ION PACLITAXEL- ELUTING CORONARY STENT SYSTEM (MONORAIL AND OVER-THE-WIRE SYSTEMS)

P100023 · Boston Scientific Corp · NIQ · Apr 22, 2011 · Cardiovascular

Device Facts

• Record ID: P100023
• Device Name: ION PACLITAXEL- ELUTING CORONARY STENT SYSTEM (MONORAIL AND OVER-THE-WIRE SYSTEMS)
• Applicant: Boston Scientific Corp
• Product Code: NIQ · Cardiovascular
• Decision Date: Apr 22, 2011
• Decision: APWD
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System (Monorail and Over-The-Wire Systems) is indicated for improving luminal diameter for the treatment of de novo lesions in native coronary arteries ≥ 2.25 mm to ≤ 4.00 mm in diameter in lesions ≤ 34 mm in length.

Device Story

Drug-eluting coronary stent system consisting of a balloon-expandable platinum chromium alloy stent coated with paclitaxel and a poly(styrene-isobutylene-styrene) (SIBS) polymer carrier. Used in percutaneous coronary intervention (PCI) to treat de novo coronary artery lesions. The device is delivered via a high-pressure catheter (Monorail or Over-The-Wire) to the target lesion site. Upon inflation, the stent expands to improve luminal diameter, and the paclitaxel is released from the polymer coating to inhibit neointimal hyperplasia. The device is operated by interventional cardiologists in a catheterization lab. Clinical output is monitored via angiography. The device benefits patients by reducing restenosis and the need for target lesion revascularization compared to bare metal stents.

Clinical Evidence

Clinical evidence from the PERSEUS program (two prospective trials). PERSEUS Workhorse (n=1262): randomized, non-inferiority trial vs. TAXUS Express; primary endpoint 12-month TLF met (99.96% posterior probability of non-inferiority). PERSEUS Small Vessel (n=224): single-arm, superiority trial vs. historical BMS control; primary endpoint 9-month in-stent late loss met (p<0.0001). Secondary endpoints (9-month %DS and 12-month TLF) also met. No significant safety concerns identified; stent thrombosis rates were low.

Technological Characteristics

Stent: Platinum Chromium Alloy (PtCr). Strut thickness: 0.081 mm (2.25-3.50 mm) or 0.086 mm (4.00 mm). Coating: 1 μg/mm² paclitaxel in SIBS polymer carrier. Delivery: Monorail or Over-The-Wire balloon catheter. MR Conditional (1.5T and 3T). Sterilization: Ethylene oxide.

Indications for Use

Indicated for patients with de novo coronary artery lesions in native vessels ≥ 2.25 mm to ≤ 4.00 mm diameter and ≤ 34 mm length. Contraindicated in patients unable to receive antiplatelet/anticoagulant therapy, patients with hypersensitivity to 316L stainless steel, platinum, paclitaxel, or polymer components, and lesions preventing complete balloon inflation or proper stent placement.

Regulatory Classification

Identification

Stent, coronary, drug-eluting -- a metal scaffold with a drug coating placed via a delivery catheter into the coronary artery or saphenous vein graft to maintain the lumen. The drug coating is intended to inhibit restenosis.

Predicate Devices

• TAXUS Express² Paclitaxel-Eluting Coronary Stent System (P030025)
• TAXUS Liberté Paclitaxel-Eluting Coronary Stent System (P060008)

Reference Devices

• Apex PTCA Dilatation Catheter (P860019/S028)

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Drug-Eluting Coronary Stent System (NIQ)
Device Trade Name: ION™ Paclitaxel-Eluting Platinum Chromium Coronary Stent System (Monorail™)
ION™ Paclitaxel-Eluting Platinum Chromium Coronary Stent System (Over-The-Wire)
Applicant's Name and Address: Boston Scientific Corporation
One Scimed Place
Maple Grove, MN 55311
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P100023
Date of FDA Notice of Approval: April 22, 2011
Expedited: Not Applicable

II. INDICATIONS FOR USE

The ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System (Monorail and Over-The-Wire Systems) is indicated for improving luminal diameter for the treatment of de novo lesions in native coronary arteries ≥ 2.25 mm to ≤ 4.00 mm in diameter in lesions ≤ 34 mm in length.

III. CONTRAINDICATIONS

Use of the ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System is contraindicated in patients with:

- Known hypersensitivity to 316L stainless steel or platinum
- Known hypersensitivity to paclitaxel or structurally related compounds
- Known hypersensitivity to the polymer or its individual components (see details in Section 4 – Product Description below)

Coronary Artery Stenting is contraindicated for use in:

- Patients who cannot receive recommended antiplatelet and/or anticoagulant therapy
- Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the stent or delivery device

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System Directions for Use (DFU).

# V. DEVICE DESCRIPTION

The ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System is a device/drug combination product comprised of two regulated components:

- A device (Element Coronary Stent System)
- A drug (a formulation of paclitaxel contained in a polymer coating).

The characteristics of the ION stent system are described in Table 1 below.

Table 1: ION Stent System Product Description

| | ION Stent
Monorail Stent Delivery System | ION Stent
Over-The-Wire Stent Delivery System |
| --- | --- | --- |
| Available Stent
Lengths (mm) | 8, 12, 16, 20, 24, 28, 32, 38 | |
| Available Stent
Diameters (mm) | 2.25*, 2.50*, 2.75, 3.00, 3.50, 4.00 | |
| Stent Material | Platinum Chromium Alloy (PtCr) | |
| Stent Strut
Thickness | 0.0032 in (0.081mm) for diameters 2.25 mm to 3.50 mm
0.0034 in (0.086 mm) for diameter 4.00 mm | |
| Drug Product | A conformal coating of a polymer carrier loaded with 1 μg/mm² paclitaxel applied to the stent with a maximum nominal drug content of 247μg on the largest stent (4.00 x 38mm) | |
| Delivery System
Effective Length | 144 cm | 143 cm |
| Delivery System
Y-Adapter Ports | Single access port to inflation lumen.
Guidewire exit port is located
approximately 26 cm from tip. Designed
for guidewire ≤ 0.014 in (0.36 mm) | Y-Connector (Side arm for access to balloon inflation/deflation lumen. Straight arm is continuous with shaft inner lumen). Designed for guidewire ≤ 0.014 in (0.36 mm) |
| Stent Delivery | A balloon, with two radiopaque markers, nominally placed 0.385 mm (0.015 in) beyond the stent at each end. | |
| Balloon Inflation
Pressure | Nominal Inflation Pressure:
• Diameters 2.25 mm, 2.50 mm, 2.75 mm, 3.00 mm, 3.50 mm, 4.00 mm; 11 atm (1115 kPa)
Rated Burst Inflation Pressure:
• Diameters 2.25 mm; 18 atm (1824 kPa)
• Diameters 2.50 mm, 2.75 mm, 3.00 mm, 3.50 mm, 4.00 mm; 16atm (1621 kPa) | |
| Catheter Shaft
Outer Diameter | 2.3 F (0.80 mm) proximal and
2.7 F (0.95 mm) distal | 3.4 F (1.20 mm) proximal for 2.25 to 4.00 mm sizes
2.4 F (0.85 mm) distal for 2.25 to 2.75 mm sizes
2.7 F (0.95 mm) distal for 3.00 to 4.00 mm sizes |
| Guide Catheter
Minimum Inner
Diameter
Requirement | ≥ 0.056 in (1.42) for 2.25 to 3.50 mm sizes
≥ 0.058 in (1.47) for 4.00 mm sizes | ≥ 0.066 in (1.68) |

* 2.25 and 2.50 mm sizes are available in 8, 12, 16, 20, 24, 28, 32 mm lengths

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# A. Device Component Description

The ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System (hereafter referred to as 'ION') consists of a drug coated balloon expandable stent, pre-mounted on a high-pressure delivery catheter, similar to the commercially available Apex PTCA Dilatation Catheter. The stent is made from a Platinum Chromium Alloy (PtCr). The drug coating is composed of two components: a polymer carrier matrix material, poly(styrene-isobutylene-styrene) referred to as SIBS (also known by its commercial name Translute™) and an active pharmaceutical ingredient, paclitaxel.

Each stent is coated with 1 µg paclitaxel per mm² of stent surface area in an 8.8% formulation (weight percent paclitaxel in the polymer coating). This is the same dose density and formulation used on the commercially available TAXUS® Express²® Paclitaxel-Eluting Coronary Stent System (P030025) and TAXUS® Liberté® Paclitaxel-Eluting Coronary Stent System (P060008). PtCr was selected as the stent material as it offers superior strength and radiopacity, thus allowing the stent to provide acute performance with thinner struts in a more flexible design.

The commercial matrix of ION stent lengths and diameters is similar to the TAXUS Express² and TAXUS Liberté device matrices. Although the matrix includes the same vessel diameter range of 2.25 – 4.00 mm, ION has four (4) stent models as compared to three (3) models for TAXUS Liberté and two (2) models for TAXUS Express². The four (4) ION stent models are:

- Small Vessel (SV): 2.25 mm
- Small Workhorse (SWH): 2.50 – 2.75 mm
- Workhorse (WH): 3.00 – 3.50 mm
- Large Vessel (LV): 4.00 mm

The commercial matrix is shown in the Table 2 below:

Table 2: ION Stent System Product Description

| A. D Stent Model | | Stent Length (mm) | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Design | Diameter (mm) | 8 | 12 | 16 | 20 | 24 | 28 | 32 | 38 |
| C SV | 2.25 | x | x | x | x | x | x | x | |
| o SWH m | 2.50 | x | x | x | x | x | x | x | |
| | 2.75 | x | x | x | x | x | x | x | x |
| p WH o | 3.00 | x | x | x | x | x | x | x | x |
| | 3.50 | x | x | x | x | x | x | x | x |
| n LV e | 4.0 | x | x | x | x | x | x | x | x |

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# B. Drug Component Description

The drug component of the ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System consists of paclitaxel (the active ingredient) and Translute™ polymer carrier (the inactive ingredient).

