Evaluation of Anti-platelet Factor 4/Heparin Antibodies in Hemodialysis Patients Implanted With the GORE® Hybrid Vascular Graft Versus Non-heparin Bonded Synthetic Vascular Grafts.
Phase: NA
Conditions: End Stage Renal Disease
Sponsor: W.L.Gore & Associates

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Nothing herein is to be disclosed in any way without the prior 
express written permission of W. L. Gore & Associates, Inc. 
 
 
Evaluation of anti-platelet factor 4/heparin antibodies in hemodialysis patients implanted with the 
GORE® Hybrid Vascular Graft versus non-heparin bonded synthetic vascular grafts. 
 
 
 
 
 
 
Protocol Number: 
 
HVG 13-01   
 
 
 
Amendment 2  
           06-Nov-2014  
 
 
 
W. L. Gore & Associates, Inc. 
Medical Products Division 
 
 
 

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Protocol Summary 
 
Study Title 
Evaluation of anti-platelet factor 4/heparin antibodies in 
hemodialysis patients implanted with the GORE® Hybrid 
Vascular Graft versus non-heparin bonded synthetic 
vascular grafts. 
Protocol Number 
HVG 13-01 
Study Type  
Post market clinical follow-up study (PMCF) 
Sponsor 
W. L. Gore & Associates, Inc.  
Medical Products Division 
1505 N. Fourth Street  
Flagstaff, AZ 86004 
Telephone: 800-437-8181 
Study Design 
Prospective, randomized, multi-center clinical study. 
Study Objective 
To characterize the GORE® Hybrid Vascular Graft as 
compared to non-heparin bonded synthetic vascular grafts in 
terms of the prevalence and persistence of anti-platelet factor 
4/heparin antibodies (anti-PF4/H antibodies). 
Study Hypothesis 
The prevalence of (i.e., percentage of patients with) anti-
platelet factor 4/heparin antibodies will not be statistically 
different (15% margin) in the GORE® Hybrid Vascular Graft 
test arm compared to the non-heparin bonded synthetic 
vascular graft study control arm at Day 7 and / or Day 14 as 
measured by a commercial poly-specific enzyme-
immunoassay (EIA-GAM).  
Study Endpoint and 
Additional 
Assessments 
Primary Endpoint: 
• 
Prevalence of a positive commercial poly-specific 
enzyme immunoassay (EIA) at Day 7 and / or Day 14  
time points 
 
Additional Assessments: 
• 
Anti-PF4/H antibody seroconversion 
• 
Anti-PF4/H antibody seroreversion 
• 
Prevalence of a positive IgG-specific EIA at Day 7 and 
/ or Day 14 time points 
• 
Prevalence of a positive full serotonin release assay 
(SRA) panel 
• 
Platelet count at pre-procedure, Day 7, 14, 30, and 90 
time points 
• 
Volume flow in circuit and venous diameter 
measurements determined by duplex ultrasound post 
Index Procedure, Day 30 and 90, Month 6 and 12 

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• 
Primary patency, cumulative patency, and revision 
rates 
Subject Population 
End-Stage Renal Disease (ESRD) patients who have been 
on hemodialysis for ≥ 1 month and require hemodialysis 
through an upper arm prosthetic vascular access graft. 
Test Arm 
GORE® Hybrid Vascular Graft  
Control Arm 
Non–heparin bonded synthetic graft  
Number of Subjects 
200 Subjects (100 per arm) 
Number of Sites 
Up to 25 sites in the U.S. 
Expected Time to 
Complete Enrollment  
18 - 24 months 
 
Schedule of Events 
• 
Pre-procedure (within 2 days of Index Procedure) – 
Collection of blood and serum samples, medical history, 
physical exam, review of inclusion and exclusion criteria, 
and proper consenting prior to any study procedure or 
data collection 
• 
Index Procedure - Implantation of vascular graft, duplex 
ultrasound measurements, adverse events 
• 
Day 7 (±2 days) -  Collection of blood and serum 
samples,  adverse events, and revisions to the circuit 
• 
Day 14 (±2 days) – Collection of blood and serum 
samples, adverse events, and revisions to the circuit 
• 
Day 30 (±7 days) – Collection of blood and serum 
samples, duplex ultrasound measurements, adverse 
events, and revisions to the circuit 
• 
Day 90 (± 14 days) – Collection of blood and serum 
samples, duplex ultrasound measurements, adverse 
events, and revisions to the circuit 
• 
Month 6 (± 14 days) – Collection of duplex ultrasound 
measurements, adverse events, and revisions to the 
circuit 
• 
Month 12 (± 14 days) – Collection of duplex ultrasound 
measurements, adverse events, and revisions to the 
circuit 
Central Laboratory 
Covance Central Laboratory Services, LP 
Core Laboratory 
McMaster University 
Platelet Immunology Laboratory 
Contract Research 
Organization 
Theorem Clinical Research 
 
  
 

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List of Abbreviations 
 
aCRF 
Annotated Case Report Form 
ACT 
Activated Clotting Time 
AE 
Adverse Event 
AT 
Antithrombin 
AV 
Arteriovenous 
CA 
Competent Authority 
CBAS® 
Carmeda BioActive Surface 
CBC 
Complete Blood Count 
CDMS 
Clinical Data Management System 
CDU 
Color Flow Duplex Ultrasound 
CFD 
Computational Fluid Dynamics 
CFR 
Code of Federal Regulations 
CIP 
Clinical Investigation Plan 
cm 
Centimeters 
CM 
Contrast Medium 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTA 
Computed Tomographic Angiography 
CVC 
Central Venous Catheter 
DIC 
Disseminated Intravascular Coagulation 
DIPA 
Drug-Induced Platelet Activation Test 
eCRF 
Electronic Case Report Form 
EIA 
Enzyme Immunoassay 
ePTFE 
Expanded Polytetrafluoroethylene 
ESRD 
End Stage Renal Disease 
FDA 
Food and Drug Administration (United States) 
Fr 
French (sizing) 
GCP 
Good Clinical Practice 
GHVG 
GORE® Hybrid Vascular Graft 
GPVG 
GORE® PROPATEN® Vascular Graft 
Hb 
Hemoglobin 
HCT 
Hematocrit 
HIPA 
Heparin-Induced Platelet Activation Test 
HIT 
Heparin-Induced Thrombocytopenia 
ICF 
Informed Consent Form 

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ICH 
International Conference on Harmonisation 
IFU 
Instructions for Use 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IRB 
Institutional Review Board (U.S.) 
ITT 
Intent-to-Treat 
LMWH 
Low Molecular Weight Heparin 
mm 
Millimeters 
NRS 
Nitinol Reinforced Section 
OD 
Optical Density 
PF4/H 
Platelet Factor 4/heparin 
PMCF 
Post Market Clinical Follow-up 
PTA 
Percutaneous Transluminal Angioplasty  
PTT 
Partial Thromboplastin Time 
SAE 
Serious Adverse Event 
SRA 
Serotonin Release Assay 
UFH 
Unfractionated Heparin 
 
 

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Protocol Summary ............................................................................................................................................. ii 
List of Abbreviations......................................................................................................................................... iv 
1. Introduction.................................................................................................................................................. 1 
1.1. 
Study Rationale ................................................................................................................................. 3 
1.2. 
Study Device Description................................................................................................................... 4 
     1.2.1.     Vascular Graft Section ................................................................................................................. 5 
     1.2.2.     Nitinol Reinforced Section............................................................................................................ 5 
     1.2.3.      Constraint / Delivery System ....................................................................................................... 5 
     1.2.4.     Carmeda® BioActive Surface ....................................................................................................... 5 
     1.2.5.     Configurations ............................................................................................................................. 6 
     1.2.6.     Indications for Use ....................................................................................................................... 6 
     1.2.7.     Contraindications ......................................................................................................................... 6 
     1.2.8.     Implantation................................................................................................................................. 6 
     1.2.9.     Unique Benefits and Features...................................................................................................... 7 
2. Study Objective............................................................................................................................................ 7 
3. Study Design ................................................................................................................................................ 8 
3.1. 
Study Design Schema ....................................................................................................................... 8 
3.2. 
Description of Study Design .............................................................................................................. 8 
3.3. 
Study Endpoint and Additional Assessments ..................................................................................... 9 
       3.3.1.   Primary Endpoint ......................................................................................................................... 9 
       3.3.2    Additional Assessments ............................................................................................................... 9 
4. Study Population ....................................................................................................................................... 10 
4.1. 
Description of Population ................................................................................................................. 10 
4.2. 
Inclusion Criteria (all responses must be YES to be eligible) ............................................................ 10 
4.3. 
Exclusion Criteria (all responses must be NO to be eligible) ............................................................. 10 
5. Study Procedures / Evaluations ................................................................................................................ 11 
5.1 
Laboratory Specimens..................................................................................................................... 11 
5.2 
Schedule of Events ......................................................................................................................... 12 
5.3 
Informed Consent Process .............................................................................................................. 12 
5.4 
Screening ........................................................................................................................................ 13 
5.5 
Enrollment ....................................................................................................................................... 13 
5.6 
Procedure ....................................................................................................................................... 13 
     5.6.1     Test Device Training Requirements ............................................................................................ 14 
     5.6.2     Implantation Technique .............................................................................................................. 14 
     5.6.3     Additional Implant Considerations ............................................................................................... 14 
     5.6.4     Anticoagulation and Antiplatelet Therapy .................................................................................... 14 
     5.6.5     Duplex Ultrasound Requirements ............................................................................................... 15 
5.7 
Follow-Up ........................................................................................................................................ 15 
5.8 
Revisions to the Vascular Access Circuit ......................................................................................... 17 
5.9 
Subject Withdrawal from the Study .................................................................................................. 17 
5.10 
Subject Lost to Follow-Up ................................................................................................................ 17 
5.11 
Subject Study Completion and Discontinuation ................................................................................ 17 
6. Clinical Study Administration ................................................................................................................... 18 
6.1 
Training ........................................................................................................................................... 18 
6.2 
Monitoring ....................................................................................................................................... 18 

