ZILVER PTX DRUG-ELUTING PERIPHERAL STENT

P100022 · Cook Ireland, Ltd. · NIU · Nov 14, 2012 · Cardiovascular

Device Facts

• Record ID: P100022
• Device Name: ZILVER PTX DRUG-ELUTING PERIPHERAL STENT
• Applicant: Cook Ireland, Ltd.
• Product Code: NIU · Cardiovascular
• Decision Date: Nov 14, 2012
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The Zilver® PTX® Drug-Eluting Stent is indicated for improving luminal diameter for the treatment of de novo or restenotic symptomatic lesions in native vascular disease of the above-the-knee femoropopliteal arteries having reference vessel diameter from 4 mm to 9 mm and total lesion lengths up to 140 mm per limb and 280 mm per patient.

Device Story

The Zilver PTX is a self-expanding nitinol stent coated with paclitaxel (3 μg/mm²) without polymers or binders. It is preloaded in a 6 Fr delivery system compatible with 0.035-inch wire guides. Used in the femoropopliteal artery, the device is deployed by a physician under fluoroscopic guidance using radiopaque gold markers. Paclitaxel is released locally to inhibit smooth muscle cell proliferation and neointimal hyperplasia, reducing restenosis. The device maintains vessel patency, improving blood flow and reducing symptoms of peripheral arterial disease. Clinical outcomes are monitored via ABI, walking questionnaires, and ultrasound/angiography. Benefits include improved primary patency and reduced need for target lesion revascularization compared to balloon angioplasty.

Clinical Evidence

Pivotal randomized controlled trial (IDE G030251) compared Zilver PTX (n=241) to PTA (n=238). Primary safety endpoint (event-free survival at 12 months) was 90.4% (Zilver PTX) vs 83.9% (PTA) (p=0.01). Primary effectiveness endpoint (primary patency at 12 months) was 82.7% (Zilver PTX) vs 32.7% (PTA) (p<0.01). Secondary randomization showed Zilver PTX superior to bare Zilver stent (90.2% vs 72.9% patency at 12 months). Single-arm study (n=787) confirmed safety/effectiveness in broader population. Pharmacokinetic substudy showed minimal systemic paclitaxel (Cmax <10 ng/mL).

Technological Characteristics

Self-expanding nitinol stent; 3 μg/mm² paclitaxel coating (no polymer/excipient). Radiopaque gold markers. Delivery system: 6 Fr, 80/125 cm lengths, 0.035-inch wire guide compatible. EtO sterilized. MR Conditional (1.5T/3T). ASTM F2129 corrosion/fretting testing; ASTM F2052/F2182/F2119 MRI testing.

Indications for Use

Indicated for patients with symptomatic peripheral arterial disease (Rutherford Category 2+) requiring treatment of de novo or restenotic native femoropopliteal artery lesions (4-9 mm diameter; up to 140 mm length/limb, 280 mm/patient). Contraindicated in pregnant/breastfeeding women, patients unable to tolerate anti-platelet/anti-coagulant therapy, or 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

• Zilver Vascular Stent (P050017)
• TAXUS® Express²® Paclitaxel-Eluting Coronary Stent System (P030025)
• TAXUS® Liberté® Paclitaxel-Eluting Coronary Stent System (P060008)
• ION™ Paclitaxel-Eluting Platinum Chromium Coronary Stent System (P100023)
• V-Flex Plus™ Paclitaxel Coated Stent

Submission Summary (Full Text)

{0}

PMA P100022: FDA Summary of Safety and Effectiveness Data

# Summary of Safety and Effectiveness Data (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Drug-Eluting Peripheral Stent

Device Trade Name: Zilver® PTX® Drug-Eluting Peripheral Stent

Applicant's Name and Address: Cook Incorporated
750 Daniels Way
Bloomington, IN 47404

Date of Panel Recommendation: October 13, 2011

Premarket Approval Application (PMA) Number: P100022

Date of FDA Notice of Approval: November 14, 2012

## II. INDICATIONS FOR U

The Zilver® PTX® Drug-Eluting Stent is indicated for improving luminal diameter for the treatment of de novo or restenotic symptomatic lesions in native vascular disease of the above-the-knee femoropopliteal arteries having reference vessel diameter from 4 mm to 9 mm and total lesion lengths up to 140 mm per limb and 280 mm per patient.

## III. CONTRAINDICATIONS

Women who are pregnant, breastfeeding, or plan to become pregnant in the next 5 years should not receive a Zilver PTX 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.

page 1

{1}

PMA P100022: FDA Summary of Safety and Effectiveness Data
page 2

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Zilver PTX Drug-Eluting Peripheral Stent labeling (Instructions for Use).

# V. DEVICE DESCRIPTION

The Zilver PTX Drug-Eluting Peripheral Stent (Zilver PTX stent) is a self-expanding nitinol stent coated on its outer surface with the drug paclitaxel (without any polymer, binder, or excipient) at a dose density of $3\ \mu\mathrm{g}/\mathrm{mm}^2$.

## Device Component Description

The Zilver PTX stent is preloaded in a 6 Fr delivery system. Upon deployment, the Zilver PTX stent is designed to establish and maintain patency in the stented region. To facilitate fluoroscopic visualization of the stent, 4 radiopaque gold markers are positioned on each end of the device (Figure 1).

Figure 1: Photograph of the Zilver stent

The delivery system is available in $80\ \mathrm{cm}$ and $125\ \mathrm{cm}$ lengths and is compatible with a 0.035 inch wire guide (Figure 2). The delivery system is identical to that used with the currently approved Zilver Vascular Stent (P050017).

{2}

Figure 2: Schematic drawing of the Zilver PTX stent and delivery system

Table 1 shows the available diameters and lengths of the Zilver PTX stent.

Table 1: Sizes of Zilver PTX stents

| Stent Outer Diameter (mm) | Stent Length (mm) | | | | |
| --- | --- | --- | --- | --- | --- |
| | 20 | 30 | 40 | 60 | 80 |
| 6 | ✓ | ✓ | ✓ | ✓ | ✓ |
| 7 | ✓ | ✓ | ✓ | ✓ | ✓ |
| 8 | ✓ | ✓ | ✓ | ✓ | ✓ |

# Drug Component Description

Paclitaxel is extracted from the bark, branches, or needles of the yew tree, then purified and concentrated by column chromatography, crystallization, and recrystallization. Zilver PTX stents are coated with paclitaxel API (active pharmaceutical ingredient) using a proprietary process. No excipients, polymers, carriers, binding agents, other materials, or other device modifications are involved. Paclitaxel is the same API as used in the currently approved TAXUS® Express²® Paclitaxel-Eluting Coronary Stent System (P030025), TAXUS® Liberté® Paclitaxel-Eluting Coronary Stent System (P060008), and ION™ Paclitaxel-Eluting Platinum Chromium Coronary Stent System (P100023). The chemical description of paclitaxel is provided in Figure 3.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{3}

# Paclitaxel

- Synonyms: Taxol, Taxol A, Hunxol I, Paclitaxelum
- IUPAC systematic name: $\beta$ -(benzoylamino)- $\alpha$ -hydroxy-,6,12b-bis(acetyloxy)-12-(benzoyloxy) 2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca(3,4)benz(1,2-b)oxet-9-yl ester,(2aR-(2a-α,4-β,4a-β,6-β,9-α(α-R*,β-S*),11-α,12-α,12a-α,2b-α))-benzenepropanoic acid
CAS registry number: 33069-62-4
Chemical formula: $\mathrm{C_{47}H_{51}NO_{14}}$
Structure of paclitaxel:

Figure 3: Chemical description of paclitaxel

The exact mechanism by which a Zilver PTX stent affects neointimal production has not been established. Paclitaxel is known to bind to microtubules and inhibit their molecular disassembly into tubulin, thus arresting mitosis. This action can prevent the smooth muscle cell proliferation and migration known to occur during the restenotic process in arteries. Several studies in animal models have shown that paclitaxel applied locally reduces restenosis by inhibiting smooth muscle cell proliferation and neointimal hyperplasia. Clinical studies of the TAXUS® stent and the V-Flex Plus™ Paclitaxel Coated Stent have demonstrated that paclitaxel reduces restenosis in coronary vasculature.

Table 2 presents the stent sizes and the nominal total quantity of paclitaxel on each stent based on the established dose density of $3\mu \mathrm{g} / \mathrm{mm}^2$

PMA P100022: FDA Summary of Safety and Effectiveness Data

{4}

Table 2: Paclitaxel total quantity by stent size (for dose density of $3\mu \mathrm{g} / \mathrm{mm}^2$

| Stent Size (diameter x length, mm) | Total Paclitaxel (μg/stent) |
| --- | --- |
| 6 x 20 | 174 |
| 7 x 20 | 174 |
| 8 x 20 | 180 |
| 6 x 30 | 261 |
| 7 x 30 | 261 |
| 8 x 30 | 270 |
| 5 x 40 | 390 |
| 6 x 40 | 390 |
| 7 x 40 | 390 |
| 8 x 40 | 360 |
| 6 x 60 | 564 |
| 7 x 60 | 564 |
| 8 x 60 | 540 |
| 6 x 80 | 738 |
| 7 x 80 | 738 |
| 8 x 80 | 762 |

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the treatment of superficial femoral and proximal popliteal artery atherosclerotic disease:

Non-invasive treatment (exercise and/or drug therapy)
- Minimally invasive treatment (balloon angioplasty, endovascular stent placement of a non-drug-coated stent, directional atherectomy)
- Surgical treatment (surgical bypass)

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 Zilver PTX stent is commercially available in the following countries:

Afghanistan, Algeria, Albania, Andorra, Argentina, Austria, Bahrain, Belgium, Belarus, Benin, Bosnia-Herzegovina, Botswana, Brazil, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Chile, Congo Dem. Rep., Congo Republic, Cyprus, Czech Republic, Denmark, Dom. Rep., Equatorial Guinea,

PMA P100022: FDA Summary of Safety and Effectiveness Data

{5}

Estonia, Ethiopia, Finland, former Yugoslav Republic, France, Gabon, Gambia, Ghana, Germany, Greece, Guinea, Hong Kong, Hungary, Iceland, Iran, Ireland, Italy, Jordan, Kenya, Latvia, Lebanon, Liechtenstein, Lithuania, Luxembourg, Madagascar, Malawi, Malaysia, Mali, Malta, Mauritania, Mauritius, Moldova, Monaco, Morocco, Mozambique, New Zealand, Niger, Nigeria, the Netherlands, Norway, Oman, Pakistan, Peru, Poland, Portugal, Qatar, Romania, Russia, Rwanda, San Marino, Saudi Arabia, Senegal, Serbia Montenegro, Sierra Leone, Singapore, Somalia, South Africa, South Korea, Slovakia, Slovenia, Spain, Sweden, Switzerland, Taiwan, Tanzania, Thailand, Togo, Tunisia, Turkey, UAE, Uganda, UK, Ukraine, Vatican City, Yemen, Zambia

As of May 31, 2011, approximately 4,472 Zilver PTX stents have been distributed outside the U.S. No products have been withdrawn from the market in any country for any reason.