# B1. Paclitaxel

The active pharmaceutical ingredient in the ION stent is paclitaxel. It is a white powder, isolated from a spectrum of Taxus species and hybrids. The chemical name of paclitaxel is: Benzenepropanoic acid, $\beta$-(benzoylamino)-$\alpha$-hydroxy-,6,12bbis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12bdodecahydro-4,11-dihydroxy-4a,8,13,13 tetramethyl-5-oxo-7,11-methano-1Hcyclodeca[3,4]benz[1,2-b]oxet-9-yl ester,[2a R-[2a$\alpha$,4$\beta$,4a$\beta$,6$\beta$,9$\alpha$ ($\alpha$R*,$\beta$S*),11$\alpha$,12$\alpha$,12a$\alpha$,12b$\alpha$]]-.

Paclitaxel is a diterpenoid with a characteristic taxane skeleton of 20 carbon atoms, a molecular weight of 853.91 g/mol and a molecular formula of $\mathrm{C_{47}H_{51}NO_{14}}$. It is highly lipophilic, insoluble in water, but freely soluble in methanol, ethanol, chloroform, ethyl acetate, and dimethyl sulfoxide.

The chemical structure of paclitaxel is shown in Figure 1. The nominal total loaded dose of paclitaxel per nominal stent length/diameter is shown in Table 3

Figure 1: Chemical Structure of Paclitaxel

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Table 3: Nominal Total Loaded Dose of Paclitaxel per Nominal Stent Length/Diameter

| | Stent Model / Nominal Stent Length (mm) | Nominal Stent Length (mm) | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | 8 | 12 | 16 | 20 | 24 | 28 | 32 | 38 |
| Total loaded dose Paclitaxel/Stent (μg) | SV (2.25 mm) | 39 | 58 | 74 | 94 | 109 | 129 | 148 | |
| | SWH (2.50 – 2.75 mm) | 40 | 62 | 80 | 97 | 115 | 133 | 155 | 181* |
| | WH (3.00 – 3.50 mm) | 43 | 61 | 86 | 104 | 123 | 141 | 166 | 197 |
| | LV (4.00 mm) | 57 | 82 | 107 | 131 | 156 | 181 | 206 | 247 |

* Applies to 2.75 mm diameter only.

## B2. Inactive Ingredients

The only inactive ingredient in the ION stent is SIBS [poly(styrene-b-isobutylene-b-styrene)], a tri-block copolymer (trade name: Translute™) that is composed of styrene and isobutylene units built on 1,3-di(2-methoxy-2-propyl)-5-tert-butylbenzene. It is a hydrophobic elastomeric copolymer with a molecular weight (Mn-number average molecular weight) of 80,000 to 130,000 g/mol and a polydispersity index of 1.0 to 2.0. The polymer is mixed with the drug paclitaxel and then applied to the stents. There is no primer or topcoat layer. The drug/polymer coating is adhered to the entire surface (i.e., luminal and abluminal) of the stent. The structural formula for the polymer is shown in Figure 2 below.

Figure 2: The Chemical Structure of Translute™ Polymer Carrier

m = repeating units of styrene
n = repeating units of isobutylene

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# C. Mechanism of Action

The mechanism (or mechanisms) by which an ION stent affects neointimal production as seen in clinical studies has not been fully established. Paclitaxel promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the treatment of patients with coronary artery disease, which may include exercise, diet, smoking cessation, drug therapy, percutaneous coronary interventions (such as angioplasty and placement of bare metal stents, coated stents, and other drug-eluting stents), and coronary artery bypass graft surgery (CABG). 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 ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System is commercially available in the following countries:

- Australia
- Austria
- Belgium
- Bulgaria
- Chile
- Cyprus
- Czech Republic
- Denmark
- Estonia
- Finland
- France
- Germany
- Great Britain
- Greece
- Hungary
- Iceland
- India
- Ireland
- Italy
- Latvia
- Lebanon
- Liechtenstein
- Lithuania
- Luxembourg
- Malaysia
- Malta
- Netherlands
- Norway
- Poland
- Portugal
- Romania
- Russia
- Saudi Arabia
- Singapore
- Slovakia
- Slovenia
- South Africa
- Spain
- Sweden
- Switzerland
- Tunisia
- United Arab Emirates

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As of March 31, 2011, approximately 29,257 ION Stents have been distributed outside the U.S. No products have been withdrawn from the market in any country for any reason.

## VIII. SUMMARY OF PRECLINICAL STUDIES

A series of non-clinical laboratory studies were performed to evaluate:

- the stent and the stent delivery system [i.e., the stent on either the Monorail (MR) or Over-The-Wire (OTW) stent delivery system (SDS)]
- the polymer substance [i.e., poly(styrene-isobutylene-styrene) (SIBS)]
- the drug substance (i.e., paclitaxel)
- the finished combination product (i.e., ION Paclitaxel-Eluting Platinum Chromium Coronary Stent)

## A. Biocompatibility Studies

A series of Good Laboratory Practice (GLP) biocompatibility tests were conducted to demonstrate that the components of the ION™ Paclitaxel-Eluting Platinum Chromium Coronary Stent System (Monorail and Over-The-Wire) are biocompatible. Testing was conducted separately for the stent implant and the stent delivery system. Tests were conducted on ethylene oxide-sterilized bare metal (Platinum Chromium Alloy (PtCr)) stents, and stent delivery systems. These test articles were processed in a manner similar to the finished ION™ product. There were some minor manufacturing differences which were determined not to impact the biocompatibility of the final device.

Biocompatibility data on the drug substance, Paclitaxel, and SIBs coating was incorporated by reference to P060008 for the Taxus Liberte Paclitaxel-Eluting Coronary Stent System and is applicable to the ION™ Paclitaxel-Eluting Platinum Chromium Coronary Stent System because the coating process, amount of coating per unit area, drug substance total dose and dose per unit area, and sterilization processes are equivalent for the Liberte and ION stents.

All biocompatibility testing was conducted in accordance with:

- Guidance for Industry and FDA Staff: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, January 13, 2005
- Draft Guidance for Industry: Coronary Drug-Eluting Stents - Nonclinical and Clinical Studies Companion Document, March 2008
- Draft Guidance for Industry: Coronary Drug-Eluting Stents - Nonclinical and Clinical Studies, March 2008
- Good Laboratory Practices Regulations (21 CFR § 58)
- ISO 10993-1, Biological Evaluation of Medical Devices: Evaluation and Testing (2003)

The biocompatibility studies are summarized in Table 4.1 and 4.2.

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Table 4.1: Biocompatibility Test Summary (Stent)

| Test / Applicable ISO 10993 Part No. | Test Article | Test Result |
| --- | --- | --- |
| Cytotoxicity (L929 MEM Elution) / Part 5 | Uncoated Element Stent | Pass |
| Cytotoxicity (Direct Contact) / Part 5 | Uncoated Element Stent | Pass |
| Sensitization (Guinea Pig Maximization) / Part 10 | Uncoated Element Stent | Pass |
| Intracutaneous Reactivity / Part 10 | Uncoated Element Stent | Pass |
| Acute Systemic Toxicity / Part 11 | Uncoated Element Stent | Pass |
| Material-Mediated Pyrogenicity (Rabbit) / Part 11 | Uncoated Element Stent | Pass |
| 14 day Repeat Dose Intravenous Toxicity / Part 11 | Uncoated Element Stent | Pass |
| 13-week Systemic Toxicity following Subcutaneous Implantation in Rats / Parts 6 and 11 | Uncoated Element Stent Control: Uncoated Express Stent | Pass |
| Ames Mutagenicity / Part 3 | Uncoated Element Stent | Pass |
| In vitro Mouse Lymphoma / Part 3 | Uncoated Element Stent | Pass |
| In vivo Mouse Micronucleus / Part 3 | Uncoated Element Stent | Pass |
| Hemolysis (Direct Contact) / Part 4 | Uncoated Element Stent | Pass |
| Hemolysis (Extract Method) / Part 4 | Uncoated Element Stent | Pass |
| Complement Activation (C3a and SC5b-9)/ Part 4 | Uncoated Element Stent | Pass |
| Supportive Analytical Chemistry Tests | | |
| Chemical Characterization (Extractables - ICP Analysis) | Uncoated Element Stent | Pass |
| Chemical Characterization (Residuals and Leachables) | Uncoated Stent | Pass |
| Chemical Characterization (Corrosion Challenge) | ION™ and Uncoated Element Stent | Pass |

Since the applicant did not conduct the traditional battery of ISO 10993 testing on the finished ION™ stent (i.e., containing the drug substance and coating); sub-chronic toxicity, in vivo thrombogenicity, and implantation of the final ION™ stent, containing all components and processing were evaluated in a porcine model of stent-mediated vascular injury. See a summary of this study in Section H - Animal Studies, below.

Chronic toxicity and carcinogenicity testing of the ION™ stent was not conducted because:

- The chemical composition of the Platinum Chromium Alloy is known and material characterization testing conducted for the bare Element Stent demonstrated that the types and quantities of residues or leachables present from the finished stent do not raise concerns for chronic toxicity or carcinogenicity.
- Paclitaxel safety has been extensively studied. The concentration of paclitaxel (1μg/mm²) and the amounts used in this application are equivalent to the concentrations used in the approved TAXUS Express² (P030025) and TAXUS Liberté (P060008) stents; therefore, the assessment of chronic toxicity and carcinogenicity provided for those products are directly applicable to the ION™ product.
- The SIBS coating process and amount is equivalent to that used in the approved TAXUS Liberté (P060008) stents; therefore, the assessment of chronic toxicity and

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carcinogenicity provided for that product is directly applicable to the ION™ product.

