Covera™ Vascular Covered Stent

P170042S002 · C.R. Bard, Inc. · PFV · Mar 1, 2019 · Cardiovascular

Device Facts

• Record ID: P170042S002
• Device Name: Covera™ Vascular Covered Stent
• Applicant: C.R. Bard, Inc.
• Product Code: PFV · Cardiovascular
• Decision Date: Mar 1, 2019
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic, Real-World Evidence

Real-World Evidence

Submission	Device	Sponsor	RWD Sources	RWE Use Summary	Key Tags
P170042S002 · Mar 1, 2019	Covera™ Vascular Covered Stent	C.R. Bard, Inc.	Post-approval study (PAS) clinical data	The applicant is conducting a post-approval study (PAS) to evaluate the long-term safety and effectiveness of the COVERA™ Vascular Covered Stent under real-world conditions in 100 subjects.	Post-approval study; Real-world conditions; Long-term safety; Effectiveness

Clinical Evidence

Study Design	Population	Comparator	Key Endpoints
COVERA™ Post Approval Study; Prospective, observational (implied by 'real world conditions'); Follow-up/Duration: 36 months	100 subjects treated with the COVERA™ Vascular Covered Stent; Sample Size: 100; Number of Sites: up to 35 sites	Not applicable for this study	Target lesion primary patency, access circuit primary patency, secondary patency, reinterventions, index of patency function, adverse events, acute technical/procedural success

Indications for Use

The COVERA™ Vascular Covered Stent is indicated for use in hemodialysis patients for the treatment of stenoses in the venous outflow of an arterio-venous (AV) fistula and at the venous anastomosis of an ePTFE or other synthetic AV graft.

Device Story

Self-expanding endoprosthesis; nitinol stent framework encapsulated in carbon-impregnated ePTFE; pre-mounted on over-the-wire delivery system. Used in interventional radiology/vascular surgery settings to treat venous outflow stenoses in hemodialysis patients. Physician deploys stent via catheter; retraction of distal sheath releases stent at target lesion. Provides mechanical scaffolding to maintain vessel patency; reduces need for target lesion reinterventions compared to angioplasty alone. Benefits include improved target lesion primary patency; clinical decision-making informed by angiographic assessment of access circuit dysfunction.

Clinical Evidence

Prospective, multi-center, randomized, concurrently-controlled study (AVeNEW, IDE G160001) of 280 subjects (142 COVERA, 138 PTA). Primary safety endpoint (30-day freedom from adverse events) met non-inferiority (95.0% vs 96.4%, p=0.0022). Primary effectiveness endpoint (6-month Target Lesion Primary Patency) met superiority (78.7% vs 47.9%, p<0.001). 12-month TLPP also superior (57.5% vs 21.2%, p<0.001). Access Circuit Primary Patency at 6 months was not statistically significant (50.7% vs 43.8%, p=0.0846).

Technological Characteristics

Self-expanding nitinol stent framework; carbon-impregnated ePTFE inner lumen; 6-10 mm diameter; 30-100 mm length. Straight and flared configurations. Radiopaque ePTFE-encapsulated tantalum markers. Over-the-wire delivery system compatible with 0.035 inch guidewires and 8F/9F introducer sheaths. Mechanical deployment via handle-actuated wheel.

Indications for Use

Indicated for hemodialysis patients with stenoses in the venous outflow of an AV fistula or at the venous anastomosis of a synthetic AV graft. No known contraindications.

Regulatory Classification

Identification

An endovascular graft for AV dialysis access is a stent graft intended for the revision of arteriovenous access circuits to maintain or re-establish vascular access (treat stenotic lesions or thromboic occlusions) for hemodialysis.

Submission Summary (Full Text)

{0}

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Endovascular Graft
Device Trade Name: COVERA™ Vascular Covered Stent
Device Procode: PFV
Applicant's Name and Address: C. R. Bard, Inc.
1625 West 3rd Street
Tempe, AZ 85281
Registration number: 2020394
Date of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P170042/S002
Date of FDA Notice of Approval: March 1, 2019

The original PMA (P170042) was approved on July 30, 2018, and is indicated for use in the treatment of stenoses at the venous anastomosis of ePTFE or other synthetic arterio-venous (AV) access grafts. The SSED to support this indication is available on the CDRH website and is incorporated by reference here.

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=P170042.

The current supplement was submitted to expand the indication for the COVERA™ Vascular Covered Stent to include the treatment of stenoses in the venous outflow of an arterio-venous fistula.

## II. INDICATIONS FOR USE

The COVERA™ Vascular Covered Stent is indicated for use in hemodialysis patients for the treatment of stenoses in the venous outflow of an arterio-venous (AV) fistula and at the venous anastomosis of an ePTFE or other synthetic AV graft.

## III. CONTRAINDICATIONS

There are no known contraindications for the COVERA™ Vascular Covered Stent.

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the COVERA™ Vascular Covered Stent labeling.

## V. DEVICE DESCRIPTION

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 1

{1}

The COVERA™ Vascular Covered Stent is a self-expanding covered stent pre-mounted on a delivery system.

## Description of Covered Stent

The COVERA™ Vascular Covered Stent is a flexible, self-expanding endoprosthesis comprised of ePTFE encapsulating a nitinol (nickel-titanium) stent framework. The expanded Polytetrafluoroethylene (ePTFE) on the inner lumen of the covered stent (blood contacting surface) is carbon impregnated. The COVERA™ Vascular Covered Stent is available in a diameter range of 6 to 10 mm and a length range of 30 to 100mm.

The COVERA™ Vascular Covered Stent is available in a straight (Figure 1) and a flared configuration (Figure 2). The distal (outflow) end of the flared configuration device is approximately 3 mm larger in diameter than the body and begins approximately 15 mm from the distal end of the device. Radiopaque ePTFE encapsulated tantalum markers are evenly distributed around the circumference of the proximal and distal ends of the covered stent.


Figure 1: Straight Configuration


Figure 2: Flared Configuration

## Description of Delivery System

The delivery system is illustrated in Figure 3. The covered stent is pre-mounted on the delivery system and compressed between the inner catheter and the covered stent delivery sheath at the distal end of the delivery system. The COVERA™ Vascular Covered Stent is an over-the-wire delivery system. The delivery system is compatible with 0.035 inch guidewires, and compatible with 8F and 9F introducer sheaths. The delivery system is available in working lengths of 80 cm and 120 cm.


Figure 3: COVERA™ Vascular Covered Stent Delivery System

Retraction of the distal catheter and deployment of the covered stent is initiated by rotating the large wheel on the handle. The large deployment wheel is used for the initiation of deployment and a slower deployment rate whereas the small deployment wheel may be used for faster deployment after initiation. A red safety lock on the handle prevents premature

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 2

{2}

release of the covered stent. Prior to covered stent deployment, the safety lock must be retracted from the locked position into the unlocked position.

## **VI. ALTERNATIVE PRACTICES AND PROCEDURES**

There are several other alternatives for the correction of stenoses at the venous outflow of AV fistulae. Alternative procedures include use of percutaneous transluminal angioplasty (PTA) with plain or drug coated balloons, surgical revisions, creation of new fistulae/grafts, and non-fistula/graft methods for dialysis access (peritoneal, central vein catheter placement). Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## **VII. MARKETING HISTORY**

The COVERA™ Vascular Covered Stent has been commercially available outside the United States since October 2015. It was first marketed in the European Union, and additionally has been commercialized in Israel, Saudi Arabia, Iran, Argentina, Bahrain, United Arab Emirates, Kuwait, Qatar, Oman, Indonesia, India, New Zealand, Singapore, and Brunei Darussalam.

The device has never been withdrawn from any market for any reason related to its safety or effectiveness.

## **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH**

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device.

- New lesions in the access circuit requiring reinterventions
- Thrombotic occlusion
- Restenosis of target lesion requiring reintervention
- Pseudoaneurysm
- Vessel rupture
- Dissection
- Extravasation
- Perforation
- Pain
- Infection
- Hemorrhage
- Hematoma
- Arm or hand edema
- Steal Syndrome
- Congestive heart failure
- Venous spasm
- Numbness

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 3

{3}

- Cerebrovascular accident
- Allergic reaction
- Rash
- Reaction to contrast
- Fever
- Sepsis
- Prolonged bleeding
- Ventricular fibrillation
- Face or neck edema
- Bleeding at access site
- Hemoptysis
- Death
- Covered stent: misplacement, migration, embolism, fracture, compression, kinking, and insufficient covered stent expansion
- Delivery system: bond joint failures, detachment of parts, incompatibility with accessory devices, premature deployment, inaccurate deployment, failure to deploy, high deployment forces, delivery system kinking, poor visibility under fluoroscopy, inability to track to target location, and blood leakage from delivery system

For the specific adverse events that occurred in the clinical study, please see Section X below.

# IX. SUMMARY OF NON-CLINICAL STUDIES

A summary of previously reported preclinical studies can be found in the SSED for the original PMA. There were no modifications made to the design or manufacturing of the device; therefore, the non-clinical studies previously conducted remain applicable.

# X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of vascular access interventions with the COVERA™ Vascular Covered Stent for the treatment of stenotic lesions in the venous outflow of hemodialysis patients dialyzing with an AV fistula in the US, Europe, Australia, and New Zealand under IDE G160001. Data from this clinical study were the basis for the PMA Panel-Track Supplement approval decision. A summary of the clinical study is presented below.

# A. Study Design

The AVeNEW study was a prospective, multi-center, randomized, concurrently-controlled study. One hundred and forty-two (142) subjects were randomized to COVERA™ Vascular Covered Stent (following PTA) and 138 subjects were randomized to standard PTA alone. The primary endpoint analyses occurred once 280 randomized subjects completed or discontinued before their 6 month follow up. The key secondary endpoint analyses occurred when 280 randomized subjects completed or discontinued

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 4

{4}

before their 12 month follow up. Additional secondary endpoint analyses without hypothesis testing will occur when 280 randomized subjects have completed or discontinued before their 24 month follow up. All subjects will be followed for 24 months post index-procedure.

Patients were treated between June 9, 2016 and July 20, 2017. The database for this Panel Track Supplement reflected data collected through December 7, 2018 and included 280 patients. There were 24 investigational sites including: one site in New Zealand (enrolled 2 patients), two sites in Australia (enrolled 6 patients), one site in Netherlands (enrolled 1 patient), one site in Germany (enrolled 1 patient), one site in Austria (enrolled 2 patients), one site in Belgium (enrolled 3 patients), one site in Switzerland (enrolled 3 patients) and 16 sites in the United States (enrolled 262 patients).

