everlinQ Endovascular Access Systems Enhancements (EASE-2) Study
Phase: NA
Conditions: Chronic Kidney Diseases
Sponsor: C. R. Bard

 
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everlinQ Endovascular Access  
Systems Enhancements (EASE-2) Study  
 
 
 
Study Protocol: CD-0038 
 
Version 01 
 
Date: August 23, 2017 
 
 
Sponsor: 
 
TVA Medical, Inc. 
7000 Bee Cave Rd., Suite 250 
Austin, TX, 78746 
USA 
Phone: (512) 582-2460 
 
NCT Number: 03708562 
NCT Number added post-approval per CT.gov requirement 
 
 
 
 
 
 
This protocol contains confidential information and is limited in its distribution to Investigational Staff 
intending to conduct the study and Ethics Committee reviewing this study. 

 
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ABBREVIATIONS 
ACT 
Activated clotting time 
ADE 
Adverse device effect 
AE 
Adverse event 
AVF 
Arteriovenous fistula 
AVG 
Arteriovenous graft 
CKD 
Chronic kidney disease 
CMS 
Center for Medicare and Medicaid Services 
CVC 
Central venous catheter 
DBI 
Digital brachial index 
DUS 
Duplex ultrasound 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
endoAVF 
Endovascular arteriovenous fistula 
EQ VAS 
EQ visual analogue scale 
ESRD 
End stage renal disease 
FFBI 
Fistula First Breakthrough Initiative 
HRQOL 
Health Related Quality of Life 
HTN 
Hypertension 
ICF 
Informed consent form 
IFU 
Instructions for Use 
KDOQI 
National Kidney Foundation Kidney Disease Outcomes Quality Initiative 
RF 
Radiofrequency 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SVS 
Society for Vascular Surgery 
USADE 
Unanticipated serious device effect 
USRDS 
United States Renal Data System 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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DEFINITIONS 
Access site - Device 
A site of catheters insertion during index procedure. 
Access site - Cannulation 
A vascular site, as a way to reach the blood for hemodialysis.  
Angiogram 
An X-ray procedure that uses contrast agent and a camera (fluoroscopy) to 
assess and capture flows or blockages in arteries and veins.  
Bleeding Diathesis 
A disorder that involves the tendency to hemorrhage, or bleed.   
Chronic Kidney Disease 
A term that includes stages such as mild, moderate and severe loss of 
kidney function based on the patient’s level of glomerular filtration rate 
(GFR).  
endoAVF abandonment – 
terminal use of endoAVF 
Abandonment of the access is defined as an access that can no longer be 
used for two needle prescribed dialysis as it may be unable to provide 
adequate flows and⁄or is deemed unsafe for the patient, and the associated 
problem cannot be corrected by any intervention, including medical, 
surgical, or radiological interventions or rest. 
 
Note: switch to peritoneal dialysis, or a kidney transplant is not considered 
an abandonment event. Additionally, if an endoAVF was reported to be 
matured; however, veins were too deep for cannulation, or if the endoAVF 
was not cannulated due to patient preference, these incidences are not 
considered abandonment. 
endoAVF related 
intervention rate 
The re-intervention rate for endoAVF (defined as any intervention required 
to maintain or re-establish patency) will be calculated at each available 
follow-up visit post index procedure. Diagnostic fistulagram and 2nd stage 
procedures will not be considered an intervention for the purpose of this 
study.  
End Stage Renal Disease 
Last stage of Chronic Kidney Disease. When the kidneys stop working 
well enough to meet the needs of daily life.    
Hypercoagulable State 
Blood clotting disorder. 
Maturation of endoAVF 
Defined as endoAVF that is free of stenosis or thrombosis, with brachial 
artery flow of at least 500 ml/min and at least 4 mm vein diameter (as 
measured by duplex ultrasound) OR patient was dialyzed using 2 needles.   
Maturation time 
The number of days between the date of AVF creation and the date of 
endoAVF maturation (based on primary efficacy endpoint definition of 
maturation). 
Dialysis subject 
Subject who was receiving hemodialysis at the time of enrollment. 
Operator 
Person who conducts index procedure. 
Pre-dialysis subject 
Subject who was not receiving dialysis at the time of enrollment. 
Primary patency 
The time from endoAVF creation until any intervention designed to 
maintain or reestablish patency, or endoAVF abandonment. 
Procedure duration 
The sum of the venography time, endoAVF creation time, coil and closure 
time. 
Protocol deviation 
Deviation from the approved Study Protocol. 
Stenosis  
For the purposes of the study, stenosis is considered flow limiting 
complications that led to fistula closure/abandonment.   
Thrombosis 
For the purposes of the study, thrombosis is considered flow limiting blood 
clot that led to fistula closure/abandonment.   

 
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DEFINITIONS 
Target fistula site 
The anatomical location in the arm where the endoAVF was attempted. 
Venogram 
An X-ray procedure that uses contrast agent and a camera (fluoroscopy) to 
assess and capture flows or blockages in veins.  
 
