  	  
A	  total	  of	  30	  subjects	  is	  planned	  at	  a	  minimum	  of	  three	  (3)	  sites.	  Ten	  subjects	  will	  be	  enrolled	  initially.	  
After	  safety	  data	  review,	  enrollment	  is	  expected	  continue	  to	  30	  subjects	  overall	  with	  no	  more	  than	  10	  
subjects	  enrolled	  at	  a	  single	  site.	  
Enrolled	  subjects	  will	  undergo	  the	  Surfacer	  System	  procedure,	  then	  exit	  the	  study	  after	  follow-­‐up	  at	  
hospital	  discharge	  and	  7-­‐days	  post	  procedure.	  BVT	  will	  utilize	  an	  Independent	  Data	  Monitoring	  
Committee	  (IDMC)	  to	  review	  the	  study’s	  safety	  data	  during	  the	  conduct	  of	  the	  study	  and	  at	  study	  
closure.	  
6.1	  	  
ASA	  Guidelines	  
The	  study,	  designed	  in	  conformance	  with	  the	  standard	  of	  care	  for	  central	  venous	  access,	  as	  defined	  by	  
the	  American	  Society	  of	  Anesthesiologists	  Task	  Force	  on	  Central	  Venous	  Access.	  Anesthesiology,	  2012	  
Mar;	  116(3):539-­‐73.xxix	  These	  guidelines	  define	  central	  venous	  access	  as	  placement	  of	  a	  catheter	  such	  
that	  the	  catheter	  is	  inserted	  into	  a	  venous	  great	  vessel.	  The	  venous	  great	  vessels	  include	  the	  superior	  
vena	  cava,	  inferior	  vena	  cava,	  brachiocephalic	  veins,	  internal	  jugular	  veins,	  subclavian	  veins,	  iliac	  veins,	  
and	  common	  femoral	  veins.	  
6.2	  	  
Subject	  Selection	  and	  Participation	  
The	  study	  population	  include	  patients	  who	  are	  candidates	  for	  vascular	  access	  with	  limited	  or	  diminishing	  
upper	  body	  venous	  access	  or	  pathology	  impeding	  standard	  access	  methods	  (see	  Inclusion	  Criteria	  #3,	  

	  
	  
	  
	  
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section	  6.3.1).	  	  
Subjects	  who	  provide	  informed	  consent	  will	  undergo	  screening	  and	  baseline	  assessments.	  Subjects	  who	  
successfully	  pass	  the	  inclusion	  and	  exclusion	  criteria	  will	  undergo	  the	  Surfacer	  System	  procedure,	  with	  
subsequent	  follow-­‐up	  assessments	  at	  hospital	  discharge	  and	  7	  days	  post	  procedure.	  	  	  
6.3	  	  
Study	  Eligibility	  Criteria	  	  
To	  qualify	  for	  study	  participation,	  subjects	  must	  meet	  all	  of	  the	  Inclusion	  Criteria	  and	  none	  of	  the	  
Exclusion	  Criteria.	  
6.3.1	   Inclusion	  Criteria	  	  
1.	  	  Subjects	  are	  between	  18-­‐80	  years	  of	  age.	  	  
2.	  	  Subjects	  referred	  for	  placement	  of	  a	  central	  venous	  access	  catheter.	  
	  	  	  	  	  	  	  3.	  	  Subjects	  have	  limited	  or	  diminishing	  upper	  body	  venous	  access	  or	  pathology	  
impeding	  standard	  access	  methods.	  
4.	  	  Subjects	  are	  willing	  and	  able	  to	  give	  written	  informed	  consent.	  
6.3.2	   Exclusion	  Criteria	  
1.	  	  	  	  Subjects	  are	  contraindicated	  for	  Surfacer	  System	  use	  if	  one	  of	  the	  following	  are	  
found	  (per	  the	  IFU):	  	  	  
a.	  	  Occlusion	  of	  the	  right	  femoral	  vein;	  
b.	  	  Occlusion	  of	  the	  right	  iliac	  vein;	  
c.	  	  Occlusion	  of	  the	  inferior	  vena	  cava.	  
2.	  	  Subjects	  contraindicated	  for	  central	  venous	  access	  based	  upon	  the	  treating	  
physician’s	  opinion	  and	  institutional	  standard	  of	  care.	  	  
3.	  	  	  Subject	  has	  acute	  thrombosis	  within	  any	  vessel	  (SVC,	  jugular,	  inferior	  vena	  cava	  (IVC),	  
brachiocephalic	  and	  subclavian)	  planned	  be	  crossed	  by	  Surfacer	  System.	  	  
4.	   Subject	  has	  tortuous	  anatomy	  which	  precludes	  a	  straight	  line	  from	  femoral	  venous	  
entry	  to	  subclavian	  exit.	  	  
5.	   Subject	  has	  been	  diagnosed	  with	  active	  pericarditis	  or	  endocarditis.	  
6.	  	  	  Subject	  has	  a	  known	  or	  suspected	  pericardial	  effusion.	  
7.	   Subject	   has	   a	   known	   or	   suspected	   aneurysm	   or	   ectasia	   of	   ascending	   aorta,	  
innominate	  artery,	  or	  subclavian	  artery.	  

	  
	  
	  
	  
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8.	   Subjects	   who	   are	   pregnant	   or	   of	   childbearing	   potential	   not	   taking	   adequate	  
contraceptive	  measures	  or	  nursing	  during	  the	  study.	  
	  
6.4	  
Study	  Endpoints	  
6.4.1	   Primary	  Efficacy	  Endpoint	  
• Rate	  of	  safe	  insertion	  and	  patency	  of	  CVCs	  created	  across	  venous	  occlusions.	  	  
6.4.2	   Primary	  Safety	  Endpoints	  
• Acute	  device	  safety,	  defined	  as	  the	  absence	  of	  procedural	  complications	  
(hemopericardium,	  hemothorax,	  pneumothorax,	  blood	  transfusion,	  resuscitation,	  
emergency	  post-­‐procedural	  intervention,	  transfer	  to	  an	  intensive	  care	  unit,	  and	  
death)	  at	  discharge	  and	  7	  days	  post	  procedure.	  
• Overall	  device	  and	  procedure	  related	  anticipated	  adverse	  events	  compared	  to	  
historical	  safety	  data	  from	  CV	  placement	  procedures.	  	  
6.4.3	   Secondary	  Efficacy	  Endpoint	  
•	   Surfacer	  System	  advancement	  from	  femoral	  vein	  to	  sub-­‐clavicular	  exit	  to	  facilitate	  
CVC	  placement	  assessed	  by	  the	  ability	  of	  the	  Surfacer	  System	  to	  facilitate	  central	  
venous	  access	  placement.	  
6.4.4	   Secondary	  Safety	  Endpoint	  
• Technique	  Conversion	  rate.	  
7.0	  	  	  	  	  	  	  	  STUDY	  PROCEDURES	  
7.1	  	  
Informed	  Consent	  
Potential	  subjects	  will	  be	  provided	  with	  study	  information	  and	  given	  an	  opportunity	  to	  ask	  questions	  
about	  the	  study	  and	  treatment	  options.	  	  If	  the	  individual	  agrees	  to	  participate;	  they	  will	  complete	  a	  
written	  informed	  consent,	  be	  assigned	  a	  unique	  study	  identifier,	  and	  undergo	  screening	  and	  baseline	  
assessments.	  	  Study	  identifier	  will	  include	  the	  site	  number	  and	  a	  sequential	  subject	  ID	  number	  (i.e.	  05-­‐
04).	  	  
7.2	  
Screening	  and	  Baseline	  Assessments	  
Screening	  and	  Baseline	  assessments	  will	  include	  the	  following:	  
• 
Inclusion	  and	  Exclusion	  Criteria	  

	  
	  
	  
	  