## 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:

- Allergic reaction to anticoagulant and/or antithrombotic therapy or contrast medium
- Allergic reaction to nitinol
- Arterial aneurysm
- Arterial rupture
- Arterial thrombosis
- Arteriovenous fistula
- Atheroembolization (Blue Toe Syndrome)
- Death
- Embolism
- Hematoma/hemorrhage
- Hypersensitivity reactions
- Infection
- Infection/abscess formation at access site
- Ischemia requiring intervention (bypass or amputation of toe, foot, or leg)
- Pseudoaneurysm formation
- Renal failure
- Restenosis of the stented artery

PMA P100022: FDA Summary of Safety and Effectiveness Data

{6}

- Stent embolization
- Stent malapposition
- Stent migration
- Stent strut fracture
- Vessel perforation or rupture
- Worsened claudication/rest pain

Although systemic effects are not anticipated, refer to the Physicians’ Desk Reference for more information on the potential adverse events observed with paclitaxel.

Potential adverse events, not described in the above source, may be unique to the paclitaxel drug coating:

- Allergic/immunologic reaction to the drug coating
- Alopecia
- Anemia
- Blood product transfusion
- Gastrointestinal symptoms
- Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia)
- Hepatic enzyme changes
- Histologic enzyme changes
- Histologic changes in vessel wall, including inflammation, cellular damage, or necrosis
- Myalgia/arthralgia
- Myelosuppression
- Peripheral neuropathy

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

## IX. SUMMARY OF PRE-CLINICAL STUDIES

### A. Laboratory Studies

#### Biocompatibility

A thorough panel of biocompatibility testing was performed on the Zilver PTX stent and delivery system in accordance with ISO 10993 and 21 CFR 58 Good Laboratory Practice (GLP) requirements to demonstrate that the components are

PMA P100022: FDA Summary of Safety and Effectiveness Data

{7}

non-toxic. Specifically, the Zilver PTX stent was assessed by tests considered appropriate under ISO 10993-1 for a permanent (&gt;30 days) implantable blood-contacting device. Similarly, biocompatibility of the Zilver PTX delivery system was assessed by tests considered appropriate under ISO 10993-1 for a limited-contact (&lt;24 hours) externally communicating device within circulating blood.

Table 3 and Table 4 summarize the test results for the Zilver PTX stent and delivery system, respectively.

Table 3: Summary of biocompatibility testing on Zilver PTX stent

| Test Name | Purpose of Test | Test Results |
| --- | --- | --- |
| Subchronic Intravenous Toxicity Study (Aqueous extract) | Determine whether the test article would cause systemic toxicity | No evidence of systemic toxicity from the test article extracts injected intravenously into rats |
| In vitro Hemolysis Study (Modified ASTM-Extraction Method) | Determine whether test article would cause in vitro hemolysis | The test article extract was considered to be nonhemolytic |
| In vitro Hemolysis Study (Direct contact) | Determine whether test article direct contact would cause in vitro hemolysis | The test article in direct contact was considered to be hemocompatible |
| Cytotoxicity Study Using the ISO Elution Method (1X MEM Extract) | Determine whether test article would cause cytotoxicity and cell lysis | The test article extract showed no evidence of causing cell lysis or toxicity |
| ISO Muscle Implantation Study-2 Week | Determine the potential for toxic response to test articles implanted in direct contact with muscle tissue | No evidence of macroscopic or microscopic reaction to the implanted test article |
| ISO Muscle Implantation Study-12 Week | | |
| C3a Complement Activation Assay (Serum extract) | Evaluate the test article's potential to activate the C3a complement system | The test article extract was considered to be non activator of the complement system |
| Plasma Recalcification Time Coagulation Study (Plasma extract) | Determine whether test article would cause a change in degree of inhibition or promotion of clotting time | The test article extract had no significant effect on recalcification time compared to the negative control |
| USP and ISO Systemic Toxicity Study (Aqueous and cottonseed oil extract) | Determine whether the test article would cause acute systemic toxicity | There was no mortality or evidence of significant systemic toxicity over the 72 hour test period from the test article extracts compared to the control blank extracts |
| ISO Intracutaneous Study (Aqueous and sesame oil extract) | Determine whether test article would cause local dermal irritation or toxic effects | There was no evidence of significant irritation over the 72 hour test period from the test article extracts injected intracutaneously into rabbits compared to the control blank extracts |
| Genotoxicity: Bacterial Reverse Mutation Study (DMSO Extract) | Determine whether test article would cause mutagenic changes in S. | The test article extract was considered non-mutagenic to S. typhimurium and E. coli tester |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{8}

PMA P100022: FDA Summary of Safety and Effectiveness Data
page 9

| Test Name | Purpose of Test | Test Results |
| --- | --- | --- |
| Genotoxicity: Bacterial Reverse Mutation Study (Saline Extract) | typhimurium and E. coli strains | strains |
| Genotoxicity: In vitro Chromosomal Aberration Study in Mammalian Cells (McCoy’s 5A medium extract ) | Determine whether test article would cause genotoxicity in Chinese hamster ovary (CHO) cells | The test article extract was considered non-mutagenic to CHO cells under both the metabolic activated and non-activated conditions |
| Genotoxicity: In vivo mouse peripheral blood micronucleus study (Saline extract) | Determine the potential of the test article to cause in vivo genotoxicity | The saline test article extract did not induce micronuclei formation, whereas the sesame oil test article extract induced micronuclei formation. Appropriate justification based on the exposure route and paclitaxel quantity delivered from Zilver PTX stent implantation was provided to ensure that this result was not considered to be a clinical concern |
| Genotoxicity: In vivo mouse peripheral blood micronucleus study (Sesame oil extract) | | |
| ISO Maximization Sensitization Study (Aqueous and sesame oil extract) | Investigate the potential for delayed dermal contact sensitization | The test article extracts showed no evidence of causing delayed dermal contact sensitization in the guinea pig |
| USP Pyrogen Study – Material Mediated | Determine whether the test article would induce a pyrogenic response following intravenous injection | The test article extract was considered as non-pyrogenic. The rise in temperature during the 3 hour observation period after extract injection in rabbits was within acceptable USP limits |
| In vivo Thromboresistance/ In vivo Thrombogenicity | Determine whether the placement of test article would cause thrombosis during simulated clinical use | Thrombogenicity evaluated as part of the in vivo animal studies showed no evidence of thromboses in vessels implanted with Zilver® PTX™ stents |

{9}

Table 4: Summary of biocompatibility testing on Zilver PTX stent delivery system

| Test Name | Purpose of Test | Test Results |
| --- | --- | --- |
| In vitro Hemolysis Study (Modified ASTM-Extraction Method) | Determine whether test article would cause in vitro hemolysis | The test article extract was considered to be nonhemolytic |
| Cytotoxicity Study Using the ISO Elution Method (1X MEM Extract) | Determine whether test article would cause cytotoxicity and cell lysis | The test article extract showed no evidence of causing cell lysis or toxicity |
| USP and ISO Systemic Toxicity Study (Aqueous and cottonseed oil extract) | Determine whether the test article would cause acute systemic toxicity | There was no mortality or evidence of significant systemic toxicity over the 72 hour test period from the test article extracts compared to the control blank extracts |
| ISO Intracutaneous Study (Aqueous and cottonseed oil extract) | Determine whether test article would cause local dermal irritation or toxic effects | There was no evidence of significant irritation over the 72 hour test period from the test article extracts injected intracutaneously into rabbits compared to the control blank extracts |
| Genotoxicity: Bacterial Reverse Mutation Study (DMSO Extract) | Determine whether test article would cause mutagenic changes in S. typhimurium and E. coli strains | The test article extract was considered non-mutagenic to S. typhimurium and E. coli tester strains |
| ISO Maximization Sensitization Study (Aqueous and cottonseed oil extract) | Investigate the potential for delayed dermal contact sensitization | The test article extracts showed no evidence of causing delayed dermal contact sensitization in the guinea pig |
| USP Pyrogen Study – Material Mediated | Determine whether the test article would induce a pyrogenic response following intravenous injection | The test article extract was considered as non-pyrogenic. The rise in temperature during the 3 hour observation period after extract injection in rabbits was within acceptable USP limits |

Evidence of safety in terms of chronic toxicity, carcinogenicity, and reproductive toxicity studies of the Zilver PTX stent, was provided based on extensive clinical history of the stent materials, no chemicals of concern from the stent and coating process, and small starting quantities of the paclitaxel drug coating.

The test results show that the Zilver PTX stent and delivery system are biocompatible and non-pyrogenic, thereby indicating that the Zilver PTX stent is safe and acceptable for clinical use.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{10}

# Non-Clinical Testing

Comprehensive in vitro laboratory testing was performed on the Zilver PTX stent and delivery system to verify that the performance attributes are sufficient for the device to perform as intended and minimize the risk of adverse events under anticipated clinical conditions. This test plan was developed in accordance with FDA "Guidance for Industry and FDA Staff: Non-clinical tests and recommended labeling for intravascular stents and associated delivery systems".

Under circumstances where in vitro non-clinical laboratory tests were conducted on the uncoated, bare Zilver stents, appropriate rationale was provided based on the stent platform being unchanged and the evaluation of the uncoated stent being fully representative of the coated stent for the purpose of these tests. Additional testing was conducted to support the integrity and stability of the coating on the Zilver PTX stent as shown in Section D: Coating testing and Section F: Stability testing, respectively.

The testing detailed in Table 5 verified that the Zilver PTX stent and delivery system met their product performance and design specifications and would perform as intended under anticipated clinical conditions.