The following hypotheses were tested:

- Primary Safety Endpoint: The safety rate in subjects treated with the COVERA™ Vascular Covered Stent (following PTA) is non-inferior to the safety rate in subjects treated with PTA alone through 30 days in the treatment of stenotic lesions.
- Primary Effectiveness Endpoint: The (survival) rate in subjects treated with the COVERA™ Vascular Covered Stent (following PTA) with respect to Target Lesion Primary Patency (TLPP) at 6-months is greater than that in subjects treated with PTA alone in the treatment of stenoses in the upper extremity venous outflow of subjects dialyzing with an AV fistula.

For sample size determinations, safety at 30 days assumed a rate of 95% for subjects treated with the study device and 95% for subjects treated with PTA alone with attrition rate assumptions of 5%. For effectiveness, TLPP at 6 months assumed a rate of 73% for subjects treated with the study device and 50% for subjects treated with PTA alone with attrition rate assumptions of 10%. A sample size of 280 randomized subjects (allocated 1:1) would provide approximately 86% power for both primary safety and effectiveness endpoints.

An independent Clinical Events Committee (CEC) reviewed all adverse events (AEs) and performed adjudications of these events in accordance with their charter. The Medical Monitor (MM) reviewed adjudicated events for AE trends. An independent Data Safety Monitoring Board (DSMB) oversaw interim safety and effectiveness analyses as well as conducted evaluations of subject safety during the study. An independent core lab reviewed and analyzed the angiographic images.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the AVeNEW study was limited to patients who met specific inclusion criteria. Eligible patients presented with a hemodynamically significant stenosis (≥ 50% by visual estimate) in the venous outflow of the AV access circuit and presented with clinical or hemodynamic evidence of AV fistula dysfunction. To be included in the study, the target lesion was required to be ≤ 9 cm in length

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 5

{5}

and have a reference vessel diameter (of the adjacent, non-stenotic vessel) between 5.0 and 9.0 mm. The AV fistula had to be located in an upper extremity and have undergone at least one successful dialysis session prior to the index procedure.

Patients were not permitted to enroll in the AVeNEW study if they met any of the exclusion criteria. Patients were excluded if they had additional stenotic lesions (≥ 50%) in the venous outflow (> 3 cm from the edge of the target lesion) that were not successfully treated (defined as ≤ 30% residual stenosis) prior to treating the target lesion, if they had an aneurysm or pseudoaneurysm present within the target lesion, or if they had a target lesion located such that treatment would require the COVERA™ Vascular Covered Stent be deployed across the elbow joint, within a stent or stent graft, in the central veins (subclavian, brachiocephalic, superior vena cava (SVC)), or across the segment of fistula utilized for dialysis needle puncture (i.e. “cannulation zone”).

# 2. Follow-up Schedule

All patients underwent a clinical evaluation at screening (prior to index procedure); treated subjects underwent a clinical evaluation prior to hospital discharge. All subjects and their respective dialysis centers were scheduled for follow-up telephone screens at 30 days, 90 days, and 12 months postoperatively. The 6 month follow up occurred via an in office visit in addition to a phone call to the dialysis center.

Preoperatively, information on subject demographics, medical history, access circuit attributes (based on the Society of Interventional Radiology (SIR) guidelines), clinical exam including overall health and assessment of the AV access in accordance with each investigational site’s standard of care, documentation of applicable medication taken within 72 hours prior to the index procedure and angiography were conducted/collected. Postoperatively, the objective parameters measured during the study included data on the AV access circuit status, AEs, reinterventions performed, and changes in applicable medications. Site investigators and dialysis centers followed their institutional procedures for hemodialysis access surveillance. Investigational sites were responsible for collecting follow-up information from subjects, dialysis centers, and any outside institutions that conducted secondary interventions on study subjects. Additionally, the majority of secondary interventions were conducted at the investigational sites.

The key timepoints are shown in the table below.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 6

{6}

* Must be

| | Screening | Index Procedure | Post-Procedure / Discharge | Post Procedure Follow Ups | | | | Un-scheduled Visit / Re-intervention |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | 30 Days (±7 days) | 90 Days (±15 days) | 6 Months (±30 days) | 12 Months (±30 days) | |
| Informed Consent | ✓ | | | | | | | |
| Demographics / Medical History | ✓ | | | | | | | |
| Physical Examination* | ✓ | | ✓ | | | ✓ | | ✓ |
| Eligibility Criteria | ✓ | ✓ | | | | | | |
| Medication Assessment | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| AV Access Status | ✓ | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| Angiographic Image Collection** | | ✓ | | | | | | ✓** |
| Randomization | | ✓ | | | | | | |
| Adverse Event Assessment | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| Re-intervention Data Collection# | | | | ✓ | ✓ | ✓ | ✓ | ✓ |

performed if there is an office visit (i.e., if there is an office visit in lieu of telephone contact).

** Angiographic images are required when a revascularization of the access circuit is performed.

# Includes all re-interventions to the access circuit post the index procedure.

### 3. Clinical Endpoints

With regards to safety, the primary composite endpoint was a measure based on safety through 30 days post index procedure. Safety is defined as freedom from any AEs (CEC adjudicated), localized or systemic, that reasonably suggests the involvement of the AV access circuit (not including stenosis or thrombosis) that require or result in any of the following alone or in combination: additional interventions (including surgery); in-patient hospitalization or prolongation of an existing hospitalization; or death. Rates of longer-term device and procedure related adverse events were also measured to evaluate safety.

With regards to effectiveness, the primary endpoint was a measure based on Target Lesion Primary Patency (TLPP) through 6 months post index procedure. TLPP was defined as the interval following the index intervention until the next clinically driven reintervention at or adjacent to (approximately 5 mm proximal or distal to, by visual estimation) the original treatment site or until the extremity was abandoned for permanent access. Primary patency ended when any of the following occurred: a) clinically driven reintervention in the treatment area; b) thrombotic occlusion within the treatment area; c) surgical intervention that excludes the original treatment area from the AV access circuit; and/or d)

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 7

{7}

abandonment of the AV access due to inability to treat the original treatment area. Vessel rupture caused by PTA was not a TLPP failure unless achieving hemostasis also caused thrombosis or required any treatment other than what the patient had been randomized to receive.

With regard to success/failure criteria, the primary safety and effectiveness endpoints were evaluated against standard PTA alone. A one-sided p-value for the safety endpoint (non-inferiority) was calculated based on the Farrington and Manning test. A one-sided p-value for the effectiveness endpoint (superiority) was calculated based on the log-rank test. The study device is considered to have achieved the safety and effectiveness objectives if the one-sided p-value is less than 0.025.

The study included two secondary endpoints with hypothesis testing, which are TLPP through 12 months and Access Circuit Primary Patency (ACPP) through 6 months. ACPP was defined as the interval following the index intervention until the next access thrombosis or clinically driven repeated intervention. ACPP ended with a clinically driven reintervention anywhere within the access circuit; from the arterial inflow to the SVC-right atrial junction. Vessel rupture caused by PTA was not an ACPP failure unless achieving hemostasis also caused thrombosis. Evaluation of the secondary endpoints with hypothesis testing is performed in a hierarchical fashion in the order listed.

Additional endpoints include: (1) TLPP through 30 days, 90 days, 18 months, and 24 months; (2) ACPP through 30 days, 90 days, 12 months, 18 months and 24 months; (3) Rate of device and procedure related AEs involving the AV access circuit through 90 days, 6 months, 12 months, 18 months and 24 months; (4) Total Number of AV Access Circuit Reinterventions through 30 days, 90 days, 6 months, 12 months, 18 months and 24 months; (5) Total Number of Target Lesion Reinterventions through 30 days, 90 days, 6 months, 12 months, 18 months and 24 months; (6) Index of Patency Function (IPF) evaluated at 30 days, 90 days, 6 months, 12 months, 18 months and 24 months; (7) Index of Patency Function – Target Lesion (IPF-T) evaluated at 30 days, 90 days, 6 months, 12 months, 18 months and 24 months; (8) Secondary Patency evaluated through 30 days, 90 days, 6 months, 12 months, 18 months and 24 months; (9) Acute Technical Success; and (10) Acute Procedure Success (Anatomic and Clinical Success).

Information was also collected regarding deaths and device deficiencies.

### **B. Accountability of PMA Cohort**

Of the 280 randomized subjects enrolled in the PMA study, two hundred seventy (270) completed their 30-day follow-up contact, two hundred fifty-three (253) completed their 6-month follow-up contact and two hundred thirty-five (235) completed their 12-month follow-up contact. Table 2 provides subject availability based on the Intent to Treat (ITT) population and by timepoint. The ITT population was defined as all subjects who signed the study’s Informed Consent Form (ICF) and

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 8

{8}

were randomized to be in the study. Table 3 describes the number of patients discontinued through 6-month follow-up and the reasons for discontinuation based on the modified Intent to Treat (mITT) population. The mITT population was defined as subjects in the ITT population who were treated with the COVERA™ Vascular Covered Stent (following PTA) or PTA alone. There were 12 PTA subjects treated with adjunctive treatment (i.e. bare metal or stent grafts) who were excluded from the mITT population. Figure 4 depicts the number of subjects available for the primary analyses.

**Table 2: Subject Availability**

| | COVERA™ | PTA | Total |
| --- | --- | --- | --- |
| **Randomized Subjects (ITT)** | **142** | **138** | **280** |
| Completed 30-Day Follow-Up | 137 (96.5) | 133 (96.4) | 270 (96.4) |
| Completed 90-Day Follow-Up | 135 (95.1) | 128 (92.8) | 263 (93.9) |
| Completed 6-Month Follow-Up | 130 (91.5) | 123 (89.1) | 253 (90.4) |
| Completed 12-Month Follow-Up | 120 (84.5) | 115 (83.3) | 235 (83.9) |

Note: The denominator for the percentages is the number of subjects randomized in the study.

**Table 3: Subject Availability/Disposition**

| | COVERA™ | PTA | Total |
| --- | --- | --- | --- |
| **Randomized Subjects (ITT)** | **142** | **138** | **280** |
| Treated | 141* (99.3) | 138 (100) | 279 (99.6) |
| Modified ITT | 141* (99.3) | 126** (91.3) | 267 (95.4) |
| Discontinued Before 6-Month Follow-Up | 12 (8.5) | 11 (8.0) | 23 (8.2) |
| *Primary Reason For Discontinuation:* | | | |
| Withdrawal of Consent | 1 (0.7) | 1 (0.7) | 2 (0.7) |
| Death | 7 (4.9) | 9 (6.5) | 16 (5.7) |
| Investigator's Decision* | 1 (0.7) | 0 | 1 (0.4) |
| Lost to Follow-Up | 2 (1.4) | 1 (0.7) | 3 (1.1) |
| Other*** | 1 (0.7) | 0 | 1 (0.4) |

Note: The denominator for the percentages is the number of subjects randomized in the study.