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• 
Medical	  history	  with	  demographics	  
• 
Physical	  exam	  with	  vital	  signs	  
• 
TCVO	  Lesion	  Type	  Determination	  
• 
Medications	  (antithrombotic	  and	  cardiovascular)	  
• 
Pregnancy	  test	  (not	  required	  if	  patient	  is	  male	  or	  non-­‐child	  bearing	  potential)	  
• 
Clinical	  laboratory	  tests	  including	  coagulation	  profile	  (APTT,	  PT,	  INR),	  CRP,	  LDH,	  ASAT,	  ALAT,	  
fibrinogen,	  D-­‐dimer	  	  
• 
Ultrasound	  or	  venous	  duplex	  venography	  of	  upper	  body	  veins	  (SVC,	  jugular,	  inferior	  vena	  cava	  
(IVC),	  brachiocephalic	  and	  subclavian)	  to	  rule	  out	  acute	  thrombosis	  within	  a	  vein	  to	  be	  crossed	  
by	  the	  Surfacer	  System	  
• 
AP	  and	  LAT	  chest	  x-­‐ray	  or	  cine	  fluoroscopy	  will	  be	  performed	  prior	  to	  the	  procedure	  to	  define	  
the	  pattern	  of	  occlusion	  and	  to	  rule	  out	  acute	  thrombosis	  
• 
12-­‐lead	  ECG	  
7.2.1	   Screen	  Failures	  
If	  the	  Principal	  Investigator	  determines	  that	  the	  subject	  is	  not	  an	  acceptable	  study	  candidate	  at	  
any	  time	  during	  screening	  and	  the	  collection	  of	  baseline	  study	  data,	  up	  to	  the	  point	  of	  
enrollment,	  the	  subject	  will	  be	  documented	  as	  a	  Screen	  Failure	  and	  no	  further	  study	  data	  will	  be	  
collected.	  	  The	  reason	  and	  cause	  for	  Screen	  Failure	  will	  be	  documented.	  	  
7.3	  	  
Subject	  Enrollment	  
A	  subject	  will	  be	  considered	  “enrolled”	  in	  the	  study	  when	  they	  have	  completed	  informed	  consent,	  are	  
qualified	  per	  all	  study	  screening	  requirements	  and	  component	  of	  the	  investigational	  study	  device	  is	  
inserted	  into	  the	  subject.	  	  
Once	  a	  subject	  has	  been	  exposed	  to	  the	  study	  device,	  even	  if	  the	  Investigator	  is	  unable	  to	  complete	  the	  
Surfacer	  treatment,	  the	  study	  subject	  will	  be	  considered	  part	  of	  the	  intent-­‐to-­‐treat	  population	  and	  will	  
be	  followed	  up	  to	  7	  days	  post-­‐procedure,	  or	  until	  any	  adverse	  events	  are	  resolved.	  	  	  
See	  Section	  8.0	  for	  description	  of	  analysis	  populations	  and	  statistical	  considerations.	  	  
7.4	  
Intra-­‐Procedural	  Assessments	  
During	  the	  Surfacer	  System	  procedure,	  the	  following	  data	  will	  be	  collected:	  

	  
	  
	  
	  
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• 
Continuous	  ECG	  monitoring	  
• 
Contrast	  angiography	  (venography)	  to	  confirm	  occlusions.	  	  
• 
Fluoroscopy	  will	  be	  performed	  to	  confirm	  catheter	  tip	  position	  (catheter	  tip	  position	  must	  be	  
visible	  on	  fluoro).	  	  
• 
Cone	  beam	  CT,	  intracardial	  echo,	  or	  other	  advanced	  imaging	  guidance	  to	  verify	  placement.	  
Investigator	  must	  be	  able	  to	  clearly	  identify	  the	  level	  of	  occlusion.	  	  With	  Type	  IV	  occlusions,	  the	  
Investigator	  must	  be	  able	  to	  definitively	  identify	  the	  remnant	  of	  SVC;	  if	  this	  cannot	  be	  
accomplished	  by	  angiography,	  the	  operator	  should	  not	  proceed	  without	  advanced	  imaging	  
guidance	  such	  as	  cone	  beam	  CT	  or	  intracardiac	  echo.	  Advanced	  imaging	  should	  also	  be	  utilized	  
for	  some	  Type	  III	  TCVO	  lesions	  characterized	  by	  unusually	  tortuous	  vessels	  or	  otherwise	  
challenging	  anatomy.	  
• 
AP	  and	  LAT	  chest	  x	  ray	  or	  cine-­‐fluoroscopy	  will	  be	  performed	  post	  procedure	  to	  check	  the	  
correct	  placement	  and	  position	  of	  the	  CVA	  Catheter	  tip,	  rule	  out	  pleuro-­‐pulmonary	  damage	  
(pneumothorax,	  hemothorax,	  etc.),	  and	  to	  detect	  pleural	  fluid	  and	  mediastinal	  widening.	  
• 
TTE	  (optional,	  only	  if	  cardiac	  events)	  
• 
Study	  Device	  Performance	  
• 
Adverse	  Events	  
• 
Protocol	  Deviations	  
7.5	  
Discharge/Post	  Procedure	  Assessments	  
Subjects	  will	  be	  carefully	  monitored	  with	  follow-­‐up	  at	  hospital	  discharge	  and	  7-­‐days	  post	  procedure.	  	  
At	  hospital	  discharge,	  the	  following	  assessments	  will	  be	  conducted	  and	  documented:	  
• 
Physical	  exam	  including	  vital	  signs	  
• 
Medications	  (antithrombotic	  and	  cardiovascular)	  
• 
Clinical	  laboratory	  tests	  including	  coagulation	  profile	  (APTT,	  PT,	  INR),	  CRP,	  LDH,	  ASAT,	  ALAT,	  
fibrinogen,	  D-­‐dimer	  
• 
AP	  and	  LAT	  chest	  x	  ray	  or	  cine-­‐fluoroscopy,	  ideally	  assessed	  immediately	  after	  the	  index	  
procedure	  is	  complete.	  	  If	  the	  Investigator	  determines	  that	  additional	  imaging	  is	  clinically	  
indicated	  at	  the	  time	  of	  discharge	  (same	  day	  or	  next	  day	  discharge),	  a	  chest	  x-­‐ray	  may	  be	  
obtained.	  
• 
TTE	  (optional,	  only	  if	  symptomatic	  cardiac	  events)	  
• 
Adverse	  Events	  

	  
	  
	  
	  
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Protocol	  Deviations	  
	  
At	  7	  Days	  (+	  7)	  post	  procedure,	  the	  following	  assessments	  will	  be	  conducted	  and	  documented.	  Although	  
a	  generous	  visit	  window	  has	  been	  provided	  to	  allow	  for	  clinic	  visit	  scheduling,	  these	  assessments	  are	  to	  
occur	  on	  Day	  7	  post	  procedure,	  or	  as	  soon	  as	  possible	  thereafter:	  
• 
Physical	  exam	  including	  vital	  signs	  
• 
Medications	  (antithrombotic	  and	  cardiovascular)	  
• 
Adverse	  Events	  
• 
Protocol	  Deviations	  
7.6	  	  
Subject	  Withdrawal	  
Subject	  study	  participation	  is	  voluntary	  and	  subjects	  may	  withdraw	  from	  the	  study	  at	  any	  time	  without	  
penalty	  or	  compromise	  to	  their	  medical	  care.	  	  Additionally,	  a	  subject	  may	  be	  withdrawn	  from	  the	  study	  
at	  any	  time	  at	  the	  discretion	  of	  the	  Principal	  Investigator,	  if	  the	  Principal	  Investigator	  believes	  that	  
continuation	  in	  the	  study	  could	  result	  in	  unnecessary	  risks	  or	  jeopardize	  the	  subject’s	  health	  and	  
welfare.	  	  	  	  
The	  reason	  for	  withdrawal	  will	  be	  documented	  at	  the	  time	  of	  study	  withdrawal.	  	  All	  study	  data	  collected	  
up	  to	  the	  point	  of	  withdrawal	  will	  be	  included	  in	  the	  data	  analysis	  and	  maintained	  as	  part	  of	  the	  study	  
documentation.	  
7.7	  
Study	  Completion	  
Once	  a	  subject	  has	  undergone	  all	  required	  study	  assessments,	  they	  will	  have	  completed	  the	  study.	  	  
All	  study	  data	  collected	  through	  study	  completion	  will	  be	  included	  in	  the	  data	  analysis	  and	  maintained	  as	  
part	  of	  the	  study	  documentation.	  	  
7.8	  	  
Study	  Discontinuation	  
The	  study	  may	  be	  discontinued	  at	  any	  time	  by	  BVT	  or	  applicable	  regulatory	  agency.	  If	  the	  study	  is	  
discontinued	  before	  study	  activities	  have	  been	  completed,	  all	  study	  data	  collected	  up	  to	  the	  point	  of	  
discontinuation	  shall	  remain	  the	  property	  of	  the	  BVT	  and	  will	  be	  subject	  to	  all	  applicable	  patient	  and	  
data	  privacy	  requirements.	  	  

