Predicate Devices

Not Found

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The device description explicitly states "Device does not contain software." and there are no mentions of AI, ML, or related concepts in the summary.

Therapeutic

Yes
The device is indicated for the creation of an arteriovenous fistula (AVF) in patients with chronic kidney disease needing hemodialysis, which is a therapeutic intervention facilitating treatment for a disease.

Diagnostic

No

This device is designed for the creation of an arteriovenous fistula (AVF) for hemodialysis access. Its primary function is to perform a medical procedure, not to diagnose a condition. While it is used in patients with chronic kidney disease (a diagnosed condition), the device itself does not provide diagnostic information.

SaMD (Software as a Medical Device)

No

The device description explicitly states that the device "consists of two single-use disposable magnetic catheters" and is used with a "commercially available electrosurgical unit (ESU) and electrosurgical pencil," indicating it is a hardware device. Furthermore, the "Software" section under "Summary of Performance Studies" states "Device does not contain software."

IVD (In Vitro Diagnostic)

Based on the provided information, the everlinQ® endoAVF System is not an In Vitro Diagnostic (IVD) device.

Here's why:

Intended Use: The intended use is the creation of an arteriovenous fistula (AVF) within the patient's body for hemodialysis access. This is a surgical/interventional procedure performed in vivo.
Device Description: The device consists of catheters and uses radiofrequency energy to create a connection between an artery and a vein inside the patient.
Lack of In Vitro Testing: The description of performance studies focuses on bench testing, animal studies, and clinical trials involving human subjects. There is no mention of testing biological samples (blood, urine, tissue, etc.) outside the body for diagnostic purposes.
Input Imaging Modality: The imaging modalities listed (fluoroscopy, duplex ultrasound, angiography/fistulogram) are used to guide the procedure and assess the created fistula in vivo.
Anatomical Site: The device is used on the ulnar artery and ulnar vein within the arm.

IVD devices are specifically designed to examine specimens derived from the human body in vitro (outside the body) to provide information for diagnostic, monitoring, or compatibility purposes. The everlinQ® system is a therapeutic/interventional device used directly on the patient's anatomy.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The everlinQ® endoAVF System is indicated for the creation of an arteriovenous fistula (AVF) using the ulnar artery and ulnar vein in patients with minimum artery and yein diameters of 2.0 mm and less than 2.0 mm separation between the artery and vein at the fistula creation site who have chronic kidney disease and need hemodialysis.

Product codes

POK

Device Description

The everlinQ® endoAVF System (everlinQ®) consists of two single-use disposable magnetic catheters: a venous catheter and an arterial catheter, both of which are 6 Fr in diameter. The venous catheter contains an electrode for delivery of radiofrequency (RF) energy while the arterial catheter contains a ceramic backstop that serves as a mechanical stop for the electrode. The everlinQ® is used with a commercially available electrosurgical unit (ESU) and electrosurgical pencil.
The venous and arterial catheters are inserted into the ulnar vein and ulnar artery, respectively. The two catheters are then aligned and rotated, and when they achieve the proper position, the magnets contained in each catheter attract to one another, approximating the vessels while simultaneously aligning the electrode with the backstop. Using the ESU, grounding pad, and electrosurgical pencil, RF energy can then be delivered through the electrode for tissue cutting. This energy creates a small, rectangular hole (approximately 5 mm x 1 mm) in the adjoining vessels, allowing blood to flow from the artery to the vein and thereby creating a nonsurgical, or endovascular, arteriovenous fistula (endoAVF).

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

ulnar artery and ulnar vein in the arm.

Indicated Patient Age Range

The study population consisted of male and female patients from Canada, Australia, and New Zealand who had chronic kidney disease (CKD), required a hemodialysis vascular access, and were at least 18 years of age.

Intended User / Care Setting

Only physicians trained and experienced in endovascular techniques, who have received appropriate training with the device, should use the device. Endovascular technique training and experience should include ultrasound vessel access in the arm, guidewire navigation, radiographic imaging, embolization coil placement, and access closure.

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

SUMMARY OF NONCLINICAL/BENCH STUDIES

Biocompatibility/Materials: The everlinQ® endoAVF System is an externally communicating device in contact with circulating blood with limited contact duration (

Regulation Number and Section

§ 870.1252 Percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access.

(a)
Identification. This device is a single use percutaneous catheter system that creates an arteriovenous fistula in the arm of patients with chronic kidney disease who need hemodialysis.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Clinical performance testing must evaluate:
(i) The ability to safely deliver, deploy, and remove the device;
(ii) The ability of the device to create an arteriovenous fistula;
(iii) The ability of the arteriovenous fistula to attain a blood flow rate and diameter suitable for hemodialysis;
(iv) The ability of the fistula to be used for vascular access for hemodialysis;
(v) The patency of the fistula; and
(vi) The rates and types of all adverse events.
(2) Animal testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be assessed:
(i) Delivery, deployment, and retrieval of the device;
(ii) Compatibility with other devices labeled for use with the device;
(iii) Patency of the fistula;
(iv) Characterization of blood flow at the time of the fistula creation procedure and at chronic followup; and
(v) Gross pathology and histopathology assessing vascular injury and downstream embolization.
(3) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested:
(i) Simulated-use testing in a clinically relevant bench anatomic model to assess the delivery, deployment, activation, and retrieval of the device;
(ii) Tensile strengths of joints and components;
(iii) Accurate positioning and alignment of the device to achieve fistula creation; and
(iv) Characterization and verification of all dimensions.
(4) Electrical performance, electrical safety, and electromagnetic compatibility (EMC) testing must be performed for devices with electrical components.
(5) Software verification, validation, and hazard analysis must be performed for devices that use software.
(6) All patient-contacting components of the device must be demonstrated to be biocompatible.
(7) Performance data must demonstrate the sterility of the device components intended to be provided sterile.
(8) Performance data must support the shelf life of the device by demonstrating continued sterility, package integrity, and device functionality over the identified shelf life.
(9) Labeling for the device must include:
(i) Instructions for use;
(ii) Identification of system components and compatible devices;
(iii) Expertise needed for the safe use of the device;
(iv) A detailed summary of the clinical testing conducted and the patient population studied; and
(v) A shelf life and storage conditions.

Summary

0

DE NOVO CLASSIFICATION REQUEST FOR EVERLINQ® ENDOAVF SYSTEM

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access. This device is a single use percutaneous catheter system that creates an arteriovenous fistula (AVF) in the arm of patients with chronic kidney disease who need hemodialysis.

NEW REGULATION NUMBER: 21 CFR 870.1252

CLASSIFICATION: II

PRODUCT CODE: POK

BACKGROUND

DEVICE NAME: everlinQ® endoAVF System

SUBMISSION NUMBER: DEN160006

DATE OF DE NOVO: February 3, 2016

CONTACT: TVA Medical, Inc. 7000 Bee Cave Rd., Suite 250 Austin, TX 78746

INDICATIONS FOR USE

The everlinQ® endoAVF System is indicated for the creation of an arteriovenous fistula (AVF) using the ulnar artery and ulnar vein in patients with minimum artery and yein diameters of 2.0 mm and less than 2.0 mm separation between the artery and vein at the fistula creation site who have chronic kidney disease and need hemodialysis.

LIMITATIONS

The sale, distribution, and use of the everlinO® endoAVF System are restricted to prescription use in accordance with 21 CFR 801.109.

Only physicians trained and experienced in endovascular techniques, who have received appropriate training with the device, should use the device. Endovascular technique training and experience should include ultrasound vessel access in the arm, guidewire navigation, radiographic imaging, embolization coil placement, and access closure,

1

The everlinQ® endoAVF System is contraindicated for patients with a distance between target artery and vein > 2mm, and patients with target vessels Acute Study
• Insert, track, deploy, and
activate device to create a
single AVF in N=2 ovine
models, then procedure time
and energy delivery were
recorded.
• After creation, fistulas
evaluated (by ultrasound,
thermal dilution and/or
fluoroscopy via contrast
injection) to determine patency
and fistula flow.
• After 0-1 hour survival,
necropsy performed to ensure
no downstream tissue effects.
• AVF site, vessels and tissue in
proximity were histologically
examined to characterize these
tissues.
• Insert, track, deploy, and
activate device to create 4 or 5
AVFs in N=2 additional ovine
models.
• After 0-1 hour survival,
necropsy performed in which
the vessels were identified and
AVFs photographed.