 

 
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Table of Contents 
 
 
1. 
INTRODUCTION ................................................................................................................................................................. 6 
1.1 
Purpose ................................................................................................................................................................................... 7 
1.2 
Device Description .................................................................................................................................................................. 7 
2 
RISKS/BENEFITS ................................................................................................................................................................. 7 
2.2 
Risks ........................................................................................................................................................................................ 8 
2.3 
Minimization of Risk ............................................................................................................................................................. 9 
3 
STUDY METHODOLOGY .................................................................................................................................................. 9 
3.2 
Study Objective ...................................................................................................................................................................... 9 
3.3 
Study Endpoints ..................................................................................................................................................................... 9 
3.4 
Investigational Site Selection ............................................................................................................................................... 10 
3.5 
Study Population .................................................................................................................................................................. 10 
3.5.1 
Inclusion Criteria ................................................................................................................................................................. 10 
3.5.2 
Exclusion Criteria ................................................................................................................................................................ 11 
4 
STUDY SCREENING AND FOLLOW-UP PROCEDURES ........................................................................................... 11 
Table 1: Schedule of Study Procedures .............................................................................................................................................. 12 
4.1 
Informed Consent ................................................................................................................................................................. 12 
4.2 
Screening Evaluation ........................................................................................................................................................... 12 
4.2.1 
Duplex Ultrasound ............................................................................................................................................................... 12 
4.2.2 
Angiography/Venography ................................................................................................................................................... 13 
4.3 
Index Procedure ................................................................................................................................................................... 13 
4.4 
Follow-Up Visits ................................................................................................................................................................... 13 
4.4.1 
Unscheduled Visit ................................................................................................................................................................. 13 
4.5 
Patient Disposition ............................................................................................................................................................... 13 
4.6 
Adverse Events ..................................................................................................................................................................... 14 
4.6.1 
Relationship to Device or Procedure .................................................................................................................................. 15 
5 
DATA ANALYSIS ............................................................................................................................................................... 15 
6 
REGULATORY OBLIGATIONS ...................................................................................................................................... 15 
6.1 
Responsibilities of the EC/EC Approval ............................................................................................................................. 15 
6.2 
Sponsor Obligations ............................................................................................................................................................. 16 
6.2.1 
Investigator’s Documents .................................................................................................................................................... 16 
6.3 
Investigator Obligations ....................................................................................................................................................... 16 
6.4 
Records and Reports ............................................................................................................................................................ 16 
6.4.1 
Investigator’s Reports .......................................................................................................................................................... 17 
6.4.2 
Sponsor’s Reports ................................................................................................................................................................ 18 
6.5 
Site Training ......................................................................................................................................................................... 18 
6.6 
Protocol Deviations .............................................................................................................................................................. 18 
6.7 
Site Non-Compliance ........................................................................................................................................................... 18 
6.8 
Device Accountability .......................................................................................................................................................... 18 
6.9 
Case Report Form Completion ........................................................................................................................................... 19 
6.10 
Monitoring Procedures ........................................................................................................................................................ 19 
REFERENCES ..................................................................................................................................................................................... 20 
 
 

 
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1. INTRODUCTION 
 
End Stage Renal Disease (ESRD) currently affects over 2 million people worldwide.1 It is projected that 
the worldwide incidence of ESRD will increase dramatically over the next 10 years, due to the 
increasing incidence of an aging population, diabetes, hypertension, and obesity.2 Currently, Renal 
Replacement Therapy for patients with ESRD consists of either hemodialysis or peritoneal dialysis.  
The rates of implementation of either hemodialysis or peritoneal dialysis vary widely per country.  
According to the United States Renal Data System (USRDS), in 2006 hemodialysis accounted for 
around 60% of Renal Replacement Therapy patients in the US, while peritoneal dialysis accounted for 
6-7% of patients in the US and the remainder is kidney transplant patients.2 
 
Vascular access is a critical component in the care of patients undergoing hemodialysis. The three 
methods of long term vascular access available to a patient requiring hemodialysis are: an autogenous 
arteriovenous access or native arteriovenous fistula (AVF), a prosthetic arteriovenous graft (AVG) or a 
tunneled dialysis catheter.3   The AVF has been shown to be superior to AVG and superior to catheter 
access in terms of both mortality and morbidity.4,5   In fact, the focus of numerous initiatives worldwide 
has been to increase the implementation of AVF as the preferred method of vascular access in 
patients requiring hemodialysis.  In 1997, the National Kidney Foundation Kidney Disease Outcomes 
Quality Initiative (KDOQI) guidelines were published to highlight the importance and to promote the 
increased placement of AVF.6    These guidelines and subsequent versions have stressed the importance 
of proactive identification of patients requiring hemodialysis, and have described procedures and 
quality initiatives to maximize access longevity.  In 2006, the updated KDOQI Guidelines 
recommended that AVF be constructed in at least 65% of prevalent hemodialysis patients.7   In 
addition, the AV Fistula First Breakthrough Initiative (FFBI), a coalition lead by the Center for 
Medicare and Medicaid Services (CMS) has set a formal goal for AVF construction of 65% in 
prevalent patients by 2009.8   The Society for Vascular Surgery (SVS) has also approved and sponsored 
initiatives around the development and publication of reporting standards for hemodialysis access and 
the development of practice guidelines for hemodialysis access.9 
 