Table 4.2: Biocompatibility Test Summary (Delivery Systems)

| Test / Applicable ISO 10993 Part No. | Test Article | Test Result |
| --- | --- | --- |
| Cytotoxicity (L929 MEM Elution) / Part 5 | ION™ MR and OTW SDS (Catheter plus stent) | Pass |
| Cytotoxicity (Direct Contact) / Part 5 | PROMUS Element MR SDS (Catheter only)¹ | Pass |
| | ION™ OTW SDS (Catheter only) | Pass |
| Sensitization (Guinea Pig Maximization) / Part 10 | ION™ MR and OTW SDS (Catheter plus stent) | Pass |
| Intracutaneous Reactivity / Part 10 | ION™ MR and OTW SDS (Catheter plus stent) | Pass |
| Acute Systemic Injection / Part 11 | ION™ MR and OTW SDS (Catheter plus stent) | Pass |
| Material-Mediated Pyrogenicity (Rabbit) / Part 11 | ION™ MR and OTW SDS (Catheter plus stent) | Pass |
| Hemolysis (Direct Contact / Part 4 | ION™ MR and OTW SDS (Catheter plus stent) | Pass |
| Hemolysis (Extract) / Part 4 | PROMUS Element MR SDS (Catheter only)¹ | Pass |
| | ION™ OTW SDS (Catheter only) | Pass |
| Complement Activation (C3a and SC5b-9) / Part 4 | ION™ MR and OTW SDS (Catheter plus stent) | Pass |
| Supportive Analytical Chemistry Tests | | |
| USP Physicochemical Test for Plastics / Part 18 | ION™ MR and OTW SDS (Catheter plus stent) | Pass |

The PROMUS Element and ION™ Monorail delivery catheters consist of the identical materials and similar processing, and data provided support that any differences will not affect the biocompatibility of the final product. Therefore the data from the PROMUS Element Monorail testing are applicable to the ION™ Monorail device.

The applicant did not conduct traditional in vivo thrombogenicity on the ION™ MR and OTW delivery systems. The potential for thrombogenicity was evaluated in a porcine model of stent mediated vascular injury. See a summary of this study in Section H – Animal studies, below. Use of the vascular implant study in the porcine model was deemed acceptable because the materials of manufacture, design, and processing methods for the delivery system are equivalent to the approved Apex balloon catheter (P860019/S028).

The handle of this delivery system incorporates nanotechnology. Detailed manufacturing information and material characterization and biocompatibility testing were provided to confirm that there is no release of nanoparticles from the handle of this device.

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Based on the testing performed for the Element stent and delivery systems, as well as the established biocompatibility and safety data on paclitaxel and SIBS, it can be concluded that ION™ Coronary Stent System is biocompatible for its intended use.

## B. In Vivo Pharmakokinetics

### B1. ION Paclitaxel-Eluting Platinum Chromium Coronary Stent

Boston Scientific has provided a letter from the drug substance manufacturer authorizing access to a Drug Master File (DMF) in support of this application. The drug substance manufacturer produces a generic form of the drug Taxol®, a Bristol Myers Squibb drug product that is approved for injection of multiple oncologic indications. In vivo animal and in vitro pharmacology and toxicology studies, as well as in vivo animal and human pharmacokinetic studies, were conducted on Taxol to provide information about systemic, regional and local toxicity, dose-related toxicity, distribution profiles, end-organ disposition, drug metabolism, and potential drug-drug interactions.

Given that the polymer coating and drug component of the ION is identical to that of the TAXUS Express² (P030025) and TAXUS Liberté (P060008), the evaluation of TAXUS Express² and TAXUS Liberté is applicable.

In the clinical studies TAXUS I, II, and III (which evaluated TAXUS® Express²®) and ATLAS (which evaluated TAXUS Liberté), no paclitaxel levels were detected after stent implantation using an analytical method with a lower limit of quantification (LLOQ) of 10 ng/ml. These findings were confirmed in preclinical studies using multiple stents with total loaded doses above the clinically available stent system and an assay with an LLOQ of 0.03 ng/ml. Hence, in the absence of systemically detectable levels, standard pharmacokinetic parameters were not established.

### B2. Drug Interactions

Paclitaxel is metabolized in the liver via CYP2C8 to 6-alpha-hydroxypaclitaxel and via CYP3A4 to 3'-p-hydroxypaclitaxel and 6-alpha, 3'-p-dihydroxypaclitaxel. Paclitaxel is a substrate of P-glycoprotein. Because metabolism appears to play an important role in the elimination of paclitaxel, agents that could compete with or inhibit the CYP2C8 and CYP3A4 isoenzymes may increase paclitaxel plasma levels. Potential drug interactions may occur with any drug that affects these isoenzymes.

Formal drug interaction studies have not been conducted with the ION stent. Consideration should be given to the potential for both systemic and local drug interactions in the vessel wall when deciding to place an ION stent in a patient who is taking a drug with known interactions to paclitaxel or when deciding to initiate therapy with such a drug in a patient that has recently received an ION stent.

## C. In Vitro Engineering Testing

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

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- FDA Guidance for Industry and Staff: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, January 13, 2005,
- FDA Draft Guidance for Industry and Staff: Coronary Drug-Eluting Stents – Nonclinical and Clinical Studies, March 2008, and
- FDA Guidance for Industry and Staff: Establishing Safety and Compatibility of Passive Implants in the Magnetic Resonance (MR) Environment, August 2008.

*In vitro* engineering testing was performed on the ION stent mounted on either the MR or OTW delivery catheters.

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

Additional testing was conducted to support the integrity of the coating on the ION™ stent as shown in Section IX D - Drug Coating Characterization Testing.

| Table 5: Stent and Delivery Catheter Engineering Testing | | |
| --- | --- | --- |
| Test | Description of Test | Test Results |
| Stent Dimensional and Functional Attributes | | |
| Material Composition | Chemical analysis was conducted on the Platinum Chromium (PtCr) ingot provided by the material supplier to confirm both chemical analysis and inclusion/impurity content as provided by ASTM F138-00 “Standard Specification for Wrought 18 Chromium-14 Nickel-2.5 Molybdenum Stainless Steel Bar and Wire for Surgical Implants (UNS S31673).” The analysis confirmed that the chemical composition matched the ASTM standard. | Pass |
| Stent Corrosion Resistance | ION stents were tested according to ASTM F2129-01 “Standard Test Method for Conducting Cyclic Potentiodynamic Measurements,” ASTM F756, ASTM G-71 to Determine the Corrosion Susceptibility of Small Implant Devices” to demonstrate that the finished stents exhibit acceptable breakdown, repassivation, and galvanic coupling corrosion characteristics. The results indicated that the corrosion resistance met product specification. Testing also included an assessment of Fretting Corrosion after pulsatile fatigue cycling. The results demonstrated that there was no evidence of fretting corrosion with ION stents under overlapping, bent, pulsatile fatigue conditions up to 400 million cycles. | Pass |
| Dimensional Verification | To measure and inspect the substrate (uncoated) Element stent to document that the un-expanded stent dimensional specifications meet the product design requirements. All products met specifications. | Pass |
| Percent Surface Area | Stent surface coverage as a function of stent diameter was measured for the ION™ stent. The percent surface area is determined by | Pass |

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| | dividing the measured total contact surface area of the coated stent by the surface area of the artery based on deployed stent measurements at the nominal stent diameter. The calculated percent surface area of the stent should be <23.9% when expanded to the lowest labeled diameter. Values were calculated for 2.00 to 4.00 mm stent diameters. | |
| --- | --- | --- |
| Foreshortening | The lengths of the stents were measured prior to and after expansion to nominal diameter. All stents met product specifications. | Pass |
| Recoil for Balloon Expandable Stents | Testing was conducted to quantify the amount of elastic recoil for the stent and correlate this parameter to the recommended sizing procedures. Results indicated that product specifications were met. | Pass |
| Stent Overexpansion | Testing was conducted to determine whether the deformation experienced by the stent undergoing expansion above the maximum rated diameter gives rise to stent or coating fractures. No stent exhibited any strut fracture or indications of coating integrity issues when visually examined at 32X following over-expansion. | Pass |
| Radial Stiffness and Radial Strength | Testing was conducted to determine the ability of the ION™ stent to resist deformation under radial loads. | Pass |
| Compression Resistance | Testing was conducted to determine the radial resistance of the ION™ stent to external compression. | Pass |
| Mechanical Properties | Ultimate tensile strength, yield strength and elongation testing was performed on tubing (pre-processing) used to fabricate the stents. Ultimate tensile strength, yield strength and elongation on pre-processed tubing met product specification. Analysis of SEM images on stent components at various process stages determined that mechanical properties were not altered by processing. | Pass |
| Magnetic Resonance Imaging (MRI) Safety and Compatibility | The ION Stent has been shown to be MR Conditional (poses no known hazards under specified conditions) through non-clinical testing of single and overlapped configurations up to 74 mm in overall length. The conditions are as follows:
• Field strengths of 1.5 and 3 Tesla
• Static magnetic field gradient < 9 T/m (extrapolated)
• Normal operational mode (maximum whole body averaged specific absorption rate (SAR) of lower than 2.0 W/kg) for a total active MR scan time (with RF exposure) of 15 minutes or less

The ION Stent should not migrate in this MRI environment. MR imaging within these conditions may be performed immediately following the implantation of the stent. This stent has not been evaluated to determine if it is MR Conditional beyond these conditions.

**3.0 Tesla Temperature Information**
Non-clinical testing of RF-induced heating was performed at 123 | Pass |

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| | MHz in a 3.0 Tesla Magnetom Trio®, Siemens Medical Solutions MR system, software version Numaris/4, Syngo® MR A30. RF power was applied for 15 minutes and the measured conductivity of the phantom material was about 0.3 S/m. The phantom average SAR was calculated using calorimetry to be 2.2 W/kg. The maximal in-vitro temperature rise was calculated as 2.6°C for a measured stent length of 74 mm with the whole-body SAR scaled to 2.0 W/kg. The calculations did not include the cooling effects due to blood flow.

