Eluvia Drug-Eluting Vascular Stent System

P180011 · Boston Scientific Corp · NIU · Sep 18, 2018 · Cardiovascular

Device Facts

• Record ID: P180011
• Device Name: Eluvia Drug-Eluting Vascular Stent System
• Applicant: Boston Scientific Corp
• Product Code: NIU · Cardiovascular
• Decision Date: Sep 18, 2018
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The ELUVIA Drug-Eluting Vascular Stent System is indicated for improving luminal diameter in the treatment of symptomatic de-novo or restenotic lesions in the native superficial femoral artery (SFA) and/or proximal popliteal artery with reference vessel diameters (RVD) ranging from 4.0 - 6.0 mm and total lesion lengths up to 190 mm.

Device Story

The ELUVIA Drug-Eluting Vascular Stent System is a self-expanding, laser-cut nitinol stent coated with a polymer matrix containing the anti-proliferative drug paclitaxel. It is delivered via a triaxial catheter system. The device is used by physicians in a clinical setting to treat peripheral artery disease in the SFA/PPA. The stent provides mechanical scaffolding to dilate the vessel and minimize recoil, while the paclitaxel coating is released locally to inhibit neointimal hyperplasia and restenosis. The physician deploys the stent by retracting the middle sheath of the delivery system, allowing the stent to expand at body temperature. This intervention improves luminal diameter, restores blood flow, and reduces the need for revascularization, thereby improving patient symptoms and quality of life.

Clinical Evidence

Evidence based on the global, prospective, randomized, multicenter IMPERIAL trial (N=465) comparing ELUVIA to Zilver PTX. Primary endpoints were 12-month MAE-free rate (safety) and 12-month primary patency (effectiveness). ELUVIA demonstrated non-inferiority to Zilver PTX: 12-month MAE-free rate 94.9% vs 91.0% (p<0.0001); 12-month primary patency 86.8% vs 81.5% (p<0.0001). Long Lesion substudy (N=50) showed 87.0% primary patency at 12 months. Pharmacokinetic substudy showed minimal systemic paclitaxel levels.

Technological Characteristics

Self-expanding, open-mesh, laser-cut nitinol stent with tantalum markers. Coating: PBMA primer layer and PVDF-HFP polymer matrix containing paclitaxel. Delivery system: Triaxial catheter, 6F profile, 75cm/130cm lengths. MR Conditional. Sterilization: Ethylene oxide. Materials conform to ASTM F2063 (nitinol) and ASTM F560 (tantalum).

Indications for Use

Indicated for patients with symptomatic peripheral artery disease (Rutherford categories 2, 3, or 4) requiring treatment of de-novo or restenotic lesions in the native superficial femoral artery (SFA) and/or proximal popliteal artery. Contraindicated in pregnant or breastfeeding women, patients unable to receive anti-platelet/anti-coagulant therapy, and patients with lesions preventing proper stent placement.

Regulatory Classification

Identification

Stent, Superficial Femoral Artery, Drug-Eluting -- a metal scaffold with a drug coating placed via a delivery catheter into the superficial femoral artery artery to maintain the lumen. The drug coating is intended to inhibit restenosis.

Reference Devices

• BSC Innova Self-Expanding Stent System (P140028)
• Zilver PTX stent

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Stent, Superficial Femoral Artery, Drug-Eluting
Device Trade Name: ELUVIA™ Drug-Eluting Vascular Stent System
Device Procode: NIU
Applicant's Name and Address: Boston Scientific Corporation
Three Scimed Place
Maple Grove, MN 55311
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P180011
Date of FDA Notice of Approval: September 18, 2018

II. INDICATIONS FOR USE

The ELUVIA Drug-Eluting Vascular Stent System is indicated for improving luminal diameter in the treatment of symptomatic de-novo or restenotic lesions in the native superficial femoral artery (SFA) and/or proximal popliteal artery with reference vessel diameters (RVD) ranging from 4.0 - 6.0 mm and total lesion lengths up to 190 mm.

III. CONTRAINDICATIONS

- Women who are pregnant, breastfeeding, or plan to become pregnant in the next 5 years should not receive an Eluvia Drug-Eluting Stent. It is unknown whether paclitaxel will be excreted in human milk, and there is a potential for adverse reaction in nursing infants from paclitaxel exposure.
- Patients who cannot receive recommended anti-platelet and/or anti-coagulant therapy.
- Patients judged to have a lesion that prevents proper placement of the stent or stent delivery system.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the ELUVIA Drug-Eluting Vascular Self-Expanding Stent System labeling.

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# V. DEVICE DESCRIPTION

The Boston Scientific ELUVIA™ Drug-Eluting Vascular Stent System is a medical device containing an ancillary medicinal substance, which provides a mechanical scaffold for vascular lumen support (the stent component) and a pharmacological agent (paclitaxel) targeted towards reducing the injury response that leads to restenosis after stent implantation.

The ELUVIA Stent System consists of a self-expanding, open mesh, laser-cut nitinol stent with tantalum markers and a triaxial stent delivery system, which includes a middle sheath to protect and constrain the stent. The stent is loaded into the triaxial delivery system. When ready to be implanted, the stent is deployed by retracting the middle sheath of the delivery system. As the stent is exposed to body temperature, it expands to appose the vessel wall.

The ELUVIA Stent System is comprised of the following components:

Stent Component
Stent Coating (Polymers and Drug Substance)
Delivery Catheter

The ELUVIA stent and catheter components are identical in material and design to the BSC Innova Self-Expanding Stent System (reference P140028, approved July 21, 2015). The ELUVIA stent is a laser cut self-expanding stent composed of a nickel titanium alloy (Nitinol). The stent delivery system is a triaxial design and is available in $75~\mathrm{cm}$ and 130 cm working lengths.

The ELUVIA stent coating is composed of a PBMA (poly (n-butyl methacrylate)) polymer primer layer, an active layer consisting of PVDF-HFP (copolymer of vinylidene fluoride and hexafluoropropylene) polymer and anti-proliferative drug paclitaxel.

The ELUVIA Stent System is illustrated in Figure 1:

Figure 1: ELUVIA™ Drug-Eluting Vascular Stent System

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The ELUVIA™ Drug-Eluting Vascular Stent System is available in multiple stent sizes (diameters and lengths), containing a range of nominal drug doses, as listed in Table 1 below:

Table 1: ELUVIA™ Drug-Eluting Vascular Stent System Matrix Product Matrix and Nominal Total Loaded Weight of Drug, Primer and Drug Matrix

| Stent Model | | Stent Length | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Design | Diameter | 40 mm | 60 mm | 80 mm | 100 mm | 120 mm |
| Total Paclitaxel Dose / Stent (μg) | 6 mm | 135 | 207 | 272 | 344 | 409 |
| | 7 mm | 135 | 207 | 272 | 344 | 409 |
| | | | | | | |
| Primer Coat Weight / stent (μg) | 6 mm | 596 | 914 | 1200 | 1518 | 1804 |
| | 7 mm | 596 | 914 | 1200 | 1518 | 1804 |
| | | | | | | |
| Drug Matrix Coat Weight / Stent (μg) | 6 mm | 1351 | 2073 | 2721 | 3442 | 4091 |
| | 7 mm | 1351 | 2073 | 2721 | 3442 | 4091 |

## Mechanism of Action

Microtubules are integral components of all eukaryotic cells and are involved in various functions including cell proliferation and migration, which are key processes in the formation of neointimal hyperplasia post-stenting.

Paclitaxel promotes the assembly of numerous decentralized and unorganized microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability inhibits the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions, resulting in reduced proliferation, migration, and signal transduction. This interruption of the restenotic cascade impedes the re-narrowing of the vessel. This antiproliferative property of the drug is the reason for its inclusion in the coating and its addition to the stent.

A stent provides the mechanical capability to dilate the vessel in order to create a larger lumen, and minimize elastic recoil. Paclitaxel is incorporated into a polymer carrier matrix, coated onto the stent and delivered to the inner arterial wall so that a reduction in restenosis may be achieved by locally controlling cell replication. Thus, the primary mode of action of the product is accomplished through mechanical dilatation and the product is assisted in its function through the ancillary pharmacologic action of the drug component, paclitaxel, to inhibit restenosis.

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VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of peripheral artery disease located in the SFA/PPA arteries. These include percutaneous transluminal angioplasty (PTA), PTA accompanied by bare metal stenting, bare metal stenting alone, atherectomy, drug coated balloons, thrombolytic therapy, conservative medical management, exercise therapy, and/or surgical procedures (i.e. bypass surgery). Atherosclerotic risk factors may be reduced through lifestyle modifications such as cessation of smoking, weight reduction, lipid control, blood pressure control, and diabetes management. 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 ELUVIA Drug Eluting Vascular Stent System (Eluvia) received CE Mark on February 18, 2016 for commercial distribution in Europe and is marketed in the countries listed in Table 2 with a general peripheral indication. In December 2017, the 150 mm stent size was removed from the OUS market as a result of trends in deployment complaints. Eluvia is available in stent diameters of 6 and 7 mm and stent lengths of 40 mm, 60 mm, 80 mm, 100 mm, and 120 mm. All stent sizes are available in both 75 cm and 130 cm catheter lengths.