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6.3 
Device Accountability and Storage .................................................................................................. 18 
6.4 
Central Laboratory........................................................................................................................... 18 
6.5 
Core Laboratory .............................................................................................................................. 19 
6.6 
Protocol Deviations ......................................................................................................................... 19 
6.7        Clinical Data Review ....................................................................................................................... 19 
6.8        Protocol Amendments ..................................................................................................................... 19 
6.9        Sponsor Representatives ................................................................................................................ 19 
6.10      Access to Source Data / Documents ............................................................................................... 19 
6.11      Study Records Retention ................................................................................................................. 20 
6.12      Clinical Trial Registration ................................................................................................................. 21 
7. Data Collection and Submission ............................................................................................................... 21 
7.1        Data Collection Methods ................................................................................................................. 21 
7.2 
Data Clarification and Correction ..................................................................................................... 21 
8. Risk Assessment ....................................................................................................................................... 21 
8.1 
Potential Risks ................................................................................................................................ 21 
8.2 
Minimization of Risks ....................................................................................................................... 22 
9. Adverse Events .......................................................................................................................................... 22 
9.1        Anticipated Adverse Events ............................................................................................................. 22 
9.2        Adverse Event Relationship ............................................................................................................. 23 
9.3        Adverse Event Classification ........................................................................................................... 23 
9.4        Adverse Event Reporting and Coding .............................................................................................. 24 
9.5        Subject Death ................................................................................................................................. 24 
10. Statistical Analysis .................................................................................................................................... 25 
10.1. 
Study Hypothesis ............................................................................................................................ 25 
10.2. 
Sample Size Assumptions ............................................................................................................... 25 
10.3. 
Sample Size Determination ............................................................................................................. 25 
10.4. 
Randomization Scheme .................................................................................................................. 25 
10.5. 
Blinding Scheme ............................................................................................................................. 25 
10.6. 
Data Analysis .................................................................................................................................. 25 
     10.6.1     Timing of Analyses ................................................................................................................... 25 
     10.6.2     Analysis Populations ................................................................................................................ 26 
     10.6.3     Pooling of Data ......................................................................................................................... 26 
     10.6.4.    Statistical Analysis of Primary Endpoint(s) ................................................................................ 26 
     10.6.5.    Statistical Analysis of Additional Assessments .......................................................................... 26 
11. Ethical and Regulatory Considerations .................................................................................................... 27 
11.1. 
Statement of Compliance ................................................................................................................ 27 
11.2. 
Compliance Responsibilities ............................................................................................................ 27 
11.3. 
Informed Consent ............................................................................................................................ 27 
11.4. 
Independent Ethical Review ............................................................................................................ 28 
11.5. 
Conflict of Interest ........................................................................................................................... 28 
11.6. 
Confidentiality ................................................................................................................................. 28 
12. References ................................................................................................................................................. 29 

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1. 
Introduction  
In the United States more than 594,000 people are being treated for End Stage Renal Disease 
(ESRD).1 Of this group, over 415,000 are on dialysis (either hemodialysis or peritoneal dialysis). 
ESRD is a growing health problem worldwide and is a strain on Medicare and other government 
health care programs. Since 2000, ESRD has increased by 23% in the US alone.1  Medicare 
spends over $87,561 per patient annually for hemodialysis patients and over 33 billion dollars on 
ESRD patients in the US each year.1  
 
Significant efforts have been made to increase the use of autogenous arteriovenous fistulas, 
however, the use of synthetic grafts still remains significant at 19.4% prevalence in 2012.2  
Expanded polytetrafluoroethylene (ePTFE) vascular grafts have been marketed in Europe and the 
United States for over 30 years. Since 1980, ePTFE has been the material of choice for small and 
medium diameter vascular grafts. The strong market presence and the extensive clinical history 
associated with ePTFE vascular grafts speak to the benefits of using these grafts for hemodialysis 
access. Distinct advantages of synthetic AV grafts include: large surface area available for 
cannulation, technically easy to cannulate, multiple insertion sites, variety of shapes and 
configurations, easy to handle, implant, and suture, and thrombosed grafts have longer patency 
rates after revision than do revised fistulas.3 
 
Graft thrombosis accounts for approximately 80% of graft failures.4 The clot is formed initially of 
platelet aggregates, and then fibrin and thrombin are laid down via activation of the coagulation 
cascade. One potential strategy to reduce this thrombogenicity is to covalently bind heparin to the 
luminal surface of the graft, imparting thromboresistant properties to the blood contact surface of 
the vascular graft. Heparin is a polysaccharide anticoagulant with a long history of clinical use in 
the prevention and treatment of thrombosis.  
 
W. L. Gore & Associates, Inc. (Gore) proprietary end-point immobilized heparin technology is 
referred to as the Carmeda® BioActive Surface (CBAS® Surface). The GORE® Hybrid Vascular 
Graft (incorporates this covalent, end-point immobilized heparin onto the luminal microstructure of 
the graft. End-point immobilization of heparin describes the method by which the reducing terminus 
of a derivatized heparin molecule is coupled by a single covalent linkage to an amino function of a 
base molecular surface. Anchored to the material surface via a single, chemically stable linkage, 
the molecule extends from the ePTFE microstructure into the blood stream and is free to interact 
with coagulation factors and inhibitors present in blood.  
 
The complications with the use of non-heparinized vascular grafts are similar to the complications 
associated with vascular grafts with the CBAS® Surface (GORE® PROPATEN® Vascular Graft).5 
These complications include: fluid leakage, intraoperative bleeding, thrombosis, non-anastomotic 
and anastomotic circumferential tears, infection, seroma, pseudoaneurysm, and hematomas, etc. 
The low frequency of these complications relative to the large number of devices that have been 
implanted demonstrate the benefit of ePTFE grafts with the CBAS® Surface.5 
 

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Heparin-Induced Thrombocytopenia (HIT) is a potentially life threatening adverse reaction to 
heparin. Two forms of HIT have been described, HIT type I and HIT type II. The latter, HIT type II, 
is an immune-mediated reaction and is the more commonly discussed and more clinically 
significant version of HIT. The focus of this study is HIT type II and will hereafter be referred to 
simply as HIT. HIT is caused by heparin-dependent platelet-activating IgG antibodies that are 
formed in relation to an immunizing exposure to heparin, either unfractionated heparin (UFH) or low 
molecular weight heparin (LMWH). These antibodies recognize complexes of platelet factor 4 
bound to heparin (PF4/H).6 In a subset of these patients, these antibodies activate. These 
antibodies are clinically significant causing activation and aggregation of platelets resulting in a 
falling platelet count. In some patients this can lead to thrombotic complications. Among patients 
receiving systemic heparin, the reported incidence of HIT is between 0.1% to 5.0% depending on 
the patient population and heparin type. HIT occurs more frequently in surgical patients and with 
unfractionated heparin (UFH) than with low molecular weight heparin (LMWH). Patients sensitive to 
heparin may frequently develop HIT antibodies, however, thrombocytopenia and thrombosis are 
relatively uncommon consequences.6 
 
The GORE® Hybrid Vascular Graft is contraindicated for use in patients with known hypersensitivity 
to heparin including those patients who have had a known incident if HIT. It remains unproven that 
the placement of a CBAS® Surface vascular graft contributes to immunization or to persistence of 
HIT antibodies. 
 
The risk of HIT for patients receiving systemic anticoagulant doses of heparin is low. Patients who 
receive the GORE® Hybrid Vascular Graft (GHVG) typically also receive systemic heparin both 
peri- and post-operatively and are therefore exposed to this low risk, independent of the 
implantation of a vascular graft with the CBAS® Surface. An analysis of the GORE® PROPATEN® 
Vascular Graft (GPVG) and GORE® VIABAHN® Endoprosthesis with PROPATEN Bioactive 
Surface suggests that there is minimal risk that the covalently bonded heparin in the CBAS® 
Surface causes or contributes to the condition of HIT.5  
 
HIT is defined as a moderate or strong positive platelet serotonin-release assay (>50% release, 
mean of 0.1 and 0.3 U/ml, in the full panel) plus either thrombocytopenia (>50% platelet count fall 
from preceding peak) and/or thrombosis, bearing a temporal relationship to a positive platelet 
serotonin-release assay (SRA) sample. 
 
