Ellipsys Vascular Access System

• K Number: DEN170004
• Device Name: Ellipsys Vascular Access System
• Manufacturer: Avenu Medical, Inc
• Date Cleared: 2018-06-22 ( 528 days)
• Product Code: PQK POK
• Regulation Number: 870.1252

Intended Use

The Ellipsys® System is indicated for the creation of a proximal radial artery to perforating vein anastomosis via a retrograde venous access approach in patients with a minimum vessel diameter of 2.0mm and less than 1.5mm of separation between the artery and vein at the fistula creation site who have chronic kidnev disease requiring dialysis.

Device Description

The Ellipsys® Vascular Access System is a catheter based system that is used to percutaneously create a vascular anastomosis between adjacent blood vessels using direct current (DC) thermal heating. The system consists of several components: - Ellipsys Catheter ● - Ellipsys Crossing Needle - Ellipsys Power Controller ●

Predicate Devices

DEN170004

Reference Devices

DEN170004

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a catheter-based system using thermal heating for creating a vascular anastomosis. There is no mention of AI, ML, image processing for analysis, or any description of training or test data sets, which are typical indicators of AI/ML use in medical devices. The software is mentioned as having a Moderate Level of Concern and being validated, but this does not imply AI/ML functionality.

Therapeutic

Yes
The device is indicated for the creation of an arteriovenous fistula in patients with chronic kidney disease requiring dialysis, which is a therapeutic intervention.

Diagnostic

No

The device is indicated for the creation of an anastomosis, which is a therapeutic procedure, not a diagnostic one. While it uses ultrasound as an imaging modality, this is for guidance during the procedure rather than for diagnosing a condition.

SaMD (Software as a Medical Device)

No

The device description explicitly lists hardware components: Ellipsys Catheter, Ellipsys Crossing Needle, and Ellipsys Power Controller. The performance studies also include bench testing on hardware components (dimensional verification, electrical performance, tensile strength, etc.).

IVD (In Vitro Diagnostic)

No, this device is not an IVD (In Vitro Diagnostic).

Here's why:

• IVD Definition: In Vitro Diagnostics are medical devices used to perform tests on samples taken from the human body (like blood, urine, tissue) to provide information about a person's health. These tests are performed outside the body.
• Ellipsys System Function: The Ellipsys System is used to create a vascular anastomosis (a connection between blood vessels) within the patient's body. It's an interventional device used for a surgical procedure, not for testing samples.

The description clearly outlines a system used for a percutaneous endovascular procedure, not for laboratory testing of biological samples.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The Ellipsys® System is indicated for the creation of a proximal radial artery to perforating vein anastomosis via a retrograde venous access approach in patients with a minimum vessel diameter of 2.0mm and less than 1.5mm of separation between the artery and vein at the fistula creation site who have chronic kidnev disease requiring dialysis.

Product codes

POK, PQK

Device Description

The Ellipsys® Vascular Access System is a catheter based system that is used to percutaneously create a vascular anastomosis between adjacent blood vessels using direct current (DC) thermal heating. The system consists of several components:

• Ellipsys Catheter ●
• Ellipsys Crossing Needle
• Ellipsys Power Controller ●

Ellipsys Catheter

The Ellipsys Catheter is a single-use, sterile, flexible catheter with a heating element on the distal tip. The catheter is tracked over a guidewire in the target anastomosis site. Then the distal tip components are extended, with part of the tip placed into the target artery, and the tip is retracted to approximate the vessels (i.e., pull the vessels together). Thermal energy is then delivered from the heating element on the tip to seal the vessels together and create an arteriovenous fistula (AVF).

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Ultrasound

Anatomical Site

proximal radial artery to perforating vein anastomosis in the arm

Indicated Patient Age Range

at least 18 years of age and no more than 80 years of age.

Intended User / Care Setting

Physicians trained in ultrasound guided percutaneous endovascular interventional techniques using appropriate clinical standards of care for fistula maintenance and maturation including balloon dilatation and coil embolization.

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)

PERFORMANCE TESTING - ANIMAL &/OR CADAVER

Study 1:

• Purpose: Evaluate the acute and chronic safety, fistula blood flow characteristics, fistula patency, handling characteristics, and histopathological response at the treatment site and off-target tissue sites using the final device design. Perform gross comparison of fistulae created with the final device design compared to a previous device design to demonstrate equivalent fistula creation. Perform study according to Good Laboratory Practices.
• Methods: GLP, N=6 ovine models. Insert, track, deploy, and activate device to create bilateral arteriovenous fistulae in each animal. The original device design was used to create a fistula in one femoral artery and the final device design was used to create a fistula in the other femoral artery. Acute and post-treatment assessments of device performance included needle and catheter access/removal, and anastomosis and sheath appearance. Immediately after fistula creation, fistulae were evaluated by ultrasound to determine fistula diameter, patency, and fistula flow. At 1, 7, and 30 days post-procedure, animals were evaluated for safety events (swelling, hematoma, thrombosis, etc.) and ultrasound was used to evaluate fistula diameter, patency, and fistula flow. Gross necropsy, including external and internal examination of the fistulae, was performed at 30 days. Histopathological examination of the fistulae and downstream organs such as the brain, heart, lungs, liver, spleen, and kidneys was conducted at 30 days to evaluate chronic safety of the fistula and any thromboembolic events. All results from fistulae created with the final device design were compared to the fistulae created with the previous device design to determine equivalence.
• Results: All fistulae were successfully created. Needle access/removal, catheter insertion/removal, anastomosis appearance, and sheath appearance were acceptable for all devices. No procedural or handling differences were observed between the two device designs. Intra-operative ultrasound demonstrated a focal seal zone around the circumference of all anastomoses. All animals appeared normal at routine health assessments. One unexpected death occurred due to anesthetic complications that occurred immediately post-sedation. 7/10 fistulae (4/5 created using final device design) were patent at 7-day follow-up. Loss of patency was due to flow reduction due to thrombosis at fistula, though the adjacent vein and artery were patent in all cases. There was no evidence of excessive submural bleeding, aneurysm, or loss of vessel approximation. The fistula sizes and flow rates for both device designs were acceptable at 30 days. Gross pathology supported the ultrasound findings. Thermal necrosis, granulation tissue, mineralization and neointimal hyperplasia were localized to the tissue site as expected. Vascular healing appeared to be normal for this type of device. No evidence of safety concerns, such as thrombo-emboli, was observed in downstream organs.

Study 2:

• Purpose: Evaluate the ability to create an endovascular fistula, acute performance, and chronic safety in an animal model using an earlier design version of the device compared to surgical fistula creation. Following the study, no major changes were made to the electro-mechanical system involved in vessel access or energy delivery.
• Methods: Non-GLP, N=6 ovine models. Insert, track, deploy, and activate device to create a fistula in one of the femoral arteries of each animal. A surgical fistula was subsequently created in the other femoral artery of each animal. Immediately after fistula creation, fistulae were evaluated by ultrasound to determine fistula diameter, patency, and fistula flow. At 15 and 30 days post-procedure, ultrasound was used to evaluate fistula diameter, patency, and fistula flow. Gross pathological examination and histopathological examination performed for N=3 animals at 15 days and N=3 animals at 30 days to evaluate safety and healing response.
• Results: Procedural performance was acceptable for all devices. 5/6 fistulae were successfully created. One fistula separated five minutes after the procedure, but no intervention was required and no clinical sequelae were observed. All successfully created fistulae were patent at all follow-up evaluations, with acceptable fistula flow. No adverse clinical events were observed in any animals. No evidence of chronic tissue damage was observed. No excessive inflammatory response, delayed healing or stenosis was observed. Fistula performance appeared to be acceptable and comparable to the surgical control fistulae.