Table 5: Summary of in vitro testing of the Zilver PTX stent and delivery system

| Test | Description of Test | Specification/ Acceptance Criteria | Test Results |
| --- | --- | --- | --- |
| Corrosion resistance | Testing was performed in accordance with ASTM F2129 to demonstrate that the Zilver PTX stents will be adequately able to resist corrosion following implantation. | Breakdown potential (EB) > 300 mV | The device met the established acceptance criteria. |
| Fretting corrosion | Testing was performed in accordance with ASTM F2129 to demonstrate that overlapped Zilver PTX stents after 3 month and 10 year simulated use will be adequately able to resist fretting corrosion following implantation. | | The device met the established acceptance criteria. |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{11}

| Test | Description of Test | Specification/ Acceptance Criteria | Test Results |
| --- | --- | --- | --- |
| Magnetic Resonance Imaging (MRI) compatibility | Testing was performed to evaluate the safety and compatibility of the Zilver PTX stent by assessment of the magnetic field interactions (ASTM F2052), MRI-related heating (ASTM F2182) and image artifacts (ASTM F2119) at 1.5 Tesla and 3 Tesla field strengths. | Magnetically induced deflection of the test article should be less than 45° (as specified in ASTM F2052) and the presence of the stent should not possess an additional unacceptable risk to patients when subjected to 1.5 T and 3 T MRI field strengths. | The device was established as MR Conditional. |
| Percent vessel covered surface area | Calculation of the percent vessel surface area covered by the expanded Zilver PTX stent following deployment | Characterization study | The vessel surface area covered by the device ranged between 10% to 21% |
| Tensile testing of stent bars | Characterization of the ultimate tensile strength and tensile strain at failure for the Zilver PTX stent strut | Characterization study | The stent axial bar tensile testing results met the specification for tensile properties of the raw nitinol tubing used for the Zilver PTX stent. |
| Delivery system profile | Testing was performed to evaluate the maximum outer diameter of the Zilver PTX delivery system and to verify that the outer diameters of the delivery system would be adequate for the intended use with the appropriate sized guiding catheter. | Maximum Outer diameter ≤ 2.11 mm (≤ 0.083 inches) | The device met the established acceptance criteria. |
| Ease of access | Testing was performed to evaluate the advancement of the Zilver PTX stent and delivery system over the wire guide, followed by stent deployment and withdrawal of the delivery system. | The Zilver PTX stent and delivery system should easily advance over the 0.035" wire guide and be radiographically visible, followed by easy withdrawal of the delivery system. | The device met the established acceptance criteria. |
| Deployment accuracy | Testing was performed to evaluate the ability of the delivery system to accurately deploy the Zilver PTX stents. | Stent must deploy within ± 4 mm of the target | The device met the established acceptance criteria |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{12}

PMA P100022: FDA Summary of Safety and Effectiveness Data
page 13

| Test | Description of Test | Specification/ Acceptance Criteria | Test Results |
| --- | --- | --- | --- |
| Deployment force | Testing was performed to evaluate the force required to deploy the Zilver PTX stents from the delivery system. | Deployment force must be < 32 N | The device met the established acceptance criteria |
| Stent length and length change | Testing was performed to evaluate the Zilver PTX stent length and length change following deployment. | Deployed stent length must be within + 2/-5 mm of nominal, labeled length and change in length between undeployed and deployed stents must be within ± 25% | The device met the established acceptance criteria |
| Stent diameter | Testing was performed to evaluate diameter and uniformity of diameter at three locations (proximal, middle and distal) on the Zilver PTX stent following deployment. | Stent Diameter must be within ± 0.3 mm of the nominal diameter for 5-9 mm diameter stents and within ± 0.4 mm of the nominal diameter for 10 mm diameter stents | The device met the established acceptance criteria |
| Stent integrity | Testing was performed to evaluate the integrity of the Zilver PTX stents following deployment. | No cracks or fractures visible at 50 to 63X magnification | The device met the established acceptance criteria |
| Radial force | Testing was performed to evaluate the normalized radial force exerted by the Zilver PTX stent as a function of the stent diameter. | At operating diameter (1 mm less than nominal diameter of the stent) radial force should be between 0.14 N/mm and 0.62 N/mm | The device met the established acceptance criteria |
| Flex/Kink evaluation | Testing was performed to evaluate the flex/kink performance of the Zilver PTX stent and delivery system. | Minimum kink radius Stent = 8.5 mm Delivery system = 19 mm | The device met the established acceptance criteria |
| Crush resistance | Testing was performed to evaluate the resistance of the Zilver PTX stent to crushing | Stent diameter must be within ± 0.3 mm of the nominal diameter for 5-9 mm diameter stents and within ± 0.4 mm of the nominal diameter for 10 mm diameter stents | The device met the established acceptance criteria |
| Finite Element Analysis | Testing was performed to evaluate the fatigue characteristics of non-overlapped and overlapped Zilver PTX stent models under pulsatile and non-pulsatile loading conditions. | Safety factor > 1 | The device met the established acceptance criteria |

{13}

| Test | Description of Test | Specification/ Acceptance Criteria | Test Results |
| --- | --- | --- | --- |
| In vitro fatigue | Testing was performed to evaluate fatigue characteristics (equivalent to 10 years) of non-overlapped and overlapped Zilver PTX stents under pulsatile and non-pulsatile loading conditions. | For Pulsatile loading No stent fractures after 100 million cycles and the stent should remain as one connected structure after 400 million cycles For Non-pulsatile loading Endurance limit (i.e. 10 years of non-pulsatile loading with no evidence of stent fractures) for axial, bending or torsional loading conditions must meet or exceed the clinically-relevant loading conditions | The device met the established acceptance criteria |
| Particulate matter testing | Testing was performed to evaluate the number of particles ≥ 10 μm and ≥ 25 μm in size associated with: • overexpanded (unconstrained) deployment of Zilver PTX stents; • simulated-use tracking and deployment of non-overlapped and overlapped Zilver PTX stents with continuous flow; • non-overlapped and overlapped Zilver PTX stents during pulsatile fatigue with continuous flow; and • non-overlapped and overlapped Zilver PTX stents during axial fatigue with continuous flow. | This testing was performed for characterization only | Characterization of the amount of particulate matter generated under conditions of unconstrained deployment (overexpansion), simulated use, pulsatile fatigue, and axial fatigue was performed for Zilver PTX stents |
| Delivery system tensile strength | Testing was performed to evaluate the force at break for different bonds between relevant components of the Zilver PTX delivery system | Various acceptance criteria for bonds in delivery system | The device met the established acceptance criteria |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{14}

# B. Animal Studies

A series of animal studies was conducted to evaluate safety, proof of concept, and overall product performance. Non-clinical in vivo testing included 413 stents tested in 180 animals to evaluate the safety and performance of the Zilver PTX stent in porcine arteries for up to six months. All the animal studies were conducted in accordance with 21 CFR 58 (Good Laboratory Practices). The animal studies performed and the acceptable study endpoints to support product safety and performance are summarized in Table 6.

Table 6: Zilver PTX stent non-clinical animal studies summary

| Test Name | Test Article Size: Dose Density (clinical dose = 3 μg/mm2) | Study Endpoints | Met Endpoints? |
| --- | --- | --- | --- |
| One-, Three- and Six-month Animal Study of Pivotal Coating Doses in Domestic Swine. GLP: Yes. | 10 x 80 mm: 0, 3, 9 μg/mm2 | Effects of non-overlapping stents at sub-clinical, clinical, and up to 4X the clinical dose density. • Evaluations for local effects included: ○ Quantitative angiography ○ Quantitative histomorphometry ○ Semi-quantitative and qualitative histopathology • Evaluations for systemic and regional effects included: ○ Complete necropsy with detailed evaluation of downstream, hind limb tissues ○ Hematology and serum chemistry • Additional evaluations included: ○ Animal health ○ Delivery system performance and stent deployment ○ Stent integrity | Yes |
| One-, Three- and Six-month Animal Study of Additional Coating Doses in Domestic Swine. GLP: Yes. | 10 x 80 mm: 2, 4, 12 μg/mm2 | | Yes |
| One-month Animal Study of Overlapped Stents in Domestic Swine. GLP: Yes. | 7 x 30 mm: 0, 3 μg/mm2 | Effects of overlapping stents at clinical dose density. • Evaluations for local effects included: ○ Quantitative angiography ○ Quantitative histomorphometry ○ Semi-quantitative and qualitative histopathology • Evaluations for systemic and regional effects included: ○ Complete necropsy with detailed evaluation of downstream, hind limb tissues ○ Hematology and serum chemistry • Additional evaluations included: ○ Animal health ○ Delivery system performance and stent deployment ○ Stent integrity | Yes |
| Three-month Animal Study of Overlapped Stents in Domestic Swine. GLP: Yes. | 7 x 30 mm: 0, 3 μg/mm2 | | Yes |
| Six-month Animal Study of Overlapped Stents in Miniature Swine. GLP: Yes. | 6 x 30 mm: 0, 3 μg/mm2 | | Yes |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{15}

| Test Name | Test Article Size: Dose Density (clinical dose = 3 μg/mm2) | Study Endpoints | Met Endpoints? |
| --- | --- | --- | --- |
| One-month Overdose Study of Regional and Systemic Effects of Coated Stents in Domestic Swine. GLP: Yes. | 6 x 20 mm: 12 μg/mm210 x 40 mm &14 x 40 mm: 9 μg/mm2 | Regional and systemic safety evaluation of response to 3X overdose (per animal and per limb) for the maximum number of stents allowed in the clinical trial. • Qualitative angiography • Complete necropsy with detailed evaluation of downstream, hindlimb tissues • Hematology and serum chemistry • Animal health • Delivery system performance and stent deployment | Yes |
| Twenty-four Hour Pharmacokinetic Study of Coated Stents in Domestic Swine. GLP: Yes. | 6 x 20 mm: 3 μg/mm2 | Acute pharmacokinetic evaluation of stents at clinical dose density. • Systemic paclitaxel levels • Complete necropsy • Hematology and serum chemistry | Yes |
| Two-month Pharmacokinetic Study of Coated Stents in Domestic Swine. GLP: Yes. | 6 x 20 mm: 3 μg/mm2 | Long-term pharmacokinetic evaluation of stents at clinical dose density. • Local, regional, and systemic paclitaxel levels • Complete necropsy • Hematology and serum chemistry | Yes |
| Acute Performance of Long Stents and Delivery Systems in Domestic Swine. GLP: Yes | 8 x 140 mm: 0 μg/mm2 | Acute performance evaluation of long stent and delivery system. • Delivery system performance and stent deployment • Stent integrity following tracking and deployment • Vessel injury following tracking and deployment | Yes |

