PROMUS ELEMENT PLUS EVEROLIMUS-ELUTING PLATINUM CHROMIUM CORONARY STENT SYSTEM

P110010 · Boston Scientific Corp · NIQ · Nov 22, 2011 · Cardiovascular

Device Facts

• Record ID: P110010
• Device Name: PROMUS ELEMENT PLUS EVEROLIMUS-ELUTING PLATINUM CHROMIUM CORONARY STENT SYSTEM
• Applicant: Boston Scientific Corp
• Product Code: NIQ · Cardiovascular
• Decision Date: Nov 22, 2011
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The PROMUS Element Plus Everolimus-Eluting Platinum Chromium Coronary Stent System is indicated for improving luminal diameter in patients with symptomatic heart disease due to de novo lesions in native coronary arteries ≥2.25 mm to ≤4.00 mm in diameter in lesions ≤28 mm in length.

Device Story

The PROMUS Element Plus is a drug-eluting coronary stent system consisting of a balloon-expandable platinum chromium (PtCr) alloy stent coated with a polymer (PVDF-HFP and PBMA) and the drug everolimus. It is delivered via a Monorail or Over-The-Wire catheter. The device is used by interventional cardiologists in a cardiac catheterization lab to treat de novo coronary artery lesions. The stent provides mechanical scaffolding to improve luminal diameter, while the everolimus coating inhibits neointimal growth to reduce restenosis. The physician navigates the delivery system to the target lesion under fluoroscopic guidance, inflates the balloon to deploy the stent, and then withdraws the delivery system. The stent remains permanently implanted, providing structural support and local drug delivery to the vessel wall, which can reduce the need for repeat revascularization and improve patient outcomes in symptomatic coronary artery disease.

Clinical Evidence

Evidence includes the PLATINUM clinical trial program (Workhorse RCT, Small Vessel sub-study, and QCA study). The Workhorse RCT (N=1530) showed 12-month target lesion failure (TLF) of 3.5% for PROMUS Element vs 3.2% for control (non-inferiority met). The Small Vessel study (N=94) showed 12-month TLF of 5.6%, meeting the performance goal of 21.1%. The QCA study (N=100) met efficacy endpoints for 9-month in-stent late loss (0.17 mm) and post-procedure incomplete apposition (5.7%). No clinical data for carcinogenicity/reproductive toxicity was generated; reliance was placed on previously approved XIENCE V data.

Technological Characteristics

Stent material: Platinum Chromium (PtCr) alloy. Coating: Primer layer (PBMA) and drug matrix layer (PVDF-HFP + 100 μg/cm² everolimus). Delivery system: Monorail or Over-The-Wire balloon-expandable catheter. Stent strut thickness: 0.0032-0.0034 inches. Sterilization: Ethylene oxide. MR Conditional at 1.5T and 3T. Connectivity: None (standalone).

Indications for Use

Indicated for patients with symptomatic heart disease due to de novo lesions in native coronary arteries ≥2.25 mm to ≤4.00 mm in diameter and ≤28 mm in length. Contraindicated in patients with hypersensitivity to 316L stainless steel, platinum, everolimus, or polymer components; patients unable to receive antiplatelet/anticoagulant therapy; or patients with 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

• XIENCE V Everolimus Eluting Coronary Stent System (P070015)
• XIENCE nano Everolimus Eluting Coronary Stent System (P070015)
• XIENCE PRIME Everolimus Eluting Coronary Stent System (P110019)
• TAXUS Express Stent (P030025)
• TAXUS Liberté Stent (P060008)
• ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System (P100023)

Reference Devices

• Apex balloon 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 |
| --- | --- |
| Device Trade Name: | PROMUS Element™ Plus Everolimus-Eluting Platinum Chromium Coronary Stent System (Monorail™ and Over-The-Wire) |
| Name and Address of Sponsor: | Boston Scientific Corporation
One Scimed Place
Maple Grove, MN 55311 |
| Premarket Approval Application (PMA) Number: | P110010 |
| Date of Panel Recommendation: | None |
| Date of FDA Notice of Approval: | November 22, 2011 |
| Expedited: | Not Applicable |

## II. INDICATIONS FOR USE

The PROMUS Element Plus Everolimus-Eluting Platinum Chromium Coronary Stent System is indicated for improving luminal diameter in patients with symptomatic heart disease due to *de novo* lesions in native coronary arteries ≥2.25 mm to ≤4.00 mm in diameter in lesions ≤28 mm in length.