1.5 Tesla Temperature Information
Non-clinical testing of RF-induced heating was performed at 64 MHz in a 1.5 Tesla Intera® Philips Medical Systems, software version Release 10.6.2.0, 2006-03-10 whole body coil MR scanner. RF power was applied for 15 minutes and the measured conductivity of the phantom material was about 0.3 S/m. The phantom average SAR was calculated using calorimetry to be 2.1 W/kg. The maximal in-vitro temperature rise was calculated as 2.6°C for a measured stent length of 74 mm with the whole-body SAR scaled to 2.0 W/kg. The calculations did not include the cooling effects due to blood flow.

In vivo, local SAR depends on MR Field strength and may be different than the estimated whole body averaged SAR, due to body composition, stent position within the imaging field, and scanner used, thereby affecting the actual temperature rise.

Image Artifact Information
The calculated image artifact extends approximately 7 mm from the perimeter of the device diameter and 5 mm beyond each end of the length of the stent when scanned in non-clinical testing using a Spin Echo sequence. With a Gradient Echo sequence the calculated image artifact extends 5 mm beyond the perimeter of the diameter and 6 mm beyond each end of the length with both sequences partially shielding the lumen in a 3.0 Tesla Intera (Achieva Upgrade), Philips Medical Solutions, software version Release 2.5.3.0 2007-09-28 MR system with a transmit/receive head coil.

Medical Registration
It is recommended that patients register the conditions under which the implant can be scanned safety with the MedicAlert Foundation (www.medicalcert.org) or equivalent organization. | |
| --- | --- | --- |
| Radiopacity | Testing was conducted on the bare metal stent as the addition of the coating did not add or detract from the radiopacity of the stent in clinical use. | Pass |
| Stent Delivery System Dimensional and Functional Attributes | | |
| Delivery, Deployment | The delivery, deployment and retraction of the ION™ Stent System was assessed by testing system track, crossing profile, stent | Pass |

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| and Retraction | deployment, guidewire movement and balloon withdrawal from a stent and into the guide catheter. Testing demonstrated that the ION™ stent system could be delivered to the target location, deployed, and retracted, thus meeting required product specifications. | |
| --- | --- | --- |
| Balloon Rated Burst Pressure (RBP) | ION™ Stent Systems were tested to failure to demonstrate that the stent system met rated burst pressure. All stent systems met specification and demonstrated with 95% confidence that at least 99.9% of balloons will not experience loss of integrity at or below the rated burst pressure. | Pass |
| Balloon Fatigue | ION™ Stent Systems across the range of stent/balloon lengths and diameters were required to complete 10 pressurization cycles to Rated Burst Pressure (RBP). The results show statistically that, with 95% confidence, 90% of the catheters will not experience balloon, shaft, or proximal/distal seal loss of integrity at or below the maximum recommended rated balloon burst pressure. | Pass |
| Stent Diameter vs. Balloon Pressure | Testing was performed to determine how the diameter of a deployed stent varies with applied balloon pressures. The stent sizing results verify that the stent systems meet the labeled compliance values. | Pass |
| Catheter Bond Strength | Representative sizes of the ION™ stent delivery system were tested to determine the balloon bond and full unit tensile strength of the delivery system. All stent systems exceeded the minimum specifications for full unit tensile strength and balloon bond. | Pass |
| Balloon Deflation Times | ION™ delivery systems across the range of balloon lengths and diameters were tested for deflation times, and all stent systems met specifications. | Pass |
| Stent Securement for Unsheathed Stents | Testing was conducted to assess the forces required to displace a crimped ION™ stent from the delivery systems (1) directly from the balloon catheters, (2) after tracking through a simulated tortuous artery model and (3) after tracking through a simulated tortuous artery model and then through a simulated lesion. All stent systems met the stent securement specification. | Pass |
| Non-Coaxial Withdrawal into a Simulated Guiding Catheter | Testing consists of withdrawing a catheter with a mounted stent non-coaxially into a simulated guide catheter tip, at a 45°C angle, following a track conditioning step, in which the ION™ Stent Delivery Systems were challenged by repeatedly tracking the crimped stent system three (3) times through a tortuous artery model. The unit was then assessed for stent movement. All samples met the product specification. | Pass |
| Balloon Catheter Withdrawal Resistance | Testing was conducted to verify that the ION™ stent system can be safely withdrawn back into the recommended guide catheter sizes both before and after stent deployment. All samples met the product specification. | Pass |
| Coating Durability | The coating durability of the ION™ stent coating was assessed via a series of acute in vitro tests performed on the coated stent and the SIBS polymer. The test results demonstrate that the paclitaxel/SIBS coating displays good durability and coating integrity. | Pass |

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| Coating Adhesion and Cohesion | Coating Adhesion and Cohesion testing has been performed to assess the adhesive and cohesive properties of the ION™ stent coating. The ION™ coating demonstrates adequate adhesion and cohesion properties. The coating has a high resistance to detachment from the stent and is therefore considered acceptable for intended use. | Pass |
| --- | --- | --- |
| Stress and Strain Analysis (Finite Element Analysis (FEA)) | Using Finite Element Analysis (FEA), stress and strain analysis was performed on the stent and the stent coating to demonstrate that they maintain acceptable safety in stress loading environments, simulating nominal and overexpansion, and bending and radial conditions. The FEA evaluated the structural integrity of the stent and coating when subjected to the expected loading conditions generated in coronary arteries. The analysis took into account manufacturing, delivery, implantation and clinical loading over the implant life, and predicted that fatigue failures will not occur over 400 million cycles (10-years) of loading. | Pass |
| Accelerated Durability Testing | Accelerated durability testing was performed on the ION™ stent and the stent coating to demonstrate that the structural integrity and/or coating integrity is maintained following exposure to the pulsatile stresses and strains exceeding those typically experienced by a human coronary artery for 10 years (400 million cycles). Testing included assessment of Post-Elution Fatigue and Overlapping Pulsatile Fatigue on a Curve (PFC). All tested stents were free from fatigue induced surface defects, and there was no evidence of coating fatigue or corrosion. The stent met the 10 year accelerated fatigue resistance requirement of the product specification. The overlapping stents were also evaluated in an accelerated in vitro test of approximately 10 year equivalent real time and met visual requirements for coating integrity and strut damage. | Pass |
| Particulate Testing | Particulate testing has been performed on the ION™ stent system in accordance with the recommendations in the draft FDA Guidance for Industry: Coronary Drug-Eluting Stents - Nonclinical and Clinical Studies, March 2008, including revisions presented during the 2008 Transcatheter Cardiovascular Therapeutics (TCT) Conference, Washington DC, October 15, 2008. Testing included assessment of Baseline Particulate (Overexpansion), Simulated Use Particulate, and Chronic Particulate (Pulsatile Particulates in a Curve (PPC)). The results demonstrate that the particulate counts are similar or lower for ION™ coated stents compared to bare Element stents. Given comparable particulate counts, and that there is no evident increase in counts on ION™ coated stent product, no chemical identification of particulates was warranted. | Pass |

## D. Drug Coating Characterization Testing

The coating characterization testing conducted on the ION stent coating is summarized in Table 6.

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Table 6: Coating Characterization Testing

| Test | Description of Test |
| --- | --- |
| Materials Analysis – Polymer | Polymer components were tested to ensure conformity to raw material specifications and incoming inspection procedures. The analysis confirmed the material met specifications. |
| Chemical Analysis- Polymer | Assays were conducted to determine Mw, Mn, polydispersity, monomer content, presence/formation of oligomers, and free monomers. The results of each assay met specifications established by the applicant. |
| Chemical Analysis - Drug | Drug substance was tested to ensure conformity to incoming Certificate of Analysis (COA); the testing confirmed conformity to the COA. |
| Drug Content | Assay was conducted to quantitatively determine the total amount of the drug substance, paclitaxel, on the ION stent. The results verified that samples met the targeted drug content specifications. |
| Dose Density | Dose per unit area was calculated. |
| Coating Uniformity/ Reproducibility | Testing was conducted to verify the reproducibility of coating uniformity from stent to stent and batch to batch. Testing confirmed adequate coating uniformity/reproducibility as outlined in USP <905>. |
| Impurities/Degradation Products | Assays were conducted to quantitatively determine the type and amount of impurities and degradation products on the ION stent. Testing confirmed acceptable levels of impurities and degradation products. |
| In vitro Elution | Assay was developed to measure the in vitro release kinetics of paclitaxel off the ION stent. An appropriate method and specifications were developed for this parameter. |
| Particulates | Particulate levels were evaluated for the ION stent system under simulated use conditions, including tracking and deployment (see Table 5 above). |

E. Chemistry, Manufacturing, and Controls (Quality) Testing

Samples from each batch of finished stents are subjected to certain tests prior to release. This testing is summarized in Table 7. Where applicable, the test methods follow International Conference on Harmonization (ICH) Guidelines. Information to support the stability of ION is summarized separately in Section IX F – Stability below.

Table 7: ION Stent Release Testing

| Test | Description of Test |
| --- | --- |
| Material Analysis - Polymer | The polymer was tested to ensure conformity to specifications. The polymer met specifications prior to utilization in finished goods. |
| Drug Identity | Assay is conducted to verify the identity of the drug substance, paclitaxel, in the ION stent. |
| Drug Content/Impurities | Assays are conducted to quantitatively verify the amount of drug and the type and amount of impurities on the ION stent. |
| Drug Content Uniformity | Multiple stents are assayed to verify the uniformity of the drug content between individual stents is within specifications established for the ION |

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Table 7: ION Stent Release Testing

| Test | Description of Test |
| --- | --- |
| | stent. |
| In vitro Drug Elution | The in vitro release profile of paclitaxel is measured to verify that the drug release is within the specifications established for the ION stent. |
| Particulates | Particulate counts are measured to verify that they remain below acceptable levels established for the ION stent. |

## F. Stability

Stability studies specific to the polymer/drug coating component were conducted in accordance with ICH guidelines to establish a shelf life/expiration date for the ION stent system. In addition, testing to establish package integrity and functional testing of the stent and delivery system were conducted on aged product to ensure that ION continues to meet specifications throughout its shelf life. The data generated support a shelf life of 18 months. Stability studies included evaluation of drug identity, assay, degradants, in vitro elution, particulates, sterility, drug content uniformity, residual solvents, and endotoxin.