The clinical features of HIT include thrombocytopenia that bears a temporal relationship to the 
preceding immunizing exposure to heparin, thrombosis (venous or arterial), disseminated 
intravascular coagulation (DIC), post-UFH bolus anaphylactic reactions, limb gangrene, necrotizing 
skin lesions at heparin injection sites, among others.7 
 

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The key pathologic criterion for HIT is the presence of “HIT antibodies” as assessed by an in vitro 
SRA. The presence of HIT antibodies can be objectively determined with the SRA in concert with 
two enzyme immunoassays (EIAs), an IgG-specific EIA and a poly-specific EIA that detects 
antibodies of the Immunoglobulin G (IgG), Immunoglobulin A (IgA), and / or Immunoglobulin M 
(IgM) classes. A positive SRA has been shown to correlate strongly with the development of 
thrombocytopenia.8 An unusual feature of “HIT antibodies” is their remarkable transience: typically, 
among patients with well-documented HIT, antibodies become undetectable after 50 to 85 days 
(depending on the assay performed).9  
 
Patients who receive the GORE® Hybrid Vascular Graft, or any other synthetic vascular graft, are 
typically given systemic heparin peri-operatively or post-operatively and / or in the dialysis unit 
during hemodialysis sessions. Therefore, these patients are exposed to the established low risk of 
HIT, independent of the CBAS® Surface. 
1.1. Study Rationale 
The GORE® Hybrid Vascular Graft has been cleared by the U.S. Food and Drug 
Administration (FDA) in March 2010 for use in dialysis access patients, patients who require 
replacement or bypass of diseased vessels, trauma patients who need a vascular graft, and 
other vascular procedures. 
 
Gore then submitted an application for CE-mark approval for the GORE® Hybrid Vascular 
Graft in 2012. The CE-mark was granted July 2012. 
 
A review by a competent authority (CA) who reviews medicinal substances such as heparin, 
stated that Gore should consider setting up a registry. The registry would be aimed at 
collecting data on patients potentially developing HIT after implantation of a device with the 
CBAS® Surface, including follow-up of antibody levels and associated platelet-activating 
properties.  
 
In order to satisfy the CA request, Gore will conduct a controlled clinical study. Gore believes 
that a randomized, two-arm study to evaluate the prevalence and persistence of anti-
PF4/heparin antibodies in GORE® Hybrid Vascular Graft patients versus a control arm (non-
heparin bonded synthetic grafts) is the appropriate approach. By performing this type of 
controlled serology study, results of the study could potentially demonstrate there is no added 
risk of developing HIT antibodies through the use of a device with the CBAS® Surface. In 
addition, the study could demonstrate that a device with the CBAS® Surface does not 
influence the persistence of anti-PF4/H antibodies.  
 
Background of HIT in Hemodialysis Patients: 
 
The GORE® Hybrid Vascular Graft is used primarily for ESRD patients requiring hemodialysis 
through a synthetic graft. This study is to demonstrate that there is no added risk of 
developing HIT antibodies through the use of a device with the CBAS® Surface (specifically 
the GHVG). The study will be conducted on a hemodialysis patient population in need of an 
upper arm synthetic arteriovenous (AV) access graft.   
 

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Unfractionated heparin for anticoagulation plays a major role in the life of the hemodialysis 
patient, however studies suggest that only a few patients who form anti-PF4/H antibodies in 
association with chronic hemodialysis develop related clinical HIT. In cross-sectional studies 
with more than 3000 patients, the percentage of patients who were positive for anti-PF4/H 
antibodies (by enzyme immunoassays) ranged from 0% to 17.9%,10 while only in a few 
patients did antibodies appear to be associated with thrombocytopenia or thromboembolic 
events. In a U.K. survey including over 10,000 ESRD patients on hemodialysis, the incidence 
and prevalence of HIT was given to be 0.32% and 0.26%, respectively.10  
 
There are a few other specific considerations for the hemodialysis population. 1) The risk of 
clinical HIT may be higher in patients just starting hemodialysis than in patients that have 
been on chronic hemodialysis treatment. However, patients can develop HIT even after years 
of regular long-term maintenance hemodialysis performed with unfractionated heparin.10   2) It 
has been shown that the hemodialysis procedure itself is associated with a relative decrease 
in platelet count. 3) Vascular access (fistula and graft) thrombosis occurs frequently in 
hemodialysis patients. 4) ESRD patients on hemodialysis undergo numerous surgical and 
interventional procedures throughout their treatment, and the highest reported rates of HIT 
are in postoperative patients receiving unfractionated heparin.10 
 
Background on HIT Assays: 
 
Two general types of laboratory assays are used to confirm the presence of heparin-
dependent IgG antibodies (“HIT” antibodies). Activation assays, such as the SRA, detect the 
antibodies based on their ability to activate platelets in a heparin-dependent fashion. Antigen 
assays, such as EIAs, detect the binding of antibodies to immobilized platelet factor 4-heparin 
complexes. The EIAs can be poly-specific (recognizing IgG, IgA and IgM immunoglobulin 
classes) or specific to detecting the IgG class alone. The antibodies associated with clinical 
HIT have been reported to be of the IgG class alone.  
 
All three types of assays (SRA and both EIAs) will be performed on each serum sample at 
each time point by the McMaster Platelet Immunology Laboratory. All laboratory assays will 
be performed by McMaster Platelet Immunology Laboratory study personnel. The study 
personnel will be blinded to the clinical information including the type of graft implanted and 
any relevant clinical information, such as platelet counts.  
 
1.2. Study Device Description 
The GORE® Hybrid Vascular Graft is an ePTFE vascular prosthesis that has a section 
reinforced with nitinol (Figures 1, 2, and 3). The nitinol reinforced section (NRS) is partially 
constrained to allow for easy insertion and deployment into a vessel. The constraint is made 
up of an ePTFE fiber which is knitted into a tubular shape. The deployment line can be pulled 
to unzip the constraint and the NRS opens to its nominal diameter. The GORE® Hybrid 
Vascular Graft has a continuous lumen and includes the CBAS® Surface consisting of a 
stable covalently bonded, reduced molecular weight heparin of porcine origin.  
 

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 Vascular Graft Section   
The GORE® Hybrid Vascular Graft is a single device that combines ePTFE and nitinol 
technologies. The device is constructed using an ePTFE base tube that extends the 
entire length of the device. The vascular graft section is comprised of ePTFE tubing, 
ePTFE reinforcing film, and ePTFE / FEP membrane, and includes an orientation line 
for ease of use during implantation. The microstructure of ePTFE consists of nodes 
and fibrils and is porous throughout. 
 
 
Figure 1. Schematic drawing of the nitinol reinforced section of the GHVG showing the 
constrained NRS with the deployment line (top) and the fully deployed NRS (bottom). 
 
 
 
Figure 2. The GORE® Hybrid Vascular Graft with the constrained nitinol reinforced section. 
 
 
 
Figure 3. The GORE® Hybrid Vascular Graft fully deployed. 
 
 Nitinol Reinforced Section 
The nitinol reinforced section (NRS) is comprised of ePTFE tubing, ePTFE reinforcing 
film, ePTFE / FEP membrane, nitinol, and an ePTFE / FEP film that bonds the nitinol 
section to the ePTFE reinforcing film. The NRS has a reducible diameter for loading 
into the constraint / delivery system and has sufficient radial force to resist migration 
when deployed into a blood vessel with proper over sizing.  
 
 
 
 Constraint / Delivery System The constraint / delivery system is comprised of an 
ePTFE fiber which is knitted into a tubular shape. A portion of the nitinol reinforced 
section is loaded into the constraint / delivery system such that the loaded section can 
be inserted into a blood vessel.  
 Carmeda® BioActive Surface  

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The GORE® Hybrid Vascular Graft also incorporates the proprietary end-point 
immobilized heparin technology, referred to as Carmeda® BioActive Surface (CBAS® 
Surface)) onto the luminal microstructure. Anchored to the material surface via a 
single, chemically stable linkage, the molecule extends from the ePTFE 
microstructure into the blood stream. The molecules are free to interact with 
coagulation factors and inhibitors present in blood and does not elute from the ePTFE 
surface. The antithrombin (AT) binding sites of heparin molecules are unaltered by 
the covalent bonding process and remain functional (Figure 4). 
 
 
 
Figure 4. The bioactive luminal surface of a GHVG (top) remains free of thrombus, while the 
non-bioactive surface of a control graft (bottom) is covered with thrombus. Grafts were 
compared in a 90 minute acute canine blood contact model. 
 Configurations 
       Below is a table of the current configurations of the GORE® Hybrid Vascular Graft. 
 
 
 
 
 
 
 Indications for Use 
GORE® Hybrid Vascular Grafts are intended for use as vascular prostheses for 
replacement or bypass of diseased vessels in patients suffering occlusive or 
aneurysmal diseases, in trauma patients requiring vascular replacement, for dialysis 
access, or for other vascular procedures. 
 