Table 2: Countries Where the ELUVIA Stent System is Commercially Available

| Austria | Baltics | Belgium | Denmark | Finland | France |
| --- | --- | --- | --- | --- | --- |
| Germany | Hong Kong | Hungary | Italy | Netherlands | New Zealand |
| Norway | Poland | Spain | Sweden | Switzerland | United Kingdom |
| Israel | Macedonia | Columbia | South Korea | Costa Rica | Argentina |
| Thailand | Australia | Macau | Taiwan | Serbia | Ukraine |
| Mexico | Saudi Arabia | Egypt | Russia | Vietnam | Indonesia |
| Philippines | Bolivia | | | | |

VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) which may be associated with the use of a peripheral stent include but are not limited to:

- Allergic reaction (to drug/polymer, contrast, device or other)
- Amputation
- Arterial aneurysm
- Arteriovenous fistula
- Death

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- Embolization (air, plaque, thrombus, device, tissue, or other)
- Hematoma
- Hemorrhage (bleeding)
- Infection/Sepsis
- Ischemia
- Need for urgent intervention or surgery
- Pseudoaneurysm formation
- Renal insufficiency or failure
- Restenosis of stented artery
- Thrombosis/thrombus
- Transient hemodynamic instability (hypotensive/hypertensive episodes)
- Vasospasm
- Vessel injury, including perforation, trauma, rupture and dissection
- Vessel occlusion

Below is a list of the potential adverse effects not captured above that may be unique to the paclitaxel drug coating:

- Allergic/immunologic reaction to drug (paclitaxel or structurally-related compounds) or the polymer stent coating (or its individual components)
- Alopecia
- Anemia
- Gastrointestinal symptoms
- Hematologic dyscrasia (including leukopenia, neutropenia, thromboctyopenia)
- Hepatic enzyme changes
- Histologic changes in vessel wall, including inflammation, cellular damage or necrosis
- Myalgia/Arthralgia
- Peripheral neuropathy

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

## IX. SUMMARY OF NON-CLINICAL STUDIES

A series of non-clinical laboratory and pharmacokinetic studies related to the product were performed to evaluate the device.

## A. Biocompatibility Studies

A series of Good Laboratory Practice (GLP) biocompatibility tests were conducted to demonstrate that the components of the ELUVIA Stent System are biocompatible.

All biocompatibility testing was conducted in accordance with:

- Guidance for Industry and FDA Staff: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems Guidance, April 2010

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- Good Laboratory Practices Regulations (§21 CFR Part 58)
- EN ISO 10993-1, Biological Evaluation of Medical Devices

The tests summarized in Table 3 have been conducted in support of the ELUVIA stent component as recommended for a permanent implantable device contacting circulating blood for &gt; 30 days.

Table 3: Biocompatibility Tests Performed on Stent

| Test Performed / Applicable EN ISO 10993 Part Number | Test Purpose | Results |
| --- | --- | --- |
| Cytotoxicity MEM Elution / Part 5 | To determine the potential for cytotoxicity | Non-cytotoxic |
| Guinea Pig Maximization Sensitization/Part 10 | To evaluate the allergenic potential or sensitizing capacity of a test article. | Non-sensitizing |
| Intracutaneous Reactivity/Part 10 | To screen test article extracts for potential irritation effects. | Non-irritant |
| Acute Systemic Injection/Part 11 | To screen test article extracts for potential systemic toxic effects. | Non-toxic |
| Subchronic Toxicity - Systemic Toxicity Study in Rats Following Subcutaneous Implantation, 13 Weeks / Part 11 and Part 6 | To evaluate the potential for local and systemic toxicity of a test article implanted subcutaneously in rats for 13 weeks. | Non-toxic |
| Implantation - Subcutaneous Implantation Study in Rabbits, 4 Weeks / Part 6 | To evaluate the potential for a local irritant or toxic response to material(s) implanted in direct contact with subcutaneous tissue of the rabbit for 4 weeks. | Non-irritant |
| Material-Mediated Rabbit Pyrogenicity / Part 11 | To determine the presence of material-mediated pyrogens in extracts of a test article. | Non-pyrogenic |
| Ames Mutagenicity /Part 3 | To evaluate the mutagenic potential of leachables from the test article. | Non-mutagenic |
| Mouse Lymphoma /Part 3 | To evaluate mutagenicity of the test agents. | Non-mutagenic |
| Hemolysis Direct and Extract/Part 4 | To assess the hemolytic activity of the test article when in direct contact with blood. | Non-hemolytic |

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| Test Performed / Applicable EN ISO 10993 Part Number | Test Purpose | Results |
| --- | --- | --- |
| Complement Activation SC5b-9 /Part 4 | Measurement of complement activation indicates whether a test article is capable of inducing a complement-induced inflammatory immune response in humans. | Not a complement activator |
| Partial Thromboplastin Time / Part 4 | To determine the time citrated plasma exposed to a test material takes to form a clot when exposed to a suspension of phospholipid particles and calcium chloride. | Non-activator |
| In vivo thrombogenicity | Assess acute thrombogenic potential of test article in the non-diseased iliac and iliofemoral arteries of domestic swine, as described in Section H below. | Non-thrombogenic |
| Chemical Characterization Extraction by NVR, LC-MS, GC-MS, ICP-MS | Chemical characterization analysis to identify and semi-quantify extractables found under exhaustive extraction conditions. | Extractables do not pose a concern for genotoxicity, carcinogenicity, or systemic toxicity |

The implantation endpoint for the stent was also leveraged from the animal safety study, as described in Section H below. The tests summarized in Table 4 have been performed in support of the ELUVIA delivery system catheter as recommended for externally communicating device contacting the circulating blood with limited exposure of $&lt; 24$ hours.

Table 4: Biocompatibility Tests Performed on ELUVIA Delivery System Catheter

| Test Performed / Applicable EN ISO 10993 Part Number | Test Purpose | Results |
| --- | --- | --- |
| Cytotoxicity MEM Elution / Part 5 | To determine the potential for cytotoxicity | Non -cytotoxic |
| Intracutaneous Reactivity/Part 10 | To screen test article extracts for potential irritation effects. | non-irritant |
| Guinea Pig Maximization Sensitization/Part 10 | To evaluate the allergenic potential or sensitizing capacity of a test article. | Non-sensitizing |

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| Test Performed / Applicable EN ISO 10993 Part Number | Test Purpose | Results |
| --- | --- | --- |
| Acute Systemic Injection/Part 11 | To screen test article extracts for potential systemic toxic effects. | Non-toxic |
| Material-Mediated Rabbit Pyrogenicity / Part 11 | To determine the presence of material-mediated pyrogens in extracts of a test article. | Non-pyrogenic |
| Hemolysis Direct and Extract | To assess the hemolytic activity of the test article when in direct/indirect contact with blood. | Non-hemolytic |
| Partial Thromboplastin Time / Part 4 | To determine the time citrated plasma exposed to a test material takes to form a clot when exposed to a suspension of phospholipid particles and calcium chloride. | Non-activator |
| Complement Activation SC5b-9 and C3a/Part 4 | Measurement of complement activation indicates whether a test article is capable of inducing a complement-induced inflammatory immune response in humans. | Not a complement activator |
| In vivo Thrombogenicity | Assess acute thrombogenic potential of test article in the non-diseased femoral arteries of domestic swine, as described in Section H below. | Non-thrombogenic |

## B. In Vitro Engineering Testing

In vitro engineering testing on the ELUVIA Stent System was conducted, as applicable, in accordance with:

- FDA Guidance for Industry and FDA Staff: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, April 18, 2010
- FDA Guidance for Industry and Staff: Establishing Safety and Compatibility of Passive Implants in the Magnetic Resonance (MR) Environment, December 11, 2014

The in vitro engineering studies are summarized in Table 5. "Pass" denotes that the test results met product specifications and/or the recommendation in the above-referenced guidance documents.

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Table 5: Stent and Delivery Catheter Engineering Testing

| Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Material Composition | To verify the composition of nitinol and tantalum stent materials and to measure the composition and thickness of the surface passivation layer. | The stent material must conform to ASTM F2063-00 for the nitinol material and to ASTM F560-04 for the tantalum material. The stent material must exhibit surface composition and passive layer depth consistent with published literature for nitinol surfaces. | Pass |
| Shape Memory and Superelasticity of Intravascular Stents | To determine the Austenite finish transition temperature (Af) of the stent. | The stent must have an Af temperature ≤ 34°C when tested per ASTM F2082 to ensure the stent will expand to its intended size and shape under normal body temperatures. | Pass |
| Stent Corrosion Resistance - Post 10-year Pulsatile Fatigue Cycling | To document the potential for fretting, pitting and crevice corrosion of the stent. | Fretting corrosion and crevice and pitting corrosion are evaluated and characterized on stents after 10-year pulsatile fatigue cycling (400 million cycles). The stent must exhibit no evidence of pitting when tested per ASTM F2129. | Pass |
| Stent Corrosion Resistance - Galvanic Corrosion | To document the potential for galvanic corrosion when coupled with stents of dissimilar materials. | The resistance to galvanic corrosion was characterized when the stent was coupled separately with dissimilar material stent. Testing shall result in “very low” or “negligible” current post testing. | Pass |
| Stent Dimensional Verification | To characterize the unconstrained diameter of the stent. | The unconstrained expanded diameter must be within -0.25 mm/+0.75 mm of its labeled diameter. | Pass |
| Percent Surface Area | To characterize the metal to lumen ratio of the stent. | The metal to lumen must be ≤ 30% for all stent sizes. | Pass |
| Foreshortening | To determine the foreshortening of the stent from the catheter constrained diameter to use diameter. | The change in stent length from catheter constrained diameter to length post deploy shall be ±10%. | Pass |
| Stent Integrity | To determine the stent's resistance to fracture upon deployment. | The stent must not exhibit strut fractures upon deployment. | Pass |
| Outward Radial Force | To characterize the minimum and maximum outward radial force for the stent within use range. | The outward radial force must be ≥ 2.9 g/mm.. | Pass |