In addition, the stability of the drug substance and inactive polymer has been independently verified.

## G. Sterilization

The ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System (Monorail and Over-The-Wire) is sterilized using ethylene oxide sterilization and has been validated per AAMI/ISO 11135:1994 “Medical Devices – Validation and Routine Control of Ethylene Oxide Sterilization.”

Results obtained from the sterilization studies show that the product satisfies a minimum Sterility Assurance Level (SAL) of $10^{-6}$.

The amount of bacterial endotoxin was verified to be within the ANSI/AAMI ST72 specification limit or ION stent delivery systems.

## H. Animal Studies

Because detailed arterial histopathology and histomorphometry and pharmacokinetic data cannot be obtained through human clinical trials, a series of animal studies were conducted to evaluate safety, vascular compatibility, in vivo drug release, and acute product performance.

The safety, vascular compatibility, and acute performance of ION paclitaxel-eluting stents were evaluated in the non-injured porcine coronary artery model. Studies were conducted in accordance with §21 CFR 58 (Good Laboratory Practices).

The consistency of the vascular response to the Element™ platform with the approved Liberté® platform was evaluated and compared in the Overlap ION Study 1133-024.

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Acute performance of ION was evaluated in Study 1133-027.

ION in vivo paclitaxel release and tissue paclitaxel levels were evaluated and compared with TAXUS® Express® in Study BJA00172 using the rabbit iliac artery model.

The results of these tests support the safety and vascular compatibility of the ION Stent. Summaries of these studies are included in the Tables 8 through 10 below.

Table 8: Summary of the Porcine Overlap Slow Release (8.8%) ION Study: 1133-024

| Stent Model | Dose Density, Release Formulation | Stent Size | Target # Stents/ Animal # Animals | Vessel Location | Evaluation Time Points | Testing Objective |
| --- | --- | --- | --- | --- | --- | --- |
| ION | 1 μg/mm² Slow Release (8.8%) | 2.75 x 12 mm | 1 overlap pair/animal 39 animals | LAD, RCA, LCX | 30, 90, and 180 days | Establish safety of small workhorse stents.
Mortality, morphology, morphometry, myocardial effects |
| Uncoated Element | N/A | 2.75 x 12 mm | 1 overlap pair/animal 39 animals | | | |
| TAXUS Liberté Controls | 1 μg/mm² Slow Release (8.8%) | 2.75 x 12 mm | 1 overlap pair/animal 39 animals | | | |
| Uncoated Liberté Controls | N/A | 2.75 x 12 mm | 1 overlap pair/animal 39 animals | | | |

Table 9: Summary of the Porcine Acute Performance ION Study: 1133-027

| Stent Model | Dose Density, Release Formulation | Stent Size | Target # Stents/ Animal # Animals | Vessel Location | Evaluation Time Points | Testing Objective |
| --- | --- | --- | --- | --- | --- | --- |
| ION | 1 μg/mm², Slow Release (8.8%) | 2.5 x 8mm
3.0 x 8mm
4.0 x 8mm | 6 or 8/animal
2 animals | LAD, RCA, LCX | Acute | Establish handling performance of stents. |

Table 10: Summary of the Rabbit In Vivo Release Slow Release (8.8%) ION and TAXUS Express Study: BJA00172

| Stent Model | Dose Density, Release Formulation | Stent Size | Target # Stents/ Animal # Animals | Vessel Location | Evaluation Time Points | Testing Objective |
| --- | --- | --- | --- | --- | --- | --- |
| ION | 1 μg/mm² Slow Release (8.8%) | 2.5 x 12 mm | 1/animal
70 animals | Iliac artery | 10, 30 45, 60, 90, 180, and 270 Days | Compare potential local vascular paclitaxel |

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| Stent Model | Dose Density, Release Formulation | Stent Size | Target # Stents/ Animal # Animals | Vessel Location | Evaluation Time Points | Testing Objective |
| --- | --- | --- | --- | --- | --- | --- |
| TAXUS Express² | | 2.5 x 12 mm | 1/animal
70 animals | | | exposure for SR Element versus SR Express² using stent content and tissue paclitaxel levels. |

## IX. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant collected clinical data through the PERSEUS Clinical Trial Program, to establish a reasonable assurance of safety and effectiveness of coronary artery stenting with the ION stent for improving luminal diameter for the treatment of *de novo* lesions. The PERSEUS program consisted of two (2) parallel studies, PERSEUS Workhorse (WH) and PERSEUS Small Vessel (SV). The PERSEUS WH included sites in the United States, New Zealand, Australia, and Singapore. The PERSEUS SV was a US-only study. Both trials were evaluated under IDE G060237. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented in Table 11 below.

## PERSEUS WH

The PERSEUS Workhorse (WH) study is a prospective, randomized, controlled, single-blind, non-inferiority trial to evaluate the safety and efficacy of the $1\ \mu\mathrm{g}/\mathrm{mm}^2$ (loaded drug/stent surface area) ION™ Stent in the treatment of *de novo* coronary lesions. Subjects with *de novo* target lesion length $\leq 28\mathrm{mm}$ and target vessel diameter $\geq 2.75\mathrm{mm}$ to $\leq 4.0\mathrm{mm}$ were considered for enrollment. The trial employs a 3:1 randomization to the ION or the TAXUS Express Paclitaxel-Eluting Stent respectively.

The primary endpoint is the rate of target lesion failure (TLF; including any ischemia-driven revascularization of the target lesion [TLR], myocardial infarction [MI; Q-wave and non-Q-wave] related to the target vessel, or cardiac death related to the target vessel) at 12 months post-index procedure, testing non-inferiority of the ION Stent relative to the TAXUS Express Paclitaxel-Eluting Stent control. In-segment percent diameter stenosis at 9 months post-index procedure as measured by quantitative coronary angiography (QCA) is the secondary endpoint.

Enrollment of 1264 subjects was planned; 1262 (942 ION Stent and 320 TAXUS Express Stent) were enrolled and randomized at 90 sites. A total of 330 subjects were randomly assigned to protocol-mandated 9-month angiographic follow-up (angiographic subset). The protocol mandated antiplatelet therapy compliance in accordance with the ACC/AHA/SCAI Guidelines for $\mathrm{PCI}^2$.

The study is now considered complete with regard to the 12-month primary endpoint. Additional follow-up is ongoing to 5 years.

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# PERSEUS SV

The PERSEUS Small Vessel (SV) study is a prospective, single-arm, superiority trial to evaluate the safety and efficacy of the $1\ \mu\mathrm{g}/\mathrm{mm}^2$ (loaded drug/stent surface area) $2.25\mathrm{mm}$ and $2.5\mathrm{mm}$ ION™ Stents in the treatment of de novo coronary lesions in small vessels. Subjects with de novo target lesion length $\leq 20\mathrm{mm}$ and target vessel diameter $\geq 2.25\mathrm{mm}$ to $&lt; 2.75\mathrm{mm}$ in a native coronary artery were considered for enrollment. The trial compares the ION Stent to a matched bare metal (Express Stent) historical control group comprised of subjects with reference vessel diameter (RVD) $\geq 2.25$ to $&lt; 2.75\mathrm{mm}$ and lesion length $\leq 20\mathrm{mm}$ from the TAXUS V trial. The TAXUS V trial is more fully described in the SSED for P030025/S028 (see http://www.accessdata.fda.gov/cdrh_docs/pdf3/P030025S028b.pdf).

All subjects in PERSEUS SV were required to undergo a 9-month angiographic assessment. The primary endpoint is in-stent late loss by quantitative coronary angiography (QCA) on 9-month follow-up (ION Stent compared to bare metal Express Stent) and the secondary endpoint is TLF at 12 months (ION Stent compared to a performance goal based on TAXUS Express Stent results from the TAXUS IV and TAXUS V trials).

A total of 224 subjects were enrolled at 28 sites. The control group consisted of 125 matched bare metal Express Stent subjects from the TAXUS V trial, including 108 with 9-month QCA follow-up. The protocol mandated antiplatelet therapy compliance in accordance with the ACC/AHA/SCAI Guidelines for $\mathrm{PCI}^2$.

The study is now considered complete with regard to the primary endpoint. Additional follow-up is ongoing to 5 years.

| Table 11: Comparison of PERSEUS Clinical Studies | | |
| --- | --- | --- |
| | PERSEUS Workhorse | PERSEUS Small Vessel |
| Purpose | Evaluation of safety and effectiveness in workhorse lesions | Evaluation of safety and effectiveness in small vessel lesions |
| Study Design | Prospective, multicenter, randomized, single-blind, non-inferiority to PES | Prospective, multicenter, single-arm, superiority to BMS |
| Primary Endpoint | 12-month TLF | 9-month in-stent late loss |
| Number of Subjects (ITT) | Total: 1264 planned; 1262 enrolled and randomized ION Stent: 922 TAXUS Express stent: 320 | Total: 224 ION Stent: 224 BMS Control Group: 125 |
| Polymer | Slow Release Translute™ Polymer | |
| PTx Dose Density | $1\ \mu\mathrm{g}/\mathrm{mm}^2$ | |
| Lesion Criteria: Vessel Diameter (by visual estimate) | $\geq 2.75\mathrm{mm}$ to $\leq 4.00\mathrm{mm}$ | $\geq 2.25\mathrm{mm}$ to $< 2.75\mathrm{mm}$ |
| Lesion Criteria: Lesion Length (by visual estimate) | $\leq 28\mathrm{mm}$ | $\leq 20\mathrm{mm}$ |
| Number of stents | Single | |