Chronic Study
• Insert, track, deploy, and
activate device to create a
single AVF in N=4 ovine
models.
• After creation, fistulas
evaluated (by ultrasound,
thermal dilution and/or
fluoroscopy via contrast
injection) to determine patency
and fistula flow.
• After 30 days survival, fistulas
again examined to determine
patency and fistula flow.
• Necropsy performed to ensure
no downstream tissue effects.
• AVF site, vessels and tissue in | • 14/15 attempts to create fistulas in the 8
animals were successful. One attempt
failed due to a procedural mistake
related to the ovine vasculature, and is
not relevant to the intended human
anatomy.
• All animals survived to the prescribed
in-life survival.
• There was no morbidity or major
unanticipated events that were related
to the use of the device.
• Fistulas were shown to be patent at 30
days following AVF creation using
fluoroscopic imagery.
• Blood flow was observed after fistula
creation and at 30 days.
• There was no evidence of mechanical
or thermal injury extending beyond the
immediate treatment site following the
procedure, and fistula sites appeared to
heal well by 30 days.
• Arterial and venous ostia appeared
acceptably uniform in size and
appearance.
• No gross findings in off-target or
downstream tissues which were
indicative of device or treatment related
events.
• Histopathology in acute animals was
negative for thromboembolic events in
the lungs or coronary bands.
• Post-procedure histopathology of
treatment sites showed focal
perforations in the artery and vein with
perivascular hemorrhage into
surrounding fat, as well as treated edges
of the ostia characterized by focal mild
compressions and subtle thermal
coagulation. The observations appeared
to be expected for the AVF creation
procedure and resolved with time.
• Histopathology at 30 days showed the
fistulae were patent and maturing, with
no evidence of thromboemboli
generation, vascular remodeling, or
injury.
• No bleeding was observed at 30 days.
• No histopathological observations
related to the device were noted in the
heart. |
| proximity were histologically
examined to characterize these
tissues.
• Mechanical and thermal injury,
inflammation, fibrin/thrombus,
fibrosis, mineralization,
necrosis, hemorrhage, and
intimal proliferation were
evaluated.
• Gross pathology of treatment
sites, subcutaneous tissues on
the downstream distal limb, and
systemic organs in acute and
chronic studies.
• Histopathology of acute
treatment sites, chronic | • No histopathological findings related to
device safety were observed in the
lungs. One small, localized fat embolus
was observed but was asymptomatic
and deemed to be coincidental as it has
not been observed to occur during
percutaneous interventional procedures
in the arteries or veins in humans. | |

Table 4: Summary of GLP Preclinical Study

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SUMMARY OF CLINICAL INFORMATION

The everlinQ® System was primarily supported by a pivotal study entitled the "Novel Endovascular Access Trial" (NEAT Study). In addition, a supportive global analysis of clinical use of the everlinQ® System ("Global Analysis") was conducted that included data from 4 prospective clinical studies (FLEX, NEAT, EU PMCF and EASE) and 1 commercial use data set (COMM). A pooled analysis of the 4 prospective clinical studies was also presented. Details of the study designs and key clinical outcomes are provided in the following sections. The study names are defined as follows:

FLEX A Prospective Pilot Clinical Evaluation of the TVA FLEX-1 Device .
NEAT Novel Endovascular Access Trial .
EU PMCF Post Market Study of the everlinQ® endoAVF System .
EASE everlinQ® Endovascular Access System Enhancements Study .
COMM commercial use data set .

| Data Source | Device Studied | Dates of Index
Procedures | # Sites
(Countries) | Total
Subjects | Subjects in Pooled
Analysis5 | |
|-------------|----------------|------------------------------|-----------------------------|-------------------|---------------------------------|---------------|
| | | | | | Safety | Effectiveness |
| FLEX1 | 6Fr FLEX-1 | Aug 2012-Sep
2013 | 1 (Paraguay) | 33 | 33 | 33 |
| NEAT | 6Fr everlinQ® | Jan 2014- Aug
2015 | 6 (Canada)
2 (Australia) | 60 | 60 | 60 |
| EASE2 | 4Fr everlinQ® | May 2016 - Nov
2016 | 1 (Paraguay) | 32 | 0 | 32 |
| EU-PMCF | 6Fr everlinQ® | Sep 2016 - Aug
2017 | 5 (Germany)
3 (England) | 32 | 32 | 32 |
| COMM- All3 | 6Fr everlinQ® | Feb 2015 - Jun
2017 | 4 (England)
16 (Germany) | 79 | 0 | 0 |

Table 5: Clinical Data Sources

9

| COMM -
Cannulated4 | Feb 2015 - Aug 2017 | 1 (Netherlands)
1 (Switzerland) | 45 | 0 | 0 |
|-----------------------|---------------------|------------------------------------|-----|-----|-----|
| Total Subjects5 | | | 236 | 125 | 157 |

The FLEX-1 device was a previous version of the subject device. After the FLEX Study, design modifications 1. were made to improve ease of use (i.e. handle ergonomics and user interface). The overall mechanism of action and device function for creating an endoAVF has remained the same throughout all revisions of the 6Fr FLEX-1 and everlinO® devices.
1. The EASE subjects were not included in the Pooled Safety Population, since the 4Fr system is a different product compared to the 6Fr systems used in the other data sources.
1. No COMM subjects were included in the Pooled Safety or Effectiveness Populations because data were unavailable in the commercial cases, precluding pooling.
The COMM-Cannulated cases comprise the subset of COMM-All cohort where follow-up data were collected. 4. including safety data and cannulation data.
The total number of subjects is less than the sum of the "Total Subjects" column because the COMM -5 Cannulated subject cohort is a subset of all the commercial subjects included in the COMM-All data.

Primary Clinical Data Set: NEAT Study

Objective: The purpose of the NEAT Study was to evaluate the safety and effectiveness of the everlinO endoAVF System among subjects undergoing endoAVF creation.

Study Design: The NEAT study was a prospective, single-arm, multi-center study that enrolled 60 "study cohort" subjects and 20 "roll-in" subjects at 9 sites in Canada, Australia and New Zealand. Candidates for this study were subjects with chronic kidney disease (CKD) who required a hemodialysis vascular access.

Eligibility Criteria Summary: The study population consisted of male and female patients from Canada, Australia, and New Zealand who had chronic kidney disease (CKD), required a hemodialysis vascular access, and were at least 18 years of age.

Key inclusion criteria included the following:

. Established, non-reversible kidney failure requiring hemodialysis.
Patients deemed eligible for a native arteriovenous fistula.
Target artery diameter and target vein diameter both ≥ 2.0 mm.
Estimated life expectancy > 1 year.
. Subject was free of clinically significant conditions or illness within 30 days prior to the AV fistula that may compromise the procedure.

Key exclusion criteria included the following:

10

Subjects who are eligible for a distal forearm fistula were excluded from the study. . Exception: If a distal forearm fistula had failed or distal forearm fistula was not the most optimum choice the subject was considered eligible to enroll.
. Known central venous stenosis or central vein narrowing > 50% based on imaging on the same side as the planned AVF creation.
. 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 everlinQ endoAV System as deemed by the interventionalists' clinical judgment.
At the time of procedure distance between target artery and vein will not allow magnets . to align vessels sufficiently to create the fistula.
Prior upper arm surgically created access or functioning surgical access in the planned ● treatment arm.
Subjects with Body Mass Index (BMI) >35 who, in an expert cannulator's opinion, are ● not appropriate candidates for cannulation.
"Planned" concomitant major surgical procedure within 6 months of enrollment or previous major surgery within 30 days of enrollment.
. Immunosuppression, defined as use of immunosuppressive medications used to treat an active condition.
. New York Heart Association (NYHA) class III or IV heart failure.