These comprehensive in vivo animal studies, including 413 stents tested in 180 animals and up to 4X the clinical dose density and total dose, showed no safety problems, complete vessel healing without negative sequelae, and no regional (downstream) or systemic effects associated with the Zilver PTX stents. Additionally, pharmacokinetic studies indicated rapid delivery of paclitaxel from the stent to the vessel wall (approximately $95\%$ by 24 hours), persistence of paclitaxel in the vessel wall for approximately 2 months, minimal paclitaxel delivered systemically, and no paclitaxel remaining in the plasma 10 hours after stent implantation. Confirmatory testing of the longest Zilver stents and delivery systems demonstrated that stents and delivery systems were tracked, the stents deployed, and the delivery systems withdrawn without difficulty or incident, and with no damage to the stents or injury to the vessels.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{16}

Overall, the animal studies have demonstrated the non-clinical safety of the Zilver PTX stent in the animal model at multiple time points. The Zilver PTX incorporates a drug loading of 3 ug/mm2 and appears to elicit similar biologic responses as the bare metal Zilver stent when implanted in the pig model. Because the animal studies were limited to obtaining sufficient overdose data to support the safety of maximum of two overlapped 80 mm Zilver PTX stents per limb with a maximum stented length of 280 mm per patient, conclusions regarding the non-clinical safety of the Zilver PTX stent could not be drawn for lesion length greater than 140 mm per limb. The stented lengths in the animal studies are consistent with the lesion lengths specified for treatment in the pivotal clinical trial protocol. The results of the animal testing of the Zilver PTX stent thereby support a reasonable assurance of device safety and performance of the stented lengths tested in the randomized trial.

## C. Additional Studies

### Coating Testing

The coating characterization test methods summarized in Table 7 were developed to set specifications for the Zilver PTX stent.

Table 7: Coating and drug component characterization testing

| Test | | Description of Test |
| --- | --- | --- |
| Chemical analysis (paclitaxel) | | Drug substance was tested for identity and to ensure conformity to incoming specifications |
| In-process testing | Whole-stent paclitaxel content | An assay was conducted to determine the whole-stent paclitaxel content |
| | Intra-stent coating uniformity | An assay was conducted to characterize the uniformity of coating along the length of the Zilver PTX stent |
| | Coated stent appearance | A visual inspection was conducted to determine the quality of the stent coating |
| Finished product testing | Coated stent appearance (after loading, packaging, sterilization, and deployment) | A visual inspection was conducted to determine the quality of the stent coating after loading the stent into the delivery system, packaging, sterilization, and deployment |
| | Assay (potency) | An assay was conducted to quantitatively determine the total amount of paclitaxel on the Zilver PTX stent |
| | Identity | An assay was conducted to determine the retention time of the major peak of the paclitaxel in the chromatogram |
| | Content uniformity | An assay was conducted to verify the content uniformity of the paclitaxel coating from stent to stent |
| | Impurities/degradants | An assay was conducted to quantitatively determine the type and amount of impurities and degradation products of the Zilver PTX stent |
| | In vitro release | An assay was developed to measure the in vitro release rate of paclitaxel from the Zilver PTX stent |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{17}

| Particulate matter | Particulate levels were measured for the Zilver PTX stent following tracking and deployment |
| --- | --- |

# Chemistry, Manufacturing, and Control (CMC) Testing

As part of the CMC testing, and where applicable, the USP, EP, and International Conference on Harmonization (ICH) Guidelines were referenced during development of the release tests for the Zilver PTX stents. Each batch of finished devices underwent CMC release tests summarized in Table 8.

Table 8: Zilver PTX release tests

| Test | | Description of Test | Test Results |
| --- | --- | --- | --- |
| Finished product testing | Coated stent appearance (after loading, packaging, sterilization, and deployment) | Visual inspection was conducted to verify that the Zilver PTX stent meets finished product coated stent appearance specification | The product met specifications for finished product coated stent appearance |
| | Assay (potency) | An assay was conducted to quantitatively verify that the total amount of paclitaxel on the Zilver PTX stent meets the finished product assay (potency) specification | The product met specifications for finished product assay (potency) |
| | Identity | An assay was conducted to verify that the identity of the paclitaxel on the Zilver PTX stent meets the finished product identity specification | The product met specifications for finished product identity |
| | Content uniformity | Multiple Zilver PTX stents were assayed to verify that the uniformity of the paclitaxel content on individual stents meets the finished product content uniformity specification | The product met specifications for finished product content uniformity |
| | Impurities/degradants | An assay was conducted to quantitatively verify that the type and the amount of impurities/degradants on the Zilver PTX stents meet the finished product impurity/degradant specification | The product met specifications for finished product impurity/degradant |
| | In vitro release | The in vitro release of paclitaxel from the Zilver PTX stent was measured to verify that the drug release profile meets the finished product in vitro release specification | The product met specifications for finished product in vitro paclitaxel release |
| | Particulate matter | Particulate matter levels for the Zilver PTX stent were measured to verify that the level of particulate matter meets the finished product particulate matter specification | The product met specifications for finished product particulate matter |

# Stability Testing

Coating stability studies were conducted according to USP, EP, and ICH guidelines to establish an expiration date/shelf life for the paclitaxel coating on the Zilver PTX stent. Stability testing evaluation of the coating included assay (potency), impurities/degradants, in vitro paclitaxel release, and particulate

PMA P100022: FDA Summary of Safety and Effectiveness Data

{18}

matter. Accelerated and thermal cycle stability testing evaluation of the coating included assay (potency) and impurities/degradants. Appropriate engineering tests were also performed on aged product to ensure that the Zilver PTX stent meets the acceptance criteria established for the non-aged devices throughout their shelf life. The data support a 6 month shelf life for the Zilver PTX stent and delivery system.

## Sterilization and Packaging

The Zilver PTX stent and delivery system were sterilized by a validated ethylene oxide (EtO) sterilization process to achieve a minimal sterility assurance level (SAL) of $10^{-6}$. The EtO and ECH residuals levels were in accordance with ISO 10993-7: 2008, Biological evaluation of medical devices-Ethylene oxide sterilization residual and the amount of bacterial endotoxins was verified to be within the specification limit for the Zilver PTX stent and delivery system.

The aged packaging evaluation under the worst case shipping simulation indicated that the packaging would remain acceptable for the shelf life of the Zilver PTX stent and delivery system.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of stenting with the Zilver PTX stent in the United States under IDE # G030251. A single arm clinical study provided additional evidence supporting the safety and effectiveness of the Zilver PTX stent in a broader patient population including more complex lesions. Data from these clinical studies were the basis for the PMA approval decision. A summary of the clinical study is presented below.

## A. Study Design

Patients were treated between March 21, 2005 and August 25, 2008. The database for this PMA reflected data collected through April 30, 2010 and included 479 patients. There were 55 investigational sites.

The Zilver PTX randomized study is a prospective, controlled, multi-center, multinational study enrolling patients in the United States, Japan, and Germany

PMA P100022: FDA Summary of Safety and Effectiveness Data

{19}

with de novo or restenotic native lesions of the above-the-knee femoropopliteal artery. Patients were randomized 1:1 to treatment with the Zilver PTX stent (treatment group) or with PTA (control group). Recognizing that balloon angioplasty may not be successful acutely, the trial design mandated provisional stent placement immediately after failure of balloon angioplasty in instances of acute PTA failure. Therefore, patients with suboptimal (failed) PTA underwent a secondary randomization (1:1) to stenting with either Zilver PTX or bare Zilver stents (Figure 4). This secondary randomization allows evaluation of the Zilver PTX stent compared to a bare metal stent.

Figure 4: Patient enrollment

The study was overseen by an independent data safety monitoring board (DSMB) comprised of physicians and a biostatistician. An independent CEC adjudicated major adverse events, including all patient deaths, and independent core laboratories provided uniformly defined imaging analysis.

1. Clinical Inclusion and Exclusion Criteria

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

- Patient has up to 2 documented stenotic or occluded atherosclerotic lesions (≤ 14 cm long, or ≤ 7 cm for the first 60 subjects enrolled) of the above-

PMA P100022: FDA Summary of Safety and Effectiveness Data
page 20

{20}

the-knee femoropopliteal artery, up to one in each limb, that meet all of the inclusion criteria and none of the exclusion criteria.

- Patient has reference vessel diameter of 4 - 9 mm.
- Patient has a de novo or restenotic lesion(s) with &gt; 50% stenosis documented angiographically and no prior stent in the target lesion.
- Patient has symptoms of peripheral arterial disease classified as Rutherford Category 2 or greater.
- Patient has a resting ABI &lt; 0.9 or an abnormal exercise ABI if resting ABI is normal. Patient with incompressible arteries (ABI &gt; 1.2) must have a TBI &lt; 0.8.

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

- Patient has significant stenosis (&gt; 50%) or occlusion of inflow tract (proximal ipsilateral, iliofemoral, or aortic lesions) not successfully treated before this procedure (success is measured as &lt; 30% residual stenosis).
- Patient has undergone an unsuccessful arterial interventional treatment of the legs (i.e., the treatment resulted in &gt; 30% residual stenosis of a treated lesion) within 30 days prior to the study procedure.
- Patient has experienced complications of an arterial access site in the legs within 30 days prior to the study procedure.
- Patient has any planned surgical or interventional procedure within 30 days after the study procedure.
- Patient has a planned procedure involving arterial interventional treatment of the study leg(s) within the 12-month follow-up period.
- Patient has had previous stenting of the target vessel.
- Patient lacks at least one patent vessel of runoff with &lt; 50% stenosis throughout its course.
- Patient has untreated angiographically-evident thrombus in the target lesion.
- Patient has a bypass graft with an anastomosis in the target vessel.
- Patient has lesions requiring atherectomy (or ablative devices), cutting balloons, cryoplasty balloons, or any other advanced device to facilitate stent delivery.