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| Stent Matrix | 2.75-4.0mm diameter
8, 12, 16, 20, 24, 28, 32mm length | 2.25-2.50mm diameter
8, 12, 16, 20, 24mm length |
| --- | --- | --- |
| Post-Procedure
Antiplatelet
Therapy | Clopidogrel or ticlopidine: at least 6 months, ideally for 12 months in
subjects who are not at high risk for bleeding.
ASA: indefinitely | |
| Follow-Up | Clinical: 30 day, 9 month, 1 year,
18 month, annually 2-5 years
Angiographic (330 subject subset):
9 month | Clinical: 30 day, 9 month, 1
year, 18 month, annually 2-5
years
Angiographic (all): 9 month |
| Abbreviations: ASA=aspirin; BMS=bare metal stent; ITT=intent-to-treat; PES=paclitaxel-
eluting stent; PTx=paclitaxel; TLF=target lesion failure | | |

# POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of potential adverse events (in alphabetical order) which may be associated with the use of a coronary stent in native coronary arteries including but are not limited to:

- Abrupt stent closure
- Acute myocardial infarction
- Allergic reaction to anti-coagulant and/or antiplatelet therapy, contrast medium, or stent materials
- Angina
- Arrhythmias, including ventricular fibrillation and ventricular tachycardia
- Arteriovenous fistula
- Cardiac tamponade
- Cardiogenic shock/pulmonary edema
- Coronary aneurysm
- Death
- Dissection
- Emboli, distal (air, tissue or thrombotic material or material from devices(s) used in the procedure)
- Heart failure
- Hematoma
- Hemorrhage, requiring transfusion
- Hypotension/hypertension
- Infection, local or systemic
- Ischemia, myocardial
- Pain, access site
- Perforation or rupture of coronary artery
- Pericardial effusion
- Pseudoaneurysm, femoral
- Renal failure
- Respiratory failure
- Restenosis of stented segment
- Stent embolization or migration
- Stent thrombosis/occlusion
- Stroke/cerebrovascular accident /TIA

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- Total occlusion of coronary artery
- Vessel spasm
- Vessel trauma requiring surgical repair or reintervention

Potential adverse events 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
- Blood product transfusion
- Gastrointestinal symptoms
- Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia)
- 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 studies, please see Section IX, Tables 13 and 20.

## A. PERSEUS WH Clinical Trial

**Primary Objective:** The primary objective of the PERSEUS WH study was to evaluate the safety and efficacy of the ION™ Paclitaxel-Eluting Platinum Chromium Coronary Stent System for the treatment of *de novo* atherosclerotic lesions of up to 28mm in length (by visual estimate) in native coronary arteries of 2.75mm to 4.0mm diameter (by visual estimate) compared to TAXUS Express Stent control.

**Design:** PERSEUS WH is a prospective, randomized, controlled, single-blind, non-inferiority trial which employs a 3:1 randomization to the ION or the TAXUS Express Paclitaxel-Eluting Stent respectively. Eligible subjects were those ≥18 years old with documented stable angina pectoris, unstable angina pectoris, or documented silent ischemia and left ventricular ejection fraction (LVEF) ≥30%. *De novo* target lesions in a native coronary artery with diameter stenosis ≥50%, reference vessel diameter ≥2.75mm to ≤4.0mm, and cumulative lesion length ≤28mm coverable by a single study stent were eligible. Multiple stenting was allowed for bail-out only. The protocol mandated antiplatelet therapy compliance in accordance with the ACC/AHA/SCAI Guidelines for PCI². While subjects in this trial could be blinded, the operators could not, as the identity of the stent could be determined by the operator on the basis of a visual comparison of stent design prior to implantation. Use of a Clinical Events Committee and an angiographic core lab minimized potential bias introduced from the inability to completely blind all study participants.

Enrollment of 1264 subjects was planned. A total of 1262 (942 ION Stent and 320 TAXUS Express Stent) were enrolled and randomized at 90 centers. Of the 1262

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subjects included in the intent-to-treat analysis set, a total of 1235 subjects (922 ION Stent and 313 TAXUS Express Stent) were evaluable for the 12-month primary endpoint. A total of 330 subjects (256 ION, 74 TAXUS Express) were randomly assigned to protocol-mandated 9-month angiographic follow-up (angiographic subset). Angiographic assessments were performed for the area of the vessel within the stent margins (in-stent) and the areas immediately 5 mm proximal and distal from the stent margins (analysis segment).

An angiographic core lab was utilized for analysis of angiography data. A Clinical Events Committee (CEC) served as a multidisciplinary expert group responsible for the independent and ongoing adjudication of prespecified clinical events, including all reported deaths, myocardial infarctions (MI), target vessel revascularizations (TVR), and stent thromboses (ST), as defined by the clinical protocol. A Data Monitoring Committee (DMC) of independent experts in cardiology, cardiovascular interventional therapy, and biostatistics worked to ensure patient safety by evaluating accumulating data from the PERSEUS Clinical Program.

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the PERSEUS WH study was limited to subjects who met the following inclusion criteria:

- Subject is ≥ 18 years old
- Eligible for percutaneous coronary intervention (PCI)
- Documented stable angina pectoris, or documented silent ischemia
- Acceptable candidate for coronary artery bypass grafting (CABG)
- Left ventricular ejection fraction (LVEF) is ≥ 30%
- Subject (or legal guardian) understands the study requirements and the treatment procedures and provides written Informed Consent before any study-specific tests or procedures are performed
- Subject willing to comply with all specified follow-up evaluations

## ANGIOGRAPHIC INCLUSION (by visual estimate)

- Target lesion located in native coronary artery
- Target lesion must be de novo
- Target lesion diameter stenosis ≥ 50%
- Reference vessel diameter (RVD): ≥ 2.75mm to ≤ 4.0mm
- Cumulative target lesion length (area to be treated must be completely coverable by one study stent): ≤ 28mm
- Target lesion is successfully pre-dilated. Subjects are enrolled only after successful balloon catheter pre-dilation of the target lesion
- One non-target lesion may be treated in a non-target vessel
- Non-target lesion in non-target vessel must be treated with a commercially available TAXUS stent if use of drug-eluting stent required
- Treatment of a non-target lesion (if performed) must be deemed a clinical angiographic success, without requiring use of unplanned additional stent(s)

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- Treatment must be completed prior to treatment of target lesion

Subjects were not permitted to enroll in the PERSEUS WH study if they met any of the following exclusion criteria:

- Contraindication to ASA, or to both clopidogrel and ticlopidine
- Known hypersensitivity to paclitaxel
- Known allergy to stainless steel
- Known allergy to platinum
- Previous treatment of the target vessel with any anti-restenotic drug-coated or drug-eluting coronary stent
- Previous treatment of the target vessel with a bare metal stent (BMS) within 9 months of the index procedure
- Previous treatment of any non-target vessel with any anti-restenotic drug-coated or drug-eluting coronary stent within 9 months of the index procedure
- Previous treatment with intravascular brachytherapy in the target vessel
- Planned PCI or CABG post-index procedure
- Planned or actual target vessel treatment with an unapproved device, directional or rotational coronary atherectomy, laser, cutting balloon or transluminal extraction catheter immediately prior to stent placement
- Myocardial infarction (MI) within 72 hours prior to the index procedure as defined per protocol definition (see Section 4.2)
- Cerebrovascular accident (CVA) within the past 6 months
- Cardiogenic shock characterized by systolic pressure &lt;80mm Hg and/or central filling pressure &gt;20mm Hg, or cardiac index &lt;1.8 liters/minute/m² or intra-aortic balloon pump or intravenous inotropes are needed to maintain a systolic pressure &gt;80mm Hg and a cardiac index &gt;1.8 liters/minute/m²
- Acute or chronic renal dysfunction (creatinine &gt;2.0 mg/dl or 177 μmol/l)
- Any prior true anaphylactic reaction to contrast agents; defined as known anaphylactoid or other non-anaphylactic allergic reactions to contrast agents that cannot be adequately pre-medicated prior to the index procedure
- Leukopenia (leukocyte count &lt;3.5 x 109/liter)
- Thrombocytopenia (platelet count &lt;100,000/mm³)
- Thrombocytosis (&gt;750,000/mm³)
- Active peptic ulcer or active gastrointestinal (GI) bleeding
- Current treatment, or past treatment within 12 months of the index procedure, with paclitaxel or other chemotherapeutic agent(s)
- Anticipated treatment with paclitaxel or oral rapamycin during any period in the 9 months after the index procedure
- Male or female with known intention to procreate within 9 months after the index procedure
- Positive pregnancy test within 7 days before the index procedure, or lactating
- Life expectancy of less than 24 months due to other medical conditions
- Co-morbid condition(s) that could limit the subject’s ability to comply with study follow-up requirements or impact the scientific integrity of the study
- Currently participating in another investigational drug or device study

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# ANGIOGRAPHIC EXCLUSION (by visual estimate)

- Target lesion in left main artery, whether protected or unprotected
- Target lesion is a chronic total occlusion (TIMI flow &lt;1)
- Target lesion is restenotic
- Target lesion is located in a saphenous vein graft or mammary artery graft
- Target lesion is accessed via saphenous vein graft or mammary artery graft
- Target lesion is &lt;5mm from bare metal stent (BMS)
- Target lesion is &lt;5mm from ostium
- Target lesion is &lt;5mm from a side branch vessel ≥2.0mm in diameter (Exceptions: subject may be enrolled if side branch is 100% occluded or if side branch is protected with a patent graft)
- Untreated lesions with ≥50% diameter stenosis or thought to impair flow remaining in target vessel at a location with ≥2.0mm RVD
- Target lesion and/or target vessel proximal to the target lesion is moderately or severely calcified
- Target lesion and/or target vessel proximal to the target lesion is severely tortuous
- Target lesion is located within or distal to a &gt;60° bend in the vessel
- Target lesion with angiographic presence of probable or definite thrombus
- Unprotected left main coronary artery disease
- Protected left main coronary artery disease with target lesion in LAD or LCX (subject may be enrolled if only lesion is target lesion in RCA)

## 2. Follow-up Schedule

All subjects were scheduled to return for follow-up examinations at 30 days, 9, 12 and 18 months, and 2, 3, 4 and 5 years post index procedure. Subjects received the examinations outlined in Table 12.