 Contraindications 
DO NOT use the GORE® Hybrid Vascular Graft in patients with known hypersensitivity 
to heparin, including those patients who have had a previous incident of HIT type II. 
DO NOT use any configuration of GORE® Hybrid Vascular Grafts for coronary artery 
bypass or cerebral reconstruction procedures. DO NOT use GORE® Hybrid Vascular 
Grafts as a patch. If cut and used as a patch, GORE® Hybrid Vascular Grafts may lack 
adequate transverse strength. Refer to Instructions for Use at goremedical.com for a 
complete description of all warnings, precautions and adverse events. 
 
 Implantation 
Catalog Number (U.S.) 
Nitinol Reinforced Section 
Vascular Graft Section 
0650HYB0605A 
6 mm x 5 cm 
6 mm x 50 cm 
0650HYB0610A 
6 mm x 10 cm 
6 mm x 50 cm 
0650HYB0705A 
7 mm x 5 cm 
6 mm x 50 cm 
0650HYB0710A 
7 mm x 10 cm 
6 mm x 50 cm 
0650HYB0805A 
8 mm x 5 cm 
6 mm x 50 cm 
0650HYB0810A 
8 mm x 10 cm 
6 mm x 50 cm 
0650HYB0905A 
9 mm x 5 cm 
6 mm x 50 cm 
0650HYB0910A 
9 mm x 10 cm 
6 mm x 50 cm 

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The GORE® Hybrid Vascular Graft includes the nitinol reinforced section which 
facilitates the fast and simple creation of an end-to-end anastomosis. There are two 
basic implantation techniques for placing the GHVG:  a standard open surgical 
technique and an over-the-wire technique.  
 
 Unique Benefits and Features 
 
As described above, the GHVG allows for two unique implantation techniques. Both 
techniques offer a number of unique benefits including: improved hemodynamics as 
compared to a sutured end-to-side anastomosis, the potential to reduce surgery time, 
ease of use, the creation of a consistent anastomosis, reduction in vessel dissection 
and manipulation, and expanded treatment options for challenging site locations and 
deep vessels.  
 
The GORE® Hybrid Vascular Graft is uniquely designed to address the three major 
causes of graft failure: 
1.   Intimal Hyperplasia:  With its nitinol reinforced section, the GORE® Hybrid 
Vascular Graft is specifically designed to significantly improve hemodynamics 
and decrease the development of intimal hyperplasia. The NRS creates an 
endoluminal anastomosis which provides a smoother hemodynamic transition 
as compared to a standard end-to-side anastomosis, as well as a reduction in 
variation of wall shear stress as compared to a conventional end-to-side 
anastomosis. Computational fluid dynamics (CFD) studies have shown that the 
directed outflow seen with the GORE® Hybrid Vascular Graft is laminar and in 
line with the host vessel for optimal wall sheer stress (Figure 5).   
 
 
 
Figure 5. Computational fluid dynamics studies performed by Gore have shown that 
the GHVG reduces the variation in wall shear stress as compared to a standard end-
to-side anastomosis. Variation in wall shear stress has been shown to correspond to 
areas that develop intimal hyperplasia.  
 
2.   Thrombosis: The entire lumen of the GORE® Hybrid Vascular Graft is coated 
with the CBAS® Surface consisting of a stable, end-point covalently bonded 
reduced molecular weight heparin of porcine origin. The result is a proven 
thromboresistant surface with a long term, safe, clinical history.  
 
3.   Fluid Leakage and Seroma: A low permeability ePTFE film embedded in the 
wall of the GORE® Hybrid Vascular Graft reduces fluid leakage and therefore 
provides a barrier to ultrafiltration.  
 
 
2. 
Study Objective 
To characterize the GORE® Hybrid Vascular Graft as compared to non-heparin bonded synthetic 
vascular grafts in terms of the prevalence and persistence of anti-platelet factor 4/heparin 
antibodies (anti-PF4/H antibodies) up to Day 90. 

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The study objective post-Day 90 is to characterize the GORE® Hybrid Vascular Graft as compared 
to non-heparin bonded synthetic vascular grafts in terms of duplex ultrasound measurements and 
patency rates. Antibody analysis will not be conducted at Month 6 and Month 12. 
 
 
 
 
 
 
3. 
Study Design 
3.1. Study Design Schema  
Screening 
Inclusion & 
Exclusion Criteria
Randomization 
(n=200)
1:1
 100 in each arm
Test Arm: 
GORE® Hybrid 
Vascular Graft
Control Arm:
Non-Heparin 
bonded synthetic 
graft
Follow-Up:
Day 7, 14, 30, 90;
Month 6 and 12
  
 
3.2. Description of Study Design 
This is a prospective, multicenter, randomized clinical evaluation to characterize the GORE® 
Hybrid Vascular Graft by comparing non-heparin bonded synthetic vascular grafts in terms of 
the prevalence and persistence of anti-PF4/H antibodies up to Day 90. 
 
The clinical evaluation post Day 90 will compare the GORE® Hybrid Vascular Graft to non-
heparin bonded synthetic vascular grafts in terms of duplex ultrasound measurements and 
patency rates. 
 

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Subjects may continue into the extended portion of this clinical study (post Day 90) provided 
the vascular graft has not been abandoned. Subjects will return for follow-up visits at Months 
6 and 12. The control device is a non-heparin bonded synthetic vascular graft that is indicated 
for use for dialysis access. The control graft may be composed of any synthetic material 
including, but not limited to:  polyester (Dacron®), ePTFE (e.g., GORE-TEX® Vascular Grafts), 
polyurethane (e.g.,Vectra®), or composite materials (FLIXENE®). The brand of the control 
device is at the discretion of the Investigator. Biological vascular grafts including xenografts 
(e.g., Artegraft® Bovine Carotid Artery Graft), cryopreserved vein (e.g., CryoVein®), or tissue 
engineered grafts are not permitted in this study.  
 
A maximum of 25 Clinical Investigative Sites (referred to as “Sites” in the remainder of this 
document) in the United States will participate in this study. Two hundred (200) patients will 
be enrolled in this study with a limit of 30 Subjects enrolled per Site. Estimated time to 
complete enrollment is 18-24 months. Total study duration 24-36 months. 
 
Follow-up Schedule 
• 
Day 7 (±2 days) -  Collection of blood and serum samples, adverse events, and revisions 
to the circuit 
• 
Day 14 (±2 days) – Collection of blood and serum samples, adverse events, and 
revisions to the circuit 
• 
Day 30 (±7 days) – Collection of blood and serum samples, duplex ultrasound 
measurements, adverse events, and revisions to the circuit 
• 
Day 90 (± 14 days) – Collection of blood and serum samples, duplex ultrasound 
measurements, adverse events, and revisions to the circuit 
• 
Month 6 (± 14 days) - Collection of duplex ultrasound measurements, adverse events, 
and revisions to the circuit 
• 
Month 12 (± 14 days) - Collection of duplex ultrasound measurements, adverse events, 
and revisions to the circuit 
 
Patients may be enrolled into the clinical study provided all inclusion and no exclusion criteria 
are met as specified in Section 4. Subjects will be evaluated through surgical discharge and 
return for follow-up visits at Days 7, 14, 30, 90, Months 6 and 12. 
 
3.3. Study Endpoint and Additional Assessments 
 Primary Endpoint 
 
Prevalence of a positive poly-specific enzyme immunoassay (EIA) at Day                                      
7 and / or Day 14 time points (Appendix B) 
 
The primary endpoint will have been satisfied when subjects complete Day 90. 
 
3.3.2    Additional Assessments 
• 
Anti-PF4/H antibody seroconversion (Appendix B) 

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• 
Anti-PF4/H antibody seroreversion (Appendix B) 
• 
Prevalence of a positive IgG-specific EIA at Day 7 and / or Day14 time points 
(Appendix B) 
• 
Prevalence of a positive full serotonin release assay (SRA) panel (Appendix B) 
• 
Platelet count at pre-procedure, Days 7, 14, 30, and 90 time points 
 
The additional assessments above will have been satisfied when subjects complete 
Day 90. 
• 
Volume flow in circuit and venous diameter measurements determined by duplex 
ultrasound post-Index Procedure, Day 30 and 90, Months 6 and 12 
• 
Primary patency, cumulative patency, and revision rates 
 
The additional assessments above will have been satisfied when subjects complete 
Month 12.  
 
4. 
Study Population  
4.1. Description of Population 
Patients with End-Stage Renal Disease are eligible for screening for participation in the study. 
The Site may screen patients that are currently receiving hemodialysis through a central 
venous catheter (CVC), graft, or fistula and are expected to require hemodialysis through an 
upper arm prosthetic vascular graft. 
 