An AVF is traditionally created during a surgical procedure under general anesthesia.  A surgical 
incision is made in the forearm or upper arm, followed by identification of target arteries and veins for 
surgical connection.  Frequently, prior to the procedure, the vessels are mapped using duplex 
ultrasound imaging, allowing for pre-operative vessel diameter measurement and vessel selection.  
Typically, the radial artery or brachial artery and the cephalic vein or basilic veins are selected.  The 
target vessels are carefully dissected and mobilized, and the vein is transected.  An arteriotomy is 
created, and an anastomosis is sewn between the vein and the artery.  After completion, the flow is 
verified using palpation and ultrasound, and the incision is closed.  Over the course of the following    
1-3 months, the AVF gradually matures, that is, the vein dilates and accepts increased flow sufficient 
for hemodialysis. 
 
Though there is widespread agreement that the AVF is the preferred method of vascular access,  
28 – 60% of AVFs do not successfully mature and are rendered unusable for hemodialysis.10, 12   This 
has unintended consequences for patients in immediate need of hemodialysis, since a tunneled 
dialysis catheter must often be placed.  Catheters are associated with higher morbidity, mortality, and 
costs and are therefore considered a last resort.11 
 
 

 
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To improve on these results, and decrease the invasiveness of the procedure, a new tool and method 
for creation of an AVF has been developed, called the everlinQ system. The system uses two devices, 
one inserted into an artery and the other inserted into a closely-positioned vein.  The devices contain 
magnets that bring a pair of electrodes into alignment. Radiofrequency energy is delivered to the 
electrodes, cutting and/or coagulating the tissue between the electrodes, creating an AVF.  The 
procedure is facilitated using fluoroscopy and ultrasound imaging, to assist in vessel selection and to 
verify creation of the AVF. Because the vessels are not dissected and not mobilized, leaving the 
surrounding tissues intact, the vessels do not need to be sewn together with a traditional surgical 
technique. This proposed method may facilitate the creation of AVF, while reducing the trauma to 
the patient and also potentially prevent future venous stenosis thought to arise from surgical trauma. 
In particular, the goal is to reduce the surgical manipulation of the blood vessels, particularly the 
veins in the arm, which typically exhibit intimal hyperplasia in surgical AVF.  Intimal hyperplasia is 
believed to be a root cause of failure in surgical AVF and AVG, and this technology and method may 
help improve the patency and maturity of AVF in patients with ESRD. 
 
1.1 
Purpose 
This clinical pilot study is being conducted to evaluate the everlinQ System when utilized to create an 
AVF.  An initial pilot study conducted under the EASE protocol demonstrated successful creation and 
high patency rates of an endoAVF in both the proximal radial and ulnar locations utilizing a 
concomitant vein percutaneous access location to perform the procedure.  This study aims to investigate 
expansion of the percutaneous venous access location to the superficial system which may provide 
additional procedural benefit.  
 
1.2 
Device Description 
The TVA Medical everlinQ System that will be used in this study is an investigational device, and is 
not cleared by the FDA or any competent authority for sale in the US or elsewhere.  
 
The everlinQ device is a single-use disposable device. The everlinQ catheter system consists of two 
flexible, magnetic catheters.  One (venous) catheter contains an electrode to deliver radiofrequency (RF) 
energy, and has a cord that is connected for a remote hand switch.  The venous catheter and hand switch, 
along with a standard grounding pad, connect to a standard electrosurgical unit for the delivery of RF 
energy.  The second (arterial) catheter is a flexible magnetic catheter that contains a backstop for the 
RF electrode of the venous catheter to interface.  Once the catheters are properly inserted and aligned, 
the magnets contained in each catheter attract to one another, approximating the vessels while 
simultaneously aligning the electrode with the backstop.  RF energy is delivered to the electrode 
whereby the arterio-venous fistula (AVF) is created. 
 
For additional details regarding device or its principal of operation, please refer to the most current 
Instruction for Use (IFU). 
 
2 
RISKS/BENEFITS 
 
2.1 
Benefits 
The everlinQ System may facilitate a less-invasive and more reproducible AVF procedure. The 
everlinQ System may allow the physician to cut and coagulate soft tissues for the creation of an AVF 
while minimizing surgical incisions. Due to the less-invasive nature of the procedure with the 

 
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everlinQ System, the AVF may exhibit improved maturation and patency characteristics compared to 
historical maturation and patency data.  In addition, patient recovery time may be decreased, 
procedural time may be decreased, and anesthesia may be minimized compared to a conventional 
surgical AVF procedure. 
 