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| Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Mechanical Properties – Preprocessing | To evaluate nitinol material prior to processing. | The mechanical properties of the nitinol material must meet the following specifications. • Loading Plateau > 60ksi • Unloading Plateau > 17ksi • Ultimate Tensile Strength > 150ksi • Strain at Peak Load > 10% • Unrecovered Strain (permanent set after 8% strain) < 0.5% | Pass |
| Mechanical Properties – Post Processing | To verify the permanent set of the nitinol material post-thermal processing. | The permanent set of the nitinol material post-thermal processing must be <1.5%. | Pass |
| Stress/Strain Analysis/Fatigue Analysis (Finite Element Analysis) | To evaluate the durability and integrity of the stent using Finite Element Analysis (FEA). The FEA analysis simulated physiological conditions in the SFA. | The FEA analysis must demonstrate that the stent maintains acceptable fatigue safety using the Goodman fatigue analysis with a safety factor > 1. | Pass |
| Accelerated Durability Testing | To characterize the accelerated durability of overlapping stents after 10-year pulsatile fatigue cycling. | No stent shall have type II or greater fracture occurrence after 400 million cycles (10 year simulation). | Pass |
| Accelerated Durability Testing | To characterize the accelerated durability of stents after 10-year fatigue cycling with relative SFA physiological motions. | Stents shall demonstrate fatigue integrity after 10 year simulated axial, twist, bend, and compression fatigue testing. | Pass |
| Magnetic Resonance Imaging (MRI) Safety and Compatibility | To evaluate the stent for magnetically induced force, magnetically induced torque, image artifact, and radio frequency (RF) induced heating when placed in field strengths of 1.5 and 3.0 Tesla. | The stent must meet the requirements of Guidance for Industry and FDA Staff: Establishing Safety and Compatibility of Passive Implants in the MR (Magnetic Resonance) Environment, ASTM F2052, ASTM F2213, ASTM F2182, and ASTM 2119 standards for MR Conditional. The conditions under which the device can be safely scanned are reflected in the Directions for Use (DFU). | Pass |
| Radiopacity | To assess the radiopacity of the stent. | The radiopacity of the stent while loaded in the delivery system and post stent deployment must be clinically acceptable when assessed during animal testing. | Pass |

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| Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Crush Resistance | To verify the ability of the stent to recover to its size and shape after applying an external load. | The recovery of the stent diameter post compression must be 90% or greater for both parallel plate and focal compression testing. | Pass |
| Kink Resistance | To characterize the smallest radius of curvature the stent can withstand without kinking. | The minimum gage pin diameter that the stent can be bent around without kinking or experiencing a diameter reduction of at least 50% in the bent condition shall be characterized. | Pass |
| Stent Marker Securement | To characterize the force required to dislodge the tantalum marker from the stent. | The force to dislodge the marker from the stent much be ≥ 0.70 lbs. | Pass |
| Delivery System Dimensional Verification | To document dimensional characteristics of the delivery system. | The delivery system working length must be ± 1.0cm of the labeled delivery system working length. The delivery system working profile must be 6F. The delivery system must track and exchange over 0.035” guide wire. | Pass |
| Delivery, Deployment and Retraction | To assess the ability of the delivery system to deliver the stent to the intended location and deploy the stent. | The delivery system must track through a simulated anatomical model, deliver the stent and be withdrawn remaining fully intact. The delivery system must fully deploy the stent. | Pass |
| Deployment Force | To ensure that the amount of force required to deploy the stent remains within intended limits. | The delivery system must deploy the stent with an acceptable deployment force. | Pass |
| Deployment Accuracy | To assess the ability of the delivery system to place the stent in the intended location in the vessel. | The delivery system must deploy the stent with an acceptable deployment accuracy. | Pass |
| Catheter Bond Strength | To evaluate the tensile strength of the delivery system bonds. | The delivery system must be able to withstand forces which may be experienced clinically. | Pass |
| Delivery System Flexibility and Kink Test | To determine the susceptibility of the delivery system to kink. | The delivery system must not kink and maintain guidewire movement when simulating worst-case clinical use. | Pass |
| Torque Strength | To assess the ability of the delivery system to withstand torsional forces. | The delivery system must be able to be subjected to clinically-relevant rotation without catheter failure. | Pass |

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| Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Delivery System Radiopacity | To assess the radiopacity of the delivery system. | The delivery system markers must exhibit clinically acceptable radiopacity. | Pass |

# C. Coating Characterization Testing

The following tests were developed to characterize and set specifications for the ELUVIA Drug-Eluting Stent System. The coating characterization testing conducted on the device is summarized in Table 6 below.

Table 6: Coating Characterization Testing

| Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Coating Thickness | To characterize coating thickness measured on the stent cross sections from the distal, middle, and proximal stent areas. | The coating thickness should be uniform and consistent along the stent's length, as well as on different stent surfaces (inner, outer, cut faces). | Pass |
| Coating Adhesion and Cohesion | To characterize the cohesive strength between polymer layers and the adhesive strength of the coating to the stent substrate. | The coating should demonstrate acceptable and consistent cohesive and adhesive strength. | Pass |
| Particulate Identification | To chemically identify particles recovered during particulate testing. | The Eluvia drug coating and catheter should be a minimal source of particulates. | Pass |
| Coating Uniformity | To characterize drug coating uniformity across stent length and circumference. | All measurements should be within 15% of target drug content values to demonstrate uniformity of across stent length and circumference. | Pass |
| Acute Coating Integrity | Measure the coating integrity at baseline and after tracking through a simulated use model | The coating should demonstrate a uniform coating along the length and circumference of the stent. All measurements should be within 15.0% percent bare area. | Pass |
| Chronic Coating Integrity | Measure the coating integrity of worst case model of overlapping stents deployed following tracking in an anatomical model and fatigue conditioning. | The coating should demonstrate a uniform coating along the length and circumference of the stent. All measurements should be within of 15.0% percent bare area. | Pass |

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| Test | Test Purpose | Acceptance Criteria | | Results |
| --- | --- | --- | --- | --- |
| Acute and Chronic Particulates | To evaluate the total number and size of particulates generated after worst case model of overlapping stents deployed following tracking in an anatomical model and fatigue conditioning. | Acute:
Device to not exceed requirements per USP 788 guidance: | | Pass |
| | | ≥ 10μm | 6,000 | |
| | | ≥ 25μm | 600 | |
| Chronic:
The number of downstream particulates collected must be consistent with clinical safety thresholds as shown by pre-clinical studies and a baseline uncoated stent of the same design. Identification of particulates must show that significant particulate matter is not generated by the stent or coating. | | | | |

## D. Chemistry, Manufacturing and Controls (CMC) Testing

Where applicable, International Conference on Harmonization (ICH) guidelines were followed for testing routinely performed on the ELUVIA stent as part of CMC. The purpose and specifications for this routine testing is summarized in Table 7 below. Information relating to ELUVIA stability testing is provided in Section IX-F.

Table 7: ELUVIA Stent CMC Specifications and Testing

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Appearance | A visual inspection is conducted to ensure the stent is retained within the middle sheath until deployment. Upon deployment, stent has metallic appearance. | Product packaging must be intact and stent is retained within the middle sheath until deployment. Upon deployment, stent has metallic appearance. |
| Paclitaxel Identity | Assay is conducted to verify the identity of the drug substance, paclitaxel via high performance liquid chromatography (HPLC).
For positive identity, the retention time and the UV spectrum of the main peak obtained from the sample preparation must correspond to that obtained from the standard preparation.
Tested per ICH Q6A. | The retention time of paclitaxel as sampled from product must be ±1% of the retention time of a paclitaxel reference standard.
The spectrum (between 195 nm and 350 nm) of the sample must match the spectrum of a paclitaxel reference standard. This is defined by the spectra matching in overall appearance and the peak maxima (around 230 nm) agree to within +/- 5 nm. |

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| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Drug Content Assay | Paclitaxel content is specified and quantitatively verified to ensure product contains the labeled dose via high performance liquid chromatography (HPLC).
Tested per ICH Q6A. | The arithmetic mean Paclitaxel content for ten (10) stents must be greater than or equal to (≥) 90.0% and less than or equal to (≤) 110.0% of the nominal content. |
| Drug Degradants and Impurities | The stent must have acceptable levels of drug degradants and impurities with the use of high performance liquid chromatography (HPLC). | Total Paclitaxel degradants and related substances must be ≤ 2.0% of the total area of the test sample. Individual Paclitaxel degradants or related substances must be ≤ 1.0% of the total area of the test sample. |
| Drug Content Uniformity | Paclitaxel content is specified to ensure product contains the labeled dose within limits for individual dosage units defined by the formula in USP <905>.
Tested per ICH Q6A and USP 905 | The requirements for Paclitaxel drug content uniformity are met if the acceptance value of the first 10 dosage units is less than or equal to L1. If the acceptance value is greater than L1, test the next 20 units, and calculate the acceptance value. The requirements are met if the final acceptance value of the 30 dosage units is less than or equal to L1, and no individual content of any dosage unit is less than [1 - (0.01)(L2)] M nor more than [1 + (0.01)(L2)] M

Acceptance value = | M - Xavg | + ks
M = Xavg when 98.5% ≤ Xavg ≤ 101.5%
M = 98.5% when Xavg < 98.5%
M = 101.5% when Xavg > 101.5%

Xavg is average of individual contents as percent of nominal Paclitaxel drug content
k = 2.4 when sample size is 10
k = 2.0 when sample size is 30
s = sample standard deviation
L1 = 15.0
L2 = 25.0 |

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| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Kinetic Drug Release
(Average and Individual Kinetic Drug Release) | Drug release is specified to ensure the product releases drug consistently within limits. This performance feature is linked to product efficacy.

Tested per USP 711 | Level L1: No individual value lies outside each of the stated ranges and no individual value is less than the stated amount at the final specified time point. (6 samples – Drug Release: Cumulative Release of Paclitaxel as percent of label claim)

Time (hours)

5 24 72

LSL: 32% 60% 80%

USL: 52% 80% N/A

Level L2: The average value of the 12 units (L1+L2) does not lie outside of the stated ranges and is not less than the stated amount at the final specified time point; no individual value is more than 10% of labeled content outside each of the stated ranges; and no individual value is below the stated amount at the final specified time point – (6 additional samples (12 samples in total) Drug Release Cumulative Release of Paclitaxel as percent of label claim)

Average:

Time (hours)

5 24 72

LSL: 32% 60% 80%

USL: 52% 80% N/A

Individuals:

Time (hours)

5 24 72

LSL: 22% 50% 70%

USL: 62% 90% N/A

Level L3: The average value of the 24 units (L1+L2+L3) does not lie outside of the stated ranges, and is not less than the stated amount at the final specified time point; no more than 2 of the 24 units are more than 10% of labeled content outside each of the stated ranges; no more than 2 of the 24 units are more than 10% of labeled content below the stated amount at the final specified time point; and no individual unit is more than 20% of labeled content outside each of the stated ranges or more than 20% of labeled content below the stated amount at the final specified time point. |

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| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Endotoxin (Pyrogens) | The average endotoxin level shall be less than 20 Endotoxin Units (EU) per device. (Where ‘device’ refers to the average endotoxin level per coated stent plus the average endotoxin level per delivery catheter).
Regulatory requirement to ensure endotoxin levels are within established safety guidelines. | The average endotoxin level shall be less than 20 Endotoxin Units (EU) per device. (Where ‘device’ refers to the average endotoxin level per coated stent + the average endotoxin level per delivery catheter). |
| Particulate Matter | Particulate matter is quantified for quality control and product safety measures.
Tested per USP 788 | The total system particulates of each of three (3) individual stent delivery systems must not exceed the following limits.
**Size** ≥ 10 μm
**Upper Specification Limit** 6,000
≥ 25 μm
600 |
| Residual Solvents | The amount of Cyclohexanone and acetone on the ELUVIA stent is measured to ensure that residual levels of the solvent used in the manufacturing process are within specification limits established for the finished stent release.
Tested per ICH Q3B | Cyclohexanone content must be ≤ 2 μg/stent
Acetone content must be ≤ 9.7 μg/stent |

## E. Packaging Testing

Packaging verification testing was performed to demonstrate that the design of the ELUVIA Stent System packaging can withstand the hazards of the distribution environment and that the sterility of the device is maintained throughout the labeled shelf life. Package integrity testing included a visual assessment, bubble leak testing, and seal strength testing at both the baseline condition and for packages aged to the products shelf life.