*One subject was randomized to receive COVERA™, however, did not receive any treatment during the index procedure and was discontinued from the study via, 'investigator decision'. Subject was erroneously enrolled.

**Twelve PTA subjects treated with adjunctive treatment (i.e. bare metal or stent grafts) were excluded.

***One subject was randomized to COVERA™, however, was only treated with PTA, due to the location of the target lesion that would have required the study device to be deployed at or across the segment of the fistula utilized for dialysis needle puncture, i.e., cannulation zone. Subject was followed through the 30-day follow-up to assess for safety events.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 9

{9}


Figure 4: Subject Accountability

### C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical of a study performed in the US on hemodialysis patients.

Demographic and background characteristics for the ITT population are provided in Table 4 below. The majority of subjects were white (68.6%) and male (61.8%). The mean age at the time of the index procedure was 63 ± 12.4 years and there was no difference between the two treatment arms with regards to age. The Body-Mass Index (BMI) was noted to be statistically different between the two treatment arms, however, more obese patients (BMI ≥ 30) were enrolled in the COVERA™ group compared to the PTA alone group, thereby favoring the outcomes of the later. A summary of relevant medical risk factors as well as selected medical history background for the ITT population is provided in Table 5. The expected comorbidities for this population were observed, with nearly all of the subjects' hypertensive (97.1%), three quarter (75.4%) diabetic, and 67.9% having cardiovascular disease. There were no differences noted between the two treatment arms for any of the relevant medical risk factors.

Table 4: Subject Demographics (ITT Subjects)

| | COVERA™ N = 142 | PTA Alone N = 138 | Total N = 280 | P-value |
| --- | --- | --- | --- | --- |
| Age Categories | n (%) | n (%) | n (%) | 0.1945 |
| < 65 years | 79 (55.6) | 76 (55.1) | 155 (55.4) | |
| ≥ 65 and < 75 years | 36 (25.4) | 45 (32.6) | 81 (28.9) | |

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 10

{10}

| ≥ 75 years | 27 (19.0) | 17 (12.3) | 44 (15.7) | |
| --- | --- | --- | --- | --- |
| **Sex** | **n (%)** | **n (%)** | **n (%)** | 0.7558 |
| Male | 89 (62.7) | 84 (60.9) | 173 (61.8) | |
| Female | 53 (37.3) | 54 (39.1) | 107 (38.2) | |
| **Ethnicity** | **n (%)** | **n (%)** | **n (%)** | 0.3776 |
| Hispanic or Latino | 48 (33.8) | 54 (39.1) | 102 (36.4) | |
| Not Hispanic or Latino | 93 (65.5) | 84 (60.9) | 177 (63.2) | |
| Missing | 1 (0.7) | 0 | 1 (0.4) | |
| **Race** | **n (%)** | **n (%)** | **n (%)** | 0.0819 |
| Asian | 0 | 6 (4.3) | 6 (2.1) | |
| Native Hawaiian or Other Pacific Island | 2 (1.4) | 0 | 2 (0.7) | |
| Black or African American | 36 (25.4) | 36 (26.1) | 72 (25.7) | |
| White | 100 (70.4) | 92 (66.7) | 192 (68.6) | |
| Other | 4 (2.8) | 4 (2.9) | 8 (2.9) | |
| **BMI Categories** | **n (%)** | **n (%)** | **n (%)** | 0.0108 |
| < 30 | 68 (47.9) | 87 (63.0) | 155 (55.4) | |
| ≥ 30 | 74 (52.1) | 51 (37.0) | 125 (44.6) | |

**Table 5: Medical History (ITT Subjects)**

| | **COVERA™ N = 142** | **PTA Alone N = 138** | **Total N = 280** | |
| --- | --- | --- | --- | --- |
| **Risk Factors** | **n (%)** | **n (%)** | **n (%)** | **P-value** |
| *Subjects With at Least One Risk Factor* | 141 (99.3) | 136 (98.6) | 277 (98.9) | 0.5449 |
| Diabetes – Total | 108 (76.1) | 103 (74.6) | 211 (75.4) | 0.7830 |
| Diabetes (Type 1) | 7 (4.9) | 9 (6.5) | 16 (5.7) | |
| Diabetes (Type 2) | 101 (71.1) | 94 (68.1) | 195 (69.6) | |
| Dyslipidemia | 95 (66.9) | 85 (61.6) | 180 (64.3) | 0.3541 |
| Hypertension | 139 (97.9) | 133 (96.4) | 272 (97.1) | 0.4481 |
| Cigarette Smoking - Total | 62 (43.7) | 62 (44.9) | 124 (44.3) | 0.8312 |
| Cigarette Smoking - Current | 8 (5.6) | 15 (10.9) | 23 (8.2) | |
| Cigarette Smoking - Former | 54 (38.0) | 47 (34.1) | 101 (36.1) | |
| **Cardiovascular Disease** | **n (%)** | **n (%)** | **n (%)** | **P-value** |
| *Subjects With at Least One Type of Cardiovascular Disease* | 95 (66.9) | 95 (68.8) | 190 (67.9) | 0.7283 |
| Congestive Heart Failure | 35 (24.6) | 40 (29.0) | 75 (26.8) | 0.4125 |
| New York Heart Association (NYHA) Class I | 1 (0.7) | 2 (1.4) | 3 (1.1) | |
| NYHA Class II | 2 (1.4) | 1 (0.7) | 3 (1.1) | |
| NYHA Class UNKNOWN | 32 (22.5) | 37 (26.8) | 69 (24.6) | |
| Stroke | 20 (14.1) | 24 (17.4) | 44 (15.7) | 0.4472 |
| Coronary Artery Disease (CAD) | 46 (32.4) | 52 (37.7) | 98 (35.0) | 0.3538 |
| Myocardial Infarction (MI) | 22 (15.5) | 18 (13.0) | 40 (14.3) | 0.5581 |
| Transient Ischemic Attack (TIA) | 2 (1.4) | 7 (5.1) | 9 (3.2) | 0.0822 |
| Valvular Heart Disease | 6 (4.2) | 4 (2.9) | 10 (3.6) | 0.5498 |
| Aortic Disease | 2 (1.4) | 4 (2.9) | 6 (2.1) | 0.3893 |

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 11

{11}

| Deep Vein Thrombosis (DVT) | 5 (3.5) | 4 (2.9) | 9 (3.2) | 0.7678 |
| --- | --- | --- | --- | --- |
| Peripheral Arterial/Vascular Disease (PAD) (PVD) | 24 (16.9) | 29 (21.0) | 53 (18.9) | 0.3797 |
| Atrial Fibrillation (A-Fib) | 15 (10.6) | 16 (11.6) | 31 (11.1) | 0.7834 |
| Other | 38 (26.8) | 37 (26.8) | 75 (26.8) | 0.9923 |
| **Other Disease** | **n (%)** | **n (%)** | **n (%)** | **P-value** |
| *Subjects With at Least One Other Disease* | 129 (90.8) | 129 (93.5) | 258 (92.1) | 0.4130 |
| Bleeding Disorder | 3 (2.1) | 3 (2.2) | 6 (2.1) | 0.9718 |
| Cancer | 17 (12.0) | 15 (10.9) | 32 (11.4) | 0.7719 |
| Steal Syndrome | 2 (1.4) | 1 (0.7) | 3 (1.1) | 0.5785 |
| Other | 128 (90.1) | 126 (91.3) | 254 (90.7) | 0.7373 |

A summary of characteristics of the AV access circuit as reported by sites is shown in Table 6. The majority of subjects had upper arm access in the left arm within inflow provided by the brachial artery and outflow through the cephalic vein. The type of fistula configuration was matched between the study arms with slight majority (57.9%) having brachiocephalic access, and an additional 22.9% having a transposed brachiobasilic fistula. Overall, 28.2% of the subjects had a vein transposed to facilitate the fistula configuration.

**Table 6: Description of Access Circuit (ITT Subjects)**

| | **COVERA™** **N = 142** | **PTA Alone** **N = 138** | **Total** **N = 280** |
| --- | --- | --- | --- |
| **Target Limb** | **n (%)** | **n (%)** | **n (%)** |
| Left Arm | 106 (74.6) | 110 (79.7) | 216 (77.1) |
| Right Arm | 36 (25.4) | 28 (20.3) | 64 (22.9) |
| **Access Position** | **n (%)** | **n (%)** | **n (%)** |
| Forearm | 9 (6.3) | 8 (5.8) | 17 (6.1) |
| Upper Arm | 132 (93.0) | 130 (94.2) | 262 (93.6) |
| Other | 1 (0.7) | 0 | 1 (0.4) |
| **Inflow Artery** | **n (%)** | **n (%)** | **n (%)** |
| Axillary | 2 (1.4) | 2 (1.4) | 4 (1.4) |
| Brachial | 128 (90.1) | 127 (92.0) | 255 (91.1) |
| Radial | 12 (8.5) | 9 (6.5) | 21 (7.5) |
| **Outflow Vein** | **n (%)** | **n (%)** | **n (%)** |
| Axillary | 2 (1.4) | 1 (0.7) | 3 (1.1) |
| Basilic | 35 (24.6) | 42 (30.4) | 77 (27.5) |
| Cephalic | 105 (73.9) | 95 (68.8) | 200 (71.4) |
| **Fistula Configuration** | **n (%)** | **n (%)** | **n (%)** |
| Radiocephalic | 12 (8.5) | 9 (6.5) | 21 (7.5) |
| Brachiocephalic | 84 (59.2) | 78 (56.5) | 162 (57.9) |
| Transposed Brachiobasilic | 27 (19.0) | 37 (26.8) | 64 (22.9) |
| All Other | 19 (13.4) | 14 (10.1) | 33 (11.8) |
| **Transposed?** | **n (%)** | **n (%)** | **n (%)** |

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 12

{12}

| | COVERA™ N = 142 | PTA Alone N = 138 | Total N = 280 |
| --- | --- | --- | --- |
| Yes | 36 (25.4) | 43 (31.2) | 79 (28.2) |
| No | 106 (74.6) | 95 (68.8) | 201 (71.8) |

Interventions within 30 days prior to the index procedure on the index AV access circuit are shown in Table 7. A total of 10 interventions were performed in eight (8) subjects (2.9%) in the index AV access circuit within 30 days of being enrolled in this study. The majority of these interventions involved the target lesion (8 of 280, 2.9%) and comprised of PTA (8) and thrombolysis and/or thrombectomies (1).