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Table 12: Examination Schedule

| | ≤ 7 days Before Procedure | ≤ 24 hours Before Procedure | Procedure^{1} | Post-Procedure/Hospital Discharge | Office Visit 1-Month^{1} ± 7 days | Office Visit 9-Month^{1} ± 14 days | Office Visit or Phone Interview Years 1-5^{1} ± 30 days |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Informed Consent (and HIPAA in US) | X | | | | | | |
| Demographics & Medical History | X | | | | | | |
| Clinical Status with Anginal Assessment | X | | | X | X | X | X |
| Ejection Fraction^{2} | X | | | | | | |
| 12-lead Electrocardiogram (ECG) | | X | | X | | | |
| Laboratory Tests: | | | | | | | |
| Serum Creatinine | X | | | | | | |
| CBC with platelets^{2} | X | | | | | | |
| Pregnancy Test^{4} | X | | | | | | |
| CK Total / CK-MB | | X | | X^{5} | | | |
| Cardiac Medications | | X | X | X | X | X | X |
| Angiography with Film Sent to Core Lab | | | | X | | X^{6} | |
| Record Antithrombotic & Antiplatelet Medications | | X | X | X | X | X | X |
| Clopidogrel or ticlopidine | | X | | X | X | X | X |
| ASA | | X | | X | X | X | X |
| Nitroglycerin | | | X | | | | |
| Heparin (or other antithrombotic) | | | X | | | | |
| AE Assessment | | | X | X | X | X | X |
| SAE & MACE Assessment | | | X | X | X | X | X |

1. All follow-up dates will be calculated from the date of the index procedure. Starting at the 2-year visit, follow-up will be limited to the Safety Population, composed of subjects who have received a study stent. If subject is not able to return for office visit within the 1-month window, assessment via telephone interview is acceptable. For subjects randomized to QCA subset, an office visit and QCA within the 9-month window are required; for subjects randomized to non-QCA subset, assessment in the office or via telephone interview is acceptable. If a subject is not able to return for an office visit within the 12-month window, assessment via telephone interview is acceptable.
2. Ejection fraction by angiography, echocardiography, or radionuclide ventriculography.
3. Complete Blood Count (CBC) with platelets (differential is required ONLY if the subject is taking ticlopidine and/or there are abnormal values of leukocytes).
4. For females of childbearing potential.
5. CK Total must be drawn at intervals as per institutional standard of care for 24 hours or until hospital discharge, whichever comes first. For subjects discharged prior to 24 hours after the procedure, the final CK Total is obtained at discharge. If CK Total values are abnormal (2x ULN), it is mandatory to also perform CK-MB.
6. Mandatory for subjects randomized to angiographic follow-up. Additional angiography performed within 5 years post index procedure must be sent to the core lab for central analysis.

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After the 12-month follow-up, the study population was reduced to a pre-specified cohort (Safety Population), which consists of all subjects who received a study stent (ION Stent or TAXUS Express Stent). The study is now considered complete with regard to the 12-month primary endpoint.

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

## 3. Clinical Endpoints

The primary endpoint is the rate of target lesion failure (TLF; including any ischemia-driven revascularization of the target lesion [TLR], myocardial infarction [MI; Q-wave and non-Q-wave] related to the target vessel, or cardiac death related to the target vessel) at 12 months post-index procedure, testing non-inferiority of the ION Stent relative to the TAXUS Express Paclitaxel-Eluting Stent control. In-segment percent diameter stenosis at 9 months post-index procedure as measured by quantitative coronary angiography (QCA) is the secondary endpoint.

Both the primary and secondary endpoints were analyzed under a Bayesian framework. Bayesian analyses can be interpreted in a more intuitive way than conventional frequentist analyses through the posterior distributions they produce. These posterior distributions give the probability that a parameter of interest (e.g. the difference in the rate of TLF across treatment groups) lies within a certain range, given the data observed. Therefore, Bayesian methods can provide a posterior probability that the non-inferiority hypothesis is true given the data observed, whereas the frequentist P value provides the probability of observing data as or more extreme than that observed assuming the non-inferiority hypothesis is false.

## A1. Accountability of PMA Cohort

At the time of database lock, of 1262 subjects enrolled in PMA study, 97.86% (1235) subjects are available for analysis at the completion of the study, the 12-month primary endpoint.

Subject Disposition for PERSEUS WH Study, ITT, All Subjects (N=1262)

| | TAXUS Express (N=320) | ION (N=942) | Total (N=1262) |
| --- | --- | --- | --- |
| All Subjects Treated | - | - | 1264 |
| Treated, Not Randomized | - | - | 2^{a} |
| Intent-to-Treat (ITT) Analysis Set | 320 | 942 | 1262 |
| Death ≤395 days with no 12-month Clinical Follow-up Performed | 2 | 6 | 8 |
| Eligible for 12-month Clinical Follow-up^{b} | 318 | 936 | 1254 |
| 12-month Clinical Follow-Up Visit Performed^{c} | 97.8% (311/318) | 97.6% (914/936) | 97.7% (1225/1254) |
| Office Visit | 41 | 136 | 177 |
| Telephone Contact | 270 | 776 | 1046 |
| No 12-month Clinical Follow-up Visit Performed | 7 | 22 | 29 |
| Premature Discontinuation | 3 | 9 | 12 |

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Subject Disposition for PERSEUS WH Study, ITT, All Subjects (N=1262)

| | TAXUS Express (N=320) | ION (N=942) | Total (N=1262) |
| --- | --- | --- | --- |
| Withdrew Consent | 0 | 4 | 4 |
| Lost to Follow-up | 1 | 2 | 3 |
| Other | 2 | 3 | 5^{d} |
| Death >395 days | 0 | 0 | 0 |
| Missed 12-month Follow-up Visit | 4 | 13 | 17 |
| With Later Follow-up Visit Performed | 1 | 3 | 4 |
| No Later Follow-up Visit Performed | 3 | 10 | 13 |
| 12-month Clinical Follow-Up or Death^{e} | 97.8% (313/320) | 97.7% (920/942) | 97.7% (1233/1262) |
| 12-month Clinical Follow-Up Subject Accountability^{f} | 97.2% (311/320) | 97.0% (914/942) | 97.1% (1225/1262) |

Numbers are % (Count/Sample Size) or Count.

a Two subjects were treated without randomization and therefore are not included in the analysis.
b Subjects who died prior to completion of follow-up window and prior to completing a 12-month clinical follow-up visit are considered censored and are excluded from calculation of proportion of subjects who completed clinical follow-up visit.
c Based on subjects eligible for 12-month clinical follow-up (excludes deaths within 395 days).
d Four subjects withdrawn at the investigator’s discretion and one coded as a “discontinuation” (all for lack of follow-up)
e Includes subjects who have died in both the numerator and the denominator; based on intent-to-treat analysis set.
f Based on intent-to-treat analysis set.

Abbreviations: ITT: intent-to-treat; TLF: target lesion failure.

## A2. Study Population Demographics and Baseline Parameters

Subjects were well-matched for baseline demographics. Age was slightly lower in the ION™ Stent group compared to the TAXUS Express Stent control (62±9.6 versus 63±9.5).

Baseline lesion characteristics: Reference vessel diameter was 2.78±0.48mm and 2.75±0.47mm in the ION Stent and TAXUS Express Stent groups, respectively, with baseline lesion length of 14.2±6.1mm and 14.1±5.8mm, respectively.

Baseline Demographic and Clinical Characteristics, ITT, All Subjects, PERSEUS WH (N=1262)

| Parameter | TAXUS Express (N=320) | ION (N=942) |
| --- | --- | --- |
| Male | 68.8% (220/320) | 70.8% (667/942) |
| Age (yr) | 63.5±9.5 (320)
(41.0, 82.0) | 62.2±9.6 (942)
(33.0, 84.0) |
| Ethnicity and Race | | |
| Hispanic or Latino | 1.9% (6/320) | 1.1% (10/942) |
| Caucasian | 92.5% (296/320) | 92.6% (872/942) |
| Asian | 1.9% (6/320) | 1.6% (15/942) |

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Baseline Demographic and Clinical Characteristics, ITT, All Subjects, PERSEUS WH (N=1262)

| Parameter | TAXUS Express (N=320) | ION (N=942) |
| --- | --- | --- |
| Black, of African heritage | 4.1% (13/320) | 3.9% (37/942) |
| Native Hawaiian or other Pacific Islander | 0.3% (1/320) | 0.4% (4/942) |
| American Indian or Alaska native | 0.0% (0/320) | 0.3% (3/942) |
| Other | 0.0% (0/320) | 0.4% (4/942) |
| Cardiac History | | |
| Previous PCI | 25.2% (80/318) | 23.0% (216/941) |
| Previous CABG | 6.3% (20/319) | 4.5% (42/942) |
| Previous MI | 19.0% (60/316) | 20.9% (195/935) |
| CHF | 7.5% (24/318) | 6.0% (56/937) |
| Stable Angina | 66.6% (213/320) | 66.8% (629/941) |
| Unstable Angina | 21.3% (68/320) | 20.7% (195/941) |
| Silent Ischemia | 12.2% (39/320) | 12.4% (117/941) |
| Ejection Fraction (%) | 57.8±9.8 (317)
(30.0, 98.0) | 58.0±9.3 (939)
(30.0, 93.0) |
| Cardiac Risk Factors | | |
| Smoking, Ever | 69.5% (216/311) | 66.7% (611/916) |
| Current | 23.5% (73/311) | 24.3% (223/916) |
| Previous | 46.0% (143/311) | 42.4% (388/916) |
| Medically Treated Diabetes | 25.0% (80/320) | 24.6% (232/942) |
| Insulin Requiring | 7.5% (24/320) | 7.3% (69/942) |
| Non-insulin Requiring | 17.5% (56/320) | 17.3% (163/942) |
| Hyperlipidemia Req. Medication | 76.4% (243/318) | 76.3% (717/940) |
| Hypertension Req. Medication | 80.3% (256/319) | 75.3% (709/941) |
| Family History of CAD | 66.4% (196/295) | 67.0% (589/879) |
| Comorbidities | | |
| History of PVD | 11.3% (36/319) | 10.6% (99/938) |
| History of TIA or CVA | 7.5% (24/320) | 5.7% (54/941) |
| History of TIA | 4.4% (14/319) | 3.2% (30/940) |
| History of CVA | 3.8% (12/318) | 3.2% (30/940) |
| Renal Disease | 3.4% (11/320) | 4.8% (45/940) |
| History of GI Bleeding | 2.2% (7/319) | 1.0% (9/939) |

Numbers are % (Count/Sample Size) or Mean±SD (N) (Min, Max).
Abbreviations: CABG: coronary artery bypass graft; CAD: coronary artery disease; CHF: congestive heart failure; CI: confidence interval; CVA: cerebrovascular accident; GI: gastrointestinal; MI: myocardial infarction; PCI: percutaneous coronary intervention; PVD: peripheral vascular disease; TIA: transient ischemic attack.