The study has been designed with standard eligibility criteria to address any known or 
foreseeable factors that may compromise the outcome of the clinical investigation or the 
interpretation of results. Only patients who meet all of the inclusion criteria and none of the 
exclusion criteria will be enrolled.  
4.2. Inclusion Criteria (all responses must be YES to be eligible) 
1. The patient is not a candidate for a native fistula. 
2. The patient requires the creation of an upper arm vascular access graft for hemodialysis 
secondary to a diagnosis of End-Stage Renal Disease. 
3. The patient has been on hemodialysis for ≥1 month. 
4. The patient is 18 years of age or older. 
5. The patient has a reasonable expectation of remaining on hemodialysis for 12 months.  
6. The patient or his / her legally authorized representative is willing to provide informed 
consent and comply with follow-up requirements. 
4.3. Exclusion Criteria (all responses must be NO to be eligible) 
1. 
The patient is scheduled for a different surgical procedure within 30 days post Index 
Procedure. 
2. 
The patient currently has a known or suspected systemic infection. 
3. 
The patient has a known hypercoagulable disorder or bleeding disorder.  

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4. 
The patient has had a previous instance of Heparin Induced Thrombocytopenia Type II 
(HIT type II) or has known sensitivity to heparin.  
5. 
The patient is likely to receive a live (living donor either related or unrelated to patient) 
donor kidney transplant within three months of device placement. 
6. 
The patient is enrolled in another investigational study. 
7. 
The patient has co-morbid conditions that may limit their ability to comply with study and 
follow-up requirements. 
8. 
The patient has a life expectancy of less than 12 months. 
9. 
The patient is pregnant at the time of informed consent signature. 
10. The patient has previously been enrolled in this study. 
11. The patient has a known, untreatable allergy to contrast agent. 
 
5. 
Study Procedures / Evaluations  
Demographic information such as age, gender, ethnicity, and race will be recorded as well as 
medical history including, but not limited to, diabetes, hypertension, coronary artery disease, 
peripheral arterial disease, tobacco use, and other co-morbid conditions. Height and weight will 
also be collected pre-procedure. Acknowledging the fact the weight of hemodialysis patients can 
vary greatly between treatments, the weight listed in the medical chart at the time of screening visit 
will be considered the pre-procedure weight. 
 
The Investigator will also collect a vascular access history which will include the following: date the 
Subject originally started hemodialysis, whether a fistula, graft, or CVC is currently being used for 
hemodialysis, and number of previous vascular accesses.  
 
It is expected that the Subject will follow the standard institutional patient care protocol at the 
discretion of the Investigator in regards to venous mapping, lab work, etc., prior to study procedure. 
5.1    Laboratory Specimens 
This clinical study is evaluating anti-PF4/H antibodies at five time points which is not standard 
of care. Sites are required to draw blood and collect serum samples at the specified follow-up 
intervals. Site personnel should have appropriate credentials / certifications to draw blood and 
collect serum per local regulations or send Subjects to an appropriate facility to have blood 
samples drawn.  
 
Each Site will be responsible for shipping the blood and serum samples to the central 
laboratory (Covance Central Laboratory Services, LP). Prior to shipping, the Site will pack and 
ship the samples per laboratory manual instructions. 
 
The Gore Clinical Study Manager will ensure the Site has an adequate amount of specimen 
kits and shipping materials. 
 
 
 

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5.2 Schedule of Events 
 
5.3 Informed Consent Process 
All patients must provide informed consent prior to any study-related procedures being 
performed. The case history (i.e., source documents / Subject chart) for each Subject shall 
document such informed consent was obtained. The Institutional Review Board (IRB) 
approved consent form (ICF) will be signed and personally dated by the Subject or his / her 
legally authorized representative, and the Investigator / designee who conducted the informed 
consent discussion. 
 
Subjects enrolled under the original protocol (3-DEC-2013) should not be re-consented under 
Amendment 2 (MD134442) if: 
• 
the vascular graft has been abandoned prior to the Day 90 follow-up visit 
• 
the vascular graft has been explanted 
 
 
Pre-
Operative 
Procedure  
 
Post Op 
Day: 7 
Post Op 
Day: 14 
Post Op 
Day: 30 
Post Op 
Day: 90 
Post Op 
Month: 6 
Post Op 
Month: 12 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
Demographics &  Medical 
History 
X 
 
 
 
 
 
 
 
Vascular Access History 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
Blood  Draw 
X 
 
X 
X 
X 
X 
 
 
Device Placement   
 
X 
 
 
 
 
 
 
Palpable Thrill and / or 
Bruit 
 
X 
X 
X 
X 
X 
X 
X 
Duplex Ultrasound  
 
X 
 
 
X 
X 
X 
X 
Revisions to Circuit 
 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 

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A long-term specimen storage informed consent form shall be provided to the Subject. Sites 
may choose to incorporate long-term specimen storage language in the main informed 
consent document or create a separate consent form document. This information will be given 
to the Subject describing the use of serum samples for possible future research.  
 
The Subject may participate in the clinical study but may refuse long-term storage of their 
serum sample for future research. In these instances, the Site shall notify the Sponsor the 
samples should be destroyed after the clinical study is completed. Covance will be 
responsible for destruction of the designated samples at study completion and provide 
documentation to the Sponsor. 
 
The original signed ICF(s) will be retained in the Subject records. A copy of the signed 
informed consent document will be given to the Subject for their records.   
 
5.4 Screening 
All patients who sign an informed consent form will be considered entered into the screening 
phase of the study. Subjects who sign an ICF are not assigned a subject ID until 
randomization.  
 
The Site will keep signed informed consent forms on all screen failures and keep a record of 
the reason the Subject failed screening. Site will also keep any laboratory reports for those 
samples that were sent to Covance for processing.  
 
If the Subject withdraws from the study prior to randomization, pre-procedure blood / serum 
samples need to be destroyed by either Covance or the Site. If the Site has the pre-procedure 
blood / serum samples, then the Site should destroy them per their institutional standards. If 
the pre-procedure blood / serum samples have already been shipped to Covance, then 
Covance will be notified by Site and / or Sponsor to destroy the samples.  
 
Case report forms (CRF) will not need to be completed for Subjects who are withdrawn from 
the study prior to randomization. 
 
5.5 Enrollment 
The patient is considered to be formally enrolled in the study when the randomization 
envelope, with the correct Subject ID number sequence, is opened before or during the Index 
Procedure.  
 
If the Subject has been randomized (randomization envelope opened) and is unable to 
complete the index procedure, then the Subject will be discontinued from the study. CRFs will 
still be completed to reflect screening activities, procedure, and discontinuation. Pre-
procedure blood and serum samples should be shipped to Covance for processing.  
 
5.6 Procedure 

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Routine surgical practice for implantation of the vascular graft as an upper arm arteriovenous 
access for hemodialysis per the Investigator’s standard of practice should be used. The test 
device, GORE® Hybrid Vascular Graft, is available in eight configurations listed in Section 
1.2.5. The GHVG will be provided at standard cost. 
5.6.1 
Test Device Training Requirements 
If the study Site has not used the GHVG, the study Site must complete device training 
prior to Subject enrollment.  
 
 
 
5.6.2 Implantation Technique 
The Investigator is expected to follow the Instructions for Use (IFU) for the test device 
or the control device, as determined by randomization. 
 
5.6.3 Additional Implant Considerations 
When implanting the GORE® Hybrid Vascular Graft or control device, the following 
considerations are recommended: 
• 
The correct graft length for each procedure should be carefully determined 
according to the Investigator’s standard practice.  
• 
Any unused portions of the vascular graft must be destroyed according to 
institutional standards.  
• 
Create a tight subcutaneous tissue tunnel. 
• 
Avoid the use of traumatic clamps on vessels or vascular graft. 
• 
If possible, avoid the use of systemic heparin during the index procedure. 
 
The study procedure is considered to be a success once a thrill and / or bruit is noted 
through the implanted vascular access graft. The total procedural time, defined as the 
time from the first incision to the completion of closing of the last incision, will be 
recorded on the Procedure CRF. 
 
5.6.4 Anticoagulation/Antiplatelet Therapy and Immunosuppressant Medications 
Effective anticoagulation therapy should be maintained at a dosage deemed 
appropriate by the Site Investigator. The presence of heparin on the GORE® Hybrid 
Vascular Graft is not intended to serve as an alternate to the Investigator’s chosen 
intra-operative or post-operative anticoagulation regimens.  
 
Antiplatelet and anticoagulation therapies such as clopidogrel, aspirin, heparin, and 
warfarin, etc. are permitted under the study protocol and should be administered 
based on the Site Investigator’s standard practice. These types of medications need to 
be captured on the Medical History and Follow-Up CRFs.  
 

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Patients currently taking maintenance immunosuppressant medications such as 
rapamycin, mycophenolate or mycophenolic acid, prednisone, cyclosporine, 
tacrolimus, or cyclophosphamide may be enrolled in the study.  These types of 
medications will be captured on the Medical History CRF. 
 
5.6.5 Duplex Ultrasound Requirements 
Duplex ultrasound examinations should be performed per institutional standards. 
Ultrasound should be performed by a trained technician or physician following the 
Index Procedure (Day 0) and at Days 30 and 90 and Months 6 and 12. Preferably the 
same technician and / or physician would perform the ultrasound measurements at all 
time points to ensure consistency. Ultrasounds conducted by different technicians and 
/ or physicians during the course of the study on a specific subject will not be 
considered protocol deviations. In addition, Gore will provide ultrasound worksheets 
as an aide for source data collection.  
 
An observed reduction of flow or reduction in diameter does not mandate treatment. 
Treatment would be entirely at the discretion of the Investigator.    
 