**Table 7: Previous Index AV Access Circuit Interventions (ITT Subjects)**

| | COVERA™ N = 142 | PTA Alone N = 138 | Total N = 280 |
| --- | --- | --- | --- |
| | n/N (%) | n/N (%) | n/N (%) |
| Number of subjects who underwent any interventions of the index AV Access Circuit within 30 days prior to the index procedure | 4/142 (2.8) | 4/138 (2.9) | 8/280 (2.9) |
| Number of subjects planning to undergo any interventions of the index AV Access Circuit within 30 days | 0 | 0 | 0 |
| **Number of Previous Interventions** | **n** | **n** | **n** |
| Total Number of Previous Interventions | 5 | 5 | 10 |
| Number of Subjects with Previous Interventions | 4 | 4 | 8 |
| Mean (Standard Deviation) | 1.3 (0.50) | 1.3 (0.50) | 1.3 (0.46) |

*Note: Some subjects had multiple interventions.*

Site-reported baseline target lesion characteristics are shown in Table 8 and Table 9. The majority of lesions (73.2%) were re-stenotic in nature and a majority of the anastomoses (72.9%) were at the cephalic vein, with the majority of stenosis located at the cephalic vein arch (52.9%).

The reference vessel diameter averaged 8.1 ± 1.14 mm, the target lesion length ranged from 2 to 80 mm, with a stenosis of 72.5 ± 12.5% on average by visual estimate.

**Table 8: Target Lesion Characteristics (ITT Subjects)**

| | COVERA™ N = 142 | PTA Alone N = 138 | Total N = 280 |
| --- | --- | --- | --- |
| **De Novo Lesion?** | **n (%)** | **n (%)** | **n (%)** |
| Yes | 35 (24.6) | 40 (29.0) | 75 (26.8) |
| No | 107 (75.4) | 98 (71.0) | 205 (73.2) |
| **Vessel** | **n (%)** | **n (%)** | **n (%)** |
| Axillary Vein | 3 (2.1) | 2 (1.4) | 5 (1.8) |
| Basilic Vein | 30 (21.1) | 35 (25.4) | 65 (23.2) |
| Cephalic Vein | 108 (76.1) | 96 (69.6) | 204 (72.9) |
| Other | 1 (0.7) | 5 (3.6) | 6 (2.1) |
| **Lesion Location** | **n (%)** | **n (%)** | **n (%)** |

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 13

{13}

| Axillary Vein | 3 ( 2.1) | 2 ( 1.4) | 5 ( 1.8) |
| --- | --- | --- | --- |
| Basilic Vein Outflow | 13 ( 9.2) | 15 ( 10.9) | 28 ( 10.0) |
| Basilic Vein Swing Point | 16 ( 11.3) | 18 ( 13.0) | 34 ( 12.1) |
| Cephalic Vein Arch | 78 ( 54.9) | 70 ( 50.7) | 148 ( 52.9) |
| Cephalic Vein Outflow | 25 ( 17.6) | 24 ( 17.4) | 49 ( 17.5) |
| Forearm Venous Outflow | 3 ( 2.1) | 2 ( 1.4) | 5 ( 1.8) |
| Juxta-Anastomotic | 2 ( 1.4) | 0 | 2 ( 0.7) |
| Axillary Basilic Junction | 2 ( 1.4) | 7 ( 5.1) | 9 ( 3.2) |

**Table 9: Angiographic Target Lesion Characteristics (ITT Subjects)**

| | COVERA™ N = 142 | PTA Alone N = 138 | Total N = 280 |
| --- | --- | --- | --- |
| | Mean (SD) | Mean (SD) | Mean (SD) |
| Reference Vessel Diameter (mm) | 8.1 (1.35) | 8.0 (0.87) | 8.1 (1.14) |
| Target Lesion Length (mm) | 28.8 (17.40) | 29.7 (16.98) | 29.3 (17.17) |
| Target Lesions Stenosis (mm) | 72.5 (12.40) | 72.5 (12.65) | 72.5 (12.50) |

**Table 10: Summary of Study Device Details (As Treated Population)**

| | COVERA™ N = 141 |
| --- | --- |
| **Stent Graft Configuration** | **n (%)** |
| Flared | 65 (46.1) |
| Straight | 76 (53.9) |
| **Stent Graft Diameter** | **n (%)** |
| 6 mm | 1 (0.7) |
| 7 mm | 4 (2.8) |
| 8 mm | 26 (18.4) |
| 9 mm | 42 (29.8) |
| 10 mm | 68 (48.2) |
| **Stent Graft Length** | **n (%)** |
| 30 mm | 3 (2.1) |
| 40 mm | 59 (41.8) |
| 60 mm | 52 (36.9) |
| 80 mm | 23 (16.3) |
| 100 mm | 4 (2.8) |
| **Placement Configuration** | **n (%)** |
| Single Stent Graft Only | 140 (99.3) |
| Other* | 1 (0.7) |
| **Was Placement Successful at intended site?** | |
| Yes | 141 (100) |

*Although only one COVERA™ Vascular Covered Stent could be implanted in each patient per the study protocol, in one subject, a second COVERA™ Vascular Covered Stent was placed in an overlap configuration during the index procedure.*

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 14

{14}

The protocol and IFU required pre-dilation of the target lesion and successful effacement of the angioplasty balloon to meet the final eligibility criterion. Residual stenosis ranged from 0.0 to 90% where 54 subjects (19.3%) were reported to have an unsuccessful pre-dilation (defined as a residual stenosis of >30%). Of which, 33 subjects (23.2%) were randomized to COVERA™ Vascular Stent post PTA and 21 subjects (15.2%) were randomized to PTA. A summary of the pre-dilation details is provided in Table 11.

**Table 11: Target Lesion Pre-Dilatation**

| | COVERA™ N = 142 | PTA Alone N = 138 | Total N = 280 |
| --- | --- | --- | --- |
| | Mean (SD) | Mean (SD) | Mean (SD) |
| Balloon Diameter (mm) | 8.5 (1.03) | 8.4 (1.11) | 8.5 (1.07) |
| Balloon Length (mm) | 46.8 (14.85) | 49.0 (16.75) | 47.9 (15.83) |
| Number of Balloon Inflations | 1.3 (0.56) | 1.3 (0.59) | 1.3 (0.58) |
| Maximum Pressure of Balloon Inflation (atm) | 20.6 (5.38) | 21.2 (5.78) | 20.9 (5.58) |
| Total Duration of Inflation (sec) | 43.4 (52.83) | 41.2 (40.96) | 42.3 (47.28) |
| Residual Stenosis (%) | 21.7 (20.52) | 15.4 (16.58) | 18.6 (18.91) |

## **D. Safety and Effectiveness Results**

### **1. Safety Results**

The analysis of safety was based on the ITT cohort of subjects available for the 30-day evaluation. The proportion of subjects free from primary safety events was 95.0% in subjects treated with the COVERA™ Vascular Covered Stent compared with a safety rate of 96.4% in subjects treated with PTA alone (p-value = 0.0022). Thus, the non-inferiority of COVERA™ Vascular Covered Stent to PTA alone with regard to this primary safety endpoint is met. The key safety outcome for this study is presented in Table 12.

**Table 12: Freedom from any Safety Event through 30 days (ITT Subjects)**

| Primary Safety Endpoint | COVERA™ n/N (%) | PTA n/N (%) | Difference 90% CI [2] | P-value [1] |
| --- | --- | --- | --- | --- |
| Proportion Free from Primary Safety Events | 133/140* (95.0) | 132/137** (96.4) | -1.4 (-7.3, 4.6) | 0.0022 |
| *Had Failure:* | 7/140 (5.0) | 5/137 (3.6) | | |
| Death | 0 | 0 | | |
| Required Additional Intervention | 7/140 (5.0) | 5/137 (3.6) | | |
| In-Patient Hospitalization or Prolongation | 0 | 1/137 (0.7) | | |

*Two subjects were excluded from the analysis due to discontinuation or death prior to day 23 of their follow-up.

**One subject was excluded from the analysis due to death prior to day 23 of their follow-up.

[1] The p-value is calculated using Farrington and Manning non-inferiority test with non-inferiority margin=10%.

[2] 95% confidence interval is estimated using the Farrington and Manning method.

Note: The safety events are based on CEC adjudicated outcomes.

### **Adverse effects that occurred in the PMA clinical study:**

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 15

{15}

A list of CEC adjudicated device and procedure related Safety Events observed in the Clinical Study at 30 days, 6 and 12 months can be found in Table 13 and Table 14, respectively. Adverse Events (AEs) are defined as 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 study device.

Overall at 12 months there were 17 subjects with at least one device related AE in the COVERA™ Vascular Covered Stent arm and 4 subjects with at least one device related AE in the PTA-only arm. There is no single reason identified for this difference in number of AE's.

There have been a total of 7 arteriovenous fistula site complications that were adjudicated to be device related. Of these, 5 were adjudicated to also be procedure related at 12 months (Tables 13 and 14 below). These AEs include site-reported event terms such as: pain in the access arm, erythematous skin over stent, swelling, thrill / bruit, and pulsatility.