SUMMARY OF CLINICAL INFORMATION

• Purpose: To demonstrate the safety and effectiveness of the Ellipsys Vascular Access System in creating a native AV fistula via percutaneous access to support future hemodialysis.
• Design: The study was a non-randomized, prospective multi-center study conducted in the United States, in which a total of 117 subjects from 5 sites were enrolled to undergo creation of an AV fistula using the Ellipsys Vascular Access System. Patients who met the study criteria and had suitable vascular anatomy, as confirmed by pre-procedure ultrasound vascular mapping, were enrolled in the study.
• Follow-up: 24 hours, 1 week, 90 days, 6 months and 1 year.
• Primary Safety Endpoint: The percent of subjects showing at least one of the following device-related serious adverse events (SAEs): vessel perforation, vessel dissection, and electrical shock during index; and embolization in a previously uninvolved arterial territory within 90 days (+/- 14 days) of the index procedure.
• Primary Effectiveness Endpoint: The maturation success rate at the 90 day follow-up visit, with maturation defined as an access site intended for dialysis needle cannulation with venous diameter > 4 mm, blood flow > 500 ml/min.
• Sample Size (ITT Population): 103 patients.
• Key Results:
  • Primary Safety Endpoint: Met, 0% of subjects experienced device-related SAEs.
  • Primary Effectiveness Endpoint: Met, 90-day maturation success rate of 89.3%.
  • Device Success Rate: 99.0% (102/103)
  • Technical Success Rate: 95.1% (98/103)
  • Assisted Primary Patency Rate at 12 months: 81%
  • Secondary Patency Rate at 12 months: 89%
  • An average of 2.7 additional procedures (Maturation Assistance and Maintenance Procedures - MAPs) were required to assist fistula maturation or maintain mature AVFs. 94.5% of MAPs were not associated with any adverse events.

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

• Primary Safety Endpoint:
  • Vessel perforation during index procedure: 0.0% (0/0)
  • Vessel dissection during index procedure: 0.0% (0/0)
  • Electrical shock during index procedure: 0.0% (0/0)
  • Embolization in previously uninvolved arterial territory: 0.0% (0/0)
  • Composite Safety Endpoint: 0.0% (0/0)
• Primary Effectiveness Endpoint (90-Day Maturation Success Rate):
  • ITT Population: 89.3% (92/103), Lower 97.5% Confidence Interval: 81.7%, p-value:

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 ELLIPSYS VASCULAR ACCESS 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: Ellipsys Vascular Access System (Ellipsys® System)

SUBMISSION NUMBER: DEN170004

DATE OF DE NOVO: January 10, 2017

| CONTACT: | Avenu Medical, Inc.
27123 Calle Arroyo, Suite 2101
San Juan Capistrano, CA 92675 |

----------	----------------------------------------------------------------------------------------

INDICATIONS FOR USE

The Ellipsys® System is indicated for the creation of a proximal radial artery to perforating vein anastomosis via a retrograde venous access approach in patients with a minimum vessel diameter of 2.0mm and less than 1.5mm of separation between the artery and vein at the fistula creation site who have chronic kidnev disease requiring dialysis.

LIMITATIONS

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

The Avenu Medical Ellipsys® System is intended to only be used by physicians trained in ultrasound guided percutaneous endovascular interventional techniques using appropriate clinical standards of care for fistula maintenance and maturation including balloon dilatation and coil embolization.

1

The Ellipsys® System is contraindicated for use in patients with target vessels that are 1.5mm.

The Ellipsys® System has only been studied for the creation of an AV fistula using the proximal radial artery and the adjacent perforating vein. It has not been studied in subjects who are candidates for surgical fistula creation at other locations, including sites distal to this location.

Additional procedures are expected to be required to increase and direct blood flow into the AVF target outflow vein and to maintain patency of the AVF. Care should be taken to proactively plan for any fistula maturation procedures when using the device.

PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

2

DEVICE DESCRIPTION

The Ellipsys® Vascular Access System is a catheter based system that is used to percutaneously create a vascular anastomosis between adjacent blood vessels using direct current (DC) thermal heating. The system consists of several components:

• Ellipsys Catheter ●
• Ellipsys Crossing Needle
• Ellipsys Power Controller ●

Ellipsys Catheter

The Ellipsys Catheter is a single-use, sterile, flexible catheter with a heating element on the distal tip. The catheter is tracked over a guidewire in the target anastomosis site. Then the distal tip components are extended, with part of the tip placed into the target artery, and the tip is retracted to approximate the vessels (i.e., pull the vessels together). Thermal energy is then delivered from the heating element on the tip to seal the vessels together and create an arteriovenous fistula (AVF). The figures below illustrate the catheter and its mechanism of action.

Image /page/2/Figure/7 description: The image shows a medical device with a long, thin probe extending from a white handle. The handle has the word "ELLIPSYS" printed on it in red letters. A blue and white connector is attached to the handle by a white cable, which is coiled up next to the device.

Figure 1: Ellipsys Catheter

Image /page/2/Picture/9 description: The image shows a medical illustration of a surgical procedure. Two surgical tools with blue handles and gold tips are positioned near red and blue vessels. The tools appear to be puncturing or accessing the vessels, possibly for a procedure like angioplasty or catheterization. The background includes a faint outline of skeletal structures, suggesting the anatomical context of the procedure.

Figure 2: Ellipsys Catheter Position in Vasculature Prior to Activation

3

Image /page/3/Picture/0 description: In the image, a medical illustration depicts a surgical procedure involving blood vessels. A golden-colored instrument with a blue handle is positioned between a red and a blue vessel, possibly indicating arteries and veins. A circular, transparent overlay with concentric hexagonal patterns surrounds the area of intervention, suggesting a focus on the surgical site or a technology being used.

Figure 3: Creation of a Fistula with the Ellipsys Catheter

Ellipsys Crossing Needle

The Ellipsys Crossing Needle is a single use, sterile, telescoping needle that is used to cross from inside the vein into the artery at the target anastomosis site. When the inner needle is retracted, it has a round, atraumatic tip that can be positioned against the wall of the adjacent vessel prior to advancing the needle. The sharp needle tip housed within the cannula can be manually deployed a distance of 10mm by pushing forward on the inner hub of the handle. The Ellipsys Crossing Needle is compatible with a non-coated .014" guidewire and a 6F introducer sheath.

Image /page/3/Figure/4 description: The image shows a diagram of a needle in both retracted and deployed positions. When retracted, the needle measures 13 cm. A detailed view labeled "DETAIL A" shows the needle tip measuring 10 mm in length. The image also includes a "FLAT SIDE" view of the needle hub.

Figure 4: Ellipsys Crossing Needle

Ellipsys Power Controller

Unlike the other components, the Ellipsys Power Controller is a reusable, non-sterile device. This portable electronic console is powered with AC inputs, has internal control electronics, and a user interface display. The catheter can connect to the controller which provides the catheter with DC power (converted from AC power) and a closed loop temperature control of the distal heating element.

4

The Power Controller performs the following functions:

• Performs a start-up sequence to verify catheter function prior to insertion into the patient. .
• Contains a visual display screen so the user can verify catheter functionality and start the . thermal cycle.
• Controls the thermal cycle. .
  • o Applies DC energy to heat the catheter
  • o Monitors the tip temperature of the catheter
  • o Monitors the tip position of the catheter
  • o Provides closed loop temperature control algorithm to ensure the temperature is maintained at the programmed parameter
• Stores patient ID, the process parameters and control calculations by the main controller . board.
• Has a USB port to allow the user to externally export procedural data to a USB flash drive. .

Image /page/4/Picture/10 description: The image shows a gray electronic device with a large rectangular screen in the center. The screen is black, suggesting it is either off or displaying a dark image. There is a red button with a yellow border in the upper left corner and a power button symbol in the upper right corner. A small circular button is located in the bottom left corner.

Figure 5: Ellipsys Power Controller

Please refer to the Instructions for Use for additional details.

SUMMARY OF NONCLINICAL/BENCH STUDIES

BIOCOMPATIBILITY/MATERIALS

The Catheter and the Crossing Needle are externally communicating components that are in direct contact with circulating blood for a limited duration (b) (4) The biocompatibility testing summarized below was performed to demonstrate that these components are biocompatible for their intended uses. All tests passed.

The Power Controller is a non-patient-contacting component and was not tested.