Demographics: The total Intent-to-Treat (ITT) population consisted of 60 subjects. Data about the patient demographics and baseline comorbidities are provided in the tables below.

Characteristic	Summary
Gender
Male	65.0% (39/60)
Female	35.0% (21/60)
Age (years)	59.9 ± 13.6 (60)
61.0 [28.0, 85.0]
BMI	27.9 ± 6.1 (60)
27.1 [16.1 ,44.1]
BMI > 25	63.3% (38/60)
Target Dialysis Weight (kg)	80.9 ± 21.9 (60)
78.7 [43.0, 138.9]
Race
Caucasian	60.0% (36/60)
Asian	31.7% (19/60)
Native Hawaiian/Pacific Islander	1.7% (1/60)
Other	6.7% (4/60)
Smoker (current or previous)	33.3% (20/60)
Previous AVF (prior to study)	31.7% (19/60)
Same arm as used for endoAVF creation	73.7% (14/19)
Contralateral arm as used for endoAVF creation	26.3% (5/19)
Pre-dialysis	56.7% (34/60)
Data displayed as Mean±SD (N);Median [Range] or % (n/N).

Table 6: NEAT Study Subject Demographics

Table 7: NEAT Study Baseline Comorbidities

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| Medical Condition/Comorbidity | Summary
% (n/N) |
|----------------------------------------------|--------------------|
| Primary Diagnosis Causing ESRD: | |
| Diabetes | 50.0% (30/60) |
| Glomerular based disease | 13.3% (8/60) |
| Hypertension | 15.0% (9/60) |
| Interstitial nephritis | 1.7% (1/60) |
| Polycystic kidney disease | 6.7% (4/60) |
| Other | 11.7% (7/60) |
| Unknown | 1.7% (1/60) |
| Comorbidities: | |
| Chronic Obstructive Pulmonary Disease (COPD) | 3.3% (2/60) |
| Cerebrovascular Disease (CVA/TIA) | 15.0% (9/60) |
| Congestive heart failure (NYHA I or II) | 11.7% (7/60) |
| Coronary artery disease (CAD) | 21.7% (13/60) |
| Diabetes | 65.0% (39/60) |
| Hypertension | 91.7% (55/60) |
| Hyperlipidemia | 48.3% (29/60) |
| Malignancy | 18.3% (11/60) |
| Prior peritoneal dialysis | 30.0% (18/60) |
| Prior renal transplant | 13.3% (8/60) |

Accountability: A total of 183 subjects were screened for participation in the study. Sixteen (16) patients declined to participate and 84 patients failed initial screening. Three (3) additional patients failed final enrollment criteria (distance between target artery and vein too great at time of procedure) and were excluded at the time of index procedure. Most subjects who were excluded from the study did not meet the target vessel criteria of ≥ 2mm. In total, 80 subjects were enrolled in the study; 60 subjects were included in the study cohort and 20 subjects comprised a roll-in cohort.

Figure 3 below depicts the subject disposition in the NEAT Study. The figure shows the number of subjects who were evaluated or exited the study at each time point. Among the 60 study cohort subjects, 3 subjects (5%) died during the study and 8 (13.3%) withdrew for other reasons. A total of 11 subjects (18.3%) exited the study before the 12-month follow-up time point, and 4 additional subjects (6.7%) were not yet eligible for their 12-month evaluation at the final NEAT study report was submitted.

In total, 45/60 subjects (75%) were evaluated at 12 months. Those 45 subjects included 24 predialysis subjects (24/34 = 70.6% of pre-dialysis subjects) and 21 dialysis subjects (21/26 = 80.8% of dialysis subjects).

12

Image /page/12/Figure/0 description: This image is a flowchart that shows the progression of subjects through a study. The study started with 183 subjects assessed for eligibility, and 80 were enrolled. Of the 183, 103 were excluded because they did not meet the inclusion criteria or declined participation. The 80 enrolled subjects were divided into two groups: 20 roll-in subjects and 60 study cohort subjects, and the flowchart shows the number of subjects who completed each follow-up visit, as well as the number of subjects who exited the study at each time point.

Figure 3: NEAT Study Subject Disposition Through End of Study

Primary Endpoints

1. Safety: The safety endpoint was the percentage of patients who experienced one or more serious study device related adverse events during the first 3 months following AVF creation as adjudicated by an independent Clinical Events Committee (CEC). There was no formal hypothesis test associated with the safety endpoint. Analysis of the safety endpoint was performed on the study cohort subjects.

13

The following definitions were used for the safety analyses:

Adverse event (AE): any untoward medical occurrence, unintended disease or injury, or . untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device.
Serious adverse event (SAE): A serious adverse event was defined as an adverse event that:
- a) Led to death,
- b) Led to serious deterioration in the health of the subject, that either resulted in
  - i. a life-threatening illness or injury, or
  - a permanent impairment of a body structure or a body function, or ii.
  - iii. in-patient or prolonged hospitalization, or
  - medical or surgical intervention to prevent life-threatening illness or injury or iv. 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, was not considered an SAE.

1. Effectiveness: The primary endpoint of the study was the percentage of patients with fistula maturation/usability at 3 months post-procedure, 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.
  Note: stenosis and thrombosis were defined as flow limiting complications that led to fistula closure at any time during the first 3 months post index procedure. Dialysis using 2 needles were assessed at any time during the first 3 months post index procedure.

This composite endpoint was chosen based on the most common three reasons for AVF failure to mature or lack of AVF usability: 1) thrombosis, 2) stenosis and 3) inadequate flow or diameter of the vein leading to abandoned AVF.

The primary effectiveness endpoint was tested for all 60 study cohort subjects ("Enrolled" population). Subjects in whom an endoAVF was attempted (i.e. RF energy was applied) but not created were included in the analysis as failures. If a patient had missing endpoint data, due to reasons not related to the endoAVF, procedure, or device, they were not included in the primary analysis.

The formal hypothesis tested for the primary endpoint was the 3-months proportion of patients with fistula maturation/usability greater than a historically derived performance goal:

Ho: π ≤ 57.5% vs. Ha: π > 57.5%,

14

where T is the proportion of patients with fistula maturation/usability and 57.5% is the historically derived performance goal (PG). The PG was derived based on surgical AVF failure rates reported in clinical literature.

The number and percentage of patients with fistula maturation/usability within 3 months were summarized. A 90% exact confidence interval (CI) was calculated. The lower bound of the confidence interval was compared to the performance goal of 57.5% to determine success.

Secondary Endpoints

Secondary endpoints were summarized using descriptive statistics. There were no formal hypotheses associated with these endpoints and these analyses were not statistically powered. Analyses for each endpoint were performed on the study cohort subjects unless otherwise noted.

Procedural success: The successful endoAVF creation rate as assessed via fistulogram . immediately post-procedure or duplex ultrasound, or via presence of thrill/bruit.
. 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).
Duration of Central Venous Catheter (CVC) Exposure: The rate of CVC use at 1, 2, 3, 6 and 12 months follow-up. The analysis was performed for pre-dialysis and on dialysis subjects.
. endoAVF-related Interventions Rate: The intervention rate for endoAVF (defined as any intervention required to maintain or re-establish patency; may be also referred as "reintervention" rate) was calculated at 3, 6 and 12 months post index procedure.
Primary Patency: The primary patency rate was 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 was determined via Kaplan-Meier methods and based on the time of endoAVF creation until access abandonment.
. Additional analyses were summarized using descriptive statistics:
- Rate of serious procedure-related AEs at 3 and 6 months. o
- o Rate of serious device-related AEs at 6 months.
- Rate of device and/or procedure-related infections at 6 months. o
- Arterial flow rates and diameters as measured via DUS at 3, 6 and 12 months post o index procedure.
- o Subject satisfaction and quality of life parameters via Vascular Access questionnaire.
- The percentage of subjects dialyzed using endoAVF (2 needles) for 2/3 of their o dialysis sessions over a 4-week period.