2.2 
Risks 
Many of the potential risks and complications associated with the everlinQ System and procedure are 
similar to the risks expected for CKD patients undergoing surgically created arteriovenous fistula 
(AVF) procedures.   The potential risks related to the everlinQ System and procedure are similar to 
surgical AVF creation and may include but not limited to: 
 
• 
Bruising 
• 
Numbness, tingling and/or coolness in the fistula extremity  
• 
Thrombosis 
• 
Stenosis 
• 
Failure to mature  
• 
Additional procedures 
• 
Venous hypertension 
• Aborted procedure 
• Swelling, irritation or pain 
• Bleeding/ Hemorrhage  
• Hematoma  
• Wound problem 
• Fever 
• Steal Syndrome 
• Ischemia  
• Embolism 
• Infection  
• Increased risk of congestive heart failure 
• Nerve damage 
• Vessel damage 
• AVF dihesence 
• Pseudoaneurysm 
• Compartment Syndrome  
• Heart problems such as arrhythmias  
• 
Burns 
• Problem due to sedation or anesthesia 
• Sepsis  
• Infiltration injury during fistula cannulation 
• Toxic or allergic reaction 
• Electrocution 
• Death  
 
 
 

 
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Most of these potential risks also exist for creation of standard (surgical) AVFs.  There may also be 
other risks related to use of the everlinQ System and procedure that are not listed or that are not known 
at this time. This study will help characterize the adverse events associated with the everlinQ System. 
 
2.3 
Minimization of Risk 
To minimize the risks, the everlinQ system has undergone pre-clinical and clinical testing under the 
EASE study. In addition, all Investigators participating in this clinical study will be trained on the 
everlinQ procedure which will contribute to minimizing risks associated with the use of the device. 
 
3 
STUDY METHODOLOGY 
 
3.1 
Study Design 
This is a prospective, single-center study to evaluate the everlinQ System when used to create an 
endoAVF in hemodialysis patients.  A total of up to 50 subjects will be enrolled and will undergo an 
endoAVF creation procedure using the everlinQ System. All subjects may be followed for up to 12 
months post index procedure based on Investigator’s discretion. The duration of the study is expected 
to be approximately two (2) years. 
 
3.2 
Study Objective 
            The primary objective of this clinical study is to evaluate the safety and efficacy of using the everlinQ 
system for the creation of an endovascular AVF (endoAVF) in patients requiring hemodialysis. 
 
3.3 
Study Endpoints 
Study endpoints will be summarized using descriptive statistics. There are no formal hypothesis 
tests associated with these endpoints. 
 
• Technical Success: Intra-procedural verification that the everlinQ device successfully created an 
endoAVF as determined by an angiogram, the presence of a bruit that is detected with 
stethoscope, or presence of thrill, or via Duplex Ultrasound.   
 
• Procedural Success: Verification that an endoAVF has been created and remains patent 1-7 
Days after the index procedure.  Patency will be determined by experienced examiner as the 
presence of a bruit that is detected with stethoscope, or presence of thrill, or via Duplex 
Ultrasound, or via angiogram. 
 
• Fistula Maturation: Defined as endoAVF that is free of stenosis or thrombosis, with brachial 
artery flow of at least 500 ml/min and at least 4 mm vein diameter (as measured by duplex 
ultrasound) OR patient was dialyzed using 2 needles.   
 
• Time to Fistula Maturation: The number of days between the date of AVF creation and the 
date of endoAVF maturation (based on primary efficacy endpoint definition of maturation).  
 
• EndoAVF-related Re-intervention Rate:  The re-intervention rate for endoAVF (defined as 
any intervention required to maintain or re-establish patency) will be calculated at each available 
follow-up visit post index procedure.  
 

 
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• Primary Patency: The primary patency rate will be determined via Kaplan-Meier methods and 
based on the time of endoAVF creation until any intervention designed to maintain or reestablish 
patency, or endoAVF abandonment.  
 
• Secondary Patency: The secondary patency rate will be determined via Kaplan-Meier methods 
and based on the time of endoAVF creation until access abandonment.  Abandonment due to 
renal transplant receipt will not be included in this endpoint assessment. Abandonment of the 
access is defined as an access that can no longer be used for two needle prescribed dialysis as it 
may be unable to provide adequate flows and⁄or is deemed unsafe for the patient, and the 
associated problem cannot be corrected by any intervention, including medical, surgical, or 
radiological interventions or rest. 
 
• Safety: The percentage of patients who experience one or more serious device-related adverse 
events during the first 3 months following AVF creation.   
 