## F. Stability/Shelf Life Testing

A formal stability study for the drug product was conducted to help establish a shelf life expiration date for the ELUVIA Stent System. This testing included appearance of stent, paclitaxel identity, drug assay, drug degradants and impurities, drug uniformity, drug release, sterility, endotoxin, and particulates.

Functional device and container closure performance testing was conducted following 18 months of aging to demonstrate that the device and packaging performs within product specifications for a labeled shelf life of 18 months.

This testing in combination supports the shelf life of 18 months.

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G. Sterilization

The ELUVIA Stent System is sterilized using ethylene oxide (EO) gas and has been validated per AAMI / ANSI / ISO 11135:2007, Sterilization of health care products - Ethylene oxide - Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices. Results from the sterilization studies show that the product satisfies a minimum Sterility Assurance Level (SAL) of 10⁻⁶ and residual levels were within acceptable ranges in accordance with EN ISO 10993-7:2008, Biological Evaluation of Medical Devices - Part 7: Ethylene Oxide Sterilization Residuals.

H. Animal Studies

Drug Release Testing and Pharmacokinetics

The objectives of BSC’s preclinical pharmacokinetic evaluations were to investigate the local target tissue and systemic blood levels of paclitaxel and to histopathologically evaluate downstream muscle beds following stent implantation. The polymer carrier of PTx for all stents tested was a copolymer of poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF).

Local Tolerance

The objective of the preclinical program for Eluvia stents was to assess the safety and vascular compatibility of Eluvia stents and to show comparability of results to the uncoated Innova stents. Safety of single and overlapped implant configurations of the stents types listed below was assessed using the non-injured porcine iliofemoral peripheral artery model.

- Single stent configurations
- Bare Epic stents
- Bare Innova stents
- Epic stents coated with the Eluvia formulation
- Epic stents coated with four other polymers plus drug formulations
- Eluvia stents
- Overlap sent configurations
- Eluvia stents
- Innova stents

Delivery System Assessments

The objective of the study was to evaluate the acute performance of the Innova Over-the-Wire Self-Expanding Stent System, which is the identical delivery system with an uncoated stent, in an in vivo model. The secondary objective of the study was to demonstrate that the Innova Over-the-Wire Self-Expanding Stent System conformed to the user needs and intended uses.

Acute performance of the Innova stent delivery system was assessed using the non-injured porcine iliofemoral peripheral artery model.

The results of the pre-clinical studies support the conclusion that the ELUVIA Stent System is safe and appropriate for intended use. Summaries of the study designs and results are included in the Table 8 below.

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Table 8: ELUVIA Animal Studies - PK

| Test and/or Study Name | Test Article | Stent (Diameter and Length in mm) and Number of Stents (n) | Total Paclitaxel per Stent (μg) | Paclitaxel Density (μg/mm²); Paclitaxel % / Coat Wt. (mg) | Vessel Location | Paclitaxel Systemic and Tissue Levels | Evaluation Time Points | Endpoints Met |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Pharmacokinetic (PK) Studies | | | | | | | | |
| PK Study 14-088G | Eluvia | 6.0 x 40 (40)
7.0 x 40 (35) | 135 | 0.167 μg/mm² | Iliac artery, profunda artery femoral artery | Measured in stents, and iliac, profunda and femoral artery, (tissue), and blood (systemic) | 1, 3, 7, 14, 30, 90, 180 and 270 Days | Yes |
| PK Study 08-044N | Test: 2% PTx DES | 5.0 x 20 (0)
6.0 x 20 (19)
7.0 x 20 (19) | 40 | 2/2.0 | Iliac artery, femoral artery | Measured in stents, and iliac and femoral artery, (tissue), and blood (systemic) | 4, 10, 30, 60, 90 and 180 Days | Yes |
| | Test: 10% PTx DES (Eluvia Formulation) | 5.0 x 20 (0)
6.0 x 20 (25)
7.0 x 20 (23) | 50 | 10/0.5 | | | | |
| | Test: 7% PTx DES | 5.0 x 20 (0)
6.0 x 20 (18)
7.0 x 20 (18) | 105 | 7/1.5 | | | | |

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PMA P180011: FDA Summary of Safety and Effectiveness Data

| Test and/or Study Name | Test Article | Stent (Diameter and Length in mm) and Number of Stents (n) | Total Paclitaxel per Stent (μg) | Paclitaxel Density (μg/mm²); Paclitaxel % / Coat Wt. (mg) | Vessel Location | Paclitaxel Systemic and Tissue Levels | Evaluation Time Points | Endpoints Met |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Test: 12% PTx DES (Safety Margin Formulation) | 5.0 x 20 (0)
6.0 x 20 (19)
7.0 x 20 (17) | 180 | 12/1.5 | | | | |
| | Test 4% PTx DES | 5.0 x 20 (0)
6.0 x 20 (18)
7.0 x 20 (20) | 12 | 4/0.3 | | | | |

Table 9: ELUVIA Animal Studies - Safety and Acute Performance

| Test and/or Study Name | Test Article | Stent (Diameter and Length in mm) and Number of Stents (n) | Total Paclitaxel per Stent (μg) | Paclitaxel Density (μg/mm²); Paclitaxel % / Coat Wt. (mg) | Vessel Location | Paclitaxel Systemic and Tissue Levels | Evaluation Time Points | Endpoints Met |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Animal Testing for Safety and Preliminary Effectiveness | | | | | | | | |
| Safety Study 14-089G (Overlap stent configuration) | DES SFA (Eluvia Formulation) | 6.0 x 40 (4)
6.0 x 60 (4)
7.0 x 40 (11)
7.0 x 60 (11) | 135
207
135
207 | 0.167 | Iliofemoral artery | None – Histology study | 14 and 90 Days | Yes |

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| Test and/or Study Name | Test Article | Stent (Diameter and Length in mm) and Number of Stents (n) | Total Paclitaxel per Stent (μg) | Paclitaxel Density (μg/mm2); Paclitaxel % / Coat Wt. (mg) | Vessel Location | Paclitaxel Systemic and Tissue Levels | Evaluation Time Points | Endpoints Met |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Innova | 6.0 x 40 (2)6.0 x 60 (2)7.0 x 40 (14)7.0 x 60 (14) | NA – Uncoated stents | NA – Uncoated stents | | | | |
| Safety Study 09-117G (Single stent configuration) | Eluvia | 6.0 x 80 (4)7.0 x 80 (24)8.0 x 80 (9) | 273272280 | 0.167 | Iliofemoral artery | None – Histology study | 30, 90 and 180 Days | Yes |
| | Innova | 6.0 x 80 (3)7.0 x 80 (20)8.0 x 80 (13) | N/A Uncoated stents | N/A Uncoated stents | | | | |
| Dose Finding Study 08-043N (Single stent configuration) | Test: Polymer-only | 5.0 x 20 (1)6.0 x 20 (13)7.0 x 20 (10) | N/A No Paclitaxel in coating | N/A No Paclitaxel in coating | Iliac artery, femoral artery | None – Histology study | 30, 90 and 180 Days | Yes |
| | Test: 2% PTx DES | 5.0 x 20 (0)6.0 x 20 (14)7.0 x 20 (10) | 20 | 2/2.0 | | | | |

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| Test and/or Study Name | Test Article | Stent (Diameter and Length in mm) and Number of Stents (n) | Total Paclitaxel per Stent (μg) | Paclitaxel Density (μg/mm²); Paclitaxel % / Coat Wt. (mg) | Vessel Location | Paclitaxel Systemic and Tissue Levels | Evaluation Time Points | Endpoints Met |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Test: 10% PTx DES (Eluvia Formulation) | 5.0 x 20 (3)
6.0 x 20 (7)
7.0 x 20 (13) | 50 | 10/ 0.5 | | | | |
| | Test: 7% PTx DES | 5.0 x 20 (0)
6.0 x 20 (13)
7.0 x 20 (11) | 105 | 7/1.5 | | | | |
| | Test: 12% PTx DES (Safety Margin Formulation) | 5.0 x 20 (0)
6.0 x 20 (12)
7.0 x 20 (12) | 180 | 12/1.5 | | | | |
| | Test: 4% PTx DES | 5.0 x 20 (1)
6.0 x 20 (11)
7.0 x 20 (12) | 12 | 4/0.3 | | | | |
| | Control: Bare Metal Epic | 5.0 x 20 (2)
6.0 x 20 (12)
7.0 x 20 (10) | N/A
Uncoated stents | N/A Uncoated stents | | | | |
| | Acute Performance study | | | | | | | |
| Acute Performance Study 14-101G | Innova | 5.0 x 40 (2)
6.0 x 40 (3)
7.0 x 40 (1)
5.0 x 120 (1)
6.0 x 120 (7)
7.0 x 120 (1) | NA – Uncoated stents | NA – Uncoated stents | Iliac artery, femoral artery | None -- Acute Performance study | Acute | Yes |

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PMA P180011: FDA Summary of Safety and Effectiveness Data
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# X. SUMMARY OF PRIMARY CLINICAL TRIAL

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of stenting with the ELUVIA Drug-Eluting Vascular Stent System to improve luminal diameter in the treatment of symptomatic de-novo or restenotic lesions in the native SFA and/or PPA with reference vessel diameters (RVD) ranging from 4.0 - 6.0 mm and total lesion lengths up to 190 mm in the US, Canada, Japan, New Zealand, and Europe under IDE G150171. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

## A. Study Design

Patients were treated between December 3, 2015 and February 15, 2017. The database for this PMA reflected data collected through April 4, 2018 and included 524 patients. The primary endpoint analysis was conducted when there were sufficient patients evaluable to meet the statistical requirements, as specified in the statistical analysis plan. The database for the primary endpoint analysis reflected data collected through January 24, 2018 and included 421 patients. There were 65 investigational sites.