	  
	  
	  
	  
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8.0	  	  	  	  	  	  	  STATISTICAL	  CONSIDERATIONS	  	  
8.1	  	  	  	  	  	  	  	  Introduction	  
This	  is	  a	  prospective,	  single-­‐arm,	  multi-­‐center	  study	  to	  demonstrate	  the	  safety	  and	  efficacy	  of	  the	  
Surfacer®	  System.	  Clinical	  data	  will	  be	  obtained	  from	  up	  to	  30	  subjects	  treated	  with	  the	  Bluegrass	  
Vascular	  Technologies	  Surfacer	  System	  device	  at	  a	  minimum	  of	  three	  (3)	  sites.	  	  
No	  site	  will	  enroll	  more	  than	  10	  subjects.	  	  The	  study	  population	  will	  include	  patients	  who	  are	  candidates	  
for	  vascular	  access	  with	  limited	  or	  diminishing	  upper	  body	  venous	  access	  or	  pathology	  impeding	  
standard	  access	  methods.	  Patients	  who	  provide	  consent	  will	  be	  enrolled	  and	  undergo	  the	  procedure	  
with	  follow-­‐up	  at	  hospital	  discharge	  and	  7	  days	  post-­‐procedure.	  Total	  study	  duration	  is	  anticipated	  to	  be	  
12	  months.	  The	  study	  objectives	  and	  analytical	  methods	  to	  be	  used	  are	  described	  herein.	  	  
8.2 
Study	  Endpoints	  
8.2.1	  Primary	  Endpoints	  
Primary	  Efficacy	  Endpoint:	  	  
• Rate	  of	  safe	  insertion	  and	  patency	  of	  CVCs	  created	  across	  venous	  occlusions.	  	  
Primary	  Safety	  Endpoints:	  
• Acute	  device	  safety,	  defined	  as	  the	  absence	  of	  procedural	  complications	  
(hemopericardium,	  hemothorax,	  pneumothorax,	  blood	  transfusion,	  resuscitation,	  
emergency	  post-­‐procedural	  intervention,	  transfer	  to	  an	  intensive	  care	  unit,	  and	  death)	  
at	  discharge	  and	  7	  days	  post	  procedure.	  
• Overall	  device	  and	  procedure	  related	  anticipated	  adverse	  events	  compared	  to	  
historical	  safety	  data	  from	  CV	  placement	  procedures.	  
	  
8.2.2	  Sample	  Size	  Justification	  
A	  statistically	  powered	  sample	  size	  calculation	  is	  not	  applicable	  given	  the	  objective	  of	  this	  study.	  
Therefore,	  the	  sample	  size	  is	  intended	  to	  provide	  sufficient	  data	  to	  assess	  basic	  safety	  and	  
potential	  for	  effectiveness	  with	  an	  acceptable	  level	  of	  outcome	  evaluation	  certainty,	  while	  not	  
overexposing	  the	  target	  population	  to	  the	  risks	  associated	  with	  an	  investigational	  device.	  The	  
selection	  of	  at	  least	  30	  subjects	  is	  consistent	  with	  the	  range	  of	  10-­‐40	  subjects	  cited	  as	  typical	  for	  
such	  studies	  in	  recent	  FDA	  Clinical	  Investigator	  Training	  materials:	  

	  
	  
	  
	  
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http://www.fda.gov/downloads/Training/ClinicalInvestigatorTrainingCourse/UCM378265.pdf,	  
(Slide	  10	  of	  43	  at	  the	  above	  link,	  Nov.	  2013).	  
Table	  12	  provides	  the	  projected	  width	  of	  the	  confidence	  interval	  for	  a	  continuous	  and	  for	  a	  
binary	  endpoint.	  
	  
Table	  12.	  Expected	  results	  for	  confidence	  intervals	  for	  continuous	  and	  binary	  endpoints	  
	  
Sample	  Size	  
Continuous	  endpoint	  
Binary	  endpoint	      
Width	  of	  95%	  CI	  
	  
	  
CIopper-­‐Pearson	  95%	  CI	  
n	  =	  30	  
+/-­‐	  0.37	  x	  SD	  
+/-­‐	  18.7%	  
	  
With	  30	  subjects,	  the	  Maximum	  Clopper-­‐Pearson	  Exact	  95%	  Confidence	  Interval	  for	  the	  binary	  
outcome	  will	  range	  from	  31.3%	  to	  68.7%,	  assuming	  an	  observed	  percentage	  of	  50%	  (Listing	  1).	  
As	  the	  observed	  rate	  increases,	  the	  confidence	  interval	  will	  narrow.	  For	  example,	  with	  30	  
subjects	  and	  an	  observed	  rate	  of	  90%	  (27	  out	  of	  30	  successes),	  the	  Clopper-­‐Pearson	  Exact	  95%	  
Confidence	  Interval	  would	  range	  from	  73.5%	  to	  97.9%.	  Note	  that	  due	  to	  the	  exact	  nature	  of	  the	  
Clopper-­‐Pearson	  Confidence	  Interval,	  the	  range	  will	  not	  be	  symmetric	  the	  more	  the	  observed	  
rate	  deviates	  from	  50%.	  
Listing	  1.	  PASS	  13	  Output	  for	  a	  Binary	  Outcome	  Evaluation	  
	  
Confidence	  Intervals	  for	  One	  Proportion	  
	  
Numeric	  Results	  for	  Two-­‐Sided	  Confidence	  Intervals	  for	  One	  Proportion	  
Confidence	  Interval	  Formula:	  Exact	  (Clopper-­‐Pearson)	  
	  
	  
Sample	   	  
	  
	  
	  
	  
	  
Confidence	  
Size	  
Target	   Actual	   Proportion	  
Lower	  
Upper	  
Width	  If	  
Level	  
(N)	  
	  
Width	  
(P)	  
Limit	  
Limit	  
P=	  0.5	  
0.950	  
30	  
	  
0.244	  
0.900	  
0.735	  
0.979	  
0.374	  
References:	  
Fleiss,	  J.	  L.,	  Levin,	  B.,	  Paik,	  M.C.	  2003.	  Statistical	  Methods	  for	  Rates	  and	  Proportions.	  Third	  Edition.	  John	  Wiley	  &	  Sons.	  
New	  York.	  
Newcombe,	  R.	  G.	  1998.	  'Two-­‐Sided	  Confidence	  Intervals	  for	  the	  Single	  Proportion:	  Comparison	  of	  Seven	  Methods.	  
Statistics	  in	  Medicine,	  17,	  pp.	  857-­‐872.	  

	  
	  
	  
	  
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8.2.1 Secondary	  Endpoints	  
Secondary	  Efficacy	  Endpoint:	  
•	  	  	  	  Surfacer	  System	  clinical	  utility	  use	  from	  insertion	  into	  the	  femoral	  vein	  to	  sub-­‐
clavicular	  exit	  assessed	  by	  the	  ability	  of	  the	  Surfacer	  System	  to	  facilitate	  central	  
venous	  access	  placement.	  
Secondary	  Safety	  Endpoint:	  
•	  	  	  Technique	  Conversion	  Rate	  
8.3 
Statistical	  Analysis	  
8.3.1 Data	  Reporting	  Convention	  
Descriptive	  statistics	  will	  be	  utilized	  to	  summarize	  the	  demographic	  and	  baseline	  data.	  
For	  continuous	  endpoints,	  descriptive	  statistics	  will	  be	  presented	  including	  the	  number	  of	  
subjects	  with	  the	  measurement,	  mean,	  standard	  deviation,	  median,	  minimum	  and	  maximum.	  
For	  categorical	  endpoints,	  descriptive	  statistics	  will	  include	  the	  number	  with	  the	  event	  or	  
characteristic,	  the	  number	  evaluated,	  the	  percentage	  presented,	  and	  95%	  exact	  binomial	  
confidence	  interval.	  A	  critical	  two–sided	  alpha	  level	  of	  0.05	  will	  be	  carried	  out	  for	  all	  statistical	  
evaluations.	  
8.3.2 Assumption	  Verification	  
As	  a	  routine	  function,	  visual	  inspection	  and	  statistical	  tests	  will	  be	  used	  during	  analysis	  to	  
determine	  if	  the	  study	  variables	  are	  consistent	  with	  the	  assumptions	  of	  statistical	  tests	  
proposed.	  For	  continuous	  outcome	  variables,	  visual	  examination	  of	  data	  symmetry	  will	  be	  
initially	  performed	  with	  test	  of	  normality	  to	  be	  done	  by	  Shapiro-­‐Wilks	  test	  or	  an	  equivalent,	  and	  
equal	  variance	  assumptions	  will	  be	  tested	  with	  Folded	  F-­‐test	  or	  an	  equivalent.	  For	  categorical	  
variables,	  exact	  tests	  will	  be	  performed	  to	  limit	  assumptions	  regarding	  testing	  where	  possible.	  
8.3.3 Pooling	  of	  Study	  Sites	  
Data	  collected	  across	  different	  study	  sites	  will	  be	  pooled.	  The	  justification	  for	  pooling	  data	  

	  
	  
	  
	  