15

Results: The principal safety and effectiveness results from patients in the study are provided below. The analyses were performed on all 60 study cohort subjects (excluding roll-in subjects) unless otherwise noted.

Primary Safety Endpoint: At 3 months post index procedure, only one subject experienced one serious device related event (pseudoaneurysm), resulting in an observed percentage of 1.67% (1/60) with a two-sided 95% exact binomial confidence interval of 0.04% - 8.94%.

Primary Effectiveness Endpoint: The primary effectiveness endpoint results are shown in the table below. The primary endpoint was met with a 90-day maturation success rate of 52/57 (91.2%).

| | Subject
Success
% (n/N) | Exact 90%
Confidence
Interval | Hypothesis | Decision | Conclusion |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|-------------------------------------|---------------------------------------------|--------------|-------------------------|
| Subject with endoAVF that is
free of stenosis or thrombosis1,
with brachial artery flow of at
least 500 ml/min and at least 4
mm vein diameter OR subject
was dialyzed using 2 needles
1As adjudicated by the CEC. | 91.2%
(52/57) | (82.4%,
96.5%) | Ho: ps $ \u2264 $ 57.5%
HA: ps > 57.5% | Reject
Ho | Performance
Goal Met |

Table 8: Primary Effectiveness Endpoint Results - 90-Day Maturation Success Rate

The primary effectiveness analysis did not include 3 subjects who either died prior to the 90-dav evaluation, unrelated to the device or procedure (1 subject) or experienced a procedural complication that led to endoAVF sacrifice (2 subjects).

If all 60 study cohort subjects were included in the primary endpoint analysis, the primary endpoint result was 52/60 = 86.7%. The primary endpoint was still met (90% CI: 77.2-93.2%).

Secondary Endpoints: A summary of the secondary endpoint analyses are provided below. All analyses presented below are based on the ITT population unless otherwise noted.

Procedural Success: Procedural success was achieved in 59/60 subjects (98.3%) per the definition above.
. Time to Fistula Maturation: The mean time to maturation based on the endpoint criteria was 14.8 days. Additional details are provided in the table below.

Table 9: Time to Fistula Maturation

16

| Maturation Time | Mean ± SD (N)
Median [Range] |
|---------------------------------------------------|----------------------------------------|
| Days to endoAVF maturation based on DUS | 14.8 ± 26.0 (52)
5.0 [1.0, 97.0] |
| Days to endoAVF maturation based on physical exam | 65.0 ± 44.3 (45)
58.0 [26.0, 213.0] |

. Duration of Central Venous Catheter (CVC) Exposure: CVC exposure was evaluated for both pre-dialysis subjects and subjects who were on dialysis. Table 10 below shows the number of subjects who had a CVC in place at each timepoint. In sum, the total NEAT study CVC exposure at 12 months was 14/60 subjects (23.3%), calculated by adding 4/35 CVC only + 0/35 CVC and endoAVF subjects from the pre-dialysis subset, in addition to 6/25 CVC-only + 4/25 CVC and endoAVF subjects from the post-dialysis subset.

Pre-Dialysis Subjects
1-Month (0-45 Days)
CVC only	3/35 (8.6%)
endoAVF only	0/35 (0.0%)
CVC + endoAVF	0/35 (0.0%)
Other	0/35 (0.0%)
3-Month (46-135 Days)
CVC only	3/35 (8.6%)
endoAVF only	8/35 (22.9%)
CVC + endoAVF	2/35 (5.7%)
Other	0/35 (0.0%)
6-Month (136-270 Days)
CVC only	3/35 (8.6%)
endoAVF only	8/35 (22.9%)
CVC + endoAVF	4/35 (11.4%)
Other	1/35 (2.9%)
12-Month (271-390 Days)
CVC only	4/35 (11.4%)
endoAVF only	10/35 (28.6%)
CVC + endoAVF	0/35 (0.0%)
Other	1/35 (2.9%)
Post-Dialysis Subjects
1-Month (0-45 Days)
CVC only	24/25 (96.0%)
endoAVF only	0/25 (0.0%)
CVC + endoAVF	0/25 (0.0%)
Other	1/25 (4.0%)
3-Month (46-135 Days)
CVC only	9/25 (36.0%)
endoAVF only	1/25 (4.0%)
CVC + endoAVF	13/25 (52.0%)
Other	1/25 (4.0%)
6-Month (136-270 Days)
CVC only	4/25 (16.0%)
endoAVF only	6/25 (24.0%)

Table 10: Duration of CVC Exposure

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Other	4/25 (16.0%)
12-Month (271-390 Days)
CVC only	6/25 (24.0%)
endoAVF only	11/25 (44.0%)
CVC + endoAVF	4/25 (16.0%)
Other	4/25 (16.0%)

endoAVF-related Interventions Rate: Table 11 below shows the number and types of . adjunctive procedures that were performed at the same time as the endoAVF index procedure. In total, 56/60 subjects (93.3%) required the implantation of at least one coil in their brachial vein at the time of the index procedure to redirect blood flow to the superficial veins and support maturation of the target cannulation area. The mean number of coils used per subject who received them was 1.6, with a range of 1.0-3.0 coils.
Table 12 shows the number of subjects who required at least one reintervention after the index procedure to assist maturation of the endoAVF or to maintain a mature endoAVF. The total number and types of reinterventions are also tabulated.

Adjunctive Procedure	# of Subjects (%)
Therapeutic embolization	56 (93.3%)
Arterial closure device use	41 (68.3%)
PTA	0 (0.0%)
Stent	0 (0.0%)
Other*	6 (10.0%)
Total Subjects with > 1 Procedure	58/60 (96.7%)

Table 11: Adjunctive Procedures Performed at Index Procedure

Other procedures include thrombolysis (1), thrombectomy (2), new surgical AVF (1), open surgical repair for an intraoperative complication (6).

Adjunctive procedures are tabulated by the procedure (i.e. one subject may have more than one adjunctive procedure), except for the last row which tabulates the data at the subject level.

Reintervention	Indication	0-90 Days	0-180 Days	0-365 Days
Coil Embolization	Maturation Assistance	2	2	5
Angioplasty	Maturation Assistance	1	1	2
Transposition	Facilitate Cannulation	0	3	5
Surgical Fistula or Graft	New Access Needed	0	0	2
EndoAVF Ligation	Adverse Event	3	3	3
Thrombin Injection for Pseudoaneurysm	Adverse Event	2	2	2
Surgical Procedure for Complication	Adverse Event	1	1	1
Total Reinterventions	-	9	12	20
Total Subjects with ≥ 1 Reintervention	-	7/60 (11.7%)	10/60 (16.7%)	17/60 (28.3%)

Table 12: endoAVF-related Reinterventions in NEAT Study

Primary Patency: The following primary patency rates were reported: .
- O Primary patency, 6 months: 81.1%

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Primary patency. 12 months: 73.4% o
o Assisted primary patency, 6 months: 84.8%
Assisted primary patency, 12 months: 77.2% O
Secondary Patency: The following secondary patency rates were reported: .
- 0 Secondary patency, 6 months: 86.4%
- Secondary patency, 12 months: 78.9% o

Additional Analyses

Rate of Serious Device- and Procedure-Related AEs

A total of eight (8) serious adverse events (SAEs) in five (5) subjects were adjudicated as procedure and/or device-related. All eight (8) SAEs were adjudicated as procedure-related, and one of the eight (1/8) SAEs (pseudoaneurysm near endoAVF) was adjudicated as related to both the device and the procedure. Seven of the eight (7/8) SAEs occurred within 24 hours of the index procedure. One (1) SAE (steal syndrome) occurred on Day 8 post index procedure, representing the maximum number of days post-index procedure for onset of a serious procedure-related event. A summary of SAEs related to the study procedure and/or device has been provided in Table 13 below.

All SAEs were able to be resolved through intervention or resolved on their own. There were no instances of permanent impairment associated with the device. No new serious procedure and/or device related events were reported beyond 3 months.