**Table 13: CEC Adjudicated Device Related AEs through 12 months (ITT Subjects)**

| Adverse Event | COVERA™ (N=142) | | | PTA (N=138) | | |
| --- | --- | --- | --- | --- | --- | --- |
| | 30 days n(%) | 6 months n(%) | 12 months n(%) | 30 days n(%) | 6 months n(%) | 12 months n(%) |
| **Subjects with at Least One Device Related AE** | **12 (8.5%)** | **15 (10.6%)** | **17 (12.0%)** | **1 (0.7%)** | **1 (0.7%)** | **4 (2.9%)** |
| Arteriovenous fistula site complication | 5 (3.5%) | 5 (3.5%) | 7 (4.9%) | 0 | 0 | 0 |
| Arteriovenous fistula site haematoma | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |
| Bradycardia | 0 | 0 | 0 | 0 | 0 | 1 (0.7%) |
| Hyperkalaemia | 0 | 0 | 0 | 0 | 0 | 1 (0.7%) |
| Musculoskeletal pain | 0 | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |
| Pain in extremity | 1 (0.7%) | 2 (1.4%) | 2 (1.4%) | 0 | 0 | 0 |
| Procedural pain | 2 (1.4%) | 2 (1.4%) | 2 (1.4%) | 0 | 0 | 0 |
| Staphylococcal bacteraemia | 0 | 0 | 1 (0.7%) | 0 | 0 | 1 (0.7%) |
| Stent malfunction | 0 | 2 (1.4%) | 2 (1.4%) | 0 | 0 | 0 |
| Steal syndrome | 0 | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |
| Subclavian artery occlusion | 0 | 0 | 0 | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) |
| Vascular pseudoaneurysm | 0 | 0 | 0 | 0 | 0 | 1 (0.7%) |
| Vasospasm | 2 (1.4%) | 2 (1.4%) | 2 (1.4%) | 0 | 0 | 0 |
| Vessel puncture site haemorrhage | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |

*Note that n=subjects with at least one event.*

*Note that events were coded using MedDRA version 16.1.*

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 16

{16}

**Table 14: CEC Adjudicated Procedure Related AEs through 12 months (ITT Subjects)**

| Adverse Event | COVERA™ (N=142) | | | PTA (N=138) | | |
| --- | --- | --- | --- | --- | --- | --- |
| | 30 days n(%) | 6 months n(%) | 12 months n(%) | 30 days n(%) | 6 months n(%) | 12 months n(%) |
| **Subjects With At Least One Procedure Related AE** | **13 (9.2%)** | **13 (9.2%)** | **13 (9.2%)** | **8 (5.8%)** | **9 (6.5%)** | **10 (7.2%)** |
| Abdominal pain lower | 0 | 0 | 0 | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) |
| Arteriovenous fistula site complication | 5 (3.5%) | 5 (3.5%) | 5 (3.5%) | 0 | 0 | 0 |
| Arteriovenous fistula site haematoma | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |
| Contrast media reaction | 0 | 0 | 0 | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) |
| Flushing | 0 | 0 | 0 | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) |
| Musculoskeletal pain | 0 | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |
| Pain in extremity | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |
| Procedural pain | 2 (1.4%) | 2 (1.4%) | 2 (1.4%) | 0 | 0 | 0 |
| Steal syndrome | 0 | 0 | 0 | 0 | 1 (0.7%) | 1 (0.7%) |
| Stent malfunction | 0 | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |
| Subclavian artery occlusion | 0 | 0 | 0 | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) |
| Vascular fragility | 0 | 0 | 0 | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) |
| Vascular procedure complication | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |
| Vascular pseudoaneurysm | 0 | 0 | 0 | 0 | 0 | 1 (0.7%) |
| Vascular rupture | 0 | 0 | 0 | 3 (2.2%) | 3 (2.2%) | 3 (2.2%) |
| Vasospasm | 2 (1.4%) | 2 (1.4%) | 2 (1.4%) | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) |
| Vessel puncture site haemorrhage | 1 (0.7%) | 1 (0.7%) | 1 (0.7%) | 0 | 0 | 0 |

*Note that n=subjects with at least one event.*

*Note that events were coded using MedDRA version 16.1.*

## 2. Effectiveness Results

The analysis of effectiveness was based on the mITT cohort of subjects at the 6-month time point. The Kaplan-Meier (K-M) estimates at day 180 for subjects receiving the COVERA™ Vascular Covered Stent was 78.7% and for subjects receiving PTA alone was 47.9% (p-value <0.001). The primary effectiveness endpoint for superiority of COVERA™ Vascular Covered Stent to PTA alone was met with a p-value of <0.001. Key effectiveness outcomes for this study are presented in Figure 5 and Table 15.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 17

{17}

**Figure 5: Kaplan-Meier Analysis of the Primary Effectiveness Endpoint (mITT Subjects)**


**Table 15: Analysis of the Primary Effectiveness Endpoint (mITT Subjects)**

| Time Point | COVERA™ | | | | PTA Alone | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | #of Subjects at Risk | #of Subjects Censored | #of Subjects with TLPP Fail | K-M Rate (95% CI) [1] | #of Subjects at Risk | #of Subjects Censored | #of Subjects with TLPP Fail | K-M Rate (95% CI) [1] |
| 30 Days | 136 | 1 | 4 | 97.2% (92.6%,98.9%) | 122 | 1 | 3 | 97.6% (92.8%,99.2%) |
| 90 Days | 124 | 4 | 13 | 90.6% (84.4%,94.5%) | 97 | 6 | 23 | 81.1% (73.0%,87.1%) |
| 180 Days | 0 | 112 | 29 | 78.7% (70.8%,84.7%) | 0 | 64 | 62 | 47.9% (38.7%,56.6%) |
| Hazard Ratio [3] (95% CI) | | | | | | | | 0.322% (0.207%, 0.503%) |
| P-value [2] | | | | | | | | <0.001 |

[1] The rates are estimated using Kaplan-Meier method and the 95% confidence interval are estimated using Greenwood's formula.

[2] One sided P-value is calculated using Log-rank test.

[3] Hazard ratio calculated using COX regression with treatment in the model.

Note: The involvement of the target lesion is based on the core lab evaluation. If images were not evaluable by the core lab, site reported evaluation was used.

### 3. Secondary Endpoints with Hypothesis Testing

#### 3.1 TLPP at 12 months

Testing of secondary endpoints was performed in a hierarchical fashion in the order listed. Thus, in order to perform hypothesis testing of ACPP at 6 months, TLPP at 12 months must be successful.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 18

{18}

Figure 6: Kaplan-Meier Analysis of TLPP at 12-Months (mITT)


Table 16: Analysis of Subjects with TLPP through 12-Months (mITT)

| | COVERATM | | | | PTA Alone | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Time Point | #of Subjects at Risk | #of Subjects Censored | #of Subjects with TLPP Fail | K-M Rate (95% CI) [1] | #of Subjects at Risk | #of Subjects Censored | #of Subjects with TLPP Fail | K-M Rate (95% CI) [1] | |
| 30 Days | 136 | 1 | 4 | 97.2(92.6,98.9) | 122 | 1 | 3 | 97.6(92.8,99.2) | |
| 90 Days | 124 | 4 | 13 | 90.6(84.4,94.5) | 97 | 6 | 23 | 81.1(73.0,87.1) | |
| 180 Days | 0 | 112 | 29 | 78.7(70.8,84.7) | 53 | 11 | 62 | 47.9(38.7,56.6) | |
| 365 Days | 0 | 86 | 55 | 57.5(48.4,65.5) | 0 | 35 | 91 | 21.2(14.2,29.2) | |
| Hazard Ratio [3](95% CI) | | | | | | | | | 0.337(0.240,0.474) |
| P-value [2] | | | | | | | | | <0.001 |

[1] The rates are estimated using Kaplan-Meier method and the 95% confidence interval are estimated using Greenwood's formula.

[2] One sided P-value is calculated using Log-rank test.

[3] Hazard ratio calculated using COX regression with treatment in the model.

Note: The involvement of the target lesion is based on the core lab evaluation. If images were not evaluable by the core lab, site reported evaluation was used.

As shown in Figure 6 and Table 16, the results of TLPP achieved statistical significance, indicating that it provides evidence that the COVERA™ Vascular Covered Stent is superior to PTA alone on this key secondary endpoint at 12 months.

### 3.2 ACPP at 6-months

ACPP is defined as the interval following the index intervention until the next access thrombosis or clinically driven repeated intervention. A survival analysis

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 19

{19}

of ACPP was performed by Kaplan-Meier estimates for 180 days. The survival curve is shown in Figure 7 and supporting data in Table 17.

Figure 7: Kaplan-Meier Analysis of ACPP (mITT Subjects)


Table 17: Kaplan-Meier Analysis of ACPP (mITT Subjects)

| | COVERATM | | | | PTA Alone | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Time Point | #of Subjects at Risk | #of Subjects Censored | #of Subjects with ACPP Failure | K-M Rate (95% CI) [1] | #of Subjects at Risk | #of Subjects Censored | #of Subjects with ACPP Failure | K-M Rate (95% CI) [1] | |
| 30 Days | 133 | 1 | 7 | 95.0% (89.8%,97.6%) | 120 | 1 | 5 | 96.0% (90.7%,98.3%) | |
| 90 Days | 109 | 4 | 28 | 79.8% (72.1%,85.6%) | 94 | 6 | 26 | 78.8% (70.4%,85.0%) | |
| 180 Days | 0 | 74 | 67 | 50.7% (42.0%,58.8%) | 0 | 59 | 67 | 43.8% (34.7%,52.5%) | |
| Hazard Ratio [3] (95% CI) | | | | | | | | | 0.787% (0.560%, 1.108%) |
| P-value[2] | | | | | | | | | 0.0846 |

[1] The rates are estimated using Kaplan-Meier method and the 95% confidence interval are estimated using Greenwood's formula.

[2] p-value is calculated using Log-rank test.

[3] Hazard ratio calculated using COX regression with treatment in the model.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 20

{20}

The results of ACPP did not meet statistical significance, indicating that it does not provide evidence that COVERA™ Vascular Covered Stent is superior to PTA alone on this key secondary endpoint at 6 months.

#### 4. Subgroup Analyses

The following preoperative characteristics were evaluated for potential association with outcomes: sex, race, age, target lesion characteristics, target lesion location, presence of secondary lesion(s), and fistula configuration. Primary endpoint and key secondary endpoints were explored in subgroups on evaluable subjects (Table 18 through Table 20).