• Additional Exploratory Analysis: 
o Rate of serious procedure-related events will be reported 
o Rate of serious device-related events will be reported 
o Rate of device and/or procedure-related infections 
o Arterial and arterialized vein flow rates and diameters will be reported 
o Other analyses may be reported as needed 
 
3.4 
Investigational Site Selection 
Investigational site selected to participate in this clinical study will be dependent on the Investigator 
at the site having the necessary resources to fulfill the clinical research requirements outlined in the 
protocol.  These resources include adequate patient population, facilities and support staff to perform 
the clinical evaluation according to all applicable requirements. 
 
3.5 
Study Population 
Candidates for this study are patients being evaluated for placement of an arteriovenous fistula for 
chronic hemodialysis. Only patients meeting the inclusion and none of the exclusion criteria who 
signed Informed Consent Form (ICF) will be enrolled in the study.  
 
3.5.1 Inclusion Criteria 
1. 
Eligible for a native arteriovenous fistula. 
2. 
Adult (age >18 years old).  
3. 
Established, non-reversible kidney failure requiring hemodialysis (including pre-dialysis  
 
patients). 
4. 
Target vein diameter(s) at fistula site ≥ 2.0 mm. 
5. 
Target artery diameter at fistula site ≥ 2.0 mm. 
6. 
Procedural access site artery and vein diameter ≥ 2.0 mm. 
7. 
At least one superficial outflow vein diameter ≥ 2.5 mm and in communication with the  
 
perforating vein.  
8. 
Estimated life expectancy > 1 year. 
9. 
Patient is free of clinically significant conditions or illness within 30 days prior to the AV  
 
fistula that may compromise the procedure. 
10. Presence of an antecubital perforating vein diameter ≥ 2.0 mm. 

 
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3.5.2 Exclusion Criteria 
1. 
Known central venous stenosis or central vein narrowing > 50% based on imaging on the  
 
same side as the planned AVF creation. 
2. 
Upper extremity venous occlusion(s) and/or vessel abnormality(ies) on the same side as the  
planned AVF creation that precludes endovascular AVF creation by the everlinQ System as 
deemed by the interventionalists’ clinical judgment. 
3. 
Prior surgically created access in the planned treatment location.  
4. 
Functioning surgical access in the planned treatment arm. 
5. 
Pregnant women. 
6. 
New York Heart Association (NYHA) class III or IV heart failure.   
7. 
Hypercoagulable state. 
8. 
Known bleeding diathesis. 
9. 
Immunosuppression, defined as use of immunosuppressive medications used to treat an  
 
active condition. 
10. Documented history of drug abuse including intravenous drugs within six months of AVF  
 
creation. 
11. “Planned” concomitant major surgical procedure within 6 months of enrollment or previous  
 
major surgery within 30 days of enrollment. 
12. Currently being treated with another investigational device or drug. 
13. Known allergy to contrast dye which cannot be adequately pre-medicated. 
14. Known adverse effects to sedation and/or anesthesia which cannot be adequately pre- 
 
medicated. 
15. Patients who do not have an ulnar or radial artery. 
16. Distance between target artery and vein or other anatomical abnormality will not permit  
catheters to be introduced, navigated to fistula site, or allow magnets to align vessels 
sufficiently to create the fistula. 
17. Evidence of calcification in vessels at the fistula site. 
18. Evidence of active infections on the day of the index procedure. 
19. Written informed consent not obtained.  
 
4 
STUDY SCREENING AND FOLLOW-UP PROCEDURES 
Patients are required to undergo a thorough screening evaluation prior to the index procedure and 
return for evaluations according to the study follow-up schedule indicated in Table 1.  Study data 
will be collected on case report forms (CRFs) provided by the Sponsor. Any site’s standard of 
care tests may be done outside of the study (e.g., prior to study participation).   
 
 
 
 
 
 
 
 
 
 

 
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Table 1: Schedule of Study Procedures 
 
Screening 
Index 
Procedure 
 
Post Index Procedure 
1-7 
Days 
30-45 
Days 
2 Months 
(Optional) 1 
3 Months 
6 Months 
(Optional)1 
12 Month 
(Optional)1 
Compliance 
window 
-60 to 0 
days 
Day 0 
1-7 
days 
30-45 
days 
Anniversary 
date + 21 days 
Anniversary 
date + 21 days 
Anniversary 
date + 60 days 
Anniversary 
date + 60 days 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
History, Physical 
Exam, Laboratory 
Evaluation 
X 
 
 
 
 
 
 
 
Ultrasound 
Evaluation 
X 
X1 
X 
X 
X1 
X 
X1 
X1 
Angiography/ 
Venography 
X1 
X 
X1 
X1 
X1 
X1 
X1 
X1 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Dialysis Access 
Data 
 
 
 
X2 
X2 
X2 
X2 
X2 
1 Optional assessment at the discretion of the Primary Investigator  
2 Will be obtained after dialysis is initiated using endoAVF created by the everlinQ System.  
 
4.1 
Informed Consent 
Prior to enrollment, all patients will be informed in detail about the nature of the clinical investigation, 
as well as its risks, potential benefits, and any anticipated discomforts. All patients must provide written 
informed consent using Ethics Committee (EC) approved informed consent document.  
 