Test	Description (Method)
Cytotoxicity	MEM Elution Assay with L-929 Mouse Fibroblast
Cells
(ISO 10993-5)
Sensitization	Guinea Pig Maximization
(ISO 10993-10)

Table 1: Biocompatibility Testing Summary

5

| Irritation | Intracutaneous Reactivity
(ISO 10993-10) | |
|-----------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--|
| Acute System Toxicity | Acute Systemic Injection
(ISO 10993-11) | |
| Hemocompatibility | ASTM Hemolysis Assay - Direct Contact &
Extract Methods
(ASTM Method F756-08) | |
| | Complement Activation C3a and SC5b-9
Determination of SC5b-9 Terminal Chain Complex
(TCC) and C3a-desArg Present in Normal Human
Serum Through Enzyme Immunoassay
(ISO 10993-4) | |
| | In-vivo Thromboresistance
(evaluated as part of the animal studies) | |
| Pyrogenicity | Material-mediated Rabbit Pyrogen
(USP Rabbit Pyrogen Test Procedure, Section 151)
Endotoxin-mediated (LAL)
(AAMI ST72) | |

SHELF LIFE/STERILITY

The shelf-life of the Ellipsys System has been established at 2 years based on accelerated aging testing equivalent to 2 years in accordance with ASTM F1980 - 07 Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices. Following 2X sterilization, environmental conditioning per ISTA 2A, distribution simulation per ASTM D4169, and accelerated aging, the devices were visually inspected for damage per ASTM F1886. bubble leak tested per ASTM F2096. and package seals were tested per ASTM F88. Aged devices also underwent repeat engineering bench testing to confirm acceptable performance.

The Ellipys Catheter and Crossing Needle are labeled as sterile and have a validated sterility assurance level (SAL) of 106. The Ellipsys Catheter and Crossing Needle have been validated to be sterilized via ethylene oxide (EO). The sterilization cycle was validated using the (b) (4) , and the EO and ECH residuals were shown to meet the limits specified by ISO 10993-7:2008.

The Ellipsys Power Controller is provided non-sterile and is labeled as such. The Power Controller user manual includes instructions for cleaning.

ELECTROMAGNETIC COMPATIBILITY AND ELECTRICAL SAFETY

The electromagnetic compatibility and electrical safety of the Ellipsys System was evaluated by demonstrating compliance to the following standards:

Standard	Name
IEC 60601-1:2005 +
CORR. 1 (2006) +
CORR. 2 (2007) +	Medical Electrical Equipment - Part 1: General
Requirements For Basic Safety And Essential
Performance

Table 2: Electrical Performance Testing Summary

6

AM12012
IEC 60601-1-2:2007	Medical Electrical Equipment - Part 1-2:
General Requirements For Basic Safety And
Essential Performance - Collateral Standard:
Electromagnetic Disturbances - Requirements
and Tests

MAGNETIC RESONANCE (MR) COMPATIBILITY

The Ellipsys System is intended as a temporary use device and has not been tested for MR compatibility.

SOFTWARE

The Ellipsys Power Controller software controls the catheter temperature. The controller also receives, analyzes, and adjusts the power output of the power control module to maintain the desired temperature. The controller reports the data via the user interface. archives recent process data for later analysis, and directs the user through most of the Ellipsys system, automating most functions. The software monitors the catheter for errors and provides alerts and instructions to the user if it cannot resolve the error automatically.

The Ellipsys Power Controller has a Moderate Level of Concern (LOC). Appropriate documentation was provided to support the validation of the Power Controller software for a Moderate LOC in accordance with FDA's 2005 guidance titled, "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices."

PERFORMANCE TESTING - BENCH

The Ellipsys System was subjected to a series of bench tests to assess its functional performance. These tests were performed on final, sterilized product. The engineering bench testing summarized in the table below was performed to demonstrate acceptable mechanical performance of the device for its intended use.

Test	Description/Acceptance Criteria
Ellipsys Catheter
Dimensional
Verification/Validation	Catheter Working
Length	The working length of the catheter must be > 15cm
	6F Sheath
Compatibility	The device must pass through a 6F sheath without
excessive friction.
	0.014" Guidewire
Compatibility	0.014" guidewire must pass through device lumen with
ease.
	Hub/Tip
Alignment	Hub must correctly identify the tip orientation; i.e., taper of
heater element must face away from thumb tab.
Electrical
Performance	Electrical
Connection to
Generator	Catheter connector shall only be connected to the generator
in one orientation.
	Control
Thermocouple
Accuracy	Ambient Temperature: $700 \pm 10$ °F
	Base
Thermocouple
Accuracy	Ambient Temperature: $700 \pm 50°F$
	Position Sensor
Function	The voltage range for the position sensor corresponding to
opening and closing of device shall have a 1-1.3 V voltage
differential.
Tensile Strength		Bonds/joints shall maintain mechanical integrity during use Each bond/joint was tested against specifications based on the clinical use of the device
Simulated Use		Catheter shall properly connect to the Power Controller. Power Controller software shall run without errors or interruption when connected to the catheter. Track device samples through vein/artery samples and activate device to create a fistula. After simulated use, the pull force required to separate the vessels must be > 20g. Device shall be free of damage.
Corrosion Resistance		Metallic components of the catheter intended for fluid path contact shall show no signs of corrosion.
Coating Integrity Testing		After simulated use in a clinically-relevant model, and
subjecting the device to 2 heat cycles, the device coating
shall not exhibit any damage or peeling when inspected
under magnification.
Ellipsys Crossing Needle
	Crossing Needle
Working Length	The working length of the needle must be $13.0 \pm 0.5$ cm.
	6F Sheath
Compatibility	The device must pass through a 6F sheath without
excessive friction.
	0.014" Guidewire
Compatibility	0.014" guidewire must pass through device lumen with
ease.
	Needle Extension
Length	Needle shall extend between 8-11mm.
Dimensional
Verification/Validation	Needle Tip
Orientation and
Grind Profile	Needle hub shall correctly indicate the position of the needle. Needle tip shall be sharp, not bent or flattened, when inspected under magnification.
	Distal End of
Outer Cannula
Protrusion	Distal end of cannula shall conform to drawing dimensions and needle shall not protrude from cannula when retracted. Tip of cannula shall be free of debris or sharp edges when inspected under magnification.
Tensile Strength		Bonds/joints shall maintain mechanical integrity during use. Each bond/joint was tested against specifications based on the clinical use of the device.
Corrosion Resistance		The crossing needle shall show no signs of corrosion.
Ellipsys Power Controller
Electrical Performance	Position Sensor
Function	Position sensor shall have an accuracy of $3.0 \pm 0.5$ mm.
	Electrical
Connection to
Catheter	The Power Controller shall connect to the catheter in only
one orientation.

Table 3: Performance Testing (Bench) Summary

7

8

PERFORMANCE TESTING - ANIMAL &/OR CADAVER

Two main in vivo animal studies were conducted to demonstrate the feasibility and safety of the Ellipsys System. The studies are summarized in the table below.