Baseline Lesion Characteristics by QCA, ITT, All Subjects, PERSEUS WH (N=1262)

| Lesion Characteristic | TAXUS Express (N=320) | ION (N=942) |
| --- | --- | --- |
| Target Lesion Vessel | | |
| LAD | 43.8% (140/320) | 43.1% (406/942) |

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| LCX | 21.6% (69/320) | 23.0% (217/942) |
| --- | --- | --- |
| RCA | 34.7% (111/320) | 33.9% (319/942) |
| Lesion Location | | |
| Ostial | 2.5% (8/320) | 2.7% (25/942) |
| Proximal | 40.0% (128/320) | 39.1% (368/942) |
| Mid | 48.1% (154/320) | 51.5% (485/942) |
| Distal | 9.4% (30/320) | 6.8% (64/942) |
| Reference Vessel | 2.8±0.5 (320) | 2.8±0.5 (942) |
| Diameter (RVD, mm) | (1.6, 4.6) | (1.4, 4.5) |
| Minimum Lumen | 0.8±0.4 (320) | 0.8±0.3 (942) |
| Diameter (MLD,mm) | (0.0, 2.1) | (0.0, 2.4) |
| Percent Diameter Stenosis | 71.7±10.9 (320) | 72.1±10.9 (942) |
| (% DS) | (40.0, 100.0) | (40.3, 100.0) |
| Lesion Length (mm) | 14.1±5.8 (320) | 14.2±6.1 (942) |
| | (4.2, 40.9) | (3.2, 40.1) |
| Eccentric Lesion | 50.3% (161/320) | 51.7% (487/942) |
| Bend (degrees) | | |
| > 45 | 6.9% (22/320) | 6.5% (61/942) |
| > 90 | 0.3% (1/320) | 0.2% (2/942) |
| Tortuosity, Any | 4.4% (14/320) | 6.3% (59/942) |
| Moderate | 4.1% (13/320) | 5.7% (54/942) |
| Severe | 0.3% (1/320) | 0.5% (5/942) |
| Calcification, Any | 26.9% (86/320) | 24.2% (228/942) |
| Moderate | 22.2% (71/320) | 17.8% (168/942) |
| Severe | 4.7% (15/320) | 6.4% (60/942) |
| Total Occlusion | 0.6% (2/320) | 0.6% (6/942) |
| Bifurcation | 40.3% (129/320) | 36.4% (343/942) |
| Sidebranch Stenosis | 25.7±28.8 (129) | 24.4±28.1 (342) |
| | (0.0, 95.0) | (0.0, 100.0) |
| Modified ACC/AHA | | |
| A | 8.8% (28/320) | 8.4% (79/942) |
| B1 | 26.6% (85/320) | 24.7% (233/942) |
| B2 | 40.6% (130/320) | 40.8% (384/942) |
| C | 24.1% (77/320) | 26.1% (246/942) |
| Pre-Procedure TIMI Flow | | |
| 0 | 0.6% (2/320) | 0.2% (2/942) |
| 1 | 0.0% (0/320) | 0.4% (4/942) |
| 2 | 1.3% (4/320) | 3.6% (34/942) |
| 3 | 98.1% (314/320) | 95.8% (902/942) |

Numbers are % (Count/Sample Size) or Mean±SD (N) (Min, Max).

Abbreviations: ACC/AHA: American College of Cardiology/American Heart Association; CI: confidence interval; DS: diameter stenosis; LAD: left anterior descending; LCX: left circumflex; MLD: minimum lumen diameter; QCA: quantitative coronary angiography; RCA: right coronary artery; RVD: reference vessel diameter; TIMI: thrombolysis in myocardial infarction.

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# A3. Safety and Effectiveness Results

## 1. Safety Results

The analysis of safety was based on the ION stent cohort of 942 subjects available for the 12-month primary endpoint evaluation. Principal adverse events for this study are presented in Table 13 below.

| Table 13: Principal Adverse Events | | |
| --- | --- | --- |
| | PERSEUS Workhorse to 1 Year | |
| | ION Stent (N=942) | TAXUS Express Stenta (N=320) |
| In-Hospital MACE | 1.9% (18/942) | 2.5% (8/320) |
| 30-Day MACE | 2.2% (21/939) | 3.1% (10/319) |
| 9-Month MACE | 5.6% (52/932) | 6.3% (20/317) |
| Cardiac Death | 0.3% (3/932) | 0.3% (1/317) |
| MI | 2.0% (19/932) | 2.8% (9/317) |
| Q-Wave MI | 0.4% (4/932) | 0.0% (0/317) |
| Non-Q-Wave MI | 1.6% (15/932) | 2.8% (9/317) |
| TVR | 4.0% (37/932) | 4.4% (14/317) |
| TLR | 2.6% (24/932) | 3.5% (11/317) |
| Non-TLR | 1.9% (18/932) | 1.3% (4/317) |
| 1-Year MACE | 7.4% (68/922) | 7.7% (24/313) |
| Cardiac Death | 0.5% (5/922) | 0.3% (1/313) |
| MI | 2.2% (20/922) | 2.9% (9/313) |
| Q-Wave MI | 0.5% (5/922) | 0.0% (0/313) |
| Non-Q-Wave MI | 1.6% (15/922) | 2.9% (9/313) |
| TVR | 5.6% (52/922) | 5.8% (18/313) |
| TLR | 3.8% (35/922) | 4.5% (14/313) |
| Non-TLR | 2.5% (23/922) | 1.9% (6/313) |
| 1-Year ARC Stent Thrombosis | | |
| Definite or Probable | 0.4% (4/918) | 0.3% (1/313) |
| Definite | 0.3% (3/918) | 0.3% (1/313) |
| Probable | 0.1% (1/918) | 0.0% (0/313) |

a DES Control

An angiographic core laboratory review of all available angiograms in the PERSEUS Clinical Trial revealed a total of 3 stent fractures - 2 ION stent fractures (Type 3³ fractures that were seen on angiograms performed at 286 and 259 days post-stent implantation) and 1 Taxus Express stent fracture (Type 4³ fracture noted on an angiogram performed 861 days post-stent implantation). Only the fracture that occurred with the Taxus Express stent was associated with a major adverse cardiovascular event (a TLR).

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# 2. Effectiveness Results

The analysis of effectiveness was based on the 942 subjects available for the 12-month primary endpoint evaluation. Key safety and effectiveness outcomes are presented in Tables 14 through 19.

| Table 14: PERSEUS Workhorse Clinical Results | | |
| --- | --- | --- |
| | 1-year (ITT population) | |
| | ION Stent (N=942) | TAXUS Express Stenta (N=320) |
| EFFICACY | | |
| TVR, Overall | 5.6% (52/922) | 5.8% (18/313) |
| TLR, Overall | 3.8% (35/922) | 4.5% (14/313) |
| TLR, PCI | 3.6% (33/922) | 4.2% (13/313) |
| TLR, CABG | 0.3% (3/922) | 0.6% (2/313) |
| Non-TLR, Overall | 2.5% (23/922) | 1.9% (6/313) |
| Non-TLR, PCI | 2.3% (21/922) | 1.6% (5/313) |
| Non-TLR, CABG | 0.3% (3/922) | 1.0% (3/313) |
| SAFETY | | |
| Total Death | 0.7% (6/922) | 0.6% (2/314) |
| Cardiac Death or MI | 2.5% (23/922) | 2.9% (9/313) |
| Cardiac Death | 0.5% (5/922) | 0.3% (1/313) |
| MI | 2.2% (20/922) | 2.9% (9/313) |
| Q-wave MI | 0.5% (5/922) | 0.0% (0/313) |
| Non-Q-wave MI | 1.6% (15/922) | 2.9% (9/313) |
| ARC Stent Thrombosis | | |
| Definite or Probable | 0.4% (4/918) | 0.3% (1/313) |
| Definite | 0.3% (3/918) | 0.3% (1/313) |
| Probable | 0.1% (1/918) | 0.0% (0/313) |

a DES Control
b Timing of non-Q-wave MI: 15/15 ION events and 8/9 TAXUS Express events occurred peri-procedurally.
This trial was not sized to determine the rate of low frequency events with a pre-specified precision.
Abbreviations: ARC=Academic Research Consortium; CABG=coronary artery bypass graft; DES=drug-eluting stent; MI=myocardial infarction; PCI=percutaneous coronary intervention; TLR=target lesion revascularization; TVR=target vessel revascularization.

Primary Endpoint (12-Month TLF): The primary endpoint was met: There is a 99.96% Bayesian posterior probability that ION Stent is non-inferior to TAXUS Express Stent (given the data observed), demonstrating non-inferiority of the ION Stent versus the TAXUS Express Stent.

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| Table 15: PERSEUS Workhorse Primary Endpoint | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| 12-Month Target Lesion Failure (TLF) | ION Stent | TAXUS Express Stent | Difference | | Δ | Posterior Probability of NI^{c} |
| | Posterior Mean (SD) | Posterior Mean (SD) | Posterior Mean (SD) | 95% CI^{b} | | |
| Per Protocol^{a} | 5.568% (0.0076) | 6.138% (0.0136) | -0.570% (0.0155)…