Proper informed consent should be obtained in accordance with local/country guidelines as needed. 
 
4.2 
Screening Evaluation 
All patients considered for enrollment must undergo a thorough screening evaluation prior to the 
scheduled treatment with the everlinQ System.  The screening evaluation includes: 
 
• Collection of demographic data; 
• A medical history and physical exam; 
• A laboratory evaluation (i.e. blood tests); and 
• A duplex ultrasound and optional angiography/venography assessment. 
 
There will be a final assessment of the suitability of the patient’s study eligibility due to vascular 
anatomy or other criteria made at the time of the index procedure and thus, there may be some 
consented subjects who are determined to be ineligible who will not be enrolled in the study. 
 
4.2.1 Duplex Ultrasound 
All patients are required to undergo duplex ultrasound assessment during screening. DUS needs to 
be performed to measure the flow rates and inner diameters of the arteries and veins of the target 
vessels based on the screening documents provided for the study. 
 
 
 

 
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4.2.2 Angiography/Venography 
Angiographic or venographic assessment of the suitability of the arteries or veins intended for the 
endoAVF will be performed during the index procedure and may be performed during follow-up at 
the discretion of the Investigator. 
 
4.3 
Index Procedure 
If a patient presents for the index procedure with an active localized infection, or other medical 
condition that precludes treatment at this time, the procedure should be delayed until the infection or 
medical condition is treated and resolved. 
 
If the Investigator is not an experienced user of the everlinQ System, a Sponsor’s representative will 
be present as needed for procedures at each site to provide technical guidance to the Investigator.   
 
4.4 
Follow-Up Visits 
See Table 1 for required and optional follow-up visits. 
 
4.4.1 Unscheduled Visit 
In addition to scheduled follow-up visits, the patient should be instructed to contact the Investigator at 
any time during the follow-up period if he/she has questions or concerns relating to the procedure or 
the endoAVF.  If the patient returns to the clinic for evaluation related to his/her participation in the 
study, an Unscheduled Visit evaluation should be performed and this data should be recorded on the 
Follow-Up Visit Case Report Form.  
 
4.5 
Patient Disposition 
The Patient Disposition Case Report Form should be completed whenever a patient exits the study.  
This includes patients enrolled in the study who: 
• complete the study protocol, 
• withdraw from the study, 
• are lost to follow-up, 
• are deceased, 
• have other reason(s) for exiting the study. 
 

 
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4.6 
Adverse Events 
For the purpose of this protocol, an AE will be defined as any adverse medical change (i.e., de novo or 
increased severity in a preexisting condition) from the subject’s baseline condition that occurs during 
the course of the clinical study, after starting treatment, whether considered treatment-related or not.  
All Adverse Events will be classified using the following definitions.    
 
AE Type 
Definition 
Serious Adverse 
Event (SAE) 
AE that: 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either resulted in 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect 
 
NOTE:  
Planned hospitalization for a pre-existing condition, or a procedure required by the 
Study Protocol, without serious deterioration in health, is not considered a SAE.13 
Adverse Device 
Effect (ADE) 
AE related to the use of study device.  
 
NOTE:  
This definition includes adverse events resulting from insufficient or inadequate IFU, 
deployment, installation, or operation, or any malfunction of the study device. 
This definition includes any event resulting from use error or from intentional misuse 
of the study device. 
Serious ADE 
(SADE) 
ADE that has resulted in any of the consequences characteristic of a SAE 
Unanticipated 
SADE (USADE) 
USADE which by its nature, incidence, severity or outcome has not been identified in 
the current version of the study protocol, IFU, or other study documentation.  
Anticipated 
SADE (ASADE) 
An effect which by its nature, incidence, severity or outcome has been identified in the 
study documentation.  
To classify the event, you may follow the steps below (please refer to additional local requirements as 
needed). 
Is this event: 
1. Serious 
Yes 
No 
2. Study device or 
procedure related 
Yes 
No 
Yes 
No 
3. Unanticipated? 
Yes 
No 
 
 
 
Event type is → 
USADE 
ASADE 
SAE 
ADE 
AE (i.e., non-SAE) 
 
 
 
 

 
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4.6.1 Relationship to Device or Procedure 
The investigator will also evaluate the relationship of the adverse event to the everlinQ device or 
procedure according to the following definitions: 
 
Definite (YES): 
The AE follows a reasonable timing from treatment (or attempted 
treatment) with the device and the possibilities of factors other than the 
device or the index procedure, such as underlying disease, concomitant 
drugs, or concurrent treatment can be excluded.  This includes an AE that 
occurs during the index (AVF creation) procedure. 
       Probable (YES): 
The AE follows a reasonable timing from treatment (or attempted 
treatment) with the device and the probability of device or procedure 
involvement cannot be excluded.  However, other factors such as 
underlying disease, concomitant medications, or concurrent treatment may 
be possible. 
 