The IMPERIAL Trial was a global, prospective, multicenter, 2:1 randomized (ELUVIA vs Zilver PTX), controlled, single-blind, non-inferiority trial (RCT). It also included a concurrent, non-blinded, non-randomized, single-arm, pharmacokinetic (PK) substudy and a concurrent, non-blinded, non-randomized, Long Lesion (LL) substudy. Subjects whose eligibility was confirmed were enrolled in the study and treated with the ELUVIA Drug-Eluting Vascular Stent System (test device) or the Zilver PTX stent (control device) on the day of the index procedure. After the index procedure, all subjects were followed to investigate the safety and effectiveness of the ELUVIA Drug-Eluting Vascular Stent System.

A Clinical Events Committee (CEC) was used to adjudicate any reported death, Target Lesion Revascularization (TLR), Target Vessel Revascularization (TVR), amputation or stent thrombosis that occurred during the IMPERIAL trial. The CEC further determined which of these events met protocol definition of a major adverse event (MAE) for the IMPERIAL trial.

### 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the IMPERIAL study was limited to patients who met the following inclusion criteria:

1. Subjects age 18 and older.
2. Subject (or Legal Guardian if applicable) is willing and able to provide consent before any study-specific test or procedure is performed, signs the consent form, and agrees to attend all required follow-up visits. NOTE: For subjects less than 20 years of age enrolled at a Japanese center, the subject’s

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legal representative, as well as the subject, must provide written informed consent.

3. Chronic, symptomatic lower limb ischemia defined as Rutherford categories 2, 3 or 4.

4. Stenotic, restenotic or occlusive lesion(s) located in the native SFA and/or PPA:

a. Degree of stenosis ≥70% by visual angiographic assessment
b. Vessel diameter ≥ 4 and ≤ 6 mm
c. Total lesion length (or series of lesions) ≥ 30 mm and ≤ 140 mm (Note: Lesion segment(s) must be fully covered with one ELUVIA stent or up to two Zilver PTX stents)

**Long Lesion Substudy**: Total lesion length (or series of lesions) &gt;140 mm and ≤ 190 mm (Note: Lesion segment(s) will require overlapping of two ELUVIA stents).

d. For occlusive lesions requiring use of re-entry device, lesion length ≤ 120 mm

**Long Lesion Substudy**: For occlusive lesions requiring use of re-entry device, lesion length &gt; 120 mm and ≤ 170 mm

e. Target lesion located at least three centimeters above the inferior edge of the femur

5. Patent infrapopliteal and popliteal artery, i.e., single vessel runoff or better with at least one of three vessels patent (&lt;50% stenosis) to the ankle or foot with no planned intervention.

Patients were not permitted to enroll in the IMPERIAL study if they met any of the following exclusion criteria:

1. Previously stented target lesion/vessel.
2. Target lesion/vessel previously treated with drug-coated balloon &lt; 12 months prior to randomization/enrollment.
3. Subjects who have undergone prior surgery of the SFA/PPA in the target limb to treat atherosclerotic disease.
4. Use of atherectomy, laser or other debulking devices in the target limb SFA/PPA during the index procedure.
5. History of major amputation in the target limb.
6. Documented life expectancy less than 24 months due to other medical co-morbid condition(s) that could limit the subject's ability to participate in the clinical trial, limit the subject's compliance with the follow-up requirements, or impact the scientific integrity of the clinical trial.
7. Known hypersensitivity or contraindication to contrast dye that, in the opinion of the investigator, cannot be adequately pre-medicated.
8. Known hypersensitivity/allergy to the investigational stent system or protocol related therapies (e.g., nitinol, paclitaxel, or structurally related compounds, polymer or individual components, and antiplatelet, anticoagulant, thrombolytic medications).

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9. Platelet count &lt; 80,000 mm³ or &gt; 600,000 mm³ or history of bleeding diathesis.
10. Concomitant renal failure with a serum creatinine &gt; 2.0 mg/dL.
11. Receiving dialysis or immunosuppressant therapy.
12. History of myocardial infarction (MI) or stroke/cerebrovascular accident (CVA) within 6 months prior to randomization/enrollment.
13. Unstable angina pectoris at the time of randomization/enrollment.
14. Pregnant, breast feeding, or plan to become pregnant in the next 5 years.
15. Current participation in another investigational drug or device clinical study that has not completed the primary endpoint at the time of randomization/enrollment or that clinically interferes with the current study endpoints (Note: studies requiring extended follow-up for products that were investigational, but have become commercially available since then are not considered investigational studies).
16. Septicemia at the time of randomization/enrollment.
17. Presence of other hemodynamically significant outflow lesions in the target limb requiring intervention within 30 days of randomization/enrollment.
18. Presence of aneurysm in the target vessel.
19. Acute ischemia and/or acute thrombosis of the SFA/PPA prior to randomization/enrollment.
20. Perforated vessel as evidenced by extravasation of contrast media prior to randomization/enrollment.
21. Heavily calcified lesions.

2. Follow-Up Schedule

All patients were scheduled to return for follow-up examinations at 1 month, 6 months, 12 months, 24 months, 36 months (via telephone or in office), 48 months (via telephone or in office) and 60 months postoperatively.

Preoperatively and during the index procedure, an inclusion/exclusion criteria assessment, medication assessment, angiogram, and adverse event assessment was performed. Postoperatively, the objective parameters measured during the study included a Rutherford Classification, Ankle-Brachial Index (ABI) measurements, a Walking Impairment Questionnaire (WIQ), EQ-5D Questionnaire, 6 Minute Hall Walk (only at 12 months), Medication Assessment, Adverse Event Assessment, Duplex Ultrasound, and X-Ray. Adverse events and complications were recorded at all visits. PK substudy subjects had baseline venous blood drawn followed by blood draws at 10 minutes, 30 minutes, 1, 2, 3, 4, 6, 12, and 24 hours and one final blood draw at either 48 hours or 72 hours after placement of the final ELUVIA stent.

The key time points are shown in Table 10 below and are included in the tables summarizing safety and effectiveness.

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Table 10: Study Event Schedule Procedures and Assessments

| Procedure/Assessment | Pre-procedure [2] | During Index Procedure | Pre-Discharge | 1-month (30±7 days) | 6-month (182±30 days) | 12-month (365±30 days) | 24-month (730±30 days) | 36-month[5] (1095±30 days) | 48-month[5] (1460 ± 30 days) | 60-month (1825 ± 30 days) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Informed Consent[1] | X | | | | | | | | | |
| Confirm Inclusion/Exclusion | X | X | | | | | | | | |
| Demographics and Medical History, Height and Weight | X | | | | | | | | | |
| Serum Creatinine | X | | | | | | | | | |
| Pregnancy Test[2] | X | | | | | | | | | |
| CBC and platelet count | X | | | | | | | | | |
| ABI Measurements | X | | | X[3] | X | X | X | | | X |
| Rutherford Categorization | X | | | X | X | X | X | | | X |
| Walking Impairment Questionnaire (WIQ) | X | | | X | X | X | X | | | X |
| EQ-5D Questionnaire | X | | | X | X | X | X | | | X |
| 6 Minute Hall Walk (6MHW) | X | | | | | X | | | | |
| Angiogram[4] | | X | | | | | | | | |
| Randomization | | X | | | | | | | | |
| Venous blood draw for subjects in PK sub-study | | X[6] | X | | | | | | | |
| Medication Assessment | X | X | X | X | X | X | X | X | X | X |
| Adverse Events Assessment | | X | X | X | X | X | X[7] | X[7] | X[7] | X[7] |
| Duplex Ultrasound[4] | | | | | X | X | X | | | X |
| X-Ray[4] | | | | | | X | X | | | X |

[1] Subject’s consent obtained and informed consent form signed prior to any study-specific tests or procedures
[2] Performed within 30 days of procedure, except urine or blood pregnancy test required for females of childbearing potential performed within 7 days of procedure
[3] ABI measurement may be collected immediately post-procedure through 1 Month Follow-up window (Day 0 – 37).
[4] Angiograms, Ultrasounds and X-rays will be sent to the respective core lab for analysis. Follow-up angiograms, ultrasounds and x-rays will not be required for any subject who underwent bypass surgery of the target lesion during the 60-month follow-up timeframe, or has a documented occluded stent.
[5] The 36 month and 48 month visit may be conducted in the office or by telephone.
[6] Up to 24 hours prior to stent placement.
[7] Reporting required through the end of trial for SAEs, UADEs and ADEs/Device Deficiencies. AEs not related to the investigational device or procedure reported only through 12 month follow-up visit.

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# 3. Clinical Endpoints

With regards to safety, the primary safety endpoint assessed the occurrence of Major Adverse Events (MAEs) defined as all causes of death through 1 month, target limb major amputation through 12 months and/or target lesion revascularization (TLR) through 12 months. This safety endpoint was designed to demonstrate that the 12-month MAE-free rate for the ELUVIA treatment group is non-inferior to the Zilver PTX control group. ELUVIA will be concluded to be non-inferior to Zilver PTX for device safety if the one-sided lower 95% confidence bound on the difference between treatment groups (ELUVIA – Zilver PTX) in 12-month MAE-free is greater than -0.1 (or -10%). The primary safety endpoint analysis was conducted when there were sufficient patients evaluable to meet the statistical requirements, as specified in the statistical analysis plan, and did not include the full patient cohort.