Purpose	Methods	Results
Evaluate the acute and
chronic safety, fistula
blood flow
characteristics, fistula
patency, handling
characteristics, and
histopathological
response at the
treatment site and off-
target tissue sites using
the final device
design. Perform gross
comparison of fistulae
created with the final
device design
compared to a
previous device design
to demonstrate
equivalent fistula
creation. Perform
study according to
Good Laboratory
Practices.	• GLP
• N=6 ovine models
• Insert, track, deploy, and
activate device to create
bilateral arteriovenous fistulae
in each animal. The original
device design was used to
create a fistula in one femoral
artery and the final device
design was used to create a
fistula in the other femoral
artery.
• Acute and post-treatment
assessments of device
performance included needle
and catheter access/removal,
and anastomosis and sheath
appearance.
• Immediately after fistula
creation, fistulae were evaluated
by ultrasound to determine
fistula diameter, patency, and
fistula flow.
• At 1, 7, and 30 days post-
procedure, animals were
evaluated for safety events
(swelling, hematoma,
thrombosis, etc.) and ultrasound
was used to evaluate fistula
diameter, patency, and fistula
flow.
• Gross necropsy, including
external and internal
examination of the fistulae, was
performed at 30 days.
• Histopathological examination
of the fistulae and downstream
organs such as the brain, heart,
lungs, liver, spleen, and kidneys
was conducted at 30 days to
evaluate chronic safety of the
fistula and any thromboembolic
events.
• All results from fistulae created
with the final device design
were compared to the fistulae	• All fistulae were successfully created.
• Needle access/removal, catheter
insertion/removal, anastomosis
appearance, and sheath appearance were
acceptable for all devices.
• No procedural or handling differences
were observed between the two device
designs.
• Intra-operative ultrasound demonstrated
a focal seal zone around the
circumference of all anastomoses.
• All animals appeared normal at routine
health assessments.
• One unexpected death occurred due to
anesthetic complications that occurred
immediately post-sedation.
• 7/10 fistulae (4/5 created using final
device design) were patent at 7-day
follow-up. Loss of patency was due to
flow reduction due to thrombosis at
fistula, though the adjacent vein and
artery were patent in all cases.
• There was no evidence of excessive
submural bleeding, aneurysm, or loss of
vessel approximation.
• The fistula sizes and flow rates for both
device designs were acceptable at 30
days.
• Gross pathology supported the
ultrasound findings.
• Thermal necrosis, granulation tissue,
mineralization and neointimal
hyperplasia were localized to the tissue
site as expected.
• Vascular healing appeared to be normal
for this type of device.
• No evidence of safety concerns, such as
thrombo-emboli, was observed in
downstream organs.
	created with the previous device
design to determine
equivalence.
Evaluate the ability to
create an endovascular
fistula, acute
performance, and
chronic safety in an
animal model using an
earlier design version
of the device
compared to surgical
fistula creation.
Following the study,
no major changes were
made to the electro-
mechanical system
involved in vessel
access or energy
delivery.	• Non-GLP
• N=6 ovine models
• Insert, track, deploy, and
activate device to create a
fistula in one of the femoral
arteries of each animal. A
surgical fistula was
subsequently created in the
other femoral artery of each
animal.
• Immediately after fistula
creation, fistulae were evaluated
by ultrasound to determine
fistula diameter, patency, and
fistula flow.
• At 15 and 30 days post-
procedure, ultrasound was used
to evaluate fistula diameter,
patency, and fistula flow.
• Gross pathological examination
and histopathological
examination performed for N=3
animals at 15 days and N=3
animals at 30 days to evaluate
safety and healing response.	• Procedural performance was acceptable
for all devices.
• 5/6 fistulae were successfully created.
One fistula separated five minutes after
the procedure, but no intervention was
required and no clinical sequelae were
observed.
• All successfully created fistulae were
patent at all follow-up evaluations, with
acceptable fistula flow.
• No adverse clinical events were observed
in any animals.
• No evidence of chronic tissue damage
was observed.
• No excessive inflammatory response,
delayed healing or stenosis was
observed.
• Fistula performance appeared to be
acceptable and comparable to the
surgical control fistulae.

Table 4: Summary of Preclinical Studies

9

SUMMARY OF CLINICAL INFORMATION

The Ellipsys System was primarily supported by a pivotal study entitled the "Ellipsys Vascular Access System Clinical Trial." Details of the study design and selected clinical results are provided below.

Purpose: To demonstrate the safety and effectiveness of the Ellipsys Vascular Access System in creating a native AV fistula via percutaneous access to support future hemodialysis.

Design: The study was a non-randomized, prospective multi-center study conducted in the United States, in which a total of 117 subjects from 5 sites were enrolled to undergo creation of an AV fistula using the Ellipsys Vascular Access System. Patients who met the study criteria and had suitable vascular anatomy, as confirmed by pre-procedure ultrasound vascular mapping, were enrolled in the study.

Follow-up visits were scheduled at 24 hours, 1 weeks, 90 days, 6 months and 1 year using the following standard of care assessments: vital signs, upper extremity vessel dimensions by ultrasound, post-procedure patency and flow rates, and adverse events.

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All study data were monitored by an independent study monitor, and adverse events were adjudicated by an independent medical monitor.

Primary Endpoints:

• 1. Safety: The primary safety endpoint was the percent of subjects showing at least one of the following device-related serious adverse events (SAEs): vessel perforation, vessel dissection, and electrical shock during index; and embolization in a previously uninvolved arterial territory within 90 days (+/- 14 days) of the index procedure.
     The following definitions were used for the safety analyses in the study:

• Adverse event (AE): any undesirable experience associated with the use of a medical product in a patient.

• Serious adverse event (SAE): an AE or any untoward medical consequence that meets ● any of the following criteria:

  • o Results in death.
  • Is life-threatening (i.e., an AE that, in the opinion of the investigator, places o the subject at immediate risk of death).
  • Requires in-patient hospitalization or prolongs an existing hospitalization O (hospitalizations for scheduled medical or surgical procedures to conduct scheduled treatments or routine examinations do not meet this criterion).
  • Results in persistent or significant disability or incapacity. о
  • Is a congenital anomaly or birth defect in the infant/newborn of a mother that O has been exposed to the research device.
  • It is considered by the investigator to be a significant medical event based on o medical criteria (e.g., puts the subject at risk or may require medical or surgical intervention to prevent one of the aforementioned results).

• . Device-related adverse event: AE that is directly attributable to the use of the device.

• . Procedure-related adverse event: AE that is directly related to accessing the vessel prior to introducing the study device and creating the AV fistula.

• 2. Effectiveness: The primary effectiveness endpoint was the maturation success rate at the 90day follow-up visit, with maturation defined as an access site intended for dialysis needle cannulation with venous diameter > 4 mm, blood flow > 500 ml/min.

Secondary Endpoints: Secondary endpoints consisted of the following:

• . Device Success Rate: Percent of Ellipsys Vascular Access Systems that successfully created an AVF upon deployment.
• . Technical Success Rate: Percent of access sites that demonstrated physical exam patency through clinic discharge:

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• Rapid Maturation Rate: Percent of access sites that could sustain three 2-needle . cannulations at the prescribed needle gauge and blood flow rate (Ob) between the 4 week and 90 day follow-up visits after initial AV fistula creation.
• Assisted Maturation Rate: Percent of access sites which achieved or maintained . maturation following intervening manipulations (surgical or endovascular) designed to promote or reestablish maturation.
• . Unassisted Maturation Rate: Percent of access sites that achieved and maintained maturation without any surgical or endovascular intervention designed to promote or reestablish maturation.
• . Assisted Patency Rate: Percent of access sites which were patent after intervening manipulations (surgical or endovascular) intended to promote or reestablish patency.
• . Unassisted Patency Rate: Percent of access sites that maintained patency without any surgical or endovascular intervention designed to maintain or reestablish blood flow in the access site.
• . Intervention Rate: Percent of subjects who had one or more surgical or endovascular interventions to maintain or reestablish blood flow in the access site
• . Transposition Rate: Percent of subjects who required one or more surgical transpositions performed to facilitate needle access.

Other Outcome Measures: Other outcome measures included the following:

• Time to First Cannulation: Elapsed time to first use of access site.
• . Ultrasound Flow: Flow rate of blood through outflow vein(s).
• Time to Access Site Abandonment: Elapsed time to abandonment of the access site. ●
• Catheter Utilization: Total number of days a catheter was used before access site maturation per subject.
• 6 Month Patency and Flow: Patency and flow at 6 months following AVF creation. .
• 1 Year (12 Month) Patency and Flow: Patency and flow at 12 months following AVF . creation.

In addition to the secondary endpoints and other outcome measures, additional analyses that were not pre-specified in the clinical protocol were performed and are discussed in the results section below.

Eligibility Criteria Summary: The study population consisted of male and female patients from the United States, at least 18 years of age and no more than 80 years of age.

Kev inclusion criteria included the following:

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• . Diagnosed with end-stage renal disease (ESRD) or chronic kidney disease requiring dialysis or anticipated start of dialysis within 6 months of enrollment.
• . Patients deemed medically eligible for upper extremity autogenous AV fistula creation, per institutional guidelines and/or clinical judgment.
• Arterial lumen diameter of ≥ 2.0mm and adjacent vein diameter of ≥ 2.0mm at the target anastomosis site.
• . Radial artery-adjacent vein proximity ≤ 1.5 mm measured lumen edge-to-lumen edge as determined by pre-procedural ultrasound and confirmed pre-procedure.
• Adequate collateral arterial perfusion and vein quality based on pre-operative assessment. . without evidence of subclavian artery stenosis on the ipsilateral side.
• Negative Allen's Test for ulnar artery insufficiency. .