Unlikely (NO): 
The AE follows an unlikely timing relationship from treatment (or 
attempted treatment) or is more likely due to other factors and there is no 
definitive information suggesting that it was related to the device or 
procedure.    
 
 Not Related (NO):  
The AE has no timing relationship from treatment (or attempted treatment) 
or it can be explained by other factors, including underlying disease, 
concomitant medication, or concurrent treatment. 
 
The investigator will also evaluate the relationship to the everlinQ portion of the procedure using the 
yes/no definitions above.  The everlinQ portion of the procedure only includes insertion, deployment 
and removal of the everlinQ catheters.  
 
5 
DATA ANALYSIS 
Data analysis will be primarily descriptive in nature.  Continuous variables, such as age, height, weight, 
will be summarized by the mean, standard deviation, median, minimum and maximum values.  Nominal 
variables, such as gender, ethnicity, presence of co-morbid conditions, will be summarized by the number 
and percentage of subjects within each category defined by the variable.  Summary statistics for discrete 
variables will consist of the number and percent of responses in each category.  Other analyses may be 
performed as needed.   
 
6 
REGULATORY OBLIGATIONS 
 
6.1 
Responsibilities of the EC/EC Approval 
The EC has the main responsibility to oversee the welfare of the subjects entered into this study.  The 
EC, by its approval of the informed consent form, also ensures that the potential subjects are aware of 
the benefits and risk of participation in the study. 
 
Each site must obtain EC approval and any other Regulatory agency’s approval as required by 
local or country guidelines prior to study initiation.  A copy of the approval notification and 

 
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the approved study specific patient informed consent must also be kept on file at the site and a 
copy provided to Sponsor prior to the enrollment of patients. If applicable, written EC 
approval of any subject’s information materials or any advertisement must also be attained 
prior to their use. 
 
6.2 
Sponsor Obligations 
The Sponsor must assume responsibilities that are not limited to the following: 
• Provide the Investigator with the necessary information (protocol and IFU) and training  
 
required to conduct the investigational study. 
• Inform study Investigators of all new information. 
• Conduct an evaluation of any USADE and report the result of such evaluation to all  
 
reviewing ECs and all participating Investigators within 10 working days of first  
 
receiving notice of the event. 
 
6.2.1 Investigator’s Documents 
The following documents will be provided to the study Sponsor by the Investigator prior to initiation 
of the study. 
• A signed and dated Study Agreement. 
• Current (within one year) curriculum vitae of the Principal Investigator and all Co- 
 
Investigators.  
• A copy of the approval letter by the EC for the study protocol and the informed consent. 
 
6.3 
Investigator Obligations 
Upon signing the Study Agreement, the Investigator agrees to assume the following responsibilities, to 
keep the required records, and to file the required reports in a timely manner. 
 
The Investigator agrees to: 
• Conduct the investigation in compliance with the signed agreement, study protocol, and  
 
applicable regulations.  Changes to the protocol will only be made after approval by the  
sponsor and the reviewing EC, or when necessary to protect the safety, rights or welfare 
of a subject. 
• Conduct the investigation in compliance with the EC and other applicable Regulatory  
 
agencies. 
• Personally conduct or supervise the investigation. 
• Ensure that all associates, colleagues and employees assisting in the conduct of the  
 
study are informed about their obligations. 
• Protect the rights, safety and welfare of research subjects.  All subjects must be  
 
informed that the device is being used for investigational purposes. 
• Assure initial and continuing review of the investigation by an EC. 
 
6.4 
Records and Reports 
All records and reports pertaining to this protocol are subject to inspection by regulatory 
agencies and must be retained for at least two years after the date on which the investigation is 
terminated or completed or for two years after the date that the records are no longer required for 
the purpose of supporting an application to regulatory agencies for commercial approval of the 
therapy/claims, or per local regulations, whichever is later. 
 

 
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6.4.1 Investigator’s Reports 
The investigator is responsible for the preparation and submission of the reports listed below: 
 
Report 
Submitted to 
Description 
Unanticipated 
Serious Adverse 
Device Events and 
Serious Adverse 
Device Effects 
Sponsor & EC 
The investigator’s report on any unanticipated serious 
adverse device event (USADE) or serious adverse 
device effect (SADE) must be submitted within 10 
working days after the investigator first learns of the 
event. 
Withdrawal of  
EC approval 
Sponsor 
The investigator must report a withdrawal of reviewing 
EC approval within 5 working days. 
Deviations from 
Study Protocol  
Sponsor & EC 
Notification must be made within 5 working days of the 
occurrence of an emergency deviation (made to protect 
the life or physical well-being of a subject). 
 
If the deviation affects the rights, safety, or welfare of 
the subjects (and is not an emergency), or the scientific 
soundness of the investigation, prior approval must be 
obtained from Sponsor, the reviewing EC and applicable 
Regulatory Authorities (when required).  For all other 
deviations, prior approval must be obtained from 
Sponsor. All deviations must be documented on a 
Protocol Deviation Form. 
Failure to obtain 
Consent Form 
Sponsor & EC Notification must be made within 5 working days of use 
of the device. 
 