With regards to effectiveness, the primary effectiveness endpoint assessed primary patency at 12 months post-procedure. This effectiveness endpoint was designed to demonstrate that the 12-month primary patency for the ELUVIA treatment group is non-inferior to the Zilver PTX control group. ELUVIA will be concluded to be non-inferior to Zilver PTX for device effectiveness if the one-sided lower 95% confidence bound on the difference between treatment groups (ELUVIA – Zilver PTX) in 12-month primary patency is greater than -0.1 (or -10%). The primary effectiveness endpoint analysis was conducted when there were sufficient patients evaluable to meet the statistical requirements, as specified in the statistical analysis plan, and did not include the full patient cohort.

Primary vessel patency was defined as the percentage of lesions (target stented segments) that reached the endpoint without a hemodynamically significant stenosis on duplex ultrasound (DUS) (Peak Systolic Velocity Ratio {PSVR} is ≤ 2.4), and without clinically-driven TLR or bypass of the target lesion before or on the DUS follow up visit. All DUS readings were assessed by an independent core laboratory.

## Additional Secondary Endpoints

- Technical success defined as delivery and deployment of the assigned study stent to the target lesion to achieve residual angiographic stenosis no greater than 30% assessed visually
- Procedural success defined as technical success with no MAEs noted within 24 hours of the index procedure
- MAE rate at 1 month post-index procedure defined as all causes of death, target limb major amputation and/or TLR
- Primary Patency and Assisted Primary Patency at 6 months, 12 months, 24 months and 60 months using different PSVRs
- Clinically-driven TLR and Target Vessel Revascularization (TVR) Rate at each time point

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- Adverse Event Rates (unanticipated, major, serious, device/procedure-related) at each time point
- Non-serious non-device/procedure-related Adverse Event Rates at each time point through 12 months
- Stent Fracture Rate at 12 months, 24 months and 60 months utilizing VIVA definitions
- Distribution of Rutherford Classification during follow-up as compared to baseline at 1 month, 6 months, 12 months, 24 months and 60 months
- Rate of Primary and Secondary Sustained Clinical Improvement as assessed by changes in Rutherford Classification from baseline at 1 month, 6 months, 12 months, 24 months and 60 months
- Rate of Hemodynamic Improvement as assessed by changes in Ankle-Brachial Index (ABI) from baseline at 1 month, 6 months, 12 months, 24 months and 60 months
- Walking Improvement at 12 months assessed by change in Six Minute Hall Walk (6MHW) from baseline
- Walking Improvement and Patient Utility Values assessed at 1 month, 6 months, 12 months, 24 months and 60 months assessed by change in Walking Impairment Questionnaire and EQ-5D from baseline
- Changes in healthcare utilization over time
- PK parameters calculated for subjects in the PK substudy

The secondary endpoint analyses were conducted on the full patient cohort at the associated time points.

## Long Lesion substudy

The Long Lesion substudy primary effectiveness endpoint assessed primary patency at 12 months post-procedure. There was a non-statistically driven performance goal (60%) which was developed from the historical long stent performance of the Innova Bare Metal Stent System and the expected enhanced performance (10%) for the ELUVIA Stent System. If the observed 12-month primary patency is greater than or equal to 60%, the ELUVIA Stent System will be considered to have acceptable effectiveness performance in the long lesion population.

The Long Lesion substudy primary safety endpoint assessed the 12-month MAE-free rate. It was expected that the MAE-free rate would be similar to the rates observed by the ELUVIA stent group in the RCT.

With regard to success/failure criteria, both the primary endpoints needed to be met, demonstrating non-inferiority to the control device.

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# B. Accountability of Full Cohort

At the time of database lock, of the 524 subjects enrolled in the PMA study, $94.6\%$ (440) RCT subjects, $98\%$ (49) LL substudy subjects and $92.3\%$ (12) PK substudy subjects were available for analysis at the completion of the study, the 12 month postoperative visit. Table 11, Table 12 and Table 13 display subject disposition at each follow-up visit for the RCT, LL substudy, and PK substudy, respectively.

Table 11: Subject Disposition - RCT

| | Eluvia N=309 Subjects | Zilver PTX N=156 Subjects | Overall N=465 Subjects |
| --- | --- | --- | --- |
| Intent to Treat (All Enrolled Subjects) | 309 | 156 | 465 |
| | | | |
| Eligible for 1-Month Clinical Follow-up | 307 | 155 | 462 |
| Not Eligible for 1-Month Clinical Follow-up | 2 | 1 | 3 |
| Death ≤ 37 Days with no 1-Month Clinical Follow-up Performed | 0 | 0 | 0 |
| Withdrawal | 2 | 1 | 3 |
| Adverse Event | 0 | 0 | 0 |
| Investigator Discretion | 0 | 0 | 0 |
| Lost to Follow-up | 0 | 0 | 0 |
| Withdrew Consent | 2 | 1 | 3 |
| Did not meet eligibility criteria | 0 | 0 | 0 |
| Other | 0 | 0 | 0 |
| 1-Month Visit Missed | 2 | 1 | 3 |
| 1-Month Clinical Follow-up Performed | 305 | 154 | 459 |
| 1-Month Clinical Follow-up or Death (Evaluable) | 305 | 154 | 459 |
| 1-Month Clinical Follow-up Compliance1 | 98.7% (305/309) | 98.7% (154/156) | 98.7% (459/465) |
| | | | |
| Eligible for 6-Month Clinical Follow-up | 303 | 150 | 453 |
| Not Eligible for 6-Month Clinical Follow-up | 6 | 6 | 12 |
| Death ≤ 212 Days with no 6-Month Clinical Follow-up Performed | 2 | 3 | 5 |
| Withdrawal | 4 | 3 | 7 |
| Adverse Event | 0 | 0 | 0 |
| Investigator Discretion | 0 | 0 | 0 |
| Lost to Follow-up | 0 | 0 | 0 |
| Withdrew Consent | 4 | 3 | 7 |
| Did not meet eligibility criteria | 0 | 0 | 0 |
| Other | 0 | 0 | 0 |
| 6-Month Visit Missed | 11 | 5 | 16 |
| 6-Month Clinical Follow-up Performed | 292 | 145 | 437 |
| 6-Month Clinical Follow-up or Death (Evaluable) | 294 | 148 | 442 |
| 6-Month Clinical Follow-up Compliance1 | 95.1% (292/307) | 94.8% (145/153) | 95.0% (437/460) |
| 6-Month Duplex Ultrasound Follow-up Compliance2 | 92.2% (283/307) | 94.1% (144/153) | 92.8% (427/460) |
| | | | |

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| | Eluvia N=309 Subjects | Zilver PTX N=156 Subjects | Overall N=465 Subjects |
| --- | --- | --- | --- |
| Eligible for 12-Month Clinical Follow-up (Full Cohort) | 294 | 146 | 440 |
| Not Eligible for 12-Month Clinical Follow-up | 15 | 10 | 25 |
| Death ≤ 395 Days with no 12-Month Clinical Follow-up Performed | 6 | 6 | 12 |
| Withdrawal | 9 | 4 | 13 |
| Adverse Event | 2 | 0 | 2 |
| Investigator Discretion | 0 | 0 | 0 |
| Lost to Follow-up | 0 | 0 | 0 |
| Withdrew Consent | 6 | 4 | 10 |
| Did not meet eligibility criteria | 0 | 0 | 0 |
| Other | 1 | 0 | 1 |
| 12-Month Visit Missed | 12 | 4 | 16 |
| 12-Month Clinical Follow-up Performed | 282 | 142 | 424 |
| 12-Month Clinical Follow-up or Death (Evaluable) | 288 | 148 | 436 |
| 12-Month Clinical Follow-up Compliance1 | 93.1% (282/303) | 94.7% (142/150) | 93.6% (424/453) |
| 12-Month Duplex Ultrasound Follow-up Compliance2 | 92.7% (281/303) | 94.7% (142/150) | 93.4% (423/453) |
| 12-Month X-ray Follow-up Compliance2 | 92.1% (279/303) | 90.7% (136/150) | 91.6% (415/453) |
| 12-Month Disposition: Primary Endpoint Cohort | | | |
| 12-Month Safety Primary Endpoint Evaluable | 273 | 133 | 406 |
| Subjects with (TLR/Major Amputation/last follow up > 335) with no 12-Month Clinical Follow-up Performed | 6 | 2 | 8 |
| Subjects with 12-Month Clinical Follow-up Performed | 267 | 131 | 398 |
| 12-Month Safety Primary Endpoint Non-Evaluable | 10 | 10 | 20 |
| Death ≤ 365 Days with no 12-Month Clinical Follow-up Performed | 5 | 5 | 10 |
| 12-month clinical follow-up unavailable for analysis | 5 | 5 | 10 |
| 12-Month Primary Effectiveness Endpoint Evaluable | 266 | 130 | 396 |
| Subjects with CD TLR but no 12-Month Clinical Follow-up Performed | 2 | 1 | 3 |
| Subjects with 12-Month Clinical Follow-up Performed | 264 | 129 | 393 |
| 12-Month Primary Effectiveness Endpoint Non-Evaluable | 16 | 12 | 28 |
| Death ≤ 365 Days with no 12-Month Clinical Follow-up Performed | 6 | 6 | 12 |
| 12-month clinical follow-up unavailable for analysis | 5 | 5 | 10 |
| Missing 12 month DUS | 5 | 1 | 6 |

1Death prior to the visit window does not contribute to the denominators and numerators of the compliance rate
2All duplex ultrasounds and x-ray imaging apply, including anyone without interpretable image