PMA P100022: FDA Summary of Safety and Effectiveness Data
page 21

{21}

Subjects eligible to be enrolled in the study had single or bilateral stenotic or occluded atherosclerotic lesions (≤ 14 cm long) of the above-the-knee femoropopliteal artery with a reference vessel diameter of 4 mm to 9 mm. Of the 479 patients enrolled, 238 were in the PTA control group and 241 were in the Zilver PTX treatment group. Five patients in the Zilver PTX group were enrolled as live cases (i.e., with no randomization) and are included in analyses of the as treated population but not the intent to treat or per protocol populations. Acute PTA failure was common, occurring in 120 patients in the control group, and these patients underwent a second randomization to provisional stenting with either Zilver PTX stents or bare Zilver stents.

## 2. Follow-up Schedule

All patients were scheduled to return for follow-up clinical assessment and ultrasound imaging prior to discharge, at 6 and 12 months, and annually thereafter. Additionally, x-rays were required prior to discharge and at 1, 3, and 5 years to assess stent integrity. Telephone contact was scheduled for 1, 3, 9, and 18 months. Patient subsets were assigned to a pharmacokinetic substudy and to an IVUS/angiography substudy.

Tables 10 – 13 detail the preoperative evaluations and postoperative objective parameters measured during the study. Adverse events and complications were recorded at all visits.

Table 10: Control group/PTA only follow-up

| Procedure | Up to 7 Days Before Procedure | During Procedure (including baseline and final) | After the Procedure before Hospital Discharge | 1 and 3 Months after the Procedure | 6 Months after the Procedure | 9 Months after the Procedure | 12 Months after the Procedure | 18 Months after the Procedure | Years 2-5 after the Procedure |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical Assessment, including ABI and Rutherford | ✓ | | ✓ | | ✓ | | ✓ | | ✓ |
| Walking and QOL Questionnaire | ✓ | | | | ✓ | | ✓ | | ✓ |
| Blood Test | ✓ | | ✓ | | | | | | |
| Angiography | | ✓ | | | | | ✓ | | |
| Ultrasound | | | ✓ | | ✓ | | ✓ | | ✓ |
| X-ray of the Stent | | | | | | | | | |
| IVUS | | | | | | | | | |
| Telephone Update | | | | ✓ | | ✓ | | ✓ | |

Rutherford not required after the procedure.
2 For patients randomized to the angiographic/IVUS substudy only.
3 For patients randomized to the ultrasound substudy only.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{22}

Table 11: Acute PTA failure/bare Zilver stent follow-up

| Procedure | Up to 7 Days Before Procedure | During Procedure (including baseline and final) | After the Procedure before Hospital Discharge | 1 and 3 Months after the Procedure | 6 Months after the Procedure | 9 Months after the Procedure | 12 Months after the Procedure | 18 Months after the Procedure | Years 2-5 after the Procedure |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical Assessment, including ABI and Rutherford | ✓ | | ✓ | | ✓ | | ✓ | | ✓ |
| Walking and QOL Questionnaires | ✓ | | | | ✓ | | ✓ | | ✓ |
| Blood Test | ✓ | | ✓ | | | | | | |
| Angiography | | ✓ | | | *2 | | | | |
| Ultrasound | | | ✓ | | ✓ | | ✓ | | ✓ |
| X-ray of the Stent | | | ✓ | | *2 | | ✓ | | ✓2 |
| IVUS | | | | | *2 | | | | |
| Telephone Update | | | | ✓ | | ✓ | | ✓ | |

1 Rutherford not required after the procedure.
2 X-ray at 3 and 5 years only; not required for the first 60 patients enrolled.
3 Additional requirements for the first 60 patients enrolled.

Table 12: Acute PTA failure/Zilver PTX stent follow-up

| Procedure | Up to 7 Days Before Procedure | During Procedure (including baseline and final) | After the Procedure before Hospital Discharge | 1 and 3 Months after the Procedure | 6 Months after the Procedure | 9 Months after the Procedure | 12 Months after the Procedure | 18 Months after the Procedure | Years 2-5 after the Procedure |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical Assessment, including ABI and Rutherford | ✓ | | ✓ | | ✓ | | ✓ | | ✓ |
| Walking and QOL Questionnaires | ✓ | | | | ✓ | | ✓ | | ✓ |
| Blood Test | ✓ | | ✓ | | ✓ | | ✓ | | ✓2 |
| Angiography | | ✓ | | | *2 | | | | |
| Ultrasound | | | ✓ | | ✓ | | ✓ | | ✓ |
| X-ray of the Stent | | | ✓ | | *2 | | ✓ | | ✓4 |
| IVUS | | *2 | | | *2 | | | | |
| Telephone Update | | | | ✓ | | ✓ | | ✓ | |

1 Rutherford not required after the procedure.
2 Blood tests required at 2-year follow-up only.
3 Additional requirements for the first 60 patients enrolled.
4 X-ray at 3 and 5 years only; not required for the first 60 patients enrolled.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{23}

Table 13: Treatment group/Zilver PTX stent follow-up

| Procedure | Up to 7 Days Before Procedure | During Procedure (including baseline and final) | After the Procedure before Hospital Discharge | 1 and 3 Months after the Procedure | 6 Months after the Procedure | 9 Months after the Procedure | 12 Months after the Procedure | 18 Months after the Procedure | Years 2-5 after the Procedure |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical Assessment, including ABI and Rutherford | ✓ | | ✓^{1} | | ✓ | | ✓ | | ✓ |
| Walking and QOL Questionnaires | ✓ | | | | ✓ | | ✓ | | ✓ |
| Blood Test | ✓ | | ✓^{3} | | ✓ | | ✓ | | ✓^{2} |
| Angiography | | ✓ | | | ✓^{4,5} | | ✓^{4} | | |
| Ultrasound | | | ✓ | | ✓ | | ✓ | | ✓ |
| X-ray of the Stent | | | ✓ | | •^{6} | | ✓ | | ✓^{5} |
| IVUS | | ✓^{4,5} | | | •^{6} | | ✓^{4} | | |
| Telephone Update | | | | ✓ | | ✓ | | ✓ | |

1 Rutherford not required after the procedure.
2 Blood tests required at 2-year follow-up only.
3 There will be an additional 3 blood draws for patients randomized to the PK substudy.
4 For patients randomized to the angiographic and IVUS substudy only.
5 X-ray at 3 and 5 years only; not required for the first 60 patients enrolled.
6 Additional requirements for the first 60 patients enrolled.

The key timepoints are shown below in the tables summarizing safety and effectiveness.

3. Clinical Endpoints

With regards to safety, the primary hypothesis was non-inferior (i.e., equivalent or superior) event-free survival (defined as freedom from the clinical events committee (CEC) adjudicated major adverse events of death, target lesion revascularization, target limb ischemia requiring surgical intervention or surgical repair of the target vessel, and freedom from worsening of the Rutherford classification by 2 classes or to class 5 or 6) at 12 months.

With regards to effectiveness, the primary hypothesis was superior primary patency at 12 months for the Zilver PTX treatment group compared to the PTA control group. Secondary analyses included evaluation of the effectiveness of the Zilver PTX stent compared to a bare metal stent.

With regards to success/failure criteria, the primary objective of the Zilver PTX randomized study was to demonstrate non-inferior (equivalent or superior) safety and superior effectiveness of the Zilver PTX stent compared to percutaneous balloon angioplasty (PTA) for the treatment of de novo or

PMA P100022: FDA Summary of Safety and Effectiveness Data

{24}

restenotic lesions of the above-the-knee femoropopliteal artery. The patients in the PTA control group included those with optimal PTA and suboptimal (failed) PTA that underwent a secondary randomization to stenting with either Zilver PTX or bare Zilver stents.

## B. Accountability of PMA Cohort

At the time of database lock, of 479 patients enrolled in PMA study, 97% of patients were available for analysis at the completion of the study, the 1-year post-operative visit.

Patient availability for study follow-up is summarized in Table 14.

PMA P100022: FDA Summary of Safety and Effectiveness Data
page 25

{25}

Table 14: Clinical and imaging follow-up data

| Follow-up | Eligible for Follow-up1 | Percent of Data Available | | | Events Occurring Before Next Visit | | | | Not Due for Next Visit (n) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Clinical Follow-up2 | Core Laboratory X-ray Follow-up | Core Laboratory Ultrasound Follow-up3 | Death | Withdrawn | Lost to Follow-up | Other Endpoint4 | |
| Control Group | | | | | | | | | |
| Procedure | 238 | 100.0% (238/238) | 97.5% (117/120)8 | 86.6% (206/238) | 2 | 3 | 0 | 1 | 0 |
| 6-month | 232 | 94.0% (218/232) | 76.5% (13/17)8,6 | 80.6% (187/232) | 2 | 4 | 2 | 2 | 0 |
| 12-month | 222 | 97.3% (216/222) | 76.0% (114/150)8 | 83.3% (185/222) | 4 | 5 | 0 | 3 | 0 |
| 2-year | 210 | 83.3% (175/210) | n/a8 | 66.7% (84/126)10 | 2 | 4 | 2 | 0 | 154 |
| 3-year | 48 | 91.7% (44/48) | n/a5,9 | 66.7% (14/21)10 | 1 | 1 | 0 | 0 | 22 |
| 4-year | 24 | 75.0% (18/24) | n/a8 | 66.7% (10/15)10 | 0 | 0 | 0 | 0 | 24 |
| Treatment Group | | | | | | | | | |
| Procedure | 2367 | 100.0% (236/236) | 96.2% (227/236) | 89.4% (211/236) | 0 | 1 | 1 | 0 | 0 |
| 6-month | 234 | 94.0% (220/234) | 86.2% (25/29)6 | 80.3% (188/234) | 9 | 4 | 4 | 0 | 0 |
| 12-month | 217 | 97.7% (212/217) | 84.3% (183/217) | 87.1% (189/217) | 9 | 4 | 3 | 3 | 0 |
| 2-year | 198 | 83.8% (166/198) | n/a8 | 51.0% (101/198) | 3 | 5 | 0 | 0 | 160 |
| 3-year | 30 | 86.7% (26/30) | n/a9 | 46.7% (14/30) | 0 | 0 | 1 | 0 | 13 |
| 4-year | 16 | 56.3% (9/16) | n/a8 | 43.8% (7/16) | 0 | 0 | 0 | 0 | 16 |

1 Eligible for follow-up = previous eligibility for follow-up – (previous death + withdrawn + LTF).
2 Includes cases with at least one of any of the following submitted: clinical form, death form, withdrawn form, or lost to follow-up form.
3 Includes only ultrasound studies considered diagnostic by the core lab.
4 Patients who reached an "other endpoint" include 5 patients whose site closed and therefore will not complete clinical follow-up, 2 patients who received a non-study stent during reintervention, 1 patient whose study lesion was bypassed, and 1 patient who moved but has not formally withdrawn from the trial.
5 Only patients implanted with stents (i.e., acute PTA failure) were required to have X-ray follow-up.
6 Only first 60 patients enrolled were required to have 6-month X-ray follow-up.
7 Five patients treated as live cases not included.
8 Patients were not required to have 2- and 4-year X-ray follow-up.
9 Three-year X-ray follow-up not required for first 60 patients enrolled.
10 Only patients implanted with stents or in the Duplex Ultrasound substudy were required to have 2-, 3-, or 4-year duplex ultrasound follow-up.