**Table 18: Analysis of TLPP by Subgroup at 6 months (mITT Subjects)**

| Subgroup | Covera™ n/N (%) | PTA Alone n/N (%) |
| --- | --- | --- |
| **Geography** | | |
| USA | 96/124 ( 77.4) | 52/110 ( 47.3) |
| Outside United States (OUS) | 9/10 ( 90.0) | 3/7 ( 42.9) |
| **Gender** | | |
| Male | 62/82 ( 75.6) | 38/71 ( 53.5) |
| Female | 43/52 ( 82.7) | 17/46 ( 37.0) |
| **Race** | | |
| White | 74/96 ( 77.1) | 36/76 ( 47.4) |
| African-American | 26/33 ( 78.8) | 15/32 ( 46.9) |
| Other | 5/5 (100.0) | 4/9 ( 44.4) |
| **Age** | | |
| <65 years | 60/77 ( 77.9) | 32/65 ( 49.2) |
| ≥65 and <75 years | 26/34 ( 76.5) | 19/39 ( 48.7) |
| ≥75 years | 19/23 ( 82.6) | 4/13 ( 30.8) |
| **Target Lesion Characteristics** | | |
| de Novo | 25/31 ( 80.6) | 21/32 ( 65.6) |
| Re-stenotic | 80/103 ( 77.7) | 34/85 ( 40.0) |
| **Target Lesion Location** | | |
| Cephalic Vein Arch | 58/77 ( 75.3) | 23/60 ( 38.3) |
| Cephalic Vein Outflow | 18/22 ( 81.8) | 12/18 ( 66.7) |
| Basilic Vein Outflow | 9/11 ( 81.8) | 6/14 ( 42.9) |
| Basilic Vein Swing-Point | 13/15 ( 86.7) | 9/15 ( 60.0) |
| Others | 7/9 ( 77.8) | 5/10 ( 50.0) |
| **Presence of Secondary Lesion(s)?** | | |
| Yes | 36/47 ( 76.6) | 17/45 ( 37.8) |
| No | 69/87 ( 79.3) | 38/72 ( 52.8) |

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 21

{21}

**Table 19: Analysis of TLPP at 12 months by Subgroup (mITT Subjects)**

| Subgroup | COVERA™ N/N (%) | PTA Alone n/N (%) |
| --- | --- | --- |
| **Geography** | | |
| USA | 62/114 (54.4) | 23/107 (21.5) |
| OUS | 7/10 (70.0) | 0/7 (0.0) |
| **Gender** | | |
| Male | 42/74 (56.8) | 13/68 (19.1) |
| Female | 27/50 (54.0) | 10/46 (21.7) |
| **Race** | | |
| White | 51/89 (57.3) | 13/73 (17.8) |
| African-American | 14/30 (46.7) | 9/32 (28.1) |
| Other | 4/5 (80.0) | 1/9 (11.1) |
| **Age** | | |
| <65 years | 40/71 (56.3) | 13/63 (20.6) |
| ≥65 and <75 years | 16/32 (50.0) | 9/38 (23.7) |
| ≥75 years | 13/21 (61.9) | 1/13 (7.7) |
| **Target Lesion Characteristics** | | |
| de Novo | 18/29 (62.1) | 12/32 (37.5) |
| Re-stenotic | 51/95 (53.7) | 11/82 (13.4) |
| **Target Lesion Location** | | |
| Cephalic Vein Arch | 38/75 (50.7) | 7/58 (12.1) |
| Cephalic Vein Outflow | 13/20 (65.0) | 9/18 (50.0) |
| Basilic Vein Outflow | 4/9 (44.4) | 2/14 (14.3) |
| Basilic Vein Swing-Point | 8/12 (66.7) | 3/15 (20.0) |
| Others | 6/8 (75.0) | 2/9 (22.2) |
| **Presence of Secondary Lesion(s)?** | | |
| Yes | 25/46 (54.3) | 7/44 (15.9) |
| No | 44/78 (56.4) | 16/70 (22.9) |
| **Fistula Configuration** | | |
| Radiocephalic | 8/11 (72.7) | 0/5 (0.0) |
| Transposed Brachiobasilic | 12/21 (57.1) | 5/33 (15.2) |
| Brachiocephalic | 43/77 (55.8) | 13/63 (20.6) |
| All Other | 6/15 (40.0) | 5/13 (38.5) |

**Table 20: Analysis of ACPP by Subgroup at 6 months (mITT Subjects)**

| Subgroup | Covera™ n/N (%) | PTA Alone n/N (%) |
| --- | --- | --- |
| **Geography** | | |
| USA | 64/124 (51.6) | 49/110 (44.5) |
| OUS | 7/10 (70.0) | 2/7 (28.6) |
| **Gender** | | |

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 22

{22}

| Male | 41/82 (50.0) | 37/71 (52.1) |
| --- | --- | --- |
| Female | 30/52 (57.7) | 14/46 (30.4) |
| **Race** | | |
| White | 50/96 (52.1) | 34/76 (44.7) |
| African-American | 17/33 (51.5) | 13/32 (40.6) |
| Other | 4/5 (80.0) | 4/9 (44.4) |
| **Age** | | |
| <65 years | 38/77 (49.4) | 30/65 ( 6.2) |
| ≥65 and <75 years | 17/34 (50.0) | 18/39 (446.2) |
| ≥75 years | 16/23 (69.6) | 3/13 (23.1) |
| **Target Lesion Characteristics** | | |
| de Novo | 17/27 (63.0) | 18/30 (60.0) |
| Re-stenotic | 54/107 (50.0) | 33/87 (37.9) |
| **Target Lesion Location** | | |
| Cephalic Vein Arch | 40/77 (51.9) | 23/60 (38.3) |
| Cephalic Vein Outflow | 16/22 (72.7) | 11/18 (61.1) |
| Basilic Vein Outflow | 3/11 (27.3) | 5/14 (35.7) |
| Basilic Vein Swing-Point | 8/15 (53.3) | 9/15 (60.0) |
| Others | 4/9 (44.4) | 3/10 (30.0) |
| **Presence of Secondary Lesion(s)?** | | |
| Yes | 19/47 (40.4) | 15/45 (33.3) |
| No | 52/87 (59.8) | 36/72 ( 50.0) |

##### 5. Additional Endpoints

Table 21 through Table 25 presents information on additional endpoints with proportional values through 12-months.

Acute Technical Success is defined as successful deployment, based on the operator's opinion, of the implant to the intended location assessed at the time of the index procedure. Acute Procedure Success was defined as anatomic success and resolution of the pre-procedural clinical indicator(s) (clinical success) of a hemodynamically significant stenosis as further defined by Anatomic and Clinical Success. Anatomic Success was determined during the primary procedure and was defined as the achievement of a post-procedure residual stenosis of less than or equal to 30%, measured at the narrowest point of the lumen when compared to the adjacent non-stenosed venous segment. Clinical Success was defined as resolution of pre-procedural clinical indicators of access malfunction in the opinion of the investigator prior to hospital discharge which could include an abnormal physical exam, abnormal pressure monitoring parameters, decreased access flow, difficulty with dialysis needle puncture, pulling thrombus, prolonged bleeding, increased recirculation, and/or inadequate dialysis clearance.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 23

{23}

Secondary Patency is defined as the interval after the index intervention until the access is abandoned. Multiple repetitive treatments can be included in post-intervention secondary patency.

**Table 21: TLPP, Proportional Values (mITT Subjects)**

| Subgroup | COVERA™ n/N (%) | PTA Alone n/N (%) |
| --- | --- | --- |
| 30 days | 136/140 (97.1%) | 122/125 (97.6%) |
| 90 days | 125/138 (90.6%) | 98/121 (81.0%) |

Note N= number of subjects in the mITT population

**Table 22: ACPP, Proportional Values (mITT Subjects)**

| Subgroup | COVERA™ n/N (%) | PTA Alone n/N (%) |
| --- | --- | --- |
| 30 days | 133/140 (95.0%) | 120/125 (96.0%) |
| 90 days | 110/138 (79.7%) | 95/121 (78.5%) |
| 12 months | 34/128 (26.6%) | 19/114 (16.7%) |

Note N= number of subjects in the mITT population

**Table 23: Additional Endpoints at Index Procedure, Proportional Values (mITT Subjects)**

| Subgroup | COVERA™ n/N^{[1]} (%) | PTA Alone n/N (%) |
| --- | --- | --- |
| Acute technical success | 140/140 (100) | -- |
| Acute procedure success | 138/140 (98.6) | 124/126 (98.4%) |

Note N= number of subjects in the mITT population

[1] One subject randomized to COVERA™ was treated with PTA only, therefore the post device residual stenosis was missing thus not evaluable for this endpoint

**Table 24: Secondary Patency, Proportional Values (mITT Subjects)**

| Subgroup | COVERA™ n/N (%) | PTA Alone n/N (%) |
| --- | --- | --- |
| 30 days | 139/140 (99.3) | 125/125 (100.0) |
| 90 days | 136/138 (98.6) | 119/120 (99.2) |
| 6 months | 131/134 (97.8) | 113/115 (98.3) |
| 12 months | 116/123 (94.3) | 102/105 (97.1) |

Note N= number of subjects in the mITT population

**Table 25: Proportion Free from Device and Procedure-Related AEs (ITT Subjects)**

| Subgroup | COVERA™ n/N (%) | PTA Alone n/N (%) |
| --- | --- | --- |
| 30 days | 127/140 (90.7) | 132/137 (96.4) |
| 90 days | 124/138 (89.9) | 127/133 (95.5) |
| 6 months | 118/134 (88.1) | 123/129 (95.3) |
| 12 months | 108/126 (85.7) | 114/ 123 (92.7) |

Note that the relationships with device/procedure of the events are based on CEC adjudications.

Note N = number of subjects in the ITT population

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 24

{24}

The following tables present information on additional timepoints with total number and mean values through 12-months.

Total Number of AV Access Circuit Reinterventions is defined as the number of reinterventions to the AV access circuit until access abandonment or through study completion. Total Number of Target Lesion Reinterventions is defined as the number of reinterventions to maintain target lesion patency.

**Table 26: Total Number of AV Access Circuit Reinterventions (mITT Subjects)**

| Subgroup | COVERA™ | | PTA Alone | |
| --- | --- | --- | --- | --- |
| | n | mean (SD) | n | mean (SD) |
| 30 Days | 7 | 0.05 (0.219) | 6 | 0.05 (0.215) |
| 90 Days | 35 | 0.25 (0.528) | 34 | 0.28 (0.609) |
| 6 Months | 103 | 0.77 (0.933) | 107 | 0.91 (0.970) |
| 12 Months | 224 | 1.74 (1.487) | 241 | 2.10 (1.606) |

**Table 27: Total Number of Target Lesion Reinterventions (mITT Subjects)**

| Subgroup | COVERA™ | | PTA Alone | |
| --- | --- | --- | --- | --- |
| | n | mean (SD) | n | mean (SD) |
| 30 Days | 5 | 0.04 (0.186) | 3 | 0.02 (0.154) |
| 90 Days | 16 | 0.12 (0.385) | 24 | 0.20 (0.442) |
| 6 Months | 40 | 0.30 (0.615) | 92 | 0.79 (0.850) |
| 12 Months | 93 | 0.76 (0.996) | 195 | 1.71 (1.335) |

**Table 28: Number of Reinterventions at 12-months Based on Site Reported Data (mITT Subjects)**

| | COVERA™ | | PTA Alone | |
| --- | --- | --- | --- | --- |
| | N^{[1]} | n^{[2]} | N^{[1]} | n^{[2]} |
| Total Number of AV Access Reinterventions | 100 | *226 | 102 | *242 |
| Total Number of Target Lesion Reinterventions | 47 | 73 | 98 | 186 |
| Non-Target Lesion at Time of Index Procedure | 28 | 59 | 24 | 45 |
| New Lesion within the Access Circuit | 75 | 142 | 49 | 98 |
| Access Thrombosis | 16 | 19 | 13 | 17 |

[1] N = number of subjects with at least one AV access circuit / target lesion intervention

[2] n = total number of AV access circuit / target lesion interventions

*Note: in the site reported data there are 3 reinterventions (2 for the COVERA arm and 1 PTA) that were captured after abandonment of the AV Access, whereas the core lab adjudicated data (Table 29 below) summarizes reinterventions prior to abandonment only.