While there are no requirements in this study to send copies of ultrasounds to the 
Sponsor or an external ultrasound core laboratory, appropriate images from all study-
related procedures should be labeled and archived for potential future review.  
 
5.7 Follow-Up 
There are six (6) scheduled follow-up visits in this study. Follow-up visits are at following 
intervals: 
• 
Day 7 (±2 days) 
• 
Day 14 (±2 days) 
• 
Day 30 (±7 days) 
• 
Day 90 (±14 days) 
• 
Month 6 (±14 days) 
• 
Month 12 (±14 days) 
 
Follow-up visits will be scheduled at appointed times after the date of treatment (Index 
Procedure). The blood and serum samples are required to be collected prior to the Subject 
going to their hemodialysis treatment session or on a non-hemodialysis day. The Sponsor 
recognizes that Subjects may not be able to return for follow-up visits on the exact day 
required, therefore a plus / minus window has been allotted for each visit.  
 
Due to the sensitivity of blood sample collection on specified follow-up visits, unscheduled 
visit data will not be collected. If a Subject is unable to attend a follow-up visit within the 
specified window, then that follow-up visit will be considered missed and recorded as such on 
the Follow-Up CRF. The Subject is expected to return to the next follow-up visit. Missed 
follow-up visits will be considered protocol deviations. 

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In the event of multiple missed visits, the Site should collect blood and serum samples from 
the Subject if the Subject returns for any future scheduled follow-up visits, even if the samples 
are not collected consecutively. For example, the Subject may have missed the Day 7 and 
Day 14 follow-up visit but data and blood samples should be collected if the Subject returns 
on Day 30 or Day 90. 
 
Study analyses can be conducted if the vascular graft is abandoned and not explanted, 
therefore Subjects should remain in the study through Day 90. 
 
Refer to the Schedule of Events (Section 5.2) for follow-up visit requirements.  
 
 

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5.8 Revisions to the Vascular Access Circuit 
Subjects may need revisions to the vascular access circuit (either test / control arm). An 
appropriate clinical indication (e.g., stenosis, thrombosis, low blood flow, elevated venous 
pressures, etc.) must be present to trigger a revision to the vascular access circuit. 
 
It is recommended that, when possible, Subjects return to the Investigator for revisions; 
however, it is understood Subjects may be unable to return to the Investigator for revision 
procedures. If a revision is not performed by the Investigator, attempts should be made to 
collect revision data from the facility that performed the procedure. This information can be 
communicated to the Site via fax, electronic communication, and / or documented phone 
communication, etc. 
5.9 Subject Withdrawal from the Study 
The Subject may voluntarily withdraw from the study at any time and should notify the 
Investigator in this event. The Investigator may also withdraw the Subject from the clinical 
study at any time based on his / her medical judgment. A Study Completion / Discontinuation 
CRF should be completed for these Subjects.  
5.10 Subject Lost to Follow-Up 
The Site will record their documented attempts to schedule follow-up visits with the Subject. 
 
The Subject will be considered lost to follow-up at the end of the study if the Subject does not 
complete the Month 12 follow up visit. If the Subject is considered lost to follow-up, the last 
follow-up visit date will be considered their date of discontinuation. 
5.11 Subject Study Completion and Discontinuation 
A Study Completion / Discontinuation CRF will be completed for each enrolled Subject at the 
conclusion of his / her participation in the study. The reason for completion or discontinuation 
for each Subject should be documented (e.g., Subject completed the study per protocol 
requirements, expired, vascular graft explanted, or lost to follow-up).  
 
If the Subject expired, the date of death will be recorded. The Investigator will assess whether 
the death was related to the vascular device, if applicable.  
5.12  Device Deficiencies    
The vascular grafts used in the test arm (GORE® Hybrid Vascular Graft) and control arm are 
not investigational. Any GORE® Hybrid Vascular Graft deficiencies will be reported through 
normal product surveillance procedures. 
5.13  Explant Procedures 
The GORE® Hybrid Vascular Graft may be explanted during a surgical procedure or as part of 
an autopsy. Sites are requested to return explanted device(s) to the Sponsor for gross and 
histological evaluation. Prior to planned or potential device retrieval, contact the Gore 
Associate managing the study to communicate that a specimen is being retrieved from a 
study Subject. A specimen shipping kit will be immediately sent to the Site. The specimen kit 
provides specific packaging and handling instructions for the specimen and contains a 
shipping container. 

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6. 
Clinical Study Administration  
6.1    Training 
Sites selected for this clinical study must be approved to use the GORE® Hybrid Vascular 
Graft.  
6.2 Monitoring 
Site monitoring for this study will be provided by Theorem Clinical Research. Monitoring 
oversight will be provided by the Sponsor.  
 
The Site monitors are qualified by training and experience to oversee the progress of the 
study at the Site and will ensure that the Investigators and their staff understand and adhere 
to both the applicable regulatory requirements and the study protocol. In addition, they may 
assist in resolution of any problems that may arise during the study.  
 
Site Initiation  
Site initiation will be performed to assure that each Investigator and his / her staff understands 
the protocol, applicable regulations, human subject protection requirements, and the 
Investigator’s obligations. This visit will ensure that required training documentation with the 
appropriate IRB approvals are in place prior to Subject enrollment.   
 
Periodic Site Monitoring  
Periodic Site monitoring will occur as necessary to ensure continuing adequacy of facilities 
and adherence to the clinical study protocol, GCPs, and applicable regulations and laws that 
pertain to the conduct of the clinical study. These activities will also include the review of 
CRFs, source documentation, resolution of any missing or inconsistent data, timely 
submission of accurate records to the Sponsor, and the maintenance of proper records. A 
report will be written following each Site visit and a follow-up letter will be provided to the Site 
with a summary of findings. Each Site will also be visited at close-out to ensure all 
documentation is complete.  
6.3 Device Accountability and Storage  
The GORE® Hybrid Vascular Graft is a commercially available device and does not require 
device accountability tracking. As part of procedure data collection, the Investigator will record 
device lot numbers and catalog numbers on the CRF.  
6.4    Central Laboratory 
Central laboratory services for this study will be provided by Covance Central Laboratory 
Services, LP. Covance will provide Sites with kits for collecting and shipping blood and serum 
samples through Day 90. Covance will also perform a hematology panel with differential and 
provide results to the Sites.   
 

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Additionally, Covance will collect and store serum cryo vials prior to shipping to the core 
laboratory. Covance will ship one set (primary sample) to the core laboratory for analysis. The 
second set (backup sample) will be stored at Covance unless it is needed by the core 
laboratory for further analysis.  
 
Long term storage of the backup serum samples will be provided by Covance for a minimum 
of three years. Additional analyses that are not associated with this clinical study may be 
performed on those serum samples for which consent by the Subject has been given. 
6.5 Core Laboratory 
Core laboratory services for this study will be provided by McMaster University Platelet 
Immunology Laboratory through Day 90. The core laboratory will analyze serum for anti-
platelet factor 4/heparin antibodies by EIA-GAM, EIA-IgG, and SRA methods. 
6.6 
Protocol Deviations 
A protocol deviation is defined as any change, divergence, or departure from the study design 
or procedures of a research protocol that is under the Investigator’s control. The Principal 
Investigator is responsible for promptly reporting protocol deviations to his or her IRB per IRB 
policy and the Sponsor. The Sponsor will determine the effect of the protocol deviation on the 
scientific soundness of the clinical study and Subject safety and determine if additional 
reports or actions are required. Additional action may include Site retraining and / or Site 
termination from participation in the trial.   
 
The Investigator will not implement any changes to the protocol without first obtaining written 
agreement from the Sponsor and documented approval from the IRB except in the event of 
an immediate hazard(s) to a Subject. The Investigator will report the deviation in accordance 
with the applicable regulations.     
6.7    Clinical Data Review  
Clinical data will be reviewed at periodic intervals to ensure consistent and accurate reporting. 
Cases to be reviewed will include, but will not be limited to, adverse events, protocol 
deviations, and study procedures. Data will be reviewed by the Clinical Study Team and will 
include the Sponsor’s Product Specialist and at least one medical director.  
6.8    Protocol Amendments 
The Investigator will obtain IRB approval on all amendments in a timely manner. The Sponsor 
will ensure proper training of Investigator and Site staff on all protocol amendments. 
6.9    Sponsor Representatives 
Sponsor field representatives / clinical staff may be present during study procedures to 
provide technical assistance to the Investigator in the use of the device. The activities of these 
Sponsor representatives will be supervised by the Investigator to avoid bias, ensure data 
quality, and protect patient rights. 
6.10  Access to Source Data / Documents 
Source data are defined as all information necessary for the reconstruction and evaluation of 
the clinical investigation.  

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The Investigator will keep all study records and source data for inspection by the Sponsor, 
Sponsor’s monitors, IRB, and regulatory authorities. 
6.11  Study Records Retention  
The Investigator will maintain complete, accurate and current study records as required by 
applicable regulatory requirements. Clinical study records will not be disposed of, nor custody 
of the records transferred, without prior written Sponsor approval.   
 