 
 

 
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6.4.2 Sponsor’s Reports 
Sponsor is responsible for the preparation and submission of the reports listed below: 
 
Report 
Submitted to 
Description 
Unanticipated 
Serious Adverse 
Device Effects 
EC & 
Investigators 
Sponsor will report on any unanticipated serious adverse 
device effect evaluation within 10 working days after 
receiving notice of the effect. 
Recall and 
Device 
Disposition 
EC & 
Investigators 
Notification will be made within 30 working days of 
Sponsor’s request that an investigator return, repair or 
otherwise dispose of any devices.  Such notification will 
state why the request was made. 
Notification of 
Termination or 
Completion 
EC & 
Investigators 
Notification will be made within 30 working days of 
completion or termination of the investigation. 
Final Report 
EC & 
Investigators 
A final report will be submitted within six months after 
study completion or termination. 
Emergency 
Deviations from 
Study Protocol 
EC 
Notification will be made within 5 working days after 
Sponsor learns of an emergency deviation from the 
Investigational Plan where the deviation was made to 
protect the life or physical well-being of a subject. 
 
 
6.5 
Site Training 
Sponsor representative(s) will be responsible for site personnel training to ensure that all site 
personnel have a thorough understanding of the protocol, case report forms and associated 
study requirements. 
 
A Sponsor’s representative(s) will meet with the Investigator at each study site prior to the 
enrollment of patients for the purpose of reviewing and discussing the protocol and supporting 
documentation to assure total understanding of the requirements involved in performing the 
clinical evaluation. 
 
6.6 
Protocol Deviations 
            A Protocol Deviation CRF must be completed for each deviation from the Study Protocol that occurred 
at the site (e.g., failure to obtain informed consent, enrolling a patient who does not meet 
inclusion/exclusion criteria, not performing required testing, missed follow-up visits, etc.). 
 
6.7 
Site Non-Compliance 
            Repeated serious protocol deviations will be closely monitored.  If excessive deviations or a failure to 
reduce deviations is noted, the Sponsor reserves the right to suspend study enrollment or terminate the 
site from the study until a sufficient system is in place at the site to reduce further deviations.  
 
6.8 
Device Accountability 
            A Device Accountability Log (DAL) will be maintained at the study site.  Devices allocated for 
investigational site use will be recorded in the DAL upon delivery to the study site and will be stored in 
a secured area until use.  No devices will be shipped until EC approvals to begin the study are received 
by the Sponsor.  Site personnel will be responsible for tracking the receipt and disposition of all study 
devices. All unused study devices must be returned to the Sponsor.  
 

 
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            The DAL will be updated as each device is used, opened, or returned.  The DAL will contain delivery 
dates of devices to the site, dates used, returned-to-Sponsor dates and the reason for the return, lot 
numbers of devices delivered to the site, and the patient ID for all used devices. 
 
6.9 
Case Report Form Completion 
Complete and accurate Case Report Forms (CRFs) must be kept for all patients enrolled in the study.  
All entries in the CRFs should be made with black or blue ink.  There must be an entry for every data 
point in the CRFs.  Corrections to the CRFs should be made by striking out the initial entry with a 
single horizontal line, with placement of the new entry just above the old.  All corrections must be 
initialed and dated by the person making the correction. 
 
All data collected in the study must be supported by source documentation.  Source documentation 
may include, but not necessarily be limited to: patient medical record notes, patient history 
questionnaires, physical examination forms, duplex ultrasound data, radiology reports, operative 
summaries or other documentation that is pertinent to the patient’s participation in the study.  In 
addition to existing patient records, a copy of the CRF for the study may be used to directly record 
study data.  If the CRF copy is the only documentation of the collection of study data, the copy should 
be signed and dated by the Investigator and kept in the patient’s record as source documentation. 
 
6.10 
Monitoring Procedures 
The Sponsor or a Sponsor representative will monitor the progress of the study as required by GCP.  
The study data will also be monitored (by utilizing remote risk-based monitoring, if feasible). The 
Sponsor will request the source documents to be submitted to them in de-identified manner (subject’s 
name and other personal identifiers must be removed and replaced with the study subject identification 
(ID) number). These source documents may include but not limited to: 
 
• Admission, procedural and discharge reports/notes 
• Any documentation relevant to SAE and procedure and device-related AEs 
Monitoring will be performed by qualified and appropriately trained monitors onsite and/or remote. 
They may be Sponsor’s employees or Sponsor’s representatives.  
On-site visits may be performed as needed based upon enrollment, data integrity and site compliance 
(e.g. repeated and serious non-compliance by the site (significant number of DCFs at the site, etc.). 
Each remote or on-site monitoring visit will be documented.  
 
 
 

 
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