	0-3 Months		3-6 Months		> 6 Months		Overall
Eventsi	Total
Events	Subjects
Experienced
% (n/N)	Total
Events	Subjects
Experienced
% (n/Nii)	Total
Events	Subjects
Experienced
% (n/Niii)	Total
Events	Subjects
Experienced
% (n/N)
Overall	8	8.3% (5/60)	0	0.0% (0/57)	0	0.0% (0/55)	8	8.3% (5/60)
Closure device embolization	2	3.3% (2/60)	0	0.0% (0/57)	0	0.0% (0/55)	2	3.3% (2/60)
Dissection of brachial artery	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)
Pseudoaneurysm near endoAVFiv	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)
Pseudoaneurysm, access site	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)
Steal syndrome	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)
Thrombosis brachial artery, not leading to fistula
closure	2	3.3% (2/60)	0	0.0% (0/57)	0	0.0% (0/55)	2	3.3% (2/60)

Table 13: NEAT Study SAEs Related to Study Procedure and/or Device (CEC-Adiudicated)

4 Based on the number of subjects still in the study at 3 Month follow-up (i.e. subjects who exited the study after 3 Month follow-up window opened) " Based on the number of subjects still in the study at 6 Month Follow-up (i.e. subjects who exited the study after 6 Month follow-up window opened) 1VThis event is also related to the study device.

A total of 28 adverse events (AEs) in 22 subjects were adjudicated as non-serious and procedure and/or device-related. Of these AEs. all were adjudicated as procedure-related (28/28) and three were adjudicated as related to both the device and the procedure (3/28). Twenty-six of the related AEs (26/28) occurred within 3 months of the index procedure. A summary of the non-serious AEs is provided in Table 14 below.

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All but two procedure-related AE occurred within 3 months post-index procedure resulting in 3month procedure-related AE rate of 33.3% (20/60) and overall rate of 36.7% (22/60) through 12 months.

	0-3 Months		3-6 Months		> 6 Months		Overall
Eventsi	Total
Events	Subjects
Experienced
% (n/N)	Total
Events	Subjects
Experienced
% (n/N)	Total
Events	Subjects
Experienced
% (n/N)	Total
Events	Subjects
Experienced
% (n/N)
Overall	26	33.3% (20/60)	2	3.5% (2/57)	0	0.0% (0/55)	28	36.7% (22/60)
Bruising	6	10.0% (6/60)	0	0.0% (0/57)	0	0.0% (0/55)	6	10.0% (6/60)
Hematoma	4	6.7% (4/60)	0	0.0% (0/57)	0	0.0% (0/55)	4	6.7% (4/60)
Numbness, tingling and/or coolness in the fistula
extremity	3	5.0% (3/60)	0	0.0% (0/57)	0	0.0% (0/55)	3	5.0% (3/60)
Pain	2	3.3% (2/60)	0	0.0% (0/57)	0	0.0% (0/55)	2	3.3% (2/60)
Perforation, related to guidewire	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)
Pseudoaneurysm near endoAVF	2	3.3% (2/60)	0	0.0% (0/57)	0	0.0% (0/55)	2	3.3% (2/60)
Pseudoaneurysm, access site	2	3.3% (2/60)	0	0.0% (0/57)	0	0.0% (0/55)	2	3.3% (2/60)
Spasm and clot	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)
Steal	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)
Swelling, irritation or pain	2	3.3% (2/60)	1	1.8% (1/57)	0	0.0% (0/55)	3	5.0% (3/60)
Thrombosis Brachial artery, Not leading to fistula
closure	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)
Thrombosis post proc of endoAVF leading to
fistula closure	0	0.0% (0/60)	1	1.8% (1/57)	0	0.0% (0/55)	1	1.7% (1/60)
Thrombosis, intra-procedural leading to fistula
closure	1	1.7% (1/60)	0	0.0% (0/57)	0	0.0% (0/55)	1	1.7% (1/60)

Table 14: NEAT Study Non-Serious Procedure-Related Adverse Events by Type and Timing
(CEC-Adjudicated)

¹As adjudicated by the Clinical Events Committee

Based on the number of subjects still in the study at 3 Month follow-up (i.e. subjects who extred the study after 3 Month follow-up window opened)

" Based on the number of subjects still in the study at 6 Month Follow-up (i.e. subjects who exited the study after 6 Month follow-up window opened)

Summary of Occlusions and Thromboses

Table 15 below provides a summary of the number of thromboses and occlusions that occurred during the study. The data are presented as acute (defined as 0-42 days to represent the data reported through the 6-week visit) and total events reported through the end of the study's 12month visit. There was 1 acute thrombosis of the endoAVF treated unsuccessfully with thrombolysis, and the endoAVF was eventually abandoned. There were 4 additional (non-acute) thromboses of the endoAVF all leading to endoAVF abandonment. In total, 5/60 (8.3%) subjects experienced thrombosis of the endoAVF at some point during the study. 3/60 (5.0%) subjects experienced thrombosis of the brachial artery during the study. All 3 of these events were acute and were treated (1 thrombolysis, 2 thrombectomy) and did not lead to endoAVF abandonment. 1/60 (1.7%) subjects experienced occlusion of the endoAVF during the study. This event was non-acute and led to endoAVF abandonment. There were no occlusions of the brachial artery during the study.

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All 4 acute thrombosis events listed in Table 15 (1 endoAVF thrombosis and 3 brachial artery thromboses) occurred at the time of the endoAVF index procedure and all were treated via thrombolysis or thrombectomy.

The events were either treated with thrombectomy/thrombolysis or no treatment was provided. 6/9 of the endoAVFs that experienced an occlusion or thrombosis were abandoned, for a total endoAVF abandonment rate of 10.0% at 12 months.

		Acute		Total
	N	Abandoned	N	Abandoned
Thrombosis - endoAVF	1/60
(1.7%)	1/1	5/60
(8.3%)	5/5	1 Thrombolysis
4 No Treatment	2/5 subjects entered study
pre-dialysis and exited study
pre-dialysis
3/5 subjects entered study on-
dialysis and exited study on
CVC
Thrombosis - Brachial Artery*	3/60
(5.0%)	0/3	3/60
(5.0%)	0/3	2 Thrombectomy
1 Thrombolysis	2/3 subjects entered study
pre-dialysis and 1 subject
exited study on CVC and 1
subject exited study early pre-
dialysis
1/3 subjects entered study on-
dialysis and exited study on
endoAVF and achieved
functional cannulation
success
Occlusion - endoAVF	0/60
(0.0%)	-	1/60
(1.7%)	1/1	1 No Treatment	1/1 subject entered study pre-
dialysis and exited study early
pre-dialysis
Occlusion - Brachial Artery	0/60
(0.0%)	-	0/60
(0.0%)	-	-	-
Total - endoAVF	1/60
(1.7%)	1/1	6/60
(10.0%)	6/6	-	-
Total - All	4/60
(6.7%)	1/4	9/60
(15.0%)	6/9
* - The brachial artery thrombosis events occurred during the index procedure.

Table 15: NEAT Study Thromboses and Occlusions

Rate of Device and/or Procedure-Related Infections

There were no device- or-procedure related infections observed in the study. There were two subjects (2/60 = 3.3%) who experienced an infection related to a CVC.

Arterial Flow Rates and Vein Diameters

Table 16 below shows the arterial flow rates through the brachial artery as measured by DUS, expressed as mL/min. The highest mean arterial flow rate was observed at 6 weeks (928.17 mL/min). Figure 4 shows the average brachial artery flow rates over time. Table 17 shows the inner diameters by vessel and study visit, expressed in millimeters (mm).