Key exclusion criteria included the following:

• Patient required creation of an arteriovenous fistula distal to the wrist. ●
• . Documented or suspected central venous stenosis including upper extremity arterial stenosis (≥ 50%).
• Prior vascular surgery at or proximal (central) to the AVF target site.
• Prior axillary dissection or mastectomy on the ipsilateral side as intended AV fistula site. ●
• Evidence of vascular disease at the radial artery/adjacent vein site on the ipsilateral side. ●
• History of steal syndrome from a previous hemodialysis vascular access on the ipsilateral . side which required intervention or abandonment.

Accountability: Figure 6 below shows the disposition of all subjects through the end of the study. In the figure, long term follow-up (LTFU) refers to the 6- and 12-month study visits.

Note: Study subjects were not consented for LTFU until after a large percentage of the study subjects had completed their 90-day study visit and some had already passed the window for their 6-month visit. As a result, 6 subjects declined to re-consent to rejoin the study for LTFU and 34 subjects completed the 12-month study visit but not the 6-month study visit.

Patients were not included in the ITT population for the following reasons:

• Roll-ins the first two patients at each clinical site who were included to facilitate in . vivo training on the device and the specific vascular anatomy.
• . Access failures - the device could not be introduced into the vessel or vessel spasm precluded continuation of the procedure.

Patients in the ITT population exited the study for the following reasons:

• . No AVF created – an AVF was attempted during the index procedure but could not be successfully created.
• Total occlusions three subjects whose access sites were abandoned within the first 30 . days due to total occlusion of the anastomosis which could not be re-opened.

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• . Death - one death was reported at the 90-day visit, two deaths were reported at the 6month visit, and five deaths were reported at the 12-month visit. Among the seven deaths that occurred after 90 days, five subjects had not consented to LTFU while two subjects had consented for LTFU.
• Lost to follow-up the patient failed to return for follow-up visits, and documented . attempts to locate and contact the subject were unsuccessful. A patient who missed a study visit but attended a subsequent visit was no longer considered lost to follow-up. A missed visit was considered a protocol deviation and the deviation was documented and reported.
• . Other - subjects who terminated the study early for various other reasons such as declining to re-join the study after completing the 90-day visit, subjects who were using other means of vascular access, or experienced an SAE unrelated to the study device or procedure.

Image /page/13/Figure/3 description: This image is a flowchart showing the enrollment and follow-up of subjects in a study. The flowchart starts with 117 subjects enrolled, then 10 roll-ins and 4 access failures. The ITT population is 103, and the potential LTFU is 98. 84 subjects consented to LTFU, and 77 completed the 12-month visit.

Figure 6: Subject Disposition Through End of Study

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Demographics: The total Intent-to-Treat (ITT) population consisted of 103 patients. Information on the patient demographics is provided in Table 5 below.

| Attribute | | ITT Patients
(N=103) |
|-------------------------------------------------------|-------------------------------------------------------|-------------------------|
| Age (mean, yrs) | | 56.6 |
| BMI (mean, kg/m²) | | 31.2 |
| Sex (%) | Male | 73.8 |
| | Female | 26.2 |
| Race (%) | White | 74.8 |
| | Black | 20.4 |
| | Asian | 1.9 |
| | Other | 2.9 |
| Ethnicity (%) | Hispanic/Latino | 35.9 |
| | Not Hispanic or Latino | 63.1 |
| Diabetes (%) | Type I | 4.9 |
| | Type II | 61.2 |
| Hypertension (%) | | 98.1 |
| Vascular Disease other than Target Site (%) | | 34.0 |
| Relevant Previous
Surgical Procedures
(%) | Prior Failed Surgical
AVF on Contralateral
Side | 6.8 |
| | Prior Nephrectomy | 4.9 |
| | Other Relevant Surgical
Procedure | 21.4 |
| Catheter Present for Hemodialysis at Screening
(%) | | 62.1 |

Table 5: Demographic Characteristics of ITT Patients

Table 6 below presents the pre-procedure vessel mapping results by ultrasound in the ITT population, and Table 7 shows the vessel locations used in the study. Table 8 presents the patients' dialysis status at screening and end of study.

Table 6: Pre-Procedure Ultrasound Vessel Characteristics, ITT Population

Attribute	# of ITT Patients (N=103)
Proximal Radial Artery Diameter (mean ± SD, mm)	$3.08 \pm 0.62$
Perforating Vein Diameter (mean ± SD, mm)	$3.48 \pm 0.88$
Artery-Vein Proximity (mean ± SD, mm)	$0.65 \pm 0.48$

Table 7: Target Vessel Locations, Completed Cases Population

Target Vessel	# of CC Patients (N=90)
Cephalic Vein	68 (75.6%)
Basilic Vein	20 (22.2%)

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Brachial Vein 1	1 (1.1%)
Brachial Vein 2	1 (1.1%)

Table 8: Dialysis Status at Screening and End of Study

	Dialysis Status
Time Period (Analysis Population)	Pre-
Dialysis
N (%)	On
Dialysis
N (%)
Screening (ITT Population, N=103)	39 (37.9)	64 (62.1)
Screening (Long Term Visit Population, N=81)	28 (34.6)	53 (65.4)
12 Months (Long Term Visit Population, N=81)	14 (17.3)	67 (82.7)

Results: The principal safety and effectiveness results from patients in the study are provided below. The primary endpoints were evaluated for the Intent-to-Treat (ITT) population.

Primary Safety Endpoint: The primary safety endpoint of the study was met as none of the subjects experienced one or more of the following device-related SAEs: vessel perforation, vessel dissection, electrical shock during index, and significant embolization in a previously uninvolved arterial territory within 90 days of the procedure. A hypothesis test was not used for the primary safety endpoint.

| Safety Endpoint | # of Subjects | % of Subjects | 95%
Confidence
Interval |
|-------------------------------------------------------------|---------------|---------------|-------------------------------|
| Vessel perforation during index
procedure | 0 | 0.0% | 0.0%, 3.5% |
| Vessel dissection during index
procedure | 0 | 0.0% | 0.0%, 3.5% |
| Electrical shock during index
procedure | 0 | 0.0% | 0.0%, 3.5% |
| Embolization in previously
uninvolved arterial territory | 0 | 0.0% | 0.0%, 3.5% |
| Composite Safety Endpoint | 0 | 0.0% | 0.0%, 3.5% |

Table 9: Primary Safety Endpoint Results - 90-Day Device Related SAE Rate

Primary Effectiveness Endpoint: The primary effectiveness endpoint was the maturation success rate at the 90 day follow-up visit, with maturation defined as an access site intended for dialysis needle cannulation with venous diameter > 4 mm and blood flow > 500 ml/min, as measured by duplex ultrasound.

16

The primary effectiveness endpoint was tested for the ITT population using a one-sample hypothesis comparing the Ellipsys Vascular Access System (Test) to a Performance Goal of 49%. The point estimate for the historical performance goal was derived from a meta-analysis of eight previous studies of open surgical AVF procedures. The null and alternative statistical hypotheses were:

Ho: PTest 49%,

where Press was the maturation success rate in the Test group. This hypothesis was tested with a one-sided binomial test. The null hypothesis was tested using a one-sided significance level of 0.025. A supportive analysis of the primary endpoint was calculated as the lower one-sided 97.5% exact binomial confidence limit based on Clopper-Pearson methods for the ITT population. Additionally, supportive analyses for the primary effectiveness endpoint were done using the same methodology for the As Treated (AT) and Completed Cases (CC) populations.

The primary endpoint was met with a 90-day maturation success rate of 89.3%.