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across	  sites	  is	  made	  on	  a	  clinical	  basis.1	  A	  common	  protocol	  has	  been	  used	  across	  different	  sites	  
with	  the	  intention	  of	  pooling	  the	  data	  for	  analysis.	  Enrollment	  will	  be	  balanced	  between	  sites,	  
with	  no	  more	  than	  10	  subjects	  enrolled	  at	  a	  single	  site	  overall.	  Every	  effort	  will	  be	  made	  to	  
promote	  consistency	  in	  study	  execution	  at	  each	  site.	  
8.3.4 Analysis	  Populations	  
Enrolled	  Population:	  
Study	  results	  will	  be	  analyzed	  and	  reported	  for	  all	  enrolled	  patients	  who	  sign	  the	  informed	  
consent,	  complete	  the	  screening	  procedures	  are	  eligible	  and	  enrolled	  in	  the	  study.	  
Intent-­‐to-­‐treat	  (ITT)	  Population:	  
The	  ITT	  safety	  subject	  population	  comprises	  all	  enrolled	  subjects	  in	  whom	  Surfacer	  System	  
usage	  was	  attempted	  (i.e.	  the	  first	  step	  in	  the	  Instructions	  for	  Use	  of	  the	  Surfacer	  System	  was	  
performed),	  regardless	  of	  whether	  or	  not	  the	  procedure	  was	  completed	  with	  the	  successful	  
placement	  of	  a	  CVC.	  
Per	  Protocol	  Population:	  	  
The	  per	  protocol	  (PP)	  population	  will	  include	  all	  enrolled	  subjects	  in	  whom	  the	  Surfacer	  System	  
procedure	  was	  completed,	  with	  a	  CVC	  implanted	  completely	  and	  correctly	  (i.e.	  the	  last	  step	  in	  
the	  Instructions	  for	  Use	  of	  the	  Surfacer	  System	  was	  performed).	  	  
All	  primary	  and	  additional	  endpoints	  will	  be	  evaluated	  in	  both	  the	  intent	  to	  treat	  (ITT)	  and	  Per	  
Protocol	  analysis	  sets.	  The	  intent	  to	  treat	  analysis	  will	  be	  considered	  primary.	  
8.3.5 Primary	  Endpoint	  Analysis	  	  
Descriptive	  statistics	  reported	  for	  both	  primary	  safety	  and	  efficacy	  endpoints	  will	  be	  
summarized	  using	  number	  with	  the	  event	  or	  characteristic,	  the	  number	  evaluated,	  frequencies,	  
percentages	  and	  two-­‐sided	  exact	  95%	  confidence	  intervals,	  or	  time	  to	  event	  analysis,	  as	  
appropriate.	  	  Fisher’s	  exact	  test	  will	  be	  carried	  out	  for	  independent	  proportions	  comparison.	  	  A	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
1	  Meinert,	  C.	  (1986).	  Clinical	  Trials:	  Design,	  Conduct,	  and	  Analysis.	  	  Oxford	  University	  Press,	  New	  York.	  
 

	  
	  
	  
	  
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critical	  two–sided	  alpha	  level	  of	  0.05	  will	  be	  used	  for	  all	  statistical	  evaluations.	  The	  primary	  
endpoint	  study	  outcomes	  will	  be	  evaluated	  in	  the	  ITT	  population.	  	  
	  
8.3.6 Secondary	  Endpoints	  Analysis	  
For	  continuous	  secondary	  endpoints,	  descriptive	  statistics	  will	  be	  presented	  including	  the	  
number	  of	  subjects	  with	  the	  measurement,	  mean,	  standard	  deviation,	  median,	  minimum	  and	  
maximum.	  For	  categorical	  endpoints,	  descriptive	  statistics	  will	  include	  the	  number	  with	  the	  
event	  or	  characteristic,	  the	  number	  evaluated,	  the	  percentage	  presented,	  and	  95%	  exact	  
binomial	  confidence	  interval.	  
8.3.7 Multiplicity	  
No	  multiplicity	  adjustment	  will	  be	  required.	  
8.3.8 Safety	  Evaluations	  and	  Analyses	  
Adverse	  Events	  will	  be	  categorized	  by	  serious	  and	  non-­‐serious,	  device	  or	  procedure-­‐related	  and	  
non-­‐device	  or	  non-­‐procedure	  related,	  and	  anticipated	  and	  unanticipated.	  	  
The	  frequency	  of	  each	  event	  will	  be	  summarized	  by	  seriousness,	  severity	  and	  by	  relationship	  to	  
the	  device.	  Since	  some	  subjects	  may	  report	  the	  same	  event	  several	  times,	  the	  occurrence	  of	  the	  
highest	  severity	  case	  of	  the	  event	  will	  be	  used	  for	  the	  purpose	  of	  analysis.	  
The	  rates	  of	  adverse	  events	  will	  be	  presented	  with	  associated	  95%	  confidence	  intervals.	  No	  
statistical	  hypothesis	  test	  will	  be	  made.	  At	  periodic	  intervals	  during	  study	  conduct,	  clinical	  
evaluation	  of	  adverse	  events	  will	  be	  performed	  by	  the	  IDMC.	  
8.3.9 Missing,	  Unused	  &	  Spurious	  Data	  
Every	  effort	  must	  be	  taken	  by	  the	  Principal	  Investigators	  and	  designated	  site	  personnel	  to	  
ensure	  that	  all	  data	  required	  on	  every	  CRF	  is	  obtained	  and	  recorded.	  Missing	  data	  is	  
documented	  as	  “ND”	  (“Not	  Determined”)	  on	  the	  CRF.	  
Additionally,	  BVT	  minimize	  the	  incidence	  of	  missing	  data	  through	  appropriate	  management	  of	  
the	  clinical	  investigation,	  proper	  screening	  of	  study	  participants	  as	  well	  as	  thorough	  training	  of	  
investigators,	  monitors	  and	  study	  coordinators.	  

	  
	  
	  
	  
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The	  analysis	  of	  the	  endpoints	  will	  be	  performed	  with	  and	  without	  missing	  data	  using	  the	  Last	  
Observation	  Carried	  Forward	  (LOCF)	  as	  main	  missing	  data	  imputation	  technique.	  	  
If	  appropriate,	  a	  set	  of	  additional	  missing	  data	  imputation	  methods	  will	  be	  employed	  to	  
determine	  the	  impact	  of	  missing	  or	  incomplete	  data	  on	  the	  study	  conclusions.	  	  
8.3.10 Interim	  Analysis	  
No	  formal	  interim	  analysis	  will	  be	  performed.	  
8.3.11 Subgroup	  Analysis	  
No	  subgroup	  analysis	  will	  be	  performed.	  
9.0	  	  	  	  	  	  	  SAFETY	  	  
Safety	  monitoring	  will	  be	  performed	  by	  the	  Principal	  Investigator	  during	  the	  conduct	  of	  this	  study.	  An	  
Adverse	  Events	  (AE)	  will	  be	  recorded	  and	  assessed	  from	  the	  time	  of	  enrolment	  through	  study	  
completion	  or	  early	  withdrawal.	  All	  AEs	  will	  be	  followed	  by	  the	  Principal	  Investigator	  until	  resolution	  or	  
stabilization.	  
9.1	  
Adverse	  Event	  Classification	  	  
9.1.1	   Adverse	  Event	  
An	  AE	  is	  any	  undesirable	  clinical	  event	  experienced	  by	  a	  subject	  participating	  in	  a	  study.	  	  
The	  intensity	  of	  an	  AE	  will	  be	  classified	  as	  one	  of	  the	  following:	  
Mild:	  transient,	  does	  not	  interfere	  with	  the	  subject’s	  daily	  activities	  and	  does	  not	  require	  
therapeutic	  measures	  
Moderate:	  Interferes	  with	  the	  subject’s	  daily	  activities	  and	  requires	  simple	  therapeutic	  measure	  
Severe:	  Intolerable	  experiences	  that	  interrupt	  the	  subject’s	  daily	  activities	  and	  requires	  
substantial	  therapeutic	  measures	  including	  surgical	  intervention	  or	  hospitalization	  
The	  relationship	  of	  the	  AE	  to	  the	  investigational	  device	  will	  be	  categorized	  as	  one	  of	  the	  
following:	  
	  
Not	  related:	  	  No	  clinical	  evidence	  supporting	  a	  causal	  relationship	  	  

	  
	  
	  
	  
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Related:	  Clinical	  evidence	  supports	  a	  definite	  and	  certain	  causal	  relationship	  
9.1.2	   Anticipated	  Adverse	  Events	  	  	  
A	  list	  of	  AEs	  which	  may	  be	  anticipated,	  resulting	  from	  use	  of	  the	  study	  device,	  are	  defined	  in	  
Instructions	  for	  Use	  (IFU)	  of	  the	  investigational	  device	  and	  in	  Section	  5.5	  of	  this	  protocol.	  
9.1.3	   Serious	  Adverse	  Event/Unanticipated	  Adverse	  Device	  Effect	  	  
A	  Serious	  Adverse	  Event	  (SAE)	  is	  an	  AE	  that	  meets	  one	  of	  the	  following	  criteria:	  
•	  
fatal	  
•	  
life	  threatening	  
•	  
results	  in	  an	  unanticipated	  or	  prolonged	  hospitalization	  
•	  
results	  in	  a	  significant	  and	  persistent	  disability/incapacity	  
•	  
results	  in	  a	  congenital	  anomaly	  or	  birth	  defect	  	  	  	  
	  