In summary, nearly all eligible patients were seen for their 12-month follow-up visit and more than 80% have been seen for their 2-year clinical follow-up visit.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{26}

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a peripheral arterial disease study performed in the US. Baseline patient characteristics were similar between the PTA control group and Zilver PTX treatment group. Demographics (Table 10) and medical history (Table 11) were similar for the two groups, with the only significant difference being a more frequent history of hypertension in the Zilver PTX group $(p = 0.02)$ . Similarly, baseline angiographic data, lesion location, and lesion characteristics indicated that the two groups were well matched, though lesions in the Zilver PTX treatment group had more severe calcification and inflow tract stenosis documented by core lab analysis (Tables 15 - 19).

Table 15: Demographics

| Demographic | Control Group | Treatment Group | Diff. (95% CI)1 | P-value2 |
| --- | --- | --- | --- | --- |
| Age (years) | 67.7 ± 10.6 (238) | 67.9 ± 9.6 (236) | -0.1 (-2.0, 1.7) | 0.88 |
| Gender | | | | |
| Male | 63.9% (152/238) | 65.7% (155/236) | -1.8 (-10.4, 6.8) | 0.70 |
| Female | 36.1% (86/238) | 34.3% (81/236) | 1.8 (-6.8, 10.4) | |
| Ethnicity | | | | |
| Asian | 14.1% (29/206) | 11.9% (25/210) | 2.2 (-4.3, 8.6) | |
| Black/African American | 11.2% (23/206) | 11.9% (25/210) | -0.7 (-6.9, 5.4) | 0.81 |
| Hispanic/Latino | 5.3% (11/206) | 7.1% (15/210) | -1.8 (-6.5, 2.8) | |
| White/Caucasian | 69.4% (143/206) | 69.0% (145/210) | 0.4 (-8.5, 9.2) | |
| Height (in) | 66.4 ± 4.4 (238) | 66.7 ± 3.6 (236) | -0.2 (-1.0, 0.5) | 0.55 |
| Weight (lbs) | 178.5 ± 44.3 (238) | 180.4 ± 40.0 (236) | -1.9 (-9.5, 5.8) | 0.62 |
| Body mass index | 28.2 ± 5.6 (238) | 28.4 ± 5.3 (236) | -0.2 (-1.2, 0.8) | 0.71 |

1 Confidence interval is the difference in means for continuous variables and difference in percentages for categorical variables.
${}^{2}P$ values are based on $t$ -test for continuous variables and Fisher's exact test for categorical variables.

Table 16: Medical history

| Condition | Control Group | Treatment Group | Diff. (95% CI)1 | P-value2 |
| --- | --- | --- | --- | --- |
| Diabetes | 42.0% (100/238) | 49.6% (117/236) | -7.6 (-16.5, 1.4) | 0.11 |
| Diabetes type | | | | |
| Type I | 13.0% (13/100) | 16.2% (19/117) | -3.2 (-12.6, 6.2) | 0.56 |
| Type II | 87.0% (87/100) | 83.8% (98/117) | 3.2 (-6.2, 12.6) | |
| Hypercholesterolemia | 69.7% (166/238) | 76.3% (180/236) | -6.5 (-14.5, 1.5) | 0.12 |
| Hypertension | 81.5% (194/238) | 89.0% (210/236) | -7.5 (-13.8, -1.1) | 0.02* |
| Carotid disease | 20.2% (48/238) | 18.2% (43/236) | 2.0 (-5.1, 9.0) | 0.64 |
| Renal disease | 10.5% (25/238) | 10.2% (24/236) | 0.3 (-5.2, 5.8) | >0.99 |
| Pulmonary disease | 16.0% (38/238) | 19.1% (45/236) | -3.1 (-9.9, 3.7) | 0.39 |
| Congestive heart failure | 10.5% (25/238) | 11.9% (28/236) | -1.4 (-7.0, 4.3) | 0.66 |
| Previous cardiac arrhythmia | 13.0% (31/238) | 10.6% (25/236) | 2.4 (-3.4, 8.2) | 0.47 |
| Previous MI | 17.2% (41/238) | 21.2% (50/236) | -4.0 (-11.0, 3.1) | 0.29 |
| Smoking status | | | | 0.70 |
| Never smoked | 15.5% (37/238) | 13.6% (32/236) | 2.0 (-4.4, 8.3) | |
| Quit | 51.7% (123/238) | 55.5% (131/236) | -3.8 (-12.8, 5.1) | |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{27}

Table 17: Baseline angiographic data (core lab reported)

| Baseline Angiographic Data | Control Group | Treatment Group | Diff. (95% CI)1 | P-value2 |
| --- | --- | --- | --- | --- |
| Stenosed lesion length (mm)3 | 53.2 ± 40.3 (248) | 54.6 ± 40.7 (242) | -1.3 (-8.5, 5.9) | 0.71 |
| Normal-to-normal Lesion length (mm)4 | 63.2 ± 40.5 (251) | 66.4 ± 38.9 (246) | -3.2 (-10.2, 3.8) | 0.36 |
| Proximal RVD (mm) | 5.0 ± 1.0 (249) | 5.1 ± 0.9 (242) | -0.05 (-0.2, 0.1) | 0.58 |
| Distal RVD (mm) | 5.0 ± 1.0 (249) | 5.0 ± 1.0 (242) | -0.01 (-0.2, 0.2) | 0.95 |
| MLD in lesion (mm) | 1.1 ± 0.9 (249) | 1.0 ± 0.9 (242) | 0.1 (-0.1, 0.2) | 0.38 |
| Percent diameter stenosis (%) | 78.4 ± 17.1 (249) | 79.8 ± 17.0 (242) | -1.3 (-4.4, 1.7) | 0.38 |

1 Confidence interval is the difference in means for continuous variables and difference in percentages for categorical variables.
${}^{2}P$ values are based on $t$ -test for continuous variables and Fisher’s exact test for categorical variables.
3 Tissue loss includes amputations, gangrene, and ischemic ulcers.
* Statistically significant.

Table 18: Lesion location

| Vessel | Control Group | Treatment Group | Diff. (95% CI)1 | P-value2 |
| --- | --- | --- | --- | --- |
| Left proximal SFA | 10.8% (27/251) | 8.9% (22/247) | 2.9 (-4.3, 10.1) | 0.63 |
| Right proximal SFA | 12.0% (30/251) | 10.9% (27/247) | | |
| Left proximal SFA/distal SFA | 3.6% (9/251) | 5.7% (14/247) | -2.1 (-6.7, 2.5) | |
| Right proximal SFA/distal SFA | 2.8% (7/251) | 2.8% (7/247) | | |
| Left distal SFA | 34.7% (87/251) | 30.4% (75/247) | -1.0 (-9.5, 7.4) | |
| Right distal SFA | 28.7% (72/251) | 34.0% (84/247) | | |
| Left distal SFA/popliteal artery | 0.4% (1/251) | 0.8% (2/247) | -1.3 (-4.3, 1.8) | |
| Right distal SFA/popliteal artery | 2.0% (5/251) | 2.8% (7/247) | | |
| Left popliteal artery | 2.0% (5/251) | 0.8% (2/247) | 1.5 (-2.1, 5.1) | |
| Right popliteal artery | 3.2% (8/251) | 2.8% (7/247) | | |

1 Confidence interval is the difference in means for continuous variables and difference in percentages for categorical variables.
${}^{2}P$ values are based on $t$ -test for continuous variables and Fisher’s exact test for categorical variables.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{28}

Table 19: Lesion characteristics

| Characteristics | | Control Group | Treatment Group | Diff. (95% CI)2 | P-value3 |
| --- | --- | --- | --- | --- | --- |
| Lesion class (TASC)1 | A | 36.0% (86/239) | 29.4% (69/235) | 6.6 (-1.8, 15.04) | 0.07 |
| | B | 25.9% (62/239) | 22.6% (53/235) | 3.4 (-4.3, 11.1) | |
| | C | 31.0% (74/239) | 42.6% (100/235) | -11.6 (-20.2, -3.0) | |
| | D | 7.1% (17/239) | 5.5% (13/235) | 1.6 (-2.8, 6.0) | |
| Accessibility | Readily accessible | 100% (215/215) | 100% (215/215) | 0 (0, 0) | N/A |
| | Moderate tortuosity | 0.0% (0/215) | 0.0% (0/215) | N/A | |
| | Excessive tortuosity | 0.0% (0/215) | 0.0% (0/215) | N/A | |
| Lesion angulation | Non-angulated | 95.2% (237/249) | 95.4% (228/241) | -0.3 (-4.0, 3.5) | >0.99 |
| | Moderate | 4.8% (12/249) | 4.6% (11/241) | 0.3 (-3.5, 4.0) | |
| Calcification | None | 4.8% (12/249) | 1.7% (4/241) | 3.2 (0.05, 6.3) | <0.01* |
| | Little | 38.2% (95/249) | 25.7% (62/241) | 12.4 (4.3, 20.6) | |
| | Moderate | 22.1% (55/249) | 35.3% (85/241) | -13.2 (-21.1, -5.3) | |
| | Severe | 34.9% (87/249) | 37.3% (90/241) | -2.4 (-10.9, 6.1) | |
| Other stenosis in artery | None | 51.4% (111/216) | 51.7% (107/207) | -0.3 (-9.8, 9.2) | 0.71 |
| | ≤ 50% | 34.3% (74/216) | 31.4% (65/207) | 2.9 (-6.1, 11.8) | |
| | > 50% | 14.4% (31/216) | 16.9% (35/207) | -2.6 (-9.5, 4.4) | |
| Inflow tract stenosis | None | 41.6% (96/231) | 37.1% (76/205) | 4.5 (-4.7, 13.7) | 0.03* |
| | ≤ 50% | 45.5% (105/231) | 40.5% (83/205) | 5.0 (-4.3, 14.3) | |
| | > 50% | 13.0% (30/231) | 22.4% (46/205) | -9.5 (-16.6, -2.3) | |
| Patent runoff vessels | 0 | 17.3% (26/150) | 14.8% (22/149) | 2.6 (-5.8, 10.9) | 0.47 |
| | 1 | 52.7% (79/150) | 47.7% (71/149) | 5.0 (-6.3, 16.3) | |
| | 2 | 21.3% (32/150) | 22.8% (34/149) | -1.5 (-10.9, 7.9) | |
| | 3 | 8.0% (12/150) | 14.1% (21/149) | -6.1 (-13.2, 1.0) | |
| Ulceration | | 19.0% (47/248) | 16.7% (40/240) | 2.3 (-4.5, 9.1) | 0.55 |

TASC lesion class was determined by the site and was not evaluated by the core lab.
2 Confidence interval is the difference in means for continuous variables and difference in percentages for categorical variables.
${}^{3}P$ values are based on $t$ -test for continuous variables and Fisher's exact test for categorical variables.
* Statistically significant.