The statistical analysis populations used in the study were defined as follows:

• . Intent-to-Treat (IT): The ITT population included all subjects enrolled following the roll-in stage in whom the procedure had been attempted and the study device deployed, whether successful or not.
• As-Treated (AT): The AT population included all subjects in the ITT population where . the study device was successfully deployed in the target vasculature and an AVF was created.
• Completed Cases (CC): The CC population included all subjects in the ITT population . with a patent AVF completing the 90-day evaluation.

| Analysis
Population | Successes (N) | Total (N) | Percent (%) | Lower
97.5%
Confidence
Interval | p-value |
|------------------------|---------------|-----------|-------------|------------------------------------------|---------|
| ITT | 92 | 103 | 89.3% | 81.7% | 2000 mL/min

1 Basile C, Lomonte C, Vernaglione L et al. The relationship between the flow of arteriovenous fistula and cardiac output in haemodialysis patients. Nephrol Dial Transplant 2008; 23: 282-287.

2 Ye WL, Fang LG, Ma J et al. Long-term effects of arteriovenous fistula on cardiac structure and function in nondiabetic hemodialysis patients. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2013; 35: 95-101.

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at one study visit (12 subjects) or more than one study visit (3 subjects). Of those 15 subjects. 11 (73.3%) did not experience steal syndrome or any adverse events that were determined to be cardiac-related by the Medical Monitor. Of the three subjects who experienced a cardiac-related adverse event (3/15 = 20%), the cardiac-related adverse events occurred before the high flow values were observed and/or the subjects had significant histories of cardiovascular disease. For one of the subjects with a cardiac-related adverse event occurred between two study visits where flow rates of 1540 mL/min and 1149 mL/min were observed. As discussed above. the one (1/15 = 6.7%) observed case of steal syndrome was related to a transposition surgery and was successfully resolved.

| Vessel | | 90 Days
(N=103) | 6 Months
(N=49) | 12 Months
(N=77) |
|----------------------------------|-------------------------------|--------------------|--------------------|---------------------|
| Brachial Artery Flow
(mL/min) | ITT Subjects Evaluable
(N) | 99 | 49 | 77 |
| | Mean (Median) | 919.3 (849.9) | 989.0 (983.8) | 1089.7 (1077.3) |
| | SD | 388.5 | 433.1 | 446.7 |
| | Min-Max | 41.6-2281.4 | 60-2277 | 79-2657 |
| Cephalic Vein Flow
(mL/min) | ITT Subjects Evaluable
(N) | 70 | 39 | 56 |
| | Mean (Median) | 631.9 (578.0) | 746.6 (607.1) | 815.1 (920.8) |
| | SD | 314.0 | 417.4 | 410.5 |
| | Min-Max | 37.6-1805.2 | 343-2435 | 0-2277 |
| Basilic Vein Flow
(mL/min) | ITT Subjects Evaluable
(N) | 23 | 7 | 20 |
| | Mean (Median) | 860.8 (699.4) | 1096.6 (994.1) | 1084.8 (920.8) |
| | SD | 586.8 | 258.9 | 899.8 |
| | Min-Max | 366.5-3058.6 | 792-1509 | 70-4343 |
| Brachial Vein Flow
(mL/min) | ITT Subjects Evaluable
(N) | 2 | 1 | 1 |
| | Mean (Median) | 1273.4 (1273.4) | 706.8 (706.8) | 421.8 (421.8) |
| | SD | 79.0 | N/A | N/A |
| | Min-Max | 1217.5-1329.2 | 706.8-706.8 | 421.8-421.8 |

Table 18: TAMMV Ultrasound Measurements of Vessel Flow (mL/min)}

Mean flow (TAMMV) was estimated as follows: TAMMV = time average mean-peak velocity (TAMPV) * 1. (0.57) as described in Rajan DK, Ebner A, Desai SB, et al. Percutaneous creation of an arteriovenous fistula for hemodialysis access. J Vasc Interv Radiol. 2015; 26:484-490.

Summary of Maturation Assistance and Maintenance Procedures (MAPs)

As noted in Table 12 above, the 90-day assisted maturation rate in the study was 82.5% and the 90-day unassisted maturation rate was 1.0%. Since the Ellipsys AVF may create multiple potential access vessels, a staged approach was taken where maturation assistance and maintenance procedures (MAPs) were performed to assist AVF maturation and maintain patency.

24

The three main situations that required MAPs included:

• 1. Salvage of low flow or occluded fistulae:
• 2. Second stage procedures to modulate and direct blood flow or transpose the vessel; and
• 3. Maintenance or restoration of AVF patency after target vessel maturation.

Many of the MAPs performed to direct blood flow included the implantation of embolization coils. In the ITT population, 97 embolization coils were placed in 66 subjects, equating to an average of 0.94 coils per ITT subject or 1.47 coils per subject receiving at least one coil. A total of 107 embolization coils were placed in a total of 71 subjects among the ITT population and 10 roll-in subjects (N=113 total subjects). All embolization coil placements were intended to direct flow from competing veins to promote maturation of the study AVF. Of the 107 coils, 49 were placed in the deep brachial veins to direct flow to the superficial outflow and 53 were branch ligations placed in more superficial veins. The remaining 5 coils were placed in the median basilic vein (3), perforating vein, and cephalic vein.

Definitions for MAP Analysis

• Surgical MAPs: vessel branch ligations or interventions such as elevation, transposition, . or superficialization of the target vessel to facilitate placement of cannulation needles which occurs only after the vessel has matured.
• Percutaneous MAPs: endovascular interventions intended to A) redirect blood flow by . increasing the flow in the target vessel by percutaneous transluminal angioplasty (PTA). stenting, or valvuolotomy or B) decrease the flow in non-target vessels by coil embolization, banding, or branch ligation. The most commonly performed MAP was PTA of the study anastomosis and/or outflow vessels.
• Maturation Procedures:
  • Subjects requiring hemodialysis: MAPs performed to increase or direct blood o flow sufficiently to mature the target vessel in subjects requiring hemodialysis. prior to the first 2-needle cannulation.
  • Subjects who were not yet on hemodialysis: MAPs that occurred before the O primary endpoint definition for maturation of the target vessel was met.
• Maintenance Procedures:
  • Subjects requiring hemodialysis: MAPs performed on or after the day of the first o 2-needle cannulation for hemodialysis, intended to treat the effects of cannulation on the access vein.
  • Subjects not yet on hemodialysis: MAPs performed after the subject met the o primary endpoint definition for maturation of the target vessel.

Tables 19 and 20 below shows the mean number of MAPs that were required during the first 90 days and cumulatively during the study. In the ITT population, 99/103 subjects (96.1%) had MAPs to mature and maintain the AVF throughout the study. The remaining four subjects

25

included three total occlusions within 24 hours of the index procedure leading to AVF abandonment and one subject in whom a fistula was not created.

Most of the MAPs occurred during the first 90 days, as 98/103 subjects (95.1%) required an average of 2.2 MAPs during the first 90 days. Among the ITT population. 7/103 subjects (6.7%) required a total of 7 MAPs (one MAP per subject) at the same time as the index procedure. A total of 18/103 subjects (17.5%) required a total of 18 MAPs (one MAP per subject) within 24 hours of the index procedure.

| Type of MAP | # of Subjects
(%) | Mean (Median) # of
MAPs | SD # of
MAPs | Min-Max # of
MAPs |
|---------------------------------------|----------------------|----------------------------|-----------------|----------------------|
| Percutaneous MAPs | 96 (93.2%)2 | 1.9 (2.0) | 1.0 | 1-5 |
| Percutaneous and/or Surgical
MAPs1 | 98 (95.1%)2 | 2.2 (2.0) | 1.0 | 1-5 |
| All ITT Subjects | 103 | 2.0 (2.0) | 1.1 | 0-5 |

Table 19: MAPs During First 90 Davs. ITT Population

Surgical MAPs in the first 90 days consisted of transpositions of mature access vessels. 1.

One subject (0.9%) with a patent AVF did not require any MAPs during the first 90 days. An additional four 2. subjects (3.9%) did not require any MAPs because they either did not have an AVF created successfully or their AVF occluded completely during the first 24 hours after the procedure.