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Table 12: Subject Disposition - LL sub-study

| | Eluvia
N=50 Subjects |
| --- | --- |
| Intent to Treat (All Enrolled Subjects) | 50 |
| | |
| Eligible for 1-Month Clinical Follow-up | 50 |
| Not Eligible for 1-Month Clinical Follow-up | 0 |
| Death ≤ 37 Days with no 1-Month Clinical Follow-up Performed | 0 |
| Withdrawal | 0 |
| Adverse Event | 0 |
| Investigator Discretion | 0 |
| Lost to Follow-up | 0 |
| Withdrew Consent | 0 |
| Did not meet eligibility criteria | 0 |
| Other | 0 |
| 1-Month Visit Missed | 0 |
| 1-Month Clinical Follow-up Performed | 50 |
| 1-Month Clinical Follow-up or Death (Evaluable) | 50 |
| 1-Month Clinical Follow-up Compliance^{1} | 100.0% (50/50) |
| | |
| Eligible for 6-Month Clinical Follow-up | 50 |
| Not Eligible for 6-Month Clinical Follow-up | 0 |
| Death ≤ 212 Days with no 6-Month Clinical Follow-up Performed | 0 |
| Withdrawal | 0 |
| Adverse Event | 0 |
| Investigator Discretion | 0 |
| Lost to Follow-up | 0 |
| Withdrew Consent | 0 |
| Did not meet eligibility criteria | 0 |
| Other | 0 |
| 6-Month Visit Missed | 1 |
| 6-Month Clinical Follow-up Performed | 49 |
| 6-Month Clinical Follow-up or Death (Evaluable) | 49 |
| 6-Month Clinical Follow-up Compliance^{1} | 98.0% (49/50) |
| 6-Month Duplex Ultrasound Follow-up Compliance^{2} | 94.0% (47/50) |
| | |
| Eligible for 12-Month Clinical Follow-up | 49 |
| Not Eligible for 12-Month Clinical Follow-up | 1 |
| Death ≤ 395 Days with no 12-Month Clinical Follow-up Performed | 0 |
| Withdrawal | 1 |
| Adverse Event | 0 |
| Investigator Discretion | 0 |
| Lost to Follow-up | 0 |
| Withdrew Consent | 1 |
| Did not meet eligibility criteria | 0 |
| Other | 0 |
| 12-Month Visit Missed | 2 |
| 12-Month Clinical Follow-up Performed | 47 |

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Table 13: Subject Disposition - PK sub-study

| | Eluvia N=13 Subjects |
| --- | --- |
| Intent to Treat (All Enrolled Subjects) | 13 |
| | |
| Eligible for 1-Month Clinical Follow-up | 13 |
| Not Eligible for 1-Month Clinical Follow-up | 0 |
| Death ≤ 37 Days with no 1-Month Clinical Follow-up Performed | 0 |
| Withdrawal | 0 |
| Adverse Event | 0 |
| Investigator Discretion | 0 |
| Lost to Follow-up | 0 |
| Withdrew Consent | 0 |
| Did not meet eligibility criteria | 0 |
| Other | 0 |
| 1-Month Visit Missed | 0 |
| 1-Month Clinical Follow-up Performed | 13 |
| 1-Month Clinical Follow-up or Death (Evaluable) | 13 |
| 1-Month Clinical Follow-up Compliance1 | 100.0% (13/13) |
| | |
| Eligible for 6-Month Clinical Follow-up | 13 |
| Not Eligible for 6-Month Clinical Follow-up | 0 |
| Death ≤ 212 Days with no 6-Month Clinical Follow-up Performed | 0 |
| Withdrawal | 0 |
| Adverse Event | 0 |
| Investigator Discretion | 0 |
| Lost to Follow-up | 0 |
| Withdrew Consent | 0 |
| Did not meet eligibility criteria | 0 |
| Other | 0 |
| 6-Month Visit Missed | 0 |
| 6-Month Clinical Follow-up Performed | 13 |
| 6-Month Clinical Follow-up or Death (Evaluable) | 13 |
| 6-Month Clinical Follow-up Compliance1 | 100.0% (13/13) |
| | |
| Eligible for 12-Month Clinical Follow-up | 12 |
| Not Eligible for 12-Month Clinical Follow-up | 1 |
| Death ≤ 395 Days with no 12-Month Clinical Follow-up Performed | 1 |

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| | Eluvia
N=13 Subjects |
| --- | --- |
| Withdrawal | 0 |
| Adverse Event | 0 |
| Investigator Discretion | 0 |
| Lost to Follow-up | 0 |
| Withdrew Consent | 0 |
| Did not meet eligibility criteria | 0 |
| Other | 0 |
| 12-Month Visit Missed | 0 |
| 12-Month Clinical Follow-up Performed | 12 |
| 12-Month Clinical Follow-up or Death (Evaluable) | 13 |
| 12-Month Clinical Follow-up Compliance^{1} | 100.0% (12/12) |
| 12-Month Duplex Ultrasound Follow-up Compliance^{2} | 100.0% (12/12) |
| 12-Month X-ray Follow-up Compliance^{2} | 100.0% (12/12) |

1Death prior to the visit window does not contribute to the denominators and numerators of the compliance rate
2All duplex ultrasounds and x-ray imaging apply, including anyone without interpretable images

## C. Study Population Demographics and Baseline Characteristics

The demographics of the study population are typical for pivotal study performed in the US. Table 14, Table 15 and Table 16 provide a summary of baseline demographics and medical history of all subjects enrolled in the RCT, PK substudy, and LL substudy, respectively. In the RCT, the baseline demographics and medical history of subjects randomized to the treatment group (Eluvia) are similar to those of the subjects randomized to the control group (Zilver PTX).

Table 14: Baseline Demographics and Medical History – RCT (N=465)

| Subject Characteristic | Eluvia
N=309 Subjects | Zilver PTX
N=156 Subjects |
| --- | --- | --- |
| Demographics | | |
| Age (Year) | 68.5±9.5 (309)
(39.0, 90.0) | 67.8±9.4 (156)
(38.0, 87.0) |
| Male Gender | 66.0% (204/309) | 66.7% (104/156) |
| Race/Ethnicity^{1} | | |
| Hispanic or Latino | 5.8% (18/309) | 3.8% (6/156) |
| Caucasian | 66.3% (205/309) | 69.2% (108/156) |
| Asian | 18.4% (57/309) | 17.9% (28/156) |
| Japanese | 18.1% (56/309) | 17.9% (28/156) |
| Black, or African heritage | 6.8% (21/309) | 7.1% (11/156) |
| Native Hawaiian or other Pacific Islander | 0.3% (1/309) | 0.0% (0/156) |
| American Indian or Alaska Native | 0.6% (2/309) | 1.3% (2/156) |
| Other | 1.0% (3/309) | 0.6% (1/156) |
| Not Disclosed | 0.6% (2/309) | 0.0% (0/156) |
| General Medical History | | |
| History of Smoking | | |

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Page 33

| Subject Characteristic | Eluvia
N=309 Subjects | Zilver PTX
N=156 Subjects |
| --- | --- | --- |
| Current | 35.3% (109/309) | 40.4% (63/156) |
| Previous | 50.8% (157/309) | 43.6% (68/156) |
| Never | 13.6% (42/309) | 14.1% (22/156) |
| Unknown | 0.3% (1/309) | 1.9% (3/156) |
| Current Diabetes Mellitus | 41.7% (129/309) | 43.6% (68/156) |
| Type 1 | 2.3% (3/129) | 4.4% (3/68) |
| Type 2 | 92.2% (119/129) | 94.1% (64/68) |
| Unknown | 5.4% (7/129) | 1.5% (1/68) |
| Current Method of Treatment | | |
| Diet | 31.0% (40/129) | 25.0% (17/68) |
| Diet (only) | 9.3% (12/129) | 4.4% (3/68) |
| Medically Treated | 89.9% (116/129) | 94.1% (64/68) |
| Oral Agent | 72.1% (93/129) | 75.0% (51/68) |
| Insulin | 38.0% (49/129) | 38.2% (26/68) |
| Other | 1.6% (2/129) | 0.0% (0/68) |
| Unknown | 0.8% (1/129) | 1.5% (1/68) |
| History of Hyperlipidemia requiring medication | 76.3% (235/308) | 75.6% (118/156) |
| History of Hypertension requiring medication | 82.2% (254/309) | 85.3% (133/156) |
| History of Chronic Obstructive Pulmonary Disease | 15.6% (48/308) | 18.1% (28/155) |
| Cardiac History | | |
| History of Coronary Artery Disease | 50.8% (156/307) | 45.2% (70/155) |
| History of Myocardial Infarction (MI) | 19.6% (60/306) | 17.5% (27/154) |
| History of Congestive Heart Failure | 8.5% (26/307) | 7.8% (12/154) |
| New York Heart Assoc.
(NYHA) Classification | | |
| I | 19.2% (5/26) | 25.0% (3/12) |
| II | 23.1% (6/26) | 41.7% (5/12) |
| III | 15.4% (4/26) | 8.3% (1/12) |
| IV | 0.0% (0/26) | 0.0% (0/12) |
| Unknown | 42.3% (11/26) | 25.0% (3/12) |
| History of Percutaneous Coronary Intervention (PCI) | 32.5% (100/308) | 34.2% (53/155) |
| History of Coronary Artery Bypass Graft (CABG) Surgery | 14.0% (43/308) | 13.5% (21/156) |
| Current Anginal Status | | |
| Stable Angina | 10.4% (32/309) | 12.2% (19/156) |
| Unstable Angina | 0.0% (0/309) | 0.0% (0/156) |
| None | 86.7% (268/309) | 86.5% (135/156) |
| Unknown | 2.9% (9/309) | 1.3% (2/156) |
| Neurologic/Renal History | | |
| History of Transient Ischemic Attacks (TIA) | 4.5% (14/308) | 3.9% (6/155) |
| History of Cerebrovascular Accident (CVA) | 9.7% (30/309) | 9.0% (14/156) |
| History of Renal Insufficiency | 8.1% (25/309) | 7.1% (11/156) |
| History of Renal Percutaneous Intervention | 1.9% (6/309) | 0.6% (1/155) |

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Page 34

| Subject Characteristic | Eluvia
N=309 Subjects | Zilver PTX
N=156 Subjects |
| --- | --- | --- |
| Peripheral Vascular History | | |
| History of Peripheral Vascular Surgery | 12.9% (40/309) | 9.6% (15/156) |
| History of endovascular interventions in Target vessel | 8.7% (27/309) | 11.0% (17/155) |
| Type of interventions | | |
| Atherectomy | 1.3% (4/309) | 3.2% (5/156) |
| Drug Coated Balloon | 2.6% (8/309) | 1.9% (3/156) |
| Percutaneous Transluminal Angioplasty (PTA) | 6.1% (19/309) | 7.7% (12/156) |
| Stenting | 0.6% (2/309) | 0.0% (0/156) |
| Other | 1.0% (3/309) | 1.9% (3/156) |
| History of Other Peripheral Endovascular Interventions (other than Target Vessel) | 36.2% (112/309) | 31.6% (49/155) |
| Type of most recent Intervention | | |
| Atherectomy | 8.4% (26/309) | 7.7% (12/156) |
| Drug Coated Balloon | 9.4% (29/309) | 7.7% (12/156) |
| Percutaneous Transluminal Angioplasty (PTA) | 16.8% (52/309) | 12.8% (20/156) |
| Stenting | 23.9% (74/309) | 21.8% (34/156) |
| Other | 0.6% (2/309) | 2.6% (4/156) |
| History of Claudication | 98.4% (303/308) | 97.4% (151/155) |

¹Subjects that are having more than one race will be considered only once in the sub category where less number of subjects are available. For example, if a subject has races ticked as “Caucasian” and “Hispanic or Latino”, the subject will be considered in “Hispanic or Latino” as this sub category has less number of subjects.