In summary, lesions were similar between the PTA control group and Zilver PTX treatment group in nearly all parameters. The core lab data demonstrated significant differences in lesion calcification and inflow tract stenosis, with lesions in the Zilver PTX treatment group having more severe calcification and higher inflow tract stenosis. While statistically significant, these differences likely do not represent a clinically significant difference between lesions in the treatment and control groups. Moreover, these data indicate that if a difference in lesion characteristics exists, the Zilver PTX treatment group contains potentially more severe lesions and patients with more severe overall peripheral arterial disease—characteristics which would be expected to have an adverse (if any) effect on safety and effectiveness outcomes in the Zilver PTX treatment group.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{29}

# D. Safety and Effectiveness Results

# 1. Safety Results

The analysis of safety was based on the treatment (Zilver PTX) group of 223 patients available for the 12 month evaluation. The key safety outcomes for this study are presented below in Table 16. Adverse effects are reported in Tables 17 and 18.

The primary safety endpoint of non-inferior (i.e., equivalent or superior) safety for the Zilver PTX stent compared to PTA was met with a superior event-free survival rate at 12 months of $90.4\%$ for the Zilver PTX treatment group compared to $83.9\%$ for the PTA control group $(p = 0.01^{1})$ , as illustrated in Figure 5 and Table 16. The most common major adverse event was TLR (Table 17), which occurred approximately twice as often in the PTA group relative to the Zilver PTX group ( $16.1\%$ vs. $9.5\%$ , respectively; $p = 0.04$ ). No patient deaths were adjudicated by the CEC as related to the device or procedure. The benefit of the Zilver PTX stent was maintained through 24 months.

1 Adjusted for multiplicity
PMA P100022: FDA Summary of Safety and Effectiveness Data

{30}

Figure 5: Kaplan-Meier curves for event-free survival

Table 20: Kaplan-Meier estimates for event-free survival

| Months Post-procedure | Event-free Survival Estimate | | Standard Error | | Cumulative Failed | | Cumulative Censored | | Number Remaining | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Control (PTA) | Treatment (Zilver PTX) | Control (PTA) | Treatment (Zilver PTX) | Control (PTA) | Treatment (Zilver PTX) | Control (PTA) | Treatment (Zilver PTX) | Control (PTA) | Treatment (Zilver PTX) |
| 0 | 100.0% | 100.0% | 0.0% | 0.0% | 0 | 0 | 0 | 0 | 236 | 235 |
| 1 | 100.0% | 99.1% | 0.0% | 0.6% | 0 | 2 | 0 | 0 | 236 | 233 |
| 6 | 94.4% | 97.0% | 1.5% | 1.1% | 13 | 7 | 6 | 3 | 217 | 225 |
| 12 | 83.9% | 90.4% | 2.4% | 1.9% | 37 | 22 | 15 | 16 | 184 | 197 |
| 24 | 77.9% | 86.6% | 2.8% | 2.3% | 50 | 30 | 22 | 33 | 164 | 172 |

# Adverse effects that occurred in the PMA clinical study:

Table 21: Rates of individual major adverse events at 12 months

| Major Adverse Event | Control (PTA)1 | Treatment (Zilver PTX)1 | P-value | Diff. (95% CI)3 |
| --- | --- | --- | --- | --- |
| Clinically-driven TLR | 16.1% (36/223)2 | 9.5% (21/220) | 0.04 | (0.4, 12.79) |
| Worsening of Rutherford classification by 2 classes or to a class 5 or 6 | 0.9% (2/223)2 | 0.0% (0/220) | 0.49 | - |
| Amputation | 0.0% (0/223) | 0.5% (1/220) | 0.49 | - |

1 Denominator is the number of patients remaining free from MAE at 12 months plus the number that have experienced a MAE or died prior to 12 months.
2 One patient experienced a worsening Rutherford and a TLR and is included in both categories in this table.
3 Confidence interval is the difference in percentages.

Table 18 provides a summary of other adverse events through 24 months, not including major adverse events, occurring in the control and treatment groups. No patient deaths were adjudicated by the CEC as related to the study device or procedure.

Table 22: Adverse events

| Event Type | Control | | Treatment | |
| --- | --- | --- | --- | --- |
| | % (n/N) | Events | % (n/N) | Events |
| Occurring within 12 months of the study procedure | | | | |
| Death | 1.7% (4/236) | 4 | 3.4% (8/236) | 8 |
| Major Adverse Events | | | | |
| Clinically-driven TLR | 15.3% (36/236) | 36 | 8.9% (21/235) | 21 |
| Worsening of Rutherford classification by 2 classes or to a class 5 or 6 | 0.8% (2/236) | 2 | 0.0% (0/235) | 0 |
| Amputation | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Cardiovascular Events | | | | |
| Cardiac ischemia requiring intervention | 3.0% (7/236) | 7 | 3.8% (9/235) | 13 |
| Non-Q-Wave MI | 0.4% (1/236) | 1 | 0.9% (2/235) | 2 |
| Congestive heart failure | 0.8% (2/236) | 2 | 3.0% (7/235) | 7 |
| Refractory hypertension | 0.4% (1/236) | 1 | 0.0% (0/235) | 0 |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{31}

| | Control | | Treatment | |
| --- | --- | --- | --- | --- |
| Arrhythmia requiring intervention or new treatment | 1.7% (4/236) | 5 | 3.4% (8/235) | 9 |
| Other cardiovascular events | 12.3% (29/236) | 41 | 7.7% (18/235) | 20 |
| Pulmonary Events | | | | |
| Pulmonary edema requiring treatment | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Ventilation greater than 24 hours in duration | 0.4% (1/236) | 1 | 1.3% (3/235) | 3 |
| Pneumonia requiring antibiotics | 2.1% (5/236) | 6 | 5.1% (12/235) | 14 |
| Supplemental oxygen at time of discharge (exclude if for high altitude) | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Re-intubation | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| COPD | 1.7% (4/236) | 5 | 0.9% (2/235) | 4 |
| Other pulmonary events | 3.0% (7/236) | 11 | 8.5% (20/235) | 28 |
| Renal Events | | | | |
| UTI requiring antibiotic treatment | 0.8% (2/236) | 3 | 2.6% (6/235) | 7 |
| Serum creatinine rise greater than 30% above baseline resulting in persistent value greater than 2 mg/dl | 0.8% (2/236) | 2 | 0.0% (0/235) | 0 |
| Other renal events | 2.5% (6/236) | 8 | 4.3% (10/235) | 12 |
| Gastrointestinal Events | | | | |
| Other gastrointestinal events | 3.8% (9/236) | 12 | 10.2% (24/235) | 30 |
| Wound Events | | | | |
| Wound infection/abscess formation | 1.3% (3/236) | 3 | 1.7% (4/235) | 5 |
| Tissue necrosis requiring debridement | 1.3% (3/236) | 3 | 0.4% (1/235) | 1 |
| Wound complication requiring return to operating room | 1.7% (4/236) | 5 | 0.9% (2/235) | 3 |
| Other wound events | 2.5% (6/236) | 6 | 0.9% (2/235) | 2 |
| Vascular Events | | | | |
| Post-procedure percutaneous intervention (e.g., PTA and/or stent) to the study vessel | 8.1% (19/236) | 22 | 5.5% (13/235) | 14 |
| Post-procedure percutaneous intervention (e.g., PTA and/or stent) to another vessel | 16.9% (40/236) | 52 | 21.3% (50/235) | 62 |
| Ischemia requiring surgical intervention (i.e., bypass or amputation) of another vessel | 2.5% (6/236) | 6 | 1.7% (4/235) | 4 |
| Embolism distal to treated study vessel | 0.4% (1/236) | 1 | 0.9% (2/235) | 2 |
| Embolism within another vessel | 0.0% (0/236) | 0 | 1.3% (3/235) | 3 |
| Thrombosis of the study lesion | 0.8% (2/236) | 2 | 2.6% (6/235) | 6 |
| Thrombosis other than study lesion | 0.0% (0/236) | 0 | 0.9% (2/235) | 2 |
| Blue toe syndrome | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Aneurysm (other) | 0.0% (0/236) | 0 | 0.9% (2/235) | 2 |
| Deep vein thrombosis | 0.4% (1/236) | 1 | 0.9% (2/235) | 2 |
| Hematoma requiring intervention at access site | 0.4% (1/236) | 1 | 0.4% (1/235) | 1 |
| Pulmonary embolism | 0.4% (1/236) | 1 | 0.0% (0/235) | 0 |
| Pseudoaneurysm or AV fistula of the study vessel | 0.8% (2/236) | 2 | 0.4% (1/235) | 1 |
| Pseudoaneurysm or AV fistula of another vessel | 0.4% (1/236) | 1 | 0.4% (1/235) | 2 |
| Study vessel spasm | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Worsened claudication/rest pain | 6.8% (16/236) | 21 | 4.3% (10/235) | 12 |
| Stroke | 0.8% (2/236) | 2 | 0.4% (1/235) | 1 |
| Vascular/surgical repair of injury to another vessel (other than amputation or bypass) | 0.4% (1/236) | 1 | 0.9% (2/235) | 3 |
| Post-procedure transfusion | 4.2% (10/236) | 15 | 5.5% (13/235) | 13 |
| Other vascular events | 16.5% (39/236) | 47 | 9.8% (23/235) | 29 |
| Miscellaneous Events | | | | |
| Drug reaction (including contrast reaction) | 2.1% (5/236) | 5 | 3.8% (9/235) | 10 |
| Hypersensitivity/allergic reaction | 2.1% (5/236) | 5 | 2.1% (5/235) | 6 |
| Other miscellaneous events | 26.7% (63/236) | 120 | 28.1% (66/235) | 115 |
| Occurring between 12 and 24 months following the study procedure | | | | |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{32}