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Study visit	Flow Rate (peak)	Flow Rate (mean)
Baseline	123.40 ± 100.45 (57)
102.10 [8.20,620.00]	81.48 ± 61.67 (56)
58.60 [8.29,300.00]
1-7 Days	1188.04 ± 768.76 (57)
1105.00 [14.35,4029.50]
P-value: 50%	Yes	Yes
Hypercoagulable state	Yes	Yes
Planned/prior procedure 72 hours, 30 days)
Pre-Training	n/N (%)	10/60 (16.6%)
Post-Training	n/N (%)	NA
Any Timepoint
Pre-Training	n/N (%)	15/60 (25.0%)
Post-Training	n/N (%)	NA
* Procedure date unavailable for 1 COMM subject
CEC-adjudicated data

Table 24: SAEs by Training Status (CEC-Adjudicated)

Effectiveness Endpoints

A summary of the Effectiveness outcomes is tabulated in the main summary table (Table 25) below. The Pooled Effectiveness Population comprised subjects treated as part of the FLEX. EU-PMCF, NEAT, and EASE studies (N=157). Subjects treated commercially were not included in this population.

Procedural success, defined as the successful creation of an endoAVF with blood flow confirmed intraoperatively by fistulography or by duplex ultrasound postoperatively, was achieved in 96.8% (152/157) of the Pooled Effectiveness Population Success (2-needle access and hemodialysis through the fistula) was achieved in 82.4% of subjects through the 6 month window and in 92.4% of subjects through the 12 month window after the index procedure.

The median time to successful cannulation was 2.1 months after a subject went on dialysis (or after the index procedure in those that were on dialysis at enrollment). The Kaplan-Meier estimate for Functional Cannulation (All Subjects), defined in the table below, was 42.4% at 6 months and 58.9% at 12 months. For patients already on dialysis at the time of enrollment, Functional Cannulation was 56.1% and 78.4% at 6 and 12 months, respectively. The reported Kaplan-Meier estimate of Primary Patency was 82.7% and 74.8% at 6 and 12 months, respectively. Similar results were observed in the commercial cases, where the corresponding data was available.

35

| | NEAT
(N=60) | FLEX
(N=33) | EU-PMCF
(N=32) | EASE
(N=32) | Pooled*
(Effectiveness=157) | COMM
(N=45) |
|--------------------------------------------------------------|------------------|-------------------|-------------------|-------------------|--------------------------------|-------------------|
| Effectiveness Endpoints: | | | | | | |
| Procedural Success | 59/60
(98.3%) | 32/33
(97.0%) | 29/32
(90.6%) | 32/32
(100.0%) | 152/157
(96.8%) | 44/45
(97.8%) |
| Time to Cannulation (Months) | | | | | | |
| Observations | 31 | 25 | 11 | 21 | 88 | 18 |
| Median [IQR] | 3.1 [2.7,5.6] | 2.1 [1.9,2.4] | 2.4 [1.4,3.4] | 1.3 [1.1,1.6] | 2.1 [1.6,3.2] | 1.7 [0.4,2.9] |
| Mean ± SD | 4.1 ± 2.3 | 2.2 ± 0.8 | 3.0 ± 1.9 | 1.4 ± 0.5 | 2.8 ± 1.9 | 2.3 ± 2.3 |
| (Min, Max) | (1.4, 10.7) | (1.1, 4.6) | (1.2, 7.2) | (1.0, 3.0) | (1.0, 10.7) | (0.3, 7.8) |
| Cannulation
Success, 6-Month | 70.6%
(±7.4%) | 100.0%
(±0.0%) | 71.2%
(±13.3%) | 90.4%
(±6.4%) | 82.4%
(±4.0%) | 94.3%
(±5.5%) |
| Cannulation
Success, 12-Month | 86.1%
(±6.6%) | NA | 100.0%
(±0.0%) | NA | 92.4%
(±3.6%) | 100.0%
(±0.0%) |
| Functional
Cannulation, 6-
Month | 36.3%
(±6.7%) | 88.6%
(±7.0%) | 63.2%
(±13.6%) | 85.8%
(±7.5%) | 42.4%
(±6.1%) | NA |
| Functional
Cannulation, 12-
Month | 53.1%
(±7.4%) | NA | 100.0%
(±0.0%) | NA | 58.9%
(±6.6%) | NA |
| Functional
Cannulation,
Dialysis Subset, 6-
Month† | 50.4%
(±8.2%) | 94.5%
(±5.1%) | 71.1%
(±13.3%) | 85.8%
(±7.5%) | 56.1%
(±7.1%) | NA |
| Functional
Cannulation,
Dialysis Subset, 12-
Month† | 74.2%
(±7.0%) | NA | NA | NA | 78.4%
(±6.7%) | NA |
| Primary Patency, 6-
Month | 81.1%
(±5.1%) | 96.4%
(±3.5%) | 78.9%
(±7.7%) | 83.3%
(±6.8%) | 82.7%
(±3.5%) | 71.3%
(±7.4%) |
| Primary Patency.
12-Month | 73.4%
(±5.9%) | N/A | 78.9%
(±7.7%) | N/A | 74.8%
(±4.9%) | 63.5%
(±8.4%) |
| Mod Primary
Patency, 6-Month | 76.5%
(±5.5%) | 53.6%
(±9.4%) | 68.4%
(±8.8%) | 83.3%
(±6.8%) | 70.5%
(±4.0%) | 71.3%
(±7.4%) |
| Mod Primary
Patency, 12-Month | 61.1%
(±8.1%) | N/A | 68.4%
(±8.8%) | N/A | 56.3%
(±7.1%) | 63.5%
(±8.4%) |
| Assist Prim Patency,
6-Month | 84.8%
(±4.7%) | 96.4%
(±3.5%) | 82.1%
(±7.3%) | 86.8%
(±6.2%) | 85.8%
(±3.2%) | 71.3%
(±7.4%) |
| Assist Prim Patency,
12-Month | 77.2%
(±5.6%) | N/A | 82.1%
(±7.3%) | N/A | 78.2%
(±4.7%) | 63.5%
(±8.4%) |
| Secondary Patency.
6-Month | 86.4%
(±4.5%) | 96.4%
(±3.5%) | 82.1%
(±7.3%) | 86.8%
(±6.2%) | 86.5%
(±3.1%) | 70.4%
(±7.5%) |

Table 25: Effectiveness Endpoint Results
------------------------------------------

36

| Secondary Patency,
12-Month | 78.9%
(±5.4%) | N/A | 82.1%
(±7.3%) | N/A | 79.0%
(±4.6%) | 62.8%
(±8.4%) |
|---------------------------------|------------------|-------------------|-------------------|-------------------|------------------|------------------|
| Functional Patency,
6-Month | 96.3%
(±3.6%) | 100.0%
(±0.0%) | 100.0%
(±0.0%) | 100.0%
(±0.0%) | 98.1%
(±1.8%) | 95.0%
(±4.9%) |
| Functional Patency,
12-Month | 96.3%
(±3.6%) | N/A | 100.0%
(±0.0%) | N/A | 98.1%
(±1.8%) | 82.3%
(±9.3%) |

This summary table is intended to provide standalone results for the most important efficacy study endooints.

The Pooled Effectiveness Population includes those studies plus EASE. The exception is Functional Cannulation, where the pooled dataset is limited to NEAT and EU-PMCF since more extensive cannulation data was available in those studies.

The 6- and 12-month windows are defined as 180 and 360 days + 30 days, respectively. The data in this table represent events through the end of the respective windows; i.e. 210 days for 6 months and 390 days for 12 months.

NA- Not applicable. Indicates that the data point is beyond the length of follow-up for a study or that the number of evaluable subjects is zero at that time point.

Procedural Success was defined as successful endo.4VF creation confirmed via intraprocedural fistulography or by duplex ultrasound performed post-procedure.

Time to Cannulation is the time between the index procedure to the first successful endoAVF cannulation. Cannulation Success was defined as successful 2-needle cannulation and dialysis through the endoAVF.

Functional Cannulation is defined as 2-needle access of the endoAVF access circuit with performance of ≥ 2/3rds of > 120-minute dialysis sessions through the endoAVF access circuit over a continuous 28-day period. Functional Cannulation is expressed as the Kaplan-Meier estimate (Standard Error).