Type of MAP	Parameter	Maturation MAPs	Maintenance MAPs	Total MAPs
Percutaneous
MAPs	# of Subjects
(%)	96 (93.2%)	24 (23.3%)	96 (93.2%)
	Mean (Median)

of MAPs | 2.0 (2.0) | 1.8 (1.0) | 2.4 (2.0) |

| | SD # of MAPs | 1.0 | 1.4 | 1.6 |
| | Min-Max # of
MAPs | 1-6 | 1-7 | 1-9 |
| Surgical MAPs | # of Subjects
(%) | 31 (30.1%) | 7 (6.8%) | 38 (36.9%) |
| | Mean (Median)

of MAPs | 1.0 (1.0) | 1.0 (1.0) | 1.0 (1.0) |

| | SD # of MAPs | 0.2 | 0.0 | 0.2 |
| | Min-Max # of
MAPs | 1-2 | 1-1 | 1-2 |
| Percutaneous
and/or Surgical | # of Subjects
(%) | 98 (95.1%) | 29 (28.2%) | 99 (96.1%) |

Table 20: Cumulative MAPs Through Last Study Visit, ITT Population

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| MAPs | Mean (Median)

of MAPs | 2.3 (2.0) | 1.7 (1.0) | 2.7 (2.0) |

|------|----------------------------|-----------|-----------|-----------|
| | SD # of MAPs | 1.1 | 1.5 | 1.7 |
| | Min-Max # of
MAPs | 1-6 | 1-8 | 1-10 |

Tables 21 and 22 below show the number of subjects stratified by the number and types of MAPs required to mature the access vein and to maintain a patent access site with adequate flow for cannulation during the study.

In general, most subjects (88/103 = 85.4%) required 1-3 MAPs to achieve maturation with 36.9% requiring two procedures. Most subjects (94/103 = 91.3%) required ≤ 1 MAP to maintain patency of a mature AVF, with 74/103 (71.8%) requiring none at all during the study.

| Parameter | # of Subjects with
Maturation MAPs
(%) | # of Subjects with
Maintenance MAPs |
|---------------------------------|----------------------------------------------|----------------------------------------|
| N/A - Not eligible for
MAPs1 | 4 (3.9%) | 0 (0.0%) |
| 0 procedures | 1 (1.0%) | 74 (71.8%) |
| 1 procedure | 25 (24.3%) | 20 (19.4%) |
| 2 procedures | 38 (36.9%) | 5 (4.9%) |
| 3 procedures | 25 (24.3%) | 2 (1.9%) |
| 4 procedures | 6 (5.8%) | 0 (0.0%) |
| 5 procedures | 2 (1.9%) | 1 (1.0%) |
| 6 or more procedures | 2 (1.9%) | 1 (1.0%) |

Table 21: Number of Procedures per Subject Through Last Study Visit, ITT Population

1. Four subjects from the ITT cohort did not have any MAPs because they either did not have an AVF successfully created or the AVF was abandoned within 24 hours of the index procedure due to total occlusion of the AVF.

27

Type of MAPs	# of Subjects with Maturation MAPS (N=103)			# of Subjects with Maintenance MAPS (N=103)
	# of MAPs	# of Subjects1	% of Subjects	# of MAPs	# of Subjects1	% of Subjects
Surgical MAPs	32	31	30.1%	7	7	6.8%
Transposition	18	18	17.5%	3	3	2.9%
Transposition – Surgical Revision	6	6	5.8%	1	1	1.0%
Surgical Revision	4	4	3.9%	2	2	1.9%
Flow Direction	3	3	2.9%	1	1	1.0%
Other2	1	1	1.0%	0	0	0.0%
Percutaneous MAPS	190	96	93.2%	42	24	23.3%
PTA	91	64	62.1%	31	20	19.4%
PTA – Flow Direction	63	54	52.4%	2	2	1.9%
Flow Direction	32	27	26.2%	2	2	1.9%
PTA – Stent	2	2	1.9%	5	4	3.9%
PTA – Stent – Flow Direction	2	2	1.9%	0	0	0.0%
Stent	0	0	0.0%	1	1	1.0%
Other3	0	0	0.0%	1	1	1.0%

Table 22: Types and Incidence of MAPs Through Last Study Visit, ITT Population

Number of subjects with one or more procedures of a given type. Subjects may appear in more 1. than one category.

One subject received a surgical PTA + stent. 2. 0

3. One subject received a catheter embolectomy.

Analysis of Adverse Events Associated with MAPs

An analysis was performed to determine any association between MAPs performed to promote maturation or maintain patency of the AVF during the study and adverse events (AEs). The analysis covered all subjects' study participation from the completion of the study procedure through last follow-up visit for each subject. To determine this relationship, all AEs that occurred within one month of a MAP procedure were reviewed to determine if they were associated with that procedure, and a complete listing of all study AEs was then reviewed to determine if there were any outliers.

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Table 23 below presents the MAPs that had associated AEs for the ITT population. Out of a total of 271 MAPs, 256 of them (94.5%) did not have any associated AEs and 15 MAPs (5.59%) had associated AEs. Of the 39 surgical MAPs performed, five of them (12.8%) had associated AEs. Of the 232 percutaneous procedures, 10 (4.3%) had associated AEs.

As discussed above, a total of 107 embolization coils were placed in a total of 71 subjects among the 113 total subjects from the ITT and roll-in populations. One AE was reported to be associated with a coil embolization procedure. In this AE, a coil did not deploy completely and migrated distally due to fistula blood flow. No clinical sequelae were reported and the AE was adjudicated as non-serious.

| Parameter | # of MAPs Through
Last Study Visit |
|--------------------------------------|---------------------------------------|
| Total # of MAPs | 271 |
| With No Associated AEs | 256/271 (94.5%) |
| With Associated AEs | 15/271 (5.5%) |
| Total Surgical MAPs | 39 |
| With No Associated AEs | 34/39 (87.2%) |
| With Associated AEs | 5/39 (12.8%) |
| Transposition | 2 |
| Transposition - Surgical
Revision | 2 |
| Other¹ | 1 |
| Total Percutaneous MAPs | 232 |
| With No Associated AEs | 222/232 (95.7%) |
| With Associated AEs | 10/232 (4.3%) |
| Flow Direction | 1 |
| PTA | 7 |
| PTA - Flow Direction | 1 |
| Stent | 1 |

Table 23: MAPs and Associated AEs During Study, ITT Population

One subject received a surgical PTA + stent. 1.

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Analysis of AVF Patency and Relationship with MAPs

Patency of the study AVF was evaluated among the ITT population. For the purposes of this patency analysis, the following definitions were used:

• Primary Patency: the interval from the time of access placement until any intervention . designed to maintain or reestablish patency, access thrombosis, access abandonment, or the time of measurement of patency.
  • o As discussed below. primary patency was analyzed two ways. In one analysis, embolization coils counted as interventions designed to maintain or reestablish patency. In the other analysis, embolization coils did not count as interventions designed to maintain or reestablish patency.
• . Assisted Primary Patency: the interval from the time of access placement until access thrombosis, access abandonment, or the time of measurement of patency.
• . Secondary Patency: The interval from the time of access placement until access abandonment, or the time of measurement of patency.

Primary patency was achieved in 1/103 subjects (1.0%) at 90 days. If procedures involving embolization coils to divert blood flow and assist maturation were excluded from the primary patency analysis, the primary patency rate was 26% at 90 days and 14% at 12 months. Assisted primary patency and secondary patency were 81% and 89% at 12 months, respectively.

Figure 7 and Table 24 below summarize the Kaplan-Meier analysis of patency rates for the ITT population, with 95% confidence intervals represented by shaded regions and subjects censored after the last available visit if they did not complete the study.

If subjects who did not complete the study were counted as patency failures after their last study visit, the primary patency (excluding procedures involving embolization coils), assisted primary patency, and secondary patency were 11%. 65%, and 72% at 12 months respectively.