An	  unanticipated	  adverse	  device	  effect	  (UADE)	  is	  any	  SAE	  as	  defined	  above	  that	  is	  caused	  by	  or	  
associated	  with	  the	  device,	  if	  that	  effect,	  problem,	  or	  death	  was	  not	  previously	  identified	  in	  
nature,	  severity,	  degree	  of	  incidence	  in	  this	  protocol.	  	  
Additionally,	  a	  UADE	  includes	  any	  other	  unanticipated	  serious	  problem	  associated	  with	  the	  
device	  that	  relates	  to	  the	  rights,	  safety,	  or	  welfare	  of	  subjects.	  
9.1.4	  	  	  SAE/UADE	  Reporting	  
BVT	  will	  be	  notified	  of	  an	  SAE/UADE	  the	  SAE/UADE	  Report	  Form.	  This	  form	  must	  be	  completed	  
by	  the	  Principal	  Investigator	  or	  designee,	  then	  faxed	  or	  scanned	  and	  emailed	  to	  BVT.	  The	  
SAE/UADE	  Report	  Form,	  fax	  number,	  and	  email	  are	  provided	  in	  the	  study	  manual.	  	  
Initial	  notification	  of	  the	  SAE/UADE	  may	  occur	  by	  telephone,	  but	  must	  always	  be	  followed	  by	  
submitting	  the	  SAE	  Report	  Form	  by	  the	  close	  of	  the	  next	  business	  day.	  	  
9.1.5	   UADE	  Regulatory	  Requirements	  
If	  it	  is	  determined	  that	  an	  UADE	  occurred,	  BVT	  will	  report	  the	  results	  of	  the	  evaluation	  to	  the	  
Independent	  Data	  Monitoring	  Committee	  (IDMC),	  the	  FDA,	  and	  Principal	  Investigators	  within	  10	  
working	  days	  after	  BVT	  first	  receives	  notice	  of	  the	  event	  (21	  CFR	  812.46(b),	  812.150(b)(1)).	  If	  
BVT	  determines	  an	  event	  or	  event	  rate	  presents	  an	  unreasonable	  risk	  to	  subjects,	  the	  study	  or	  
parts	  of	  the	  study	  presenting	  that	  risk	  will	  be	  terminated,	  as	  soon	  as	  possible.	  Termination	  of	  the	  

	  
	  
	  
	  
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study	  will	  occur	  no	  later	  than	  five	  (5)	  working	  days	  after	  BVT	  makes	  this	  determination	  and	  no	  
later	  than	  fifteen	  (15)	  days	  after	  BVT	  or	  its	  designee	  first	  receives	  notice	  of	  the	  event.	  
10.0	  	  	  	  	  	  STUDY	  MANAGEMENT	  	  
10.1	  
Data	  Collection	  	  
All	  study	  data	  will	  be	  collected	  on	  standardized	  electronic	  Case	  Report	  Forms	  (eCRFs)	  provided	  by	  BVT.	  	  
Electronic	  CRFs	  must	  be	  signed	  electronically	  by	  the	  Principal	  Investigator	  listed	  in	  the	  Clinical	  Trial	  
Agreement	  and	  Delegation	  of	  Authority	  Log.	  If	  for	  any	  reason	  an	  eCRF	  is	  unavailable	  and/or	  inaccessible,	  
a	  paper	  CRF	  will	  be	  provided	  by	  the	  trial	  Sponsor	  to	  be	  completed,	  signed	  by	  the	  Principal	  Investigator	  or	  
designee	  and	  submitted	  to	  BVT.	  	  	  Case	  Report	  Form	  Completion	  Instructions	  will	  be	  provided	  by	  BVT	  to	  
assist	  the	  Principal	  Investigator(s)	  and	  appropriate	  staff	  with	  eCRF	  completion	  and	  data	  entry	  processes.	  
BVT	  or	  their	  designee	  is	  responsible	  for	  database	  development,	  validation,	  control	  and	  management	  
using	  systems	  that	  are	  compliant	  with	  21	  CFR	  Part	  11.	  Databases	  shall	  include	  input(s)	  from	  each	  eCRF,	  
issuance	  and	  resolution	  of	  queries,	  database	  maintenance,	  and	  statistical	  support.	  	  	  
10.2	  
Source	  Documentation	  	  
BVT	  and	  their	  representatives,	  review	  boards	  (IRB/IEC),	  and	  applicable	  regulatory	  authorities	  will	  be	  
granted	  access	  to	  a	  subject’s	  medical	  records	  related	  to	  this	  study.	  Original	  or	  certified	  copies	  of	  all	  
relevant	  clinical	  findings,	  observations,	  and	  other	  activities	  throughout	  the	  study	  must	  be	  recorded	  and	  
maintained.	  
10.3	  
Data	  Confidentiality	  
To	  protect	  subject	  confidentiality,	  a	  unique	  study	  identifier	  will	  be	  used	  on	  all	  data	  collected	  for	  study	  
purposes.	  	  	  Any	  data,	  imaging	  media,	  or	  other	  form	  of	  study	  record	  collected	  shall	  be	  de-­‐identified.	  
Original	  copies	  of	  all	  data	  must	  be	  kept	  at	  the	  site.	  	  
10.4	  
Record	  Retention	  
Study	  documentation	  and	  records	  shall	  be	  retained	  in	  accordance	  BVT’s	  internal	  procedures	  or	  those	  of	  
authorized	  designee	  Per	  FDA	  regulation	  21	  CFR,	  812.140,	  records	  of	  each	  subject’s	  participation	  in	  the	  
study	  must	  be	  maintained	  for	  a	  period	  of	  two	  (2)	  years	  after	  trial	  closure	  and	  submission	  of	  the	  final	  
report	  to	  the	  IRB.	  

	  
	  
	  
	  
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At	  a	  minimum,	  a	  copy	  of	  the	  study	  documents	  must	  be	  retained	  by	  the	  Site	  for	  at	  least	  five	  (5)	  years	  
following	  the	  study	  completion.	  
Study	  documentation	  will	  not	  be	  destroyed	  without	  prior	  written	  agreement	  between	  BVT	  and	  the	  
Principal	  Investigator.	  
The	  Principal	  Investigator	  is	  to	  allow	  representatives	  of	  BVT	  to	  inspect	  all	  study-­‐related	  documentation	  
throughout	  the	  duration	  of	  the	  study.	  
10.5	  
Study	  Monitoring	  
BVT	  or	  its	  designee	  will	  conduct	  periodic	  site	  monitoring	  to	  ensure	  that	  all	  Principal	  Investigators	  are	  in	  
compliance	  with	  the	  protocol	  and	  the	  investigator’s	  agreement.	  The	  monitor	  will	  verify	  source	  
documentation	  against	  completed	  eCRFs	  and	  resolve	  any	  queries/discrepancies.	  	  
10.6	  
Study	  Oversight	  and	  Compliance	  
Each	  study	  site	  will	  be	  visited	  periodically	  to	  ensure	  that	  the	  study	  is	  conducted	  in	  full	  compliance	  with	  
all	  applicable	  regulations	  and	  this	  protocol.	  
BVT	  or	  designee	  shall	  maintain	  regular	  contact	  with	  the	  study	  site	  throughout	  the	  investigation	  by	  
telephone,	  mail,	  e-­‐mail,	  and	  on-­‐site	  visits.	  Periodic	  monitoring	  visit	  shall	  be	  conducted	  to	  ensure	  
continued	  protocol	  compliance,	  adequate	  subject	  enrolment,	  and	  accurate	  data	  reporting.	  
Following	  study	  closure	  at	  the	  study	  site,	  BVT	  or	  its	  designee	  will	  make	  a	  final	  study	  visit,	  to	  collect	  any	  
outstanding	  documentation,	  ensure	  that	  the	  Principal	  Investigator’s	  files	  are	  accurate	  and	  complete,	  
review	  record	  retention	  requirements	  with	  the	  Principal	  Investigator,	  make	  a	  final	  accounting	  of	  all	  
study	  supplies	  shipped	  to	  the	  Principal	  Investigator,	  provide	  for	  appropriate	  disposition	  of	  any	  remaining	  
study	  supplies,	  and	  ensure	  that	  all	  applicable	  requirements	  for	  the	  study	  are	  met.	  	  
10.6.1	   	  Study	  Non-­‐Compliance	  
If	  BVT	  or	  its	  designee	  becomes	  aware	  that	  a	  Principal	  Investigator	  is	  not	  complying	  with	  all	  study	  
requirements,	  BVT	  will	  evaluate	  the	  non-­‐compliance	  and	  if	  necessary,	  either	  secure	  compliance	  
or	  take	  other	  actions	  until	  the	  non-­‐compliance	  has	  been	  resolved.	  	  	  
If	  the	  non-­‐compliance	  is	  severe	  or	  cannot	  be	  resolved,	  BVT	  retains	  the	  right	  to	  remove	  either	  the	  
Principal	  Investigator	  or	  a	  study	  site	  from	  the	  trial.	  	  