PMA P100022: FDA Summary of Safety and Effectiveness Data
page 33

| | Control | | Treatment | |
| --- | --- | --- | --- | --- |
| Death | 3.0% (7/236) | 7 | 5.5% (13/235) | 13 |
| **Major Adverse Events** | | | | |
| Clinically-driven TLR | 4.7% (11/236) | 11 | 3.4% (8/235) | 8 |
| Worsening of Rutherford classification by 2 classes or to a class 5 or 6 | 1.7% (4/236) | 4 | 0.0% (0/235) | 0 |
| **Cardiovascular Events** | | | | |
| Cardiac ischemia requiring intervention | 3.0% (7/236) | 7 | 3.4% (8/235) | 8 |
| Non-Q-Wave MI | 0.8% (2/236) | 2 | 0.4% (1/235) | 1 |
| Congestive heart failure | 1.3% (3/236) | 4 | 1.3% (3/235) | 6 |
| Refractory hypertension | 0.4% (1/236) | 1 | 0.0% (0/235) | 0 |
| Arrhythmia requiring intervention or new treatment | 0.8% (2/236) | 2 | 1.7% (4/235) | 5 |
| Other cardiovascular events | 7.6% (18/236) | 30 | 3.8% (9/235) | 10 |
| **Pulmonary Events** | | | | |
| Pulmonary edema requiring treatment | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Pneumonia requiring antibiotics | 1.3% (3/236) | 3 | 1.7% (4/235) | 4 |
| Supplemental oxygen at time of discharge (exclude if for high altitude) | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| COPD | 0.8% (2/236) | 2 | 0.0% (0/235) | 0 |
| Pleural effusion requiring treatment | 0.0% (0/236) | 0 | 0.4% (1/235) | 2 |
| Other pulmonary events | 3.0% (7/236) | 7 | 3.4% (8/235) | 10 |
| **Renal Events** | | | | |
| UTI requiring antibiotic treatment | 0.8% (2/236) | 2 | 0.4% (1/235) | 1 |
| Serum creatinine rise greater than 30% above baseline resulting in persistent value greater than 2 mg/dl | 0.8% (2/236) | 2 | 0.0% (0/235) | 0 |
| Other renal events | 1.7% (4/236) | 8 | 2.1% (5/235) | 5 |
| **Gastrointestinal Events** | | | | |
| Other gastrointestinal events | 3.4% (8/236) | 9 | 2.6% (6/235) | 6 |
| **Wound Events** | | | | |
| Wound infection/abscess formation | 0.4% (1/236) | 2 | 1.3% (3/235) | 3 |
| Wound complication requiring return to operating room | 0.4% (1/236) | 1 | 0.0% (0/235) | 0 |
| Other wound events | 0.0% (0/236) | 0 | 1.3% (3/235) | 3 |
| **Vascular Events** | | | | |
| Post-procedure percutaneous intervention (e.g., PTA and/or stent) to the study vessel | 5.1% (12/236) | 14 | 3.8% (9/235) | 9 |
| Post-procedure percutaneous intervention (e.g., PTA and/or stent) to another vessel | 5.9% (14/236) | 16 | 6.0% (14/235) | 16 |
| Ischemia requiring surgical intervention (i.e., bypass or amputation) of another vessel | 0.8% (2/236) | 2 | 1.7% (4/235) | 4 |
| Embolism distal to treated study vessel | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Embolism within another vessel | 0.4% (1/236) | 1 | 0.0% (0/235) | 0 |
| Thrombosis of the study lesion | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Blue toe syndrome | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Deep vein thrombosis requiring surgical or lytic therapy | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Worsened claudication/rest pain | 2.5% (6/236) | 6 | 3.4% (8/235) | 9 |
| Stroke | 1.7% (4/236) | 4 | 1.3% (3/235) | 3 |
| Vascular/surgical repair of injury to the study vessel (other than amputation or bypass) | 0.0% (0/236) | 0 | 0.4% (1/235) | 2 |
| Vascular/surgical repair of injury to another vessel (other than amputation or bypass) | 0.4% (1/236) | 1 | 0.0% (0/235) | 0 |
| Post-procedure transfusion | 0.0% (0/236) | 0 | 1.7% (4/235) | 5 |
| Other vascular events | 4.7% (11/236) | 12 | 3.4% (8/235) | 10 |
| **Miscellaneous Events** | | | | |

{33}

| | Control | | Treatment | |
| --- | --- | --- | --- | --- |
| Hypersensitivity/allergic reaction | 0.0% (0/236) | 0 | 0.4% (1/235) | 1 |
| Other miscellaneous events | 14.0% (33/236) | 44 | 15.7% (37/235) | 55 |

In summary, event-free survival at 12 months was 90.4% in the Zilver PTX treatment group and 83.9% in the PTA control group (p &lt; 0.01), with the most common major adverse event being TLR, which occurred significantly more often in the PTA group (16.1%) compared to the Zilver PTX group (9.5%). In conclusion, the primary safety hypothesis of the study was met, indicating that treatment with the Zilver PTX stent is as safe as or safer than treatment with PTA—even when including provisional stenting (bare and PTX coated) in the PTA group.

2. Effectiveness Results

The analysis of effectiveness was based on the 471 evaluable lesions at the 12-month time point. Key effectiveness outcomes are presented in Tables 19 to 21.

The primary effectiveness endpoint of superior primary patency (conservatively defined as a PSV ratio &lt; 2.0) for the Zilver PTX stent compared to PTA was met (p &lt; 0.01²) with a primary patency rate at 12 months of 82.7% for the Zilver PTX treatment group and 32.7% for the PTA control group, as illustrated in Figure 6 and Table 19. The benefit of the Zilver PTX stent was maintained through 24 months.

2 Adjusted for multiplicity.

PMA P100022: FDA Summary of Safety and Effectiveness Data

{34}

Figure 6: Kaplan-Meier curves for primary patency

Table 23: Kaplan-Meier estimates for primary patency

| Months Post-procedure | Primary Patency Estimate | | Standard Error | | Cumulative Failed | | Cumulative Censored | | Number Remaining | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Control (PTA) | Treatment (Zilver PTX) | Control (PTA) | Treatment (Zilver PTX) | Control (PTA) | Treatment (Zilver PTX) | Control (PTA) | Treatment (Zilver PTX) | Control (PTA) | Treatment (Zilver PTX) |
| 0 | 50.2% | 99.6% | 3.2% | 0.4% | 125 | 1 | 0 | 0 | 126 | 245 |
| 1 | 50.2% | 99.6% | 3.2% | 0.4% | 125 | 1 | 0 | 1 | 126 | 244 |
| 6 | 41.6% | 95.1% | 3.1% | 1.4% | 146 | 12 | 5 | 4 | 100 | 230 |
| 12 | 32.7% | 82.7% | 3.0% | 2.5% | 167 | 41 | 11 | 23 | 73 | 182 |
| 24 | 26.5% | 74.8% | 3.1% | 2.9% | 177 | 58 | 41 | 39 | 33 | 149 |

Comparison of the results for patients treated with the Zilver PTX Drug-Eluting Stent to those treated with the bare metal Zilver stent when used in a similar patient population (i.e., those patients who had acute failure of PTA) provides an evaluation of the paclitaxel drug effect. Both patient populations were selected in the same way (and randomized), and both stents have the identical stent platform; therefore, this comparison provides a direct measurement of the effectiveness of the Cook PTX® drug coating on the Zilver PTX stent. As illustrated in Figure 7

PMA P100022: FDA Summary of Safety and Effectiveness Data

{35}

and Table 20, there was a significant difference in patency outcomes between the groups $(p &lt; 0.01^3)$ , with the Zilver PTX group exhibiting a higher primary patency rate at 12 months of $90.2\%$ compared to $72.9\%$ for the bare Zilver group. The benefit of the Zilver PTX stent was maintained through 24 months with a 24-month patency rate of $83.4\%$ for the Zilver PTX group compared to $64.1\%$ for the bare Zilver group. Therefore, stenting with the paclitaxel-coated Zilver PTX stent is significantly more effective in maintaining primary patency through 24 months than stenting with a bare (uncoated) stent—indicating that the PTX® coating has a significant effect, and further supporting the effectiveness of the Zilver PTX stent.

Figure 7: Kaplan-Meier curves for primary patency for provisional bare Zilver vs. provisional Zilver PTX

Table 24: Kaplan-Meier estimates for bare Zilver vs. Zilver PTX

| Months Post-procedure | Primary Patency Estimate | | Standard Error | | Cumulative Failed | | Cumulative Censored | | Number Remaining | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Bare Zilver | Zilver PTX | Bare Zilver | Zilver PTX | Bare Zilver | Zilver PTX | Bare Zilver | Zilver PTX | Bare Zilver | Zilver PTX |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |

PMA P100022: FDA Summary of Safety and Effectiveness Data

{36}

PMA P100022: FDA Summary of Safety and Effectiveness Data
page 37

| 0 | 100.0% | 100.0% | 0.0% | 0.0% | 0 | 0 | 0 | 0 | 62 | 63 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 1 | 100.0% | 100.0% | 0.0% | 0.0% | 0 | 0 | 0 | 0 | 62 | 63 |
| 6 | 88.4% | 96.8% | 4.1% | 2.2% | 7 | 2 | 2 | 1 | 53 | 60 |
| 12 | 72.9% | 90.2% | 5.8% | 3.8% | 16 | 6 | 5 | 3 | 41 | 54 |
| 24 | 64.1% | 83.4% | 6.3% | 4.8% | 21 | 10 | 6 | 7 | 35 | 46 |

In summary, the primary patency rate at 12 months was 82.7% in the Zilver PTX treatment group and 32.7% in the PTA control group. The effect of covariates, including diabetes, lesion length, and occluded/stenosed lesions, was n…