Patency definitions are from the Society of Vascular Surgery Reporting Standards document; Sidawy et al. Recommended standards for reports dealing with arteriovenous hemodialysis accesses, J Vasc Surg 2002;35:603-10. Primary patency is the interval of time of access placement until any intervention designed to maintain or re-establish patency, access thrombosis, access abandomment, or the time of measurement of patency. Assisted is the interval from access placement to thrombosis or abandonment; not triggered by access circuit interventions performed in the absence of occlusion. Secondary patency is the of access placement until access abandonment, lost to thrombosis, or the time of patency measurement including intervening manipulations (surgical or endovascular interventions) designed to re-establish functionality in thrombosed access. Functional patency is the interval of time from the first 2-needle dialysis utilizing the access abandonment.

Patency rates are expressed as Kaplan-Meier estimates (Standard Error,

Data is site-reported, with independent Medical Monitor classifications and CEC-adjudicated data

For all effectiveness endpoints except Functional Cannulation, pooled studies include NEAT, FLEX, EU-PMCF, and EASE. The pooled studies for Functional Cannulation excluded FLEX and EASE, since the extent of available cannulation data was less than for the NEAT and EU-PMCF studies.

f Functional Cannulation, specified in the dialysis subset defined as the cohort of subjects who were enrolled on dialysis or eventually went on dialysis during follow-up. The data include the NEAT and EU-PMCF studies alone.

The 6- and 12-month timepoints were calculated at the end of the follow-up windows, through 210 and 390 days, respectively.

Patency Results

As shown in Table 25 above, the 6-month primary patency rates among the EU-PMCF (78.9%) and EASE (83.3%) studies were numerically similar to the 6-month primary patency rate in the NEAT study (81.1%). Among the entire pooled effectiveness population, the 6-month primary patency rate was 82.7%.

The figures below show patency rates for the pooled effectiveness population expressed as Kaplan-Meier estimates with shaded regions showing the 95% confidence interval. The 12

37

month primary patency rate for the pooled effectiveness population was 74.8%, although only 29 subjects were evaluable at this 12 months as shown by the corresponding life table.

Image /page/37/Figure/1 description: The image shows a survival probability graph with days on the x-axis and survival probability on the y-axis. The graph displays a curve that starts near 1.0 and gradually decreases over time, with a shaded area representing the 95% equal precision band. A table below the graph provides data on the number at risk, censored, failures, success rate, Greenwood SE, and 95% CI for different time intervals in days, ranging from day 0 to 361-390. For example, at day 0, the success rate is 98.1%, while at days 361-390, the success rate is 74.8%.

Figure 6: Primary Patency, Pooled Effectiveness Population

38

Image /page/38/Figure/0 description: The image shows a survival probability graph with days on the x-axis and survival probability on the y-axis. The graph includes a blue line representing the survival probability over time, along with a shaded blue area indicating the 95% equal precision band. A table below the graph provides detailed data for different time intervals, including the number at risk, censored, failures, success rate, Greenwood SE, and 95% CI. For example, at day 0, there were 157 at risk, 4 censored, 2 failures, and a success rate of 98.7%.

Figure 7: Assisted Primary Patency, Pooled Effectiveness Population

Functional Cannulation

Functional Cannulation is defined as successful 2-needle cannulations with at least 2 hours of hemodialysis through the access circuit, for two-thirds or more of the dialysis sessions in any continuous 28-day period. The time to Functional Cannulation is the duration from the index procedure to the start of the 28-day period.

Table 26 below shows the proportion of subjects in each category who had achieved functional cannulation at each timepoint. Additionally, the table shows the number of subjects who were evaluable in each category (N), as well as the median (months), mean ± SD (months), and range

39

of months subjects required to reach the 28-day period when they achieved Functional Cannulation success. The data come from the NEAT and EU-PMCF studies, as these studies used detailed cannulation logs.

| Measure | On dialysis at enrollment | Pre-dialysis at enrollment
who eventually went on
dialysis | On dialysis at enrollment
or pre-dialysis at
enrollment who eventually
went on dialysis |
|--------------------------------------------------------------------|---------------------------|------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|
| Functional Cannulation, 6-Month* | 59.4% ( $\pm$ 9.3%) | 52.5% ( $\pm$ 10.8%) | 56.1% ( $\pm$ 7.1%) |
| Functional Cannulation, 12-Month* | 73.9% ( $\pm$ 9.1%) | 85.1% ( $\pm$ 9.1%) | 78.4% ( $\pm$ 6.6%) |
| N | 40 | 26 | 66 |
| Median [IQR] | 0.7 [0.0,3.5] | 3.5 [1.9,7.4] | 3.4 [2.1,7.2] |
| Mean $\pm$ SD | 2.1 $\pm$ 2.6 | 5.0 $\pm$ 3.6 | 4.7 $\pm$ 3.7 |
| Range (min, max) | (0.0, 9.5) | (0.3, 12.1) | (0.0, 12.4) |
| The 6- and 12-Month windows end at 210 and 390 days, respectively. | | | |

Table 26: Functional Cannulation, Subjects Requiring Dialysis

Table 27 below shows the number of subjects who were evaluable for functional cannulation success from each data source: i.e., the number of subjects who initiated hemodialysis during each study. It also shows the percentage of subjects from each study who were on hemodialysis and achieved functional cannulation success at 6 months and 12 months, as well as the time to achieve functional cannulation success broken out by subjects who were on dialysis at enrollment and subjects who were pre-dialysis at the beginning of the study and eventually required hemodialysis.

Among the Pooled functional cannulation - which includes only subjects from the NEAT and EU-PMCF studies because only these studies contained detailed cannulation logs the functional cannulation success was 56.1% at 6 months and 78.4% at 12 months. Among these subjects, the average time to achieve functional cannulation success was 2.1 months for subjects who were on dialysis at enrollment and 5.0 months for subjects who were pre-dialysis at the time of study enrollment.

40

Metric	NEAT	FLEX	EU-PMCF	EASE	Pooled
Total N	60	33	32	32	92
Exited study
predialysis	17	2	9	0	26
Total
included in
analysis	43	31	23	32	66
Functional
Cannulation
Success
6-Month+	50.4%
CI[34.3% - 66.5%]	94.5%
CI[84.5% - 100%]	71.1%
CI[45.1%-97.1%]	85.8%
CI[71.1%-100%]	56.1%
CI[42.2%-69.9%]
Functional
Cannulation
Success
12-Month+	74.2%
[58.7%-89.6%]	NA	NA	NA	78.4%
CI[65.3%-91.4%]
Time to
Cannulation
(months)	Dialysis 3.9 ± 1.5
Predialysis 4.2 ± 3.0	Dialysis 2.2 ± 0.8
Predialysis NA	Dialysis 3.1 ± 1.4
Predialysis 2.9 ±
2.5	Dialysis 1.4 ± 0.5
Predialysis NA	Dialysis 2.1 ± 2.6
Predialysis 5.0 ±
3.6
* Excludes predialysis patients that never were on to dialysis through study exit
Pooled includes NEAT and EU-PMCF only as these studies contained detailed cannulation logs.

The 6- and 12-month windows end at 210 and 390 days, respectively | | | | | |

Table 27: Functional Cannulation Success* by Data Source

Conclusions: The NEAT Study and the Global Analysis demonstrated that there is a reasonable assurance of safety and effectiveness that the everlinQ® endoAVF System creates an arteriovenous fistula that can mature as a method of vascular access for hemodialysis. In the NEAT Study, a fistula was successfully created in 59/60 (98.3%) subjects and 52/60 (86.7%) met the primary endpoint success criteria for fistula maturation at 90 days. The rate of SAEs related to the device and/or procedure through 12 months was 8 SAEs in 5/60 subjects (8.3%), and the primary safety endpoint was met. Although 2 of the SAEs in the NEAT Study were related to vascular closure device embolization, safety data collected from the EU-PMCF and commercial cases after the implementation of a training program showed that all subjects (20/20) achieved hemostasis by manual compression of the brachial artery instead of using vascular closure devices, and no subjects (0/20 = 0%) experienced any SAEs after the implementation of the training program, as summarized in Table 24 above. Among NEAT Study subjects who went on hemodialysis during the study, the functional cannulation endpoint was met by 50.4% of subjects at 6 months and by 74.2% of subjects at 12 months. In the NEAT Study, the reported Kaplan-Meier estimate for primary patency was 81.1% at 6 months and 73.4% at 12 months. The reported Kaplan-Meier estimate for assisted primary patency at 12 months was 77.2%. In the NEAT Study, 56/60 subjects (93.3%) required the implantation of at least one embolization coil in their brachial vein at the time of the index procedure, with an average of 1.6 coils. After the index procedure, 17/60 subjects (28.3%) required at least one reintervention, with a total of 20 reinterventions among those 17 subjects.