	  
	  
	  
	  
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10.7	  	   Investigational	  Device	  Inventory	  
An	  initial	  shipment	  of	  investigational	  devices	  will	  be	  supplied	  by	  BVT	  to	  IRB/IEC	  approved	  study	  sites.	  
Additional	  investigational	  devices	  will	  be	  supplied	  to	  the	  study	  site	  as	  needed	  throughout	  the	  conduct	  of	  
the	  study.	  
10.7.1	  Investigational	  Device	  Accountability	  	  
Device	  accountability	  will	  be	  documented	  and	  maintained	  by	  the	  Principal	  Investigator	  at	  the	  
study	  site,	  to	  include	  all	  investigational	  devices	  received,	  used,	  and	  disposed	  at	  the	  end	  of	  the	  
study.	  Investigational	  device	  accountability	  records	  shall	  be	  maintained	  with	  clinical	  study	  files	  
and	  be	  available	  for	  review	  during	  monitoring	  visits.	  
10.7.2	  Investigational	  Device	  Storage	  
Investigational	  devices	  for	  use	  in	  this	  study	  will	  be	  stored	  in	  a	  locked,	  cool,	  dry	  and	  clean	  area,	  
with	  controlled	  accessibility.	  Only	  study	  staff	  authorized	  by	  the	  investigation	  will	  have	  access	  to	  
the	  investigational	  device.	  
10.7.3	  Investigational	  Device	  Return	  
BVT	  will	  provide	  directions	  for	  investigational	  device	  return	  at	  either	  study	  termination	  or	  
closure.	  	  All	  unused	  devices	  and/or	  those	  in	  opened	  packages	  must	  be	  returned	  to	  BVT.	  The	  
Principal	  Investigator	  must	  document	  any	  unused	  devices	  that	  are	  returned.	  	  
10.8	  	   Protocol	  Deviations	  
A	  protocol	  deviation	  occurs	  when	  the	  Principal	  Investigator	  or	  study	  staff	  do	  not	  conduct	  the	  study	  in	  
accordance	  with	  the	  protocol	  or	  other	  agreed	  upon	  study	  terms	  without	  prior	  approval	  from	  BVT.	  Any	  
deviation	  will	  be	  documented	  and	  reported	  to	  BVT	  regardless	  of	  severity	  or	  rationale	  for	  deviation.	  	  	  
10.9	  	   Investigator/Site	  Training	  	  
Investigators	  and	  site	  staff	  will	  be	  trained	  on	  the	  study	  in	  total,	  use	  of	  the	  investigational	  device,	  and	  any	  
specialized	  procedures	  required	  for	  the	  study.	  BVT	  will	  provide	  clinical	  support	  to	  site	  for	  any	  questions	  
or	  concerns	  related	  to	  the	  investigational	  device;	  however,	  BVT	  will	  not	  have	  influence	  on	  subject	  care.	  

	  
	  
	  
	  
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10.10	   Study	  Changes	  	  
10.10.1	  	  	  Change	  to	  the	  Protocol	  	  
BVT	  will	  initiate	  and	  document	  any	  changes	  to	  the	  protocol	  in	  writing.	  	  BVT	  shall	  submit	  such	  
changes	  to	  the	  Principal	  Investigators	  and	  applicable	  regulatory	  authorities.	  Approval	  of	  the	  
changes	  must	  be	  received	  by	  BVT	  in	  writing	  before	  the	  may	  be	  implemented	  at	  the	  study	  sites.	  	  
10.10.2	  	  	  IRB/IEC	  Approval	  Withdrawal	  
Withdrawal	  of	  IRB/IEC	  approval	  must	  be	  submitted	  to	  BVT	  within	  five	  (5)	  business	  days	  of	  the	  
change.	  	  
10.11	   	  Study	  Completion	  	  
Each	  Principal	  Investigator	  shall	  be	  notified	  in	  writing	  upon	  termination	  or	  conclusion	  of	  the	  study.	  	  BVT	  
retains	  the	  right	  to	  suspend	  or	  terminate	  this	  study	  at	  any	  time.	  	  	  
10.12	  	  	  	  Study	  Reports	  
Study	  progress	  reports	  shall	  be	  prepared	  and	  submitted	  to	  regulatory	  authorities	  per	  the	  applicable	  
regulations,	  or	  upon	  request.	  	  
A	  final	  clinical	  study	  report	  (CSR)	  will	  be	  compiled	  and	  submitted	  once	  all	  data	  collection	  and	  analyses	  
have	  been	  completed.	  CSRs	  shall	  include	  all	  information	  required	  and	  outlined	  in	  this	  protocol	  that	  is	  
available	  at	  the	  time	  of	  the	  report.	  	  A	  copy	  of	  the	  final	  CSR	  will	  be	  provided	  to	  applicable	  regulatory	  
agencies	  and	  participating	  Principal	  Investigators.	  The	  final	  CSR	  will	  be	  filed	  and	  maintained	  with	  study	  
documentation.	  	  
11.0	  	  	  	  	  	  STUDY	  ADMINISTRATION	  
11.1	  	   Statement	  of	  Compliance	  
This	  study	  will	  be	  conducted	  in	  compliance	  with	  GCP	  guidelines,	  all	  applicable	  US	  Federal	  regulations	  
pertaining	  to	  investigational	  devices	  including	  but	  not	  limited	  to:	  21	  CFR	  Part	  50,	  Part	  54,	  Part	  56,	  Part	  
812,	  Good	  Clinical	  Practice	  (GCP)	  standards,	  and	  Health	  and	  Insurance	  Portability	  and	  Accountability	  Act	  
(HIPAA),	  and	  all	  other	  applicable	  standards,	  regulations,	  guidelines,	  and	  institutional	  policies.	  
11.2	  	  	  	  	  CLINICALTRIALS.GOV	  REGISTRATION	  
A	  description	  of	  this	  study	  will	  be	  available	  on	  http://www.ClinicalTrials.gov	  as	  required	  by	  U.S.	  law.	  	  This	  

	  
	  
	  
	  
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website	  will	  not	  include	  information	  that	  identifies	  study	  subjects.	  	  At	  most,	  the	  website	  will	  include	  a	  
summary	  of	  the	  results	  of	  the	  study	  and	  will	  be	  available	  for	  public	  review	  at	  any	  time.	  
11.3	  
Investigator	  Responsibilities	  
Investigator(s)	  and	  study	  staff	  will	  adhere	  to	  the	  Statement	  of	  Compliance	  governing	  this	  study	  (Section	  
11.1).	  	  The	  investigator	  is	  responsible	  for	  obtaining	  proper	  regulatory	  approvals,	  and	  reporting	  study	  
information	  to	  regulatory	  authorities	  per	  all	  applicable	  regulations.	  	  A	  summary	  of	  specific	  Investigator	  
responsibilities	  per	  21	  CFR,	  812.100	  given	  below:	  	  
• 
Investigator	  must	  wait	  for	  regulatory	  approval	  to	  conduct	  the	  study.	  
• 
Investigator	  shall	  conduct	  the	  study	  in	  accordance	  with	  a	  signed	  agreement	  with	  BVT	  
• 
Investigator	  shall	  permit	  an	  investigational	  device	  to	  be	  used	  only	  with	  subjects	  under	  the	  
investigator's	  supervision.	  An	  investigator	  shall	  not	  supply	  an	  investigational	  device	  to	  any	  
person	  not	  authorized	  under	  this	  part	  to	  receive	  it.	  
• 
Investigator	  shall	  disclose	  to	  BVT	  sufficient	  financial	  information	  to	  allow	  for	  financial	  disclosure	  
as	  described	  in	  CFR	  Part	  54.	  
Upon	  completion	  or	  termination	  of	  a	  clinical	  study	  or	  Investigator's	  part	  in	  the	  study,	  or	  at	  BVT's	  
request,	  an	  investigator	  shall	  return	  to	  BVT	  any	  remaining	  supply	  of	  the	  device	  or	  otherwise	  dispose	  of	  
the	  device	  as	  BVT	  directs.	  
12.0	  	  	  	  	  BVT	  GENERAL	  RESPONSIBILITIES	  
BVT	  is	  responsible	  for	  selecting	  qualified	  investigators	  and	  providing	  them	  with	  the	  information	  they	  
need	  to	  conduct	  this	  study	  properly,	  ensuring	  proper	  monitoring	  of	  the	  study,	  ensuring	  that	  IRB	  review	  
and	  approval	  are	  obtained,	  and	  ensuring	  that	  the	  FDA	  and	  participating	  investigators	  are	  promptly	  
informed	  of	  significant	  new	  information	  about	  the	  study.	  	  
13.0	  	  	  	  	  PUBLICATION	  POLICY	  
All	  clinical	  information	  obtained	  in	  this	  study	  will	  be	  considered	  confidential.	  The	  identity	  of	  individual	  
subjects	  will	  be	  kept	  confidential	  in	  so	  far	  as	  the	  law	  and	  safe	  medical	  practice	  allow.	  It	  is	  planned	  that	  
the	  results	  of	  this	  study	  will	  be	  submitted	  for	  publication	  in	  scientific	  journals;	  patient	  identities	  will	  not	  
be	  disclosed.	  
BVT	  will	  be	  furnished	  with	  a	  copy	  of	  any	  proposed	  publication	  for	  review	  and	  comment	  prior	  to	  