**Table 29: Number of Reinterventions at 12-months Based on Core Lab Adjudicated Data (mITT Subjects)**

| | COVERA™ | | PTA Alone | |
| --- | --- | --- | --- | --- |
| | N^{[1]} | n^{[2]} | N^{[1]} | n^{[2]} |
| Total Number of AV Access Reinterventions | 100 | *224 | 102 | *241 |
| Total Number of Target Lesion Reinterventions | 57 | 93 | 100 | 195 |
| Non-Target Lesion at Time of Index Procedure | 25 | 54 | 23 | 44 |

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 25

{25}

| | COVERA™ | | PTA Alone | |
| --- | --- | --- | --- | --- |
| | N^{[1]} | n^{[2]} | N^{[1]} | n^{[2]} |
| New Lesion within the Access Circuit | 60 | 103 | 40 | 72 |
| Access Thrombosis | 12 | 12 | 10 | 12 |

[1] N = number of subjects with at least one AV access circuit / target lesion intervention.

[2] n = total number of AV access circuit / target lesion interventions.

*Note: 3 reinterventions (2 for the COVERA arm and 1 PTA) occurred after the AV access was abandoned, and hence were not included in this table.

**Table 30: All Access Circuit Reinterventions at 12 months (mITT Subjects)**

| | COVERA™ n/N (%) | PTA n/N (%) |
| --- | --- | --- |
| AV Access Circuit Reinterventions Performed | 226 | 242 |
| Vessel | | |
| Cephalic Vein | 122 ( 54.2%) | 124 ( 51.2%) |
| Basilic Vein | 42 ( 18.7%) | 77 ( 31.8%) |
| Subclavian Vein | 13 ( 5.8%) | 4 ( 1.7%) |
| Axillary Vein | 3 ( 1.3%) | 3 ( 1.2%) |
| Brachial Vein | 0 | 1 ( 0.4%) |
| Other | 45 ( 20.0%) | 33 ( 13.6%) |
| Location | | |
| Cephalic Vein Arch | 37 ( 16.4%) | 68 ( 28.1%) |
| Cephalic Vein Outflow | 36 ( 16.0%) | 11 ( 4.5%) |
| Juxta-Anastomotic | 21 ( 9.3%) | 3 ( 1.2%) |
| Basilic Vein Outflow | 17 ( 7.6%) | 27 ( 11.2%) |
| Basilic Vein Swing Point | 2 ( 0.9%) | 24 ( 9.9%) |
| Subclavian Vein | 13 ( 5.8%) | 3 ( 1.2%) |
| Anastomotic | 7 ( 3.1%) | 2 ( 0.8%) |
| Brachio Cephalic Vein | 6 ( 2.7%) | 0 |
| Cannulation Zone | 4 ( 1.8%) | 3 ( 1.2%) |
| Forearm Venous Outflow | 0 | 2 ( 0.8%) |
| Axillary Vein | 2 ( 0.9%) | 2 ( 0.8%) |
| Arterial Inflow | 1 ( 0.4%) | 1 ( 0.4%) |
| Superior Vena Cava (SVC) | 1 ( 0.4%) | 0 |
| Other | 78 ( 34.7%) | 96 ( 39.7%) |

Reinterventions were performed within the access circuit to treat target lesions, non-target lesions, new lesions, access thrombosis or for a combination of these factors. Considering all of these clinical factors for reintervention in the access circuit, subjects within the COVERA™ Vascular Covered Stent arm had 142 reinterventions that included at least one new lesion and subjects in the PTA-only arm had 98 reinterventions that included at least one new lesion. Table 31 identifies the treatment that was performed during these reinterventions and treatment outcome for each study arm.

**Table 31: Access Circuit Reinterventions Involving New Lesion (mITT Subjects)**

| | COVERA™ n / N^{[1]} (%) | PTA Alone n / N^{[1]} (%) |
| --- | --- | --- |
| Total Number of AV Access Circuit Reinterventions Involving New Lesion | 142 | 98 |
| Total Number of Subjects with at least one Reintervention involving New Lesion | 75 | 49 |

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 26

{26}

| | COVERA™ n / N^{[1]} (%) | PTA Alone n / N^{[1]} (%) |
| --- | --- | --- |
| Treatment | | |
| Standard PTA | 140 (81.9%) | 97 (78.9%) |
| Bare Metal Stent | 11 (6.4%) | 16 (13.0%) |
| Thrombectomy/Thrombolysis | 11 (6.4%) | 5 (4.1%) |
| Stent Graft | 5 (2.9%) | 4 (3.3%) |
| *Treatment, Other | 3 (1.75%) | 1 (0.6%) |
| Reintervention Successful | | |
| Yes | 138 (97.2%) | 97 (99.0%) |
| **No | 4 (2.8%) | 1 (1.0%) |

[1] N = total number of treatments involving new lesions

*Other treatment include: one surgical revision in each cohort, one thrombin injection for one subject in the Covera™ cohort and one procedure abandonment due to guidewire prolapse in the Covera™ cohort.

**Site reported reasons for unsuccessful reintervention include; inability to gain retrograde AV access, thus procedure abandoned, persistent spasm and poor flow, insufficient fistula, high clot burden, and largely compliant lesion. The Covera™ device did not play a role in the reintervention outcome being negative.

Index of Patency Function (IPF) is defined as the time from the index study procedure to study completion or access abandonment divided by the number of visits for a reintervention performed on the AV access circuit in order to maintain vascular access for hemodialysis. A visit is defined as one (1) procedural event, regardless of the number or type of interventions performed during the visit. The index procedure is counted as the first visit to ensure all subjects have a denominator of at least one. Index of Patency Function – Target Lesion (IPF-T) is defined as the time from the index study procedure to study completion or complete access abandonment divided by the number of visits for a reintervention performed at the target lesion in order to maintain vascular access for hemodialysis.

**Table 32: Analysis of Index of Patency Function, Mean Values (mITT Subjects)**

| | COVERA™ Mean (SD) | PTA Alone Mean (SD) |
| --- | --- | --- |
| Index of Patency Function (days) | | |
| 30 Days | 29.22 (3.420) | 29.28 (3.219) |
| 90 Days | 79.41 (20.511) | 78.98 (20.770) |
| 6 Months | 126.06 (54.449) | 116.11 (53.175) |
| 12 Months | 174.25 (109.601) | 146.09 (89.723) |
| Index of Patency Function – Target Lesion (days) | | |
| 30 Days | 29.44 (2.958) | 29.64 (2.305) |
| 90 Days | 85.15 (15.349) | 81.35 (18.243) |
| 6 Months | 156.32 (43.724) | 121.75 (51.940) |
| 12 Months | 259.77 (115.373) | 160.64 (87.338) |

## 6. Summary of Deaths

There were thirty five (35) deaths reported in the 12-month follow-up period, of which fifteen (15) subjects (10.6%) were randomized to COVERA™ Vascular Covered Stent (following PTA) and twenty (20) subjects (14.5%) were

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 27

{27}

randomized to PTA. Deaths were not considered to be related to the study device or index procedure.

**Table 33: Number of Deaths by Primary Reason of Death through 12 Months (ITT Subjects)**

| Primary Reason of Death | COVERA™ (N=142) | PTA (N=138) |
| --- | --- | --- |
| Total Number of Deaths | 15 (10.6%) | 20 (14.5%) |
| Brain Aneurysm/Subdermal Hematoma | 0 (0.0%) | 1 (0.7%) |
| Cardiac Arrest | 3 (2.1%) | 6 (4.3%) |
| Cardiac Arrest - Cause Unknown | 0 (0.0%) | 1 (0.7%) |
| Cardiac Arrest Due To Ischemic Heart Disease | 1 (0.7%) | 0 (0.0%) |
| Cardio-Pulmonary Arrest | 1 (0.7%) | 0 (0.0%) |
| Cardiopulmonary Arrest | 1 (0.7%) | 0 (0.0%) |
| ESRD hospice- Stopped Dialysis | 1 (0.7%) | 0 (0.0%) |
| ESRD | 0 (0.0%) | 1 (0.7%) |
| ESRD Hospice- Stopped Dialysis | 1 (0.7%) | 0 (0.0%) |
| ESRD, Elective Withdrawal From Dialysis | 1 (0.7%) | 0 (0.0%) |
| Heart Failure And Traumatic Bleeding | 0 (0.0%) | 1 (0.7%) |
| Hospital Acquired Pneumonia | 0 (0.0%) | 1 (0.7%) |
| Hyperkalemia | 0 (0.0%) | 2 (1.4%) |
| Hypoglycaemia | 1 (0.7%) | 0 (0.0%) |
| Hypotension, Respiratory Failure | 1 (0.7%) | 0 (0.0%) |
| Metastatic Gastric Adenocarcinoma | 0 (0.0%) | 1 (0.7%) |
| Possible Infection Vs Encephalitis With Hyperkalemia | 0 (0.0%) | 1 (0.7%) |
| Profound Shock, Bradycardia, Altered Mental Status | 0 (0.0%) | 1 (0.7%) |
| Pulmonary Embolism | 0 (0.0%) | 1 (0.7%) |
| Respiratory Failure | 1 (0.7%) | 0 (0.0%) |
| Respiratory Failure; Persistent Refractory Septic Shock Due To Recurrent Infections With Waxing/Waning Lactic Acidosis | 1 (0.7%) | 0 (0.0%) |
| Sepsis. | 1 (0.7%) | 0 (0.0%) |
| Staph. Aureus Sepsis | 1 (0.7%) | 0 (0.0%) |
| Subject Terminated Dialysis | 0 (0.0%) | 1 (0.7%) |
| Terminal Colon carcinoma With Liver And Lung Metastasis | 0 (0.0%) | 1 (0.7%) |
| Suspected MI | 0 (0.0%) | 1 (0.7%) |

## 7. Device Deficiencies

There have been two (2) device deficiencies reported as shown in Table 34. One patient had an uneventful index procedure and was successfully treated with a COVERA™ Vascular Covered Stent. During the 6 month follow-up physical exam the patient was found to have palpable high venous pressure, pulsatility of the access, and a pointed thrill in the central veins. The subsequent fistulagram showed an 80% stenosis and stent graft compression in the center portion of the device which was successfully resolved with balloon angioplasty.