Investigator records will include, but not be limited to:  
• 
All correspondence with another investigator, an IRB, the Sponsor, a monitor, a 
regulatory body, including required reports. 
• 
Records of each Subject’s case history and exposure to the device. The case history 
for each Subject shall document that informed consent was obtained prior to 
participation in the study. Case histories include the following: 
o Case report forms 
o Signed and dated consent forms and documents evidencing informed consent 
o Medical records (e.g., progress notes of the physician, the Subject’s hospital 
chart(s), and the nurses’ notes 
o For any use of a device without informed consent, a written concurrence of a 
licensed physician and a brief description of the circumstances justifying the 
failure to obtain the informed consent.  
o All relevant observations, including records and date and condition of each 
Subject upon entering, and information about relevant previous medical history 
and the results of all diagnostic tests. 
• 
The protocol, any amendments, and documentation of any deviations from the 
protocol, including the dates and the reasons for such deviations. 
• 
A certification stating the IRB is in compliance with FDA regulations. 
• 
Any other records as required by the IRB and the Sponsor. 
The Investigator will prepare and submit the following reports: 
• 
Withdrawal of IRB approval: The Investigator will report any withdrawal of approval 
within five working days after the Investigator has been notified of the withdrawal. 
• 
Progress reports: Progress reports documenting the procedure, AEs, and follow-up 
data concerning individual Subjects will be submitted to the Sponsor on standardized 
CRFs. The Investigator may also be required to submit progress reports and final 
reports to the IRB and to the Sponsor summarizing the Investigator’s experience 
during the study.  
• 
Protocol Deviations shall be reported as described in Section 6.6. 
• 
Other: Any other reports as reasonably requested by the Sponsor or required by 
applicable local regulations. 
 

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6.12  Clinical Trial Registration 
If applicable, the Sponsor will register the study and post results as required by applicable 
U.S. laws and regulations.  
 
7. 
Data Collection and Submission 
The Clinical Data Management System (CDMS) for this study will be provided by Medidata 
Solutions, Inc.  
7.1    Data Collection Methods  
This study will report clinical data using the software utilized by Medidata Solutions, Inc.  
The CDMS will be the database of record for the protocol and subject to regulatory 
inspections. All users will be trained to use the CDMS and will comply with study-specific 
guidelines / instructions as well as applicable regulatory requirements. 
 
Subject data will be collected using protocol-specific CRFs. Site staff and core laboratory will 
enter data directly into the CRF for transmission to the Sponsor. The Sites will be notified of 
any significant amendments to the CRFs. 
7.2 Data Clarification and Correction  
Once entered, data will be evaluated to ensure it is complete, consistent, and logically sound. 
If changes to the data in the CDMS are required, all changes, reasons for changes, and 
persons making the changes will be captured in the CDMS' audit trail. 
 
8. 
Risk Assessment  
8.1 Potential Risks  
The risks associated with the GORE® Hybrid Vascular Graft for use in hemodialysis are 
expected to be similar to the risks associated with the use of non-heparin bonded synthetic 
vascular grafts. 
 
Risks associated with these devices, including the GORE® Hybrid Vascular Graft, or the 
surgical procedure include but are not limited to: 
Access-related Limb Ischemia (Steal  
Syndrome) 
Infection: Systemic 
Anastomotic Disruption  
Infection: Wound 
Arm edema 
Inflammation 
Bacteremia 
Myocardial Infarction (MI) 
Bleeding 
Perforation or Rupture 
Congestive Heart Failure  
Perigraft Hematoma 
Device deployment failure  
Perigraft Seroma  
Device fracture  
Pseudoaneurysm  
Device malposition 
Thromboembolism  

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In comparison to patients receiving standard vascular grafts for hemodialysis, the only 
additional potential risks to Subjects enrolled in this clinical study are the bioactive heparin on 
the luminal surface and the insertion of the NRS of the GHVG. All other aspects of the 
vascular graft are equivalent.  
8.2 Minimization of Risks 
Potential risks associated with the use of the GORE® Hybrid Vascular Graft may be minimized 
by the following activities: 
• 
Testing: The Sponsor has performed qualification testing on the device and device 
components and appropriate quality control measures have been implemented into 
production. Investigators will be selected who are knowledgeable and experienced in 
vascular graft implantation procedures.  
• 
Training: Comprehensive Site Investigator and staff training will be conducted to share 
information regarding design and proper use of the GORE® Hybrid Vascular Graft.  
• 
Training: The Site Investigator, Sub-Investigators, Study Coordinator(s) or designee at 
each Site will be trained to the protocol and Subject follow-up requirements.  
• 
Screening: Protocol inclusion / exclusion criteria and follow-up schedule are designed 
to select appropriate Subjects and identify potential complications early. Subjects will 
be assessed post-procedure and subsequently on a regular basis at their follow-up 
visits.  
• 
Monitoring: Data completed by the clinical Sites will be monitored to evaluate protocol 
compliance, accuracy, and Subject safety.  
• 
Sharing: Data during the clinical study will be shared with the Site Investigators to aid 
understanding of the device and potential complications associated with its use. 
 
9. 
Adverse Events 
Adverse events (AEs) are defined as any untoward medical occurrences in a Subject whether 
device-related or not. 
9.1    Anticipated Adverse Events  
Anticipated adverse events are complications that are known to be associated with 
hemodialysis patients undergoing the creation of vascular graft access. See Section 8, Risk 
Assessment.  
 
The Sponsor considers occurrences of thrombosis and stenosis to be efficacy outcomes and 
not adverse events. These occurrences should be reported on a Revision to Circuit CRF. 
Should there be clinical sequelae associated with thrombosis and stenosis, these sequelae 
are considered adverse events and should be reported. 
Heparin Induced Thrombocytopenia  
(HIT) 
Ultrafiltration 
Infection Graft (early) 
Venous Hypertension  
Infection Graft (late)  
Other 

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9.2   Adverse Event Relationship 
Each reported AE will be assessed by the Investigator for its primary suspected relationship 
to the device, procedure, or disease.  
 
Study Device-related (Hybrid or Control Graft) 
The functioning or characteristics of the device caused or contributed to the AE.  
 
Study Procedure-related (Index Procedure) 
The index procedure (and not the device) caused or significantly contributed to the AE.  
 
Disease-related (ESRD only) 
The AE was a result of the underlying disease progression, for which the study procedure is 
being performed, and not the device or procedure.  
 
Not-related  
An AE which cannot be attributed to the device, procedure, or disease.  
 
Unknown relationship  
The relationship of the AE to the device, procedure, or disease cannot be determined.  
 
9.3    Adverse Event Classification    
The Investigator at each Investigative Site is ultimately responsible for reporting AEs to the 
Sponsor. The Investigator is required to complete the appropriate CRFs to report the 
occurrence of AEs.  
 
Each AE will be assessed by the Investigator to determine if it is a serious adverse event 
(SAE). 
  
A Serious Adverse Event (ISO 14155 definition) is an Adverse Event that 
• 
led to death 
• 
led to serious deterioration in the health of the Subject that either resulted in 
o a life threatening illness or injury, or 
o a permanent impairment of a body structure or body function, or  
o inpatient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function 
• 
led to fetal distress, fetal death, or a congenital abnormality or birth defect.  
 
Emergency room visits and 23-hours observations are not considered hospitalizations. 
 

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9.4    Adverse Event Reporting and Coding 
AEs will be reported on the appropriate case report form and documented in the Subject’s 
permanent medical record.  
 
The following information on each reported adverse event will be collected:  
• 
Adverse Event Term 
• 
Adverse Event Onset Date 
• 
Relationship 
• 
Severity  
• 
Treatment 
• 
Outcome 
• 
Resolution Date 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
 
AE submission guidelines: 
• 
AE reporting begins once the patient is enrolled in the study. All AEs should be 
reported from enrollment (study procedure) through study completion / 
discontinuation. 
• 
Provide a diagnosis if possible. If unable to provide a diagnosis, report the symptoms 
as separate events. AEs should be reported using the full name without abbreviations 
or narratives. 
• 
AEs with an outcome status of “Ongoing” should be assessed at each follow-up 
evaluation to determine if the event has resolved. AEs ongoing at study completion / 
discontinuation should be completed as “Ongoing” on the AE CRF.  
9.5    Subject Death 
When a Subject in the study expires, the primary cause of death will be identified as the AE. If 
any AEs have been reported as “Ongoing” up through the time of a Subject’s death, these 
events would then become resolved with the date of death. 
 
An effort by the Site should be made to collect additional information regarding the Subject’s 
death. Documents include, but are not limited to: autopsy reports, death certificates, lab 
reports, and other applicable medical records. 
 
A Study Completion / Discontinuation CRF will be completed for each Subject who expired 
during the course of the study. 
 
 
 
 

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10. Statistical Analysis    
10.1. Study Hypothesis 
The study is designed to test the null hypothesis that the prevalence of anti-PF4/H antibodies 
on the GORE® Hybrid Vascular Graft is not statistically higher as compared to non-heparin 
bonded synthetic vascular grafts by more than a pre-specified margin of 15% at Day 7 and / 
or Day 14.  
 