	  
	  
	  
	  
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submission	  for	  publication.	  Manuscripts	  will	  be	  forwarded	  to	  BVT	  at	  least	  30	  days	  prior	  to	  submission	  
and	  abstracts	  at	  least	  7	  days	  prior	  to	  submission.	  At	  the	  expiration	  of	  the	  30	  or	  7-­‐day	  period,	  the	  
investigator	  may	  proceed	  with	  submission	  for	  publication.	  
In	  addition,	  each	  investigator	  must	  agree	  that	  no	  publications	  will	  be	  submitted	  without	  permission	  of	  
BVT	  or	  that	  will	  jeopardize	  a	  multi-­‐center	  publication,	  and	  all	  clinical	  data	  gathered	  during	  the	  study	  will	  
be	  pooled	  in	  a	  common	  database	  that	  is	  the	  property	  of	  BVT.	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  

	  
	  
	  
	  
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14.0	  	   REFERENCES	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
i	  American	  Cancer	  Society.	  How	  will	  the	  chemo	  be	  given	  to	  me?	  	  	  
http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/	  
chemotherapy/understandingchemotherapyaguideforpatientsandfamilies/understanding-­‐
chemotherapy-­‐how-­‐will-­‐i-­‐get-­‐chemo.	  
ii	  Camp-­‐Sorrell	  D,	  ed.	  Access	  Device	  Guidelines:	  Recommendations	  for	  Nursing	  Practice	  and	  Education.	  
2nd	  ed.	  Pittsburgh,	  PA:	  Oncology	  Nursing	  Society;	  2004.	  
iii	  Brown	  M.	  The	  impact	  of	  safety	  product	  use	  on	  catheter-­‐related	  infections.	  J	  Infus	  Nurs.	  
2004;27(4):245-­‐250.	  
iv	  Richardson	  D.	  Vascular	  access	  nursing:	  standards	  of	  care,	  and	  strategies	  in	  the	  prevention	  of	  infection:	  
a	  primer	  on	  central	  venous	  catheters	  (part	  2	  of	  a	  3-­‐part	  series).	  JAVA.	  2007;12:19-­‐27.	  
v	  Infusion	  Nurses	  Society.	  Infusion	  nursing	  standards	  of	  practice.	  J	  Infus	  Nurs.	  2011;34(1	  Suppl):S1-­‐S110.	  
vi	  Mohiaddin	  RH,	  Wann	  SL,	  Underwood	  R,	  Firmin	  DN,	  Rees	  S,	  Longmore	  DB.	  Vena	  caval	  flow:	  assessment	  
with	  cine	  MR	  velocity	  mapping.Radiology.	  1990;177(2):537-­‐541.	  
vii	  Bishop	  L	  et	  al.	  Guidelines	  on	  the	  insertion	  and	  management	  of	  central	  venous	  access	  devices	  in	  adults.	  
Int.	  Jnl.	  Lab.	  Hem.	  2007,	  29,	  261–278.	  
viii	  Pervez,	  2007,	  Techniques	  and	  Tips	  for	  Quick	  and	  Safe	  Temporary	  Catheter.	  
ix	  Stephens	  LC,	  Haire	  WD,	  Kotulak	  GD.	  Are	  clinical	  signs	  accurate	  indicators	  of	  the	  cause	  of	  central	  
venous	  catheter	  occlusion?	  JPEN	  Parenter	  Enteral	  Nutr.	  1995;19(1):75-­‐79.	  
x	  McKnight	  S.	  Nurse's	  guide	  to	  understanding	  and	  treating	  thrombotic	  occlusion	  of	  central	  venous	  access	  
devices.	  Medsurg	  Nurs.	  2004;13(6):377-­‐382	  
xi	  National	  Institutes	  of	  Health.	  Management	  of	  central	  venous	  catheter	  occlusions.	  Pharm	  Update.	  
1999;1-­‐4	  	  
xii	  Pittiruti,	  2009,	  Guidelines	  on	  Parenteral	  Nutrition	  Central	  Venous	  Catheters.	  
xiii	  Schiffer,	  2013,	  Central	  Venous	  Catheter	  Care	  for	  the	  Patient	  with	  Cancer.	  
xiv	  Management	  of	  occlusion	  and	  thrombosis	  associated	  with	  longterm	  indwelling	  central	  venous	  
catheters.	  Jacquelyn	  L.	  Baskin.	  Lancet.	  2009	  July	  11;	  374(9684):	  159.	  
xv	  Rupp,	  2012,	  practice	  guidelines	  for	  central	  venous	  access.	  
xviAl-­‐Hwiesh,	  A.K.	  2007,	  Tunneled	  femoral	  vein	  catheterization	  for	  long-­‐term	  hemodialysis:	  a	  single	  
center	  experience.	  
xvii	  Ryder	  M.	  The	  role	  of	  biofilm	  in	  vascular	  catheter-­‐related	  infections.	  N	  Dev	  Vasc	  Dis.	  2001;2:15-­‐25.	  
xviii	  Hadaway	  LC.	  Reopen	  the	  pipeline	  for	  IV	  therapy.	  Nursing.	  2005;35(8):54-­‐61.	  
xix	  Gale	  M1,	  Craxford	  S1,	  Taylor	  L1,	  Montgomery	  H1,	  Pickering	  S1,	  Thrombosis	  of	  the	  external	  jugular	  
vein:	  a	  rare	  complication	  of	  a	  proximal	  humerus	  fracture	  treated	  with	  collar	  and	  cuff	  immobilization.	  
Case	  Rep	  Orthop.	  2014;2014:283790	  
xx	  Dariushnia,	  2010,	  Quality	  Improvement	  guidelines	  for	  CVA.	  
xxi	  Frykholm,	  2014,	  Clinical	  guidelines	  on	  central	  venous	  catheterization.	  
xxii	  Elayi	  CS,	  Allen	  CL,	  Leung	  S,	  Lusher	  S,	  Morales	  GX,	  Wiisanen	  M,	  Aikat	  S,	  Kakavand	  B,	  Shah	  JS,	  Moliterno	  
DJ,	  Gurley	  JC.	  Inside-­‐out	  access:	  a	  new	  method	  of	  lead	  placement	  for	  patients	  with	  central	  venous	  
occlusions.	  Heart	  Rhythm.	  2011	  Jun;8(6):851-­‐7	  

	  
	  
	  
	  
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xxiii	  John	  C	  Gurley,	  MD.	  Inside-­‐out	  Central	  Venous	  Access	  -­‐	  Presentation	  (University	  of	  Kentucky	  May	  9,	  
2012).	  Heart	  Rhythm	  Society	  2012,	  May	  9-­‐12,	  Boston	  MA	  
	  
xxiv	  Elayi	  CS,	  Allen	  CL,	  Leung	  S,	  Lusher	  S,	  Morales	  GX,	  Wiisanen	  M,	  Aikat	  S,	  Kakavand	  B,	  Shah	  JS,	  Moliterno	  
DJ,	  Gurley	  JC.	  Inside-­‐out	  access:	  a	  new	  method	  of	  lead	  placement	  for	  patients	  with	  central	  venous	  
occlusions.	  Heart	  Rhythm.	  2011	  Jun;8(6):851-­‐7	  
xxv	  John	  C	  Gurley,	  MD.	  Inside-­‐out	  Central	  Venous	  Access	  -­‐	  Presentation	  (University	  of	  Kentucky	  May	  9,	  
2012).	  Heart	  Rhythm	  Society	  2012,	  May	  9-­‐12,	  Boston	  MA	  
xxvi	  Epstein	  AE,	  DiMarco	  JP,	  Ellenbogen	  KA,	  et	  al.	  ACC/AHA/HRS	  2008	  Guidelines	  for	  Device-­‐Based	  
Therapy	  of	  Cardiac	  Rhythm	  Abnormalities:	  a	  report	  of	  the	  American	  College	  of	  Cardiology/American	  
Heart	  Association	  Task	  Force	  on	  Practice	  American	  Association	  for	  Thoracic	  Surgery;	  Society	  of	  Thoracic	  
Surgeons.	  Circulation	  2008;	  
xxvii	  Adrian	  Ebner,	  MD;	  Santiago	  Gallo,	  MD;	  Carlos	  Cetraro,	  RT(R);	  John	  Gurley,	  MD;	  and	  Laura	  Minarsch,	  
CVT,	  RT(R).	  Inside-­‐Out	  Upper	  Body	  Venous	  Access:	  The	  first-­‐in-­‐human	  experiences	  with	  a	  novel	  
approach	  using	  the	  Surfacer	  Inside-­‐out	  Access	  Catheter	  System.	  Endovascular	  Today	  June	  2013.	  
xxviii	  American	  Society	  of	  Anesthesiologists	  Task	  Force	  on	  Central	  Venous	  Access.	  Anesthesiology,	  2012	  
Mar;116(3):539-­‐73	  
xxix	  Fleiss,	  J.	  L.,	  Levin,	  B.,	  Paik,	  M.C.	  2003.	  Statistical	  Methods	  for	  Rates	  and	  Proportions.	  Third	  Edition.	  
John	  Wiley	  &	  Sons.	  New	  York.	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  

	  
	  
	  
	  
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15.0	  	   APPENDIX	  A	  
DEFINITIONS	  OF	  POTENTIAL	  RISKS	  
	  
• 
Pain	  -­‐	  Acute	  discomfort	  conveyed	  to	  the	  brain	  by	  sensory	  neurons	  associated	  with	  a	  symptom	  or	  
disease.	  	  
• 
Infection–	  An	  infection	  is	  invasion	  and	  multiplication	  of	  microorganisms	  in	  body	  tissues	  
accompanied	  by	  pain,	  fever,	  drainage	  and/or	  leukocytosis	  that	  is	  treated	  by	  anti-­‐microbial	  
agents	  (non-­‐prophylactic).	  
	  