Another patient had an uneventful index procedure and was successfully treated with a COVERA™ Vascular Covered Stent. Two months later, the patient presented with elevated venous pressure. A fistulagram was performed and the study device presented with stent graft compression at the proximal end. The narrowing was successfully treated with balloon angioplasty. During the 6-month follow up the patient did not experience any further AV access dysfunction or re-intervention.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 28

{28}

These events were confirmed, however, a definite root cause could not be determined.

Table 34: Summary of Device Deficiencies through 12-months (As Treated Population)

| | COVERA™ (N=140) n (%) | PTA (N=139) n (%) | Total (N=279) n (%) |
| --- | --- | --- | --- |
| Device Malfunction | | | |
| Yes | 2 (1.4) | 0 | 2 (0.7) |
| Failure Code | | | |
| Insufficient Stent Graft | 1 (0.7) | 0 | 1 (0.4) |
| Other | 1 (0.7) | 0 | 1 (0.4) |
| Was Device Used to Treat Subject? | | | |
| Yes | 2 (1.4) | 0 | 2 (0.7) |

8. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 122 investigators of which none were full-time or part-time employees of the sponsor and 9 had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) and described below:

- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0
- Significant payment of other sorts: 9
- Proprietary interest in the product tested held by the investigator: 0
- Significant equity interest held by investigator in sponsor of covered study: 1

The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. The information provided does not raise any questions about the reliability of the data.

XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Circulatory Systems Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 29

{29}

## **XII. CONCLUSIONS DRAWN FROM CLINICAL STUDY**

### **A. Effectiveness Conclusions**

To demonstrate clinically acceptable effectiveness, the primary effectiveness endpoint was evaluated against the rate of Target Lesion Primary Patency (TLPP) at 6 months for standard PTA alone. TLPP at 6 months post-index procedure was evaluated using the Kaplan-Meier analysis and results were 78.7% in the COVERA™ group and 47.9% in the PTA group. The results demonstrated that, with respect to TLPP, the COVERA™ Vascular Covered Stent was superior to the PTA control (p < 0.001) for treatment of stenoses in the venous outflow of patients dialyzing with an arteriovenous fistula. The key secondary effectiveness endpoint of TLPP at 12 months was also met. At 12 months, TLPP was 57.5% for COVERA™ treated subjects versus 21.2% in the PTA group.

The significant benefit in TLPP did not carry over to Access Circuit Primary Patency (ACPP). At 6 months, ACPP was 50.7% for COVERA™ treated subjects versus 43.8% in the PTA group. The key secondary effectiveness endpoint for ACCP at 6 months was not met (p-value = 0.0846).

Reintervention data for the two study cohorts at 12 months are tabulated below:

**Table 35: Reintervention Data for the two study cohorts**

| | COVERA™ Group | PTA Group |
| --- | --- | --- |
| Total number of access circuit reinterventions | 226 | 242 |
| Total number of target lesion reinterventions | 93 | 195 |
| Total number of reinterventions for new lesions in the access circuit | 142 | 98 |
| Number of subjects requiring access circuit reinterventions | 100 | 102 |
| Number of subjects requiring target lesion reinterventions | 57 | 100 |
| Number of subjects with reinterventions for new lesions in the access circuit | 75 | 49 |

While the total number of reinterventions for access circuit were similar, there was a considerable reduction in the number of reinterventions for the target lesions after treatment with COVERA™ Vascular Covered Stent compared to PTA alone. However, more reinterventions for new lesions in the access circuit were required in the COVERA™ treated group compared to the PTA alone group. Secondary patency for the COVERA™ treated subjects was 94.3% and for the PTA group was 97.1%.

With regards to enhancing primary patency of the target lesion, the clinical study results are adequate to provide a reasonable assurance of the effectiveness of the COVERA™ Vascular Covered Stent.

### **B. Safety Conclusions**

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 30

{30}

The risks of the device are based on non-clinical laboratory and animal studies, as well as data collected in a clinical study conducted to support PMA approval, as described above.

The primary safety endpoint was a measure of safety through 30 days post-index procedure. The primary safety endpoint was evaluated against standard PTA alone. Freedom from protocol-defined primary safety events through 30 days post-index procedure was 95.0% in the COVERA™ group and 96.4% in the PTA group. This confirms non-inferiority of the COVERA™ device with respect to primary safety with a p-value of 0.0022.

The rate of arteriovenous fistula site complications was higher in the COVERA™ group compared to the PTA group, which reported no AV site complications. For the COVERA™ group, at 12 months, a total of 7 of these events were adjudicated by the CEC as device related, of which 5 of them were adjudicated as procedure related as well. The events included pain in the access arm, erythematous skin over stent, swelling, thrill/ bruit and pulsatility. These minor events do not impact the safety profile of the COVERA™ Vascular Covered Stent.

A total of 35 deaths were reported in the study (15 in the COVERA™ group and 20 in the PTA group) and none of the deaths were considered to be related to the study device or index procedure.

Overall, the clinical study results are adequate to provide a reasonable assurance of the safety of the COVERA™ Vascular Covered Stent to treat stenoses at the venous outflow of AV fistulae.

### C. Benefit-Risk Determination

The probable benefits of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The probable benefit of using the COVERA™ Vascular Covered Stent to treat stenoses in the venous outflow of AV fistulae is improved target lesion primary patency. The likelihood of a patient experiencing a benefit is high, based on the TLPP rate of 78.7% at 6 months compared to 47.9% in the PTA arm. The significant improvement in TLPP after treatment with COVERA™ did not equate to a similar degree of improvement in ACPP. ACPP at 6 months was 50.7% in subjects treated with COVERA™ compared to 43.8% in the PTA arm.

The probable risks of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The proportion of subjects free from primary safety events was 95.0% (133/140) in subjects treated with the COVERA™ Vascular Covered Stent as compared to 96.4% (132/137) in subjects treated with PTA alone. The use of the COVERA™ Vascular Covered Stent was associated with little added risk over PTA alone.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 31

{31}

1. Patient Perspectives: This submission did not include specific information on patient perspectives for this device.

In conclusion, given the available information above, the data support that for treatment of stenoses at the venous outflow of AV fistula, the probable benefits in improved TLPP after COVERA™ treatment outweigh the probable risks of safety events.

### D. Overall Conclusions

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indication for use. The results of the AVeNEW study demonstrate safety and effectiveness for treatment of stenoses in the venous outflow of AV fistulas. The benefits of the use of the COVERA™ Vascular Covered Stent include superior TLPP at 6 months, as well as reduction in the need for target lesion reintervention at 12 months, as compared to standard PTA alone. ACPP at 6 months was numerically better for subjects treated with the COVERA™ Vascular Covered Stent than those treated with PTA alone, however, the difference was not statistically significant. The difference in ACPP rates between the two treatment arms increased slightly at 12 months, favoring the COVERA™ Vascular Covered Stent. The number of access circuit reinterventions was similar between the two treatment arms. The benefits in enhanced TLPP are clinically meaningful and were achieved with minimal added risk of safety events through 30 days when considered in the context of known risks of PTA alone.

### XIII. CDRH DECISION

CDRH issued an approval order on March 1, 2019. The final conditions of approval cited in the approval order are described below.

Bard has agreed to provide a Clinical Update to physician users of the ongoing experience with the COVERA™ Vascular Covered Stent to physician users at least annually through completion of the AVeNEW study and the COVERA™ Post Approval Study. At a minimum, this update will include a summary of the number of patients for whom data are available, with the rates of acute technical success, acute procedural success, target lesion primary patency, access circuit primary patency, and secondary patency, index of patency function, index of patency function-target lesion, total number of reinterventions for the access circuit, total number of reinterventions for the target lesion, and device/procedure related adverse events. Reasons for reinterventions, along with their description and outcome, and reasons for loss of secondary patency are to be provided. Additional relevant information from commercial experience within and outside the United States is also to be included as well as a summary of pertinent published literature. The clinical update for physician users must be provided to the FDA in the Annual Report.

In addition to the Annual Report requirements, Bard has agreed to provide the following data in post-approval study (PAS) reports for each PAS listed below.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 32

{32}

1. Completion of AVeNEW Study: This study includes continued follow up of the previously enrolled IDE subjects (142 in the COVERA™ group and 138 in the PTA alone group) at 24 sites. The purpose of the study is to evaluate the long-term safety and effectiveness of the COVERA™ Vascular Covered Stent. All study subjects are to be followed through 36 months. A telephone screen to the subject and the dialysis center is to be performed at all follow-up visits. Clinical outcomes at 18, 24, and 36 months will include target lesion primary patency, access circuit primary patency, secondary patency, total number of target lesion reinterventions and access circuit reinterventions, index of patency function, index of patency function – target lesion, and rate of device and procedure related adverse events. These endpoints will be analyzed descriptively.

2. COVERA™ Post Approval Study: The COVERA™ Post Approval Study includes new enrollment of 100 subjects at up to 35 sites who will be treated using the COVERA™ Vascular Covered Stent only. The purpose of the study is to evaluate clinical outcomes under real world conditions and to evaluate the long-term safety and effectiveness of the COVERA™ Vascular Covered Stent. All study subjects are to be followed through 36 months. A telephone screen to the subject and the dialysis center is to be performed at all follow-up visits. The 6-month follow-up is to occur via an office visit to the investigational site in addition to the phone call to the dialysis center. Clinical outcomes at 30 days, 90 days, 6, 12, 18, 24, and 36 months will include target lesion primary patency, access circuit primary patency, secondary patency, total number of target lesion reinterventions and access circuit reinterventions, index of patency function, index of patency function – target lesion, and rate of device and procedure related adverse events. Acute technical success and acute procedural success will also be evaluated. These endpoints will be analyzed descriptively and presented both separately and combined with the AVeNEW study cohort.

The applicant's manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

# XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.

Post-approval Requirements and Restrictions: See approval order.

PMA P170042/S002: FDA Summary of Safety and Effectiveness Data

Page 33