Pediatric Extrapolation

In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric patient population.

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POSTMARKET EVALUATION

A postmarket evaluation will be conducted to collect data on the safety and effectiveness of the everlinO® endoAVF System in U.S. patients. This is a postmarket, prospective. multi-center study of U.S. patients with chronic kidney disease who need hemodialysis and are candidates for the creation of an arteriovenous fistula with the everlinO® endoAVF System. Safety and effectiveness data will be collected and compared to the pivotal study data that supported this De Novo application.

LABELING

The everlinQ® endoAVF System labeling consists of Instructions for Use and packaging labels. The Instructions for Use include the indications for use; a description of the device, contraindications, warnings, precautions; a list of commercially available electrosurgical devices that are compatible with the device; a detailed summary of the clinical data collected in support of the device: a list of potential adverse events; a shelf life; the expertise needed for the safe use of the device; and instructions for the safe use of the device. The labeling satisfies the requirements of 21 CFR 801.109.

Please see the Limitations section above for important contraindications, warnings and precautions presented in the device labeling.

RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of a percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access and the measures necessary to mitigate these risks.

Identified Risks to Health	Mitigation Measures
Unintended vascular or tissue injury	Non-clinical performance testing
Animal testing
Clinical performance testing
Labeling
Adverse hemodynamic effects	Non-clinical performance testing
Animal testing
Clinical performance testing
Labeling
Failure to create a durable fistula that is usable
for hemodialysis	Animal testing
Clinical performance testing
Use of the device adversely impacts future
vascular access sites	Clinical performance testing
Labeling
Adverse tissue reaction	Biocompatibility evaluation
Labeling
Infection	Sterilization validation

Table 28: Identified Risks to Health and Mitigation Measures

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| | Shelf life testing
Labeling | |
|-----------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|--|
| Electrical malfunction or interference leading
to electrical shock, device failure, or
inappropriate activation | Non-clinical performance testing
Electrical safety testing
Electromagnetic compatibility (EMC) testing | |
| Software malfunction leading to device failure
or inappropriate activation | Software verification, validation, and hazard
analysis | |

SPECIAL CONTROLS:

In combination with the general controls of the FD&C Act, the percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access is subject to the following special controls:

1. Clinical performance testing must evaluate:
- The ability to safely deliver, deploy, and remove the device; a.
- b. The ability of the device to create an arteriovenous fistula;
- c. The ability of the arteriovenous fistula to attain a blood flow rate and diameter suitable for hemodialysis:
- d. The ability of the fistula to be used for vascular access for hemodialysis;
- e. The patency of the fistula; and
- f. The rates and types of all adverse events.
1. Animal testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be assessed:
- a. Delivery, deployment, and retrieval of the device:
- b. Compatibility with other devices labeled for use with the device:
- Patency of the fistula: C.
- d. Characterization of blood flow at the time of the fistula creation procedure and at chronic follow-up; and
- Gross pathology and histopathology assessing vascular injury and downstream e. embolization.
1. Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested:
- Simulated-use testing in a clinically relevant bench anatomic model to assess the a. delivery, deployment, activation, and retrieval of the device:
- b. Tensile strengths of joints and components;
- c. Accurate positioning and alignment of the device to achieve fistula creation: and
- d. Characterization and verification of all dimensions.
1. Electrical performance, electrical safety, and electromagnetic compatibility (EMC) testing must be performed for devices with electrical components.

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1. Software verification, validation, and hazard analysis must be performed for devices that use software.
1. All patient-contacting components of the device must be demonstrated to be biocompatible.
1. Performance data must demonstrate the sterility of the device components intended to be provided sterile.
1. Performance data must support the shelf life of the device by demonstrating continued sterility, package integrity, and device functionality over the identified shelf life.
1. Labeling for the device must include:
- a. Instructions for use:
- b. Identification of system components and compatible devices;
- c. Expertise needed for the safe use of the device;
- d. A detailed summary of the clinical testing conducted and the patient population studied: and
- e. A shelf life and storage conditions.

BENEFIT/RISK DETERMINATION

The risks of the device are based on nonclinical laboratory and/or animal studies as well as data collected in the clinical studies described above. Types of harmful events include access site complications, pseudoaneurysm, thrombosis, closure device embolization, brachial artery dissection, hematoma, bruising, steal, swelling and pain. Among the NEAT study population described in the clinical data section above, the rate of serious device- and/or procedure-related harmful events was 5/60 (8.3%) and the rate of non-serious device- and/or procedure-related harmful events was 22/60 (36.7%). There were no deaths adjudicated as related to the device or procedure. A total of 9 occlusion and/or thrombosis events were observed in 9 subjects (15.0%); for 4 of these 9 subjects (44.4%) the occlusion event was acute (occurred within 0-42 days of the index procedure). A total of 6 endoAVFs (6/60 = 10%) were abandoned due to thrombosis or occlusion of the endoAVF at 12 months. The endoAVF procedure requires adjunctive procedures at the time of the index procedure, as 56/60 subjects (93.3%) in the NEAT study required the implantation of an average of 1.6 embolization coils in a brachial vein to redirect blood flow to the superficial veins and support maturation of the target cannulation area.

The probable benefits of the device are also based on nonclinical laboratory and/or animal studies as well as data collected in clinical studies as described above. In the NEAT Study, there was a high rate of procedural success as 59/60 subjects (98.3%) had an endoAVF successfully created. The 90-day maturation success rate, defined as the rate of subjects with an endoAVF that was free of stenosis or thrombosis with brachial artery flow of at least 500 mL/min and at least 4mm vein diameter OR subject was dialyzed using 2 needles, was 52/60 (86.7%). Out of the subjects who required hemodialysis during the NEAT study. 70.6% achieved cannulation success at 6 months and 86.1% achieved cannulation success at 12 months. Among those subjects who required hemodialysis during the study, functional cannulation success was

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achieved in 50.4% of the subjects at 6 months and in 74.2% of the subjects at 12 months. Primary patency was achieved in 81.1% of subjects at 6 months and 73.4% of subjects at 12 months.

Additional factors to be considered in determining probable risks and benefits for the everlin(® endoAVF System include: Physician training may reduce the rate of access site complications, and a physician training program will be used in the post-market study. The Global Analysis data and initial physician training data suggest that hemostasis of the brachial artery access site can be achieved with manual compression instead of vascular closure devices. The device requires embolization coils to be implanted in the deep veins at the index procedure to assist fistula maturation, so any adjunctive procedures should be planned for each patient prior to the procedure. The device was not studied with any Black subjects, but this subgroup will be evaluated in a U.S. post-market study. All serious device- and/or procedure-related complications observed in the NEAT Study were reversible through intervention or were selfresolving. There were no device- or procedure-related infections observed in the NEAT Study.

Patient Perspectives

This submission included patient perspective information from a subset of patients treated in the NEAT Study. However, due to the limitations of the data, it was not considered in the benefit/risk analysis of the device.

Benefit/Risk Conclusion

In conclusion, given the available information above, the data support that for the creation of an arteriovenous fistula in patients with chronic kidney disease who need hemodialysis, the probable benefits outweigh the probable risks for the everlinO® endoAVF System. The device provides benefits and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

The De Novo request for the everlinQ® endoAVF System is granted and the device is classified under the following:

Product Code:	PQK
Device Type:	Percutaneous catheter for creation of an arteriovenous fistula for hemodialysis access
Class:	II
Regulation:	21 CFR 870.1252