• 
Bleeding	  –	  overt	  bleeding	  either	  associated	  with	  a	  drop	  in	  the	  hemoglobin	  level	  of	  at	  least	  3.0	  
g/dL	   or	   requiring	   transfusion	   of	   two	   or	   three	   units	   of	   whole	   blood/RBC	   and	   does	   not	   meet	  
criteria	  of	  life	  threatening	  or	  disabling	  bleeding.	  	  
• 
Adverse	  Tissue	  Reaction;	  Allergic	  Reaction	  -­‐	  Localized	  or	  systemic	  hypersensitivity	  to	  contrast	  
media,	  anesthesia	  or	  other	  medications	  used	  characterized	  by	  rash,	  nausea,	  vomiting,	  itching,	  
shortness	  of	  breath,	  vasovagal	  reaction	  or	  anaphylaxis.	  	  The	  specific	  allergen	  should	  be	  reported	  
if	  known.	  	  
• 
Cardiovascular	   Sequela,	   including	   perforation,	   tamponade,	   spasm	   or	   effusion;	   Perforation-­‐	  
Perforation	  detected	  by	  the	  clinical	  site	  requiring	  additional	  treatment	  including	  efforts	  to	  seal	  
the	   perforation.	   	   Tamponade	   -­‐	   The	   term	   cardiac	   tamponade	   will	   be	   used	   to	   describe	   a	  
pericardial	   effusion	   sufficiently	   to	   cause	   circulatory	   compromise	   and	   require	   drainage.	   Any	  
cardiac	   tamponade	   is	   considered	   serious	   and	   procedure	   related.	   	   	   	   Spasm	   -­‐	   A	   transient	  
constriction	  of	  the	  lumen	  of	  one	  or	  more	  vessels	  due	  to	  contraction	  of	  vascular	  smooth	  muscle	  
effusion	  –	  Pericardial	  effusion	  is	  defined	  as	  a	  new	  fluid	  collection	  within	  the	  pericardial	  space,	  
with	  or	  without	  cardiac	  tamponade,	  as	  identified	  by	  echocardiography	  or	  CT	  imaging.	  
• 
Lymphatic	  System	  Sequelae	  -­‐	  Lymphatic	  system	  sequelae	  is	  recognized	  by	  the	  new	  occurrence	  
of	  lymph	  drainage	  at	  the	  procedure	  site,	  or	  a	  new	  accumulation	  of	  lymphatic	  fluid	  (lymphocele)	  
near	  the	  procedure	  site.	  

	  
	  
	  
	  
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
pg	  72	  of	  73 
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• 
Pulmonary	   Sequelae	   including:	   pneumothorax	   and	   pulmonary	   embolism	   –	   Pneumothorax	   -­‐	  
abnormal	   collection	   of	   air	   in	   the	  pleural	   space	  that	   causes	   an	   uncoupling	   of	   the	  lung	  from	  
the	  chest	   wall.	   	   Pulmonary	   embolism	   is	   defined	   as	   obstruction	   of	   one	   or	   more	   pulmonary	  
arteries	  by	  dislodged	  venous	  thrombi	  or	  foreign	  materials.	  
• 
Vascular	   sequelae	   including	   vasospasm,	   vessel	   perforation,	   dissection,	   or	   aneurysm;	  
Vasospasm	  -­‐	  A	  transient	  constriction	  of	  the	  lumen	  of	  one	  or	  more	  vessels	  due	  to	  contraction	  of	  
vascular	  smooth	  muscle.	  Vessel	  Perforation	  -­‐	  Complete	  penetration	  of	  the	  vessel	  wall,	  with	  or	  
without	   self-­‐limited	   extravasation	   of	   blood	   into	   surrounding	   tissues.	   Vessel	   Dissection-­‐	   This	  
term	   applies	   to	   unintended	   injury	   of	   femoral	   or	   pelvic	   vessels	   or	   the	   inferior	   vena	   cava.	  
Dissection	   is	   defined	   as	   disruption	   of	   the	   intimal	   layer	   that	   can	   be	   detected	   by	   contrast	  
angiography,	   ultrasound,	   or	   other	   imaging	   modalities.	   Aneurysm-­‐	   an	   abnormal	   blood-­‐filled	  
bulge	  of	  a	  blood	  vessel	  and	  especially	  an	  artery	  resulting	  from	  weakening	  (as	  from	  disease)	  of	  
the	  vessel.	  
• 
Unintended	  Embolization	  or	  Thrombosis	  -­‐	  Embolism	  is	  defined	  as	  the	  unintended	  entry	  of	  air,	  
thrombus,	  or	  foreign	  bodies	  into	  the	  circulation.	  	  Thrombosis	  -­‐	  local	  coagulation	  or	  clotting	  of	  
the	  blood	  in	  a	  part	  of	  the	  circulatory	  system.	  
• 
Arrhythmias-­‐	   Development	   of	   a	   new	   atrial	   and/or	   ventricular	   arrhythmia,	   exacerbation	   of	   a	  
prior	  arrhythmia	  or	  a	  significant	  increase	  in	  the	  severity	  of	  the	  current	  arrhythmia.	  Event	  that	  
requires	   cardioversion	   or	   introduction	   of	   a	   pacemaker	   will	   be	   considered	   a	   Serious	   Adverse	  
Event.	  
• 
Neurologic	  Sequelae	  including	  stroke;	  transient	  ischemic	  attack;	  nerve	  injury:	  Stroke	  -­‐	  Acute	  
cerebral	   infarction	   or	   hemorrhage	   confirmed	   by	   brain	   imaging	   (CT	   or	   MRI),	   or	   with	   new	  
neurological	  abnormalities	  persisting	  more	  than	  72	  hours.	  A	  stroke	  that	  occurs	  within	  24	  hours	  
of	  the	  procedure	  will	  be	  considered	  procedure	  related.	  	  	  All	  stroke	  events	  are	  considered	  serious.	  
Transient	  Ischemic	  Attack	  (TIA)	  -­‐	  New	  focal	  neurological	  deficit	  with	  rapid	  symptom	  resolution	  
(usually	  1-­‐2h),	  always	  within	  24	  h.	  	  Nerve	  Injury-­‐	  includes	  total	  or	  partial	  transection	  of	  a	  nerve	  
from	  stretching,	  cutting	  (laceration),	  compression,	  shearing,	  or	  crushing	  injuries	  

	  
	  
	  
	  
BVT.Surfacer.17-­‐01	  v	  2.0,	  07Dec17 
pg	  73	  of	  73 
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• 
Arteriovenous	  fistula	  -­‐	  A	  dilation	  of	  an	  artery	  with	  actual	  disruption	  of	  one	  or	  more	  layers	  of	  its	  
walls,	   rather	   than	   with	   expansion	   of	   all	   wall	   layers.	   An	   arteriovenous	   fistula	   is	   an	   abnormal	  
channel	  or	  passage	  between	  an	  artery	  and	  a	  vein.	  	  
• 
Death	  -­‐	  Cessation	  of	  brain	  and	  heart	  activity	  documented	  by	  physician,	  laboratory	  or	  diagnostic	  
test.	  	  Device	  related	  death	  is	  defined	  as	  death	  related	  to	  the	  investigational	  device.	  	  This	  may	  be	  
a	  device	  malfunction,	  misuse,	  or	  any	  death	  in	  which	  the	  relation	  of	  the	  device	  cannot	  be	  ruled	  
out.	  
• 
Surfacer	  System	  component	  failure	  or	  malfunction	  -­‐	  Any	  failure	  or	  malfunction	  of	  the	  device	  or	  
a	  component	  when	  used	  as	  intended	  per	  the	  Clinical	  Investigational	  Plan	  or	  Instructions	  for	  Use.	  	  
System	  or	  component	  failures	  are	  by	  definitions	  device	  related.