The hypothesis is specified as follows: 
 
H0: PH-PN >= 0.15 versus H1: PH-PN<0.15,  
 
where PH=Prevalence of anti-PF4/H antibodies on GORE® Hybrid Vascular Graft and 
PN=Prevalence of anti-PF4/H antibodies on non-heparin grafts at Day 7 and / or Day14.  
10.2. Sample Size Assumptions 
The sample size approach used for the study is for testing the non-inferiority hypothesis. An 
absolute margin of up to 15% excess is considered clinically acceptable. This implies the 
GORE® Hybrid Vascular Graft would be deemed to have shown non-inferior to the control in 
terms of the anti-PF4/H antibodies positive prevalence, if the upper bound of the 95% 
confidence interval of the difference between proportions (PH-PN) stays below 0.15. 
 
Our assumption is the prevalence of antibodies in the control arm would be less than 15%.  
10.3. Sample Size Determination 
The sample size is calculated using PASS 12 software based on test for the difference of 
proportions. With the one-sided level of significance of 2.5%, prevalence of less than 15% on 
non-heparin graft and an absolute non-inferiority margin of 15%, a total of 100 subjects per 
arm are required to rule out inferiority of GORE® Hybrid Vascular Graft with at least 80% 
power.  
10.4. Randomization Scheme  
The randomization will be organized using randomization envelopes. Subjects will be 
stratified by Site and will be considered randomized as soon as the randomization envelope is 
opened after determining the eligibility for inclusion in the study. Any irregularity in the 
randomization process will be documented and reported to the Sponsor.  
10.5. Blinding Scheme  
The Subjects, as well as treating physicians, will be aware of the type of implanted graft. 
However, the core laboratory responsible for analyzing the blood samples will be blinded to 
the actual type of graft.  
10.6. Data Analysis 
 Timing of Analyses 
The analysis to formally test the primary hypothesis will be performed when Day 90 
follow-up information would have been available for all subjects. All subjects with 

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available blood results at Day 7 and / or Day 14 will be included in the analysis of the 
primary outcome. The analysis for some of the additional assessments including 
patency and revision rates will performed at the end of the study. 
 Analysis Populations 
10.6.2.1. Intent-To-Treat (ITT) 
The intent-to-treat population is defined as all enrolled subjects analyzed 
by the assigned treatment arm at the time of randomization. 
10.6.2.2. As Treated 
The “as treated” population is defined as all subjects analyzed by type of 
the actual implanted device.  
 
Unlike a superiority trial in which ITT analysis is considered more 
conservative, in a non-inferiority trial the non-adherence to the assigned 
treatment can bias the result towards ‘null’ and favor the alternate 
hypothesis. For this reason, the primary analysis will be conducted on “As 
treated” population along with ITT as a sensitivity analysis.  
 Pooling of Data 
Data will be pooled from all Sites participating in the trial. To help ensure homogeneity 
of data across Sites, the protocol will be administered and monitored in a uniform 
manner at all Sites.  
To assure the appropriateness of pooling data across Sites, a logistic model for the 
primary endpoint will be developed that includes Site as a covariate beside a variable 
for treatment and an interaction term between treatment and Site. If the interaction 
term is significant at 0.10 level, then the stratified analysis of the primary endpoint will 
be presented separately for each center.  
 Statistical Analysis of Primary Endpoint(s) 
The primary analysis will be performed as difference of proportions (PH-PN) in the two 
arms. The 95% Confidence Interval of difference will be constructed using standard 
normal distribution. If the upper bound of the confidence interval is below 0.15 that 
would result in rejection of the null hypothesis and conclusion the GORE® Hybrid 
Vascular Graft is not inferior to the non-heparin coated synthetic graft by more than 
15%. All patients with the missing test results at both Day 7 and Day 14 time points 
will be excluded from the analysis.  
 Statistical Analysis of Additional Assessments 
There is no specific hypothesis for the additional assessments. The results will be 
presented as frequencies and percentages for the categorical and will be presented as 
means and standard deviations for the continuous or quantitative variables for all 
additional assessments of interest.  
 

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11. Ethical and Regulatory Considerations 
11.1. Statement of Compliance 
The study will be conducted in compliance with this protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP), and applicable regulatory requirements.  
The following are applicable to this study:   
 
21 CFR Part 11 
Electronic Records; Electronic 
Signatures 
21 CFR Part 50 
Protection of Human Subjects 
21 CFR Part 56 
Institutional Review Boards 
ICH-GCP E6 
International Conference on 
Harmonisation Regulations 
Guideline For Good Clinical 
Practice 
 
11.2.  Compliance Responsibilities 
The Sponsor will conduct the clinical study in accordance with all applicable regulations and 
laws. The Sponsor will be responsible for documenting that Investigators have the necessary 
skills, training, and information to properly conduct the clinical study. The Sponsor will ensure 
proper monitoring of the clinical study and ensure the Site has obtained IRB approval prior to 
enrollment. The Sponsor will provide information to the Investigators and the reviewing IRB 
concerning the progress of and any new material information about the clinical study.  
 
The Investigator will conduct the clinical study in accordance with all applicable regulations 
and laws, any relevant agreements, the study protocol, and all approval conditions of the 
reviewing IRB. The Investigator will ensure IRB approval is obtained prior to enrollment, 
maintained throughout the course of the study, and all IRB reporting requirements are met. 
The Investigator is responsible for protecting the rights, safety, and welfare of Subjects under 
the Investigator’s care and for the control of devices under investigation. The Investigator is 
also responsible for ensuring informed consent is properly obtained.  
11.3.  Informed Consent  
The Investigator shall ensure all potential Subjects for this study are provided with a consent 
form describing this study and sufficient information to make an informed decision about their 
participation.  

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The formal consent of a Subject, using the IRB-approved consent form, must be obtained by 
the Investigator before that Subject undergoes any study-related procedure. The consent 
form will be signed and personally dated by the Subject or legally authorized representative, 
and the person who conducted the informed consent discussion. The original signed informed 
consent form will be retained in the Subject records. A copy of the signed informed consent 
document will be given to the Subject for his or her records. Any significant, new information 
which emerges while the study is in progress that may influence a Subject’s willingness to 
continue to take part in the study will be provided to the Subject. 
 
The Investigator shall ensure documentation of the acquisition of informed consent is 
recorded in each Subject’s records in accordance with applicable regulations. 
11.4. Independent Ethical Review  
The Investigator shall not enroll any Subjects prior to obtaining approval for the study from a 
properly constituted independent IRB. 
  
The Investigator will submit the protocol, informed consent forms, other information to be 
provided to Subjects such as survey instruments or questionnaires, and any proposed 
advertising / recruitment materials to the IRB for written approval. 
11.5. Conflict of Interest 
All Investigators will follow their Institution’s conflict of interest policies.  
11.6. Confidentiality 
All Subject records will be kept confidential to the extent provided by applicable laws and 
regulations. The study monitors and other authorized representatives of the Sponsor may 
inspect all documents and records required to be maintained by the Investigator, including but 
not limited to medical records.  
 
Such records may also be reviewed by the Site’s IRB and other regulatory bodies.  
 
The Investigator will inform the Subjects their records will be reviewed.  
 
 

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12. References 
1. The United States Renal Data System. USRDS 2012 Annual Data Report: atlas of chronic 
kidney disease and endstage renal disease in the United States, National Institutes of Health, 
National Institute of Diabetes and Digestive and Kidney Diseases. 
http://www.usrds.org/atlas.aspx. Accessed June 13, 2013. 
2. Fistula First Data. Arteriovenous Fistula First, July 2003- April 2012 AVF, AVG, and CVC Data. 
Accessed on June 13, 2013 at http:/ / www.fistulafirst.org/ AboutFistulaFirst/ FFBIData.aspx 
3. Schild AF, Perez E, Gillaspie E, Seaver C, Livingstone J, Thibonnier A. Arteriovenous fistulae 
vs. arteriovenous grafts: a retrospective review of 1,700 consecutive vascular access cases. J 
Vasc Access. 2008 Oct-Dec;9(4):231-5.  
4. Maya I, Allon M. Vascular access: core curriculum. Am J Kidney Dis. 2008;51(4):702-708. 
5. Clinical Evaluation of the GORE® Hybrid Vascular Graft (Gore internal document) 
6. Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-
associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular 
PF4-heparin complex as the major antigen. Thromb Haemost 71: 247-51, 1994. 
7. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, 
Greinacher A, eds. Heparin-Induced Thrombocytopenia, 5th ed. Boca Raton, FL: CRC Press; 
pp. 24-76, 2013a. 
8. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG. Heparin-
induced thrombocytopenia in patients treated with low-molecular-weight heparin or 
unfractionated heparin. N Engl J Med 332: 1330-1335, 1995. 
9. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J 
Med 2001; 344: 1286-1292. 
10. Fischer, Karl-Georg. Hemodialysis in heparin-induced thrombocytopenia. In: Warkentin TE, 
Greinacher A, eds. Heparin-Induced Thrombocytopenia, 5th edn. Boca Raton, FL: CRC Press; 
pp. 520-549, 2013a.