Table 15: Baseline Demographics and Medical History – PK (N=13)

| Subject Characteristic | Eluvia
N=13 Subjects |
| --- | --- |
| Demographics | |
| Age (Year) | 66.4±6.1 (13)
(57.0, 78.0) |
| Male Gender | 76.9% (10/13) |
| Race/Ethnicity¹ | |
| Hispanic or Latino | 0.0% (0/13) |
| Caucasian | 100.0% (13/13) |
| Asian | 0.0% (0/13) |
| Japanese | 0.0% (0/13) |
| Black, or African heritage | 0.0% (0/13) |
| Native Hawaiian or other Pacific Islander | 0.0% (0/13) |
| American Indian or Alaska Native | 0.0% (0/13) |
| Other | 0.0% (0/13) |
| Not Disclosed | 0.0% (0/13) |
| General Medical History | |
| History of Smoking | |

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Page 35

| Subject Characteristic | Eluvia
N=13 Subjects |
| --- | --- |
| Current | 23.1% (3/13) |
| Previous | 76.9% (10/13) |
| Never | 0.0% (0/13) |
| Unknown | 0.0% (0/13) |
| Current Diabetes Mellitus | 53.8% (7/13) |
| Type 1 | 0.0% (0/7) |
| Type 2 | 100.0% (7/7) |
| Unknown | 0.0% (0/7) |
| Current Method of Treatment | |
| Diet | 42.9% (3/7) |
| Diet (only) | 14.3% (1/7) |
| Medically Treated | 85.7% (6/7) |
| Oral Agent | 71.4% (5/7) |
| Insulin | 71.4% (5/7) |
| Other | 0.0% (0/7) |
| Unknown | 0.0% (0/7) |
| History of Hyperlipidemia requiring medication | 92.3% (12/13) |
| History of Hypertension requiring medication | 92.3% (12/13) |
| History of Chronic Obstructive Pulmonary Disease | 15.4% (2/13) |
| Cardiac History | |
| History of Coronary Artery Disease | 53.8% (7/13) |
| History of Myocardial Infarction (MI) | 15.4% (2/13) |
| History of Congestive Heart Failure | 7.7% (1/13) |
| New York Heart Assoc. (NYHA) Classification | |
| I | 0.0% (0/1) |
| II | 100.0% (1/1) |
| III | 0.0% (0/1) |
| IV | 0.0% (0/1) |
| Unknown | 0.0% (0/1) |
| History of Percutaneous Coronary Intervention (PCI) | 25.0% (3/12) |
| History of Coronary Artery Bypass Graft (CABG) Surgery | 23.1% (3/13) |
| Current Anginal Status | |
| Stable Angina | 0.0% (0/13) |
| Unstable Angina | 0.0% (0/13) |
| None | 92.3% (12/13) |
| Unknown | 7.7% (1/13) |
| Neurologic/Renal History | |
| History of Transient Ischemic Attacks (TIA) | 7.7% (1/13) |
| History of Cerebrovascular Accident (CVA) | 30.8% (4/13) |
| History of Renal Insufficiency | 15.4% (2/13) |
| History of Renal Percutaneous Intervention | 0.0% (0/13) |
| Peripheral Vascular History | |
| History of Peripheral Vascular Surgery | 7.7% (1/13) |
| History of endovascular interventions in Target vessel | 7.7% (1/13) |

{35}

| Subject Characteristic | Eluvia
N=13 Subjects |
| --- | --- |
| Type of interventions | |
| Atherectomy | 0.0% (0/13) |
| Drug Coated Balloon | 0.0% (0/13) |
| Percutaneous Transluminal Angioplasty (PTA) | 7.7% (1/13) |
| Stenting | 0.0% (0/13) |
| Other | 0.0% (0/13) |
| History of Other Peripheral Endovascular Interventions (other than Target Vessel) | 38.5% (5/13) |
| Type of most recent intervention | |
| Atherectomy | 0.0% (0/13) |
| Drug Coated Balloon | 0.0% (0/13) |
| Percutaneous Transluminal Angioplasty (PTA) | 38.5% (5/13) |
| Stenting | 30.8% (4/13) |
| Other | 0.0% (0/13) |
| History of Claudication | 100.0% (13/13) |

¹Subjects that are having more than one race will be considered only once in the sub category where less number of subjects are available. For example, if a subject has races ticked as “Caucasian” and “Hispanic or Latino”, the subject will be considered in “Hispanic or Latino” as this sub category has less number of subjects.

Table 16: Baseline Demographics and Medical History – LL (N=50)

| Subject Characteristic | Eluvia
N=50 Subjects |
| --- | --- |
| Demographics | |
| Age (Year) | 68.2±8.9 (50)
(51.0, 84.0) |
| Male Gender | 64.0% (32/50) |
| Race/Ethnicity¹ | |
| Hispanic or Latino | 6.0% (3/50) |
| Caucasian | 60.0% (30/50) |
| Asian | 22.0% (11/50) |
| Japanese | 22.0% (11/50) |
| Black, or African heritage | 12.0% (6/50) |
| Native Hawaiian or other Pacific Islander | 0.0% (0/50) |
| American Indian or Alaska Native | 0.0% (0/50) |
| Other | 0.0% (0/50) |
| Not Disclosed | 0.0% (0/50) |
| General Medical History | |
| History of Smoking | |
| Current | 32.0% (16/50) |
| Previous | 52.0% (26/50) |
| Never | 16.0% (8/50) |
| Unknown | 0.0% (0/50) |
| Current Diabetes Mellitus | 40.0% (20/50) |

¹Subjects that are having more than one race will be considered only once in the sub category where less number of subjects are available. For example, if a subject has races ticked as “Caucasian” and “Hispanic or Latino”, the subject will be considered in “Hispanic or Latino” as this sub category has less number of subjects.

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Page 37

| Subject Characteristic | Eluvia
N=50 Subjects |
| --- | --- |
| Type 1 | 5.0% (1/20) |
| Type 2 | 90.0% (18/20) |
| Unknown | 5.0% (1/20) |
| Current Method of Treatment | |
| Diet | 20.0% (4/20) |
| Diet (only) | 5.0% (1/20) |
| Medically Treated | 95.0% (19/20) |
| Oral Agent | 85.0% (17/20) |
| Insulin | 40.0% (8/20) |
| Other | 0.0% (0/20) |
| Unknown | 0.0% (0/20) |
| History of Hyperlipidemia requiring medication | 82.0% (41/50) |
| History of Hypertension requiring medication | 92.0% (46/50) |
| History of Chronic Obstructive Pulmonary Disease | 18.0% (9/50) |
| Cardiac History | |
| History of Coronary Artery Disease | 56.0% (28/50) |
| History of Myocardial Infarction (MI) | 18.0% (9/50) |
| History of Congestive Heart Failure | 16.0% (8/50) |
| New York Heart Assoc. (NYHA) Classification | |
| I | 25.0% (2/8) |
| II | 50.0% (4/8) |
| III | 0.0% (0/8) |
| IV | 0.0% (0/8) |
| Unknown | 25.0% (2/8) |
| History of Percutaneous Coronary Intervention (PCI) | 36.0% (18/50) |
| History of Coronary Artery Bypass Graft (CABG) Surgery | 14.3% (7/49) |
| Current Anginal Status | |
| Stable Angina | 10.0% (5/50) |
| Unstable Angina | 0.0% (0/50) |
| None | 88.0% (44/50) |
| Unknown | 2.0% (1/50) |
| Neurologic/Renal History | |
| History of Transient Ischemic Attacks (TIA) | 10.0% (5/50) |
| History of Cerebrovascular Accident (CVA) | 18.0% (9/50) |
| History of Renal Insufficiency | 6.0% (3/50) |
| History of Renal Percutaneous Intervention | 0.0% (0/50) |
| Peripheral Vascular History | |
| History of Peripheral Vascular Surgery | 4.0% (2/50) |
| History of endovascular interventions in Target vessel | 4.0% (2/50) |
| Type of interventions | |
| Atherectomy | 2.0% (1/50) |
| Drug Coated Balloon | 0.0% (0/50) |
| Percutaneous Transluminal Angioplasty (PTA) | 2.0% (1/50) |
| Stenting | 0.0% (0/50) |
| Other | 0.0% (0/50) |

{37}

| Subject Characteristic | Eluvia N=50 Subjects |
| --- | --- |
| History of Other Peripheral Endovascular Interventions (other than Target Vessel) | 40.0% (20/50) |
| Type of most recent intervention | |
| Atherectomy | 16.0% (8/50) |
| Drug Coated Balloon | 12.0% (6/50) |
| Percutaneous Transluminal Angioplasty (PTA) | 26.0% (13/50) |
| Stenting | 26.0% (13/50) |
| O…