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Figure 7: Kaplan-Meier Analysis of Patency

Image /page/30/Figure/1 description: The image is a Kaplan-Meier Analysis graph showing the probability of patency over time in days. There are four different patency types plotted on the graph: Primary Patency (Including procedures involving embolization), Primary Patency (Excluding procedures involving embolization), Assisted Primary Patency, and Secondary Patency. The graph shows that the probability of patency decreases over time for all four types, with Primary Patency (Including procedures involving embolization) having the lowest probability of patency and Secondary Patency having the highest.

1 Pointwise confidence limits are displayed for the survival curves.

Days
Patency Type		0	90	180	270	360	450	540
Primary Patency (Including procedures involving	No. at Risk	103	1	0
embolization)	Prob. of Patency	0.92	0.01
	Standard Error	0.03	0.01
Primary Patency (Excluding procedures involving	No. at Risk	103	27	15	13	3	0
embolization)	Prob. of Patency	0.92	0.26	0.18	0.15	0.14
	Standard Error	0.03	0.04	0.04	0.04	0.04
Assisted Primary Patency	No. at Risk	103	86	72	70	26	3	0
	Prob. of Patency	0.93	0.86	0.85	0.85	0.81	0.81
	Standard Error	0.02	0.03	0.04	0.04	0.04	0.04
Secondary Patency	No. at Risk	103	95	78	76	30	3	0
	Prob. of Patency	0.99	0.95	0.92	0.92	0.89	0.89
	Standard Error	0.01	0.02	0.03	0.03	0.04	0.04

Table 24: Life Table for Patency, ITT Population

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The assisted primary patency rate at one year was 91% for subjects with one MAP, and the assisted primary patency rate decreased as the number of MAPs increased. For subjects with 4 or more MAPs, the assisted primary patency rate at one year was 79%. Secondary patency at one year ranged from 91% to 100% for subjects with one or more MAPs. Figure 8 and Table 25 below show the rates of assisted primary patency at one year stratified by the number of MAPs performed throughout the study, with shaded areas indicating the 95% confidence intervals. Subjects with zero MAPs throughout the study were primary failures; one subject who achieved primary patency at 90 days is not included in the "0 MAP" category because they received a MAP at a later timepoint.

Image /page/31/Figure/1 description: The image is a Kaplan-Meier analysis of assisted primary patency by the number of additional procedures. The x-axis represents days, ranging from 0 to 540, while the y-axis represents the probability of patency, ranging from 0.0 to 1.0. There are five lines on the graph, each representing a different number of additional procedures: 0, 1, 2, 3, and 4+. The graph shows how the probability of patency changes over time for each group, with the lines generally decreasing over time.

Figure 8: Kaplan-Meier Analysis of Assisted Primary Patency, by # of MAPs Throughout Study Kaplan-Meier Analysis1, ITT Population

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	Days
No. of Procedures	0	90	180	270	360	450	540
0 No. at Risk	4	0
0 Prob. Of Patency	0.75
0 Standard Error	0.22
1 No. at Risk	23	21	16	16	2	0
1 Prob. Of Patency	0.91	0.91	0.91	0.91	0.91
1 Standard Error	0.06	0.06	0.06	0.06	0.06
2 No. at Risk	28	24	19	19	8	0
2 Prob. Of Patency	0.93	0.89	0.89	0.89	0.89
2 Standard Error	0.05	0.06	0.06	0.06	0.06
3 No. at Risk	26	22	18	16	7	3	0
3 Prob. Of Patency	1.00	0.92	0.87	0.87	0.82	0.82
3 Standard Error	0.00	0.05	0.07	0.07	0.08	0.08
4+ No. at Risk	22	19	19	19	9	0
4+ Prob. Of Patency	0.91	0.86	0.86	0.86	0.79
4+ Standard Error	0.06	0.07	0.07	0.07	0.10

Table 25: Life Table for Assisted Primary Patency, by # of MAPs

Conclusions: The clinical study demonstrated that there is a reasonable assurance of safety and effectiveness that the Ellipsys System creates an arteriovenous fistula that can mature as a method of vascular access for hemodialysis. A fistula was successfully created in 99.0% of subjects and 89.3% of subjects 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 1.9%, and the primary safety endpoint was met. The Ellipsys AVF was used for hemodialysis for an estimated average of 228.3 days out to 12 months, among study subjects who were on hemodialysis and evaluable at 12 months. At least 72.8% of subjects had a functional AVF at 12 months. Primary patency was only achieved in 1.0% of subjects at 90 days, as an average of 2.7 additional procedures (or MAPs) were required to assist fistula maturation or maintain mature AVFs. The majority of the MAPs included PTA of the anastomosis to improve blood flow and embolization coil implantation to direct blood flow to the target vein(s). However, 94.5% of the MAPs were not associated with any adverse safety events, and the assisted primary patency rate at 12 months was 81%.

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.

POSTMARKET EVALUATION

A postmarket evaluation will be required to collect data on the long-term safety and effectiveness of the Ellipsys System in U.S. patients who have chronic kidney disease, need hemodialysis, and are candidates for the creation of an arteriovenous fistula with the Ellipsys System.

LABELING

The Ellipsys System labeling consists of Instructions for Use, a user manual, and packaging labels. The Instructions for Use include the indications for use; a description of the device,

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contraindications, warnings, precautions; 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
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

Table 26: Identified Risks to Health and Mitigation Measures

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:

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• The ability to safely deliver. deploy, and remove the device: a.
• b. The ability of the device to create an arteriovenous fistula:
• The ability of the arteriovenous fistula to attain a blood flow rate and diameter c. 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.
• 2. Animal testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be assessed:
  • Delivery, deployment, and retrieval of the device; a.
  • b. Compatibility with other devices labeled for use with the device;
  • c. Patency of the fistula:
  • 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.
• 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:
  • 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.
• 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:
  • a. Instructions for use;
  • b. Identification of system components and compatible devices:
  • c. Expertise needed for the safe use of the device:

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• 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 study described above. Types of harmful events include stenosis at the arteriovenous anastomosis, thrombus or occlusion at the anastomosis, steal syndrome, embolization coil migration, pulmonary embolism, arterial extravasation, deep vein pseudoaneurysm, mild paresthesia, infection, venous stenosis, infiltration, hemorrhage, hematoma, and death. Through the 12-month duration of the clinical study, the rate of device-related harmful events was 0%, the rate of serious procedure-related harmful events was 2/103 (1.9%), and the rate of non-serious harmful events was 53/103 (51.5%). There were no deaths adjudicated as related to the device or procedure. A total of 25 occlusion events were observed in 19 subjects (17.5%): for 15 of these 19 subjects (78.9%) the occlusion event occurred within 24 hours of the study procedure, and 20/25 (80%) of the occlusions were successfully resolved.

The probable benefits of the device are also based on nonclinical laboratory and/or animal studies as well as data collected in the clinical study as described above. The 90-day maturation success rate, defined as the rate of access sites intended for dialysis needle cannulation with venous diameter > 4 mm and blood flow > 500 ml/min as measured by duplex ultrasound, was 92/103 (89.3%). Out of a total of 81 subjects eligible for hemodialysis at any time during the study, 71 subjects (87.7%) achieved 2-needle cannulation of the AVF. Among 63 subjects who were evaluable for AVF utilization, the AVF was used for an estimated 228.3 study days (at 12 months) on average. At least 75/103 subjects (72.8%) had a functional AVF at 12 months. Primary patency was only achieved in 1.0% of subjects at 90 days, as an average of 2.7 additional procedures were required to assist fistula maturation or maintain mature AVFs. The assisted primary patency rate at 12 months was 81%.

Additional factors to be considered in determining probable risks and benefits for the Ellipsys System include: The device requires a staged maturation approach with additional procedures such as PTA and embolization of non-target veins to assist maturation. Despite the high rate of additional procedures, 94.5% of them were not associated with any adverse events. Fistula flow rates at 12 months appeared to fall below 1200 mL/min on average, and cardiac-related adverse events appeared to be related to underlying cardiovascular disease rather than high blood flow. For subjects who were on dialysis with a central venous catheter (CVC) at the time of enrollment, the duration of CVC exposure after the index procedure was comparable to the duration of CVC exposure for surgical AVFs.

Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

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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 Ellipsys 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 Ellipsys Vascular Access 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