## III. CONTRAINDICATIONS

Use of the PROMUS Element Plus Everolimus-Eluting Platinum Chromium Coronary Stent System is contraindicated in patients with known hypersensitivity to:

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- 316L stainless steel or platinum
- everolimus or structurally-related compounds
- the polymers or their individual components (see details in Section V – DEVICE DESCRIPTION)

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

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the PROMUS Element Plus Everolimus-Eluting Platinum Chromium Coronary Stent System Directions for Use (DFU).

## V. DEVICE DESCRIPTION

The PROMUS Element Plus Everolimus-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 everolimus contained in a polymer coating).

The characteristics of the PROMUS Element Plus Stent System are described in Table 1.

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Table 1: PROMUS Element Plus Stent System Product Description

| | PROMUS Element Plus
Monorail Stent Delivery System | PROMUS Element Plus
Over-the-Wire Stent Delivery System |
| --- | --- | --- |
| Available Stent
Lengths (mm) | 8, 12, 16, 20, 24, 28, 32* | |
| 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 inches (0.081 mm) for diameters 2.25 mm to 3.50 mm
0.0034 inches (0.086 mm) for diameter 4.00 mm | |
| Drug Product | A conformal coating of a polymer carrier loaded with 100 μg/cm² everolimus applied to the stent with a maximum nominal drug content of 177.3 μg on the largest stent (4.00 x 28 mm). | |
| Delivery System | | |
| Effective Length | 144 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 inches (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 inches (0.36 mm) |
| Stent Delivery | A balloon, with two radiopaque balloon markers, nominally placed 0.4 mm (0.016 inches) 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 (1117 kPa) | |
| | Rated Burst Inflation Pressure:
• Diameters 2.25 mm – 2.75 mm: 18 atm (1827 kPa)
• Diameters 3.00 mm – 4.00 mm: 16 atm (1620 kPa) | |
| Catheter Shaft Outer
Diameter | 2.3 F (≤0.80 mm) proximal and 2.7 F (≤0.95 mm) distal. | 3.4F (≤1.20 mm) proximal for 2.25 to 4.00 mm sizes
2.4F (≤0.85 mm) distal for 2.25 to 2.75 mm sizes
2.7F (≤0.95 mm) distal for 3.00 to 4.00 mm sizes |
| Guide Catheter
Minimum Inner
Diameter Requirement | ≥0.056 inches (1.42 mm) | ≥0.066 inches (1.68 mm) |

* 32 mm length is only available in the 2.25 mm diameter

## A. Device Component Description

The PROMUS Element Plus Everolimus-Eluting Platinum Chromium Coronary Stent System is a device/drug combination product consisting of a drug/polymer-coated balloon-expandable stent, pre-mounted on a Monorail (MR) or Over-The-Wire (OTW) delivery catheter. The stent is made from a platinum chromium alloy (PtCr). The drug/polymer coating consists of a polymer, PVDF-HFP, and the active pharmaceutical ingredient, everolimus.

Each stent is coated with 100 μg/cm² of everolimus of per mm² stent surface area in a formulation of 1:4.9 (w/w) drug-to-polymer ratio. This is the same dose density and formulation

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used on the commercially available The XIENCE V® and XIENCE nano Everolimus Eluting Coronary Stent System (P070015) and XIENCE PRIME Everolimus Eluting Coronary Stent System (P110019). The PtCr alloy used for the PROMUS Element Stent provides increased strength and radiopacity compared to the 316L stainless steel used in several first-generation stents from BSC such as TAXUS Express² and TAXUS Liberté stents (P030025 and P060008, respectively). The same PtCr Element stent platform is used in the ION™ Paclitaxel-Eluting Platinum Chromium Coronary Stent System (P100023).

The PROMUS Element Stent is the everolimus-coated member of the platinum chromium (PtCr) Element Stent Series. The Element stent is available in four stent models each engineered for specific diameters to provide consistent stent-to-artery ratios across the range of reference vessel diameters indicated:

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

The commercial matrix is shown in Table 2 below:

Table 2: PROMUS Element Plus Stent System Commercial Size Matrix

| Stent Model | Diameter (mm) | Stent Length in mm | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | 8 | 12 | 16 | 20 | 24 | 28 | 32 |
| SV | 2.25 mm | X | X | X | X | X | X | X |
| SWH | 2.50 mm | X | X | X | X | X | X | NA |
| | 2.75 mm | X | X | X | X | X | X | NA |
| WH | 3.00 mm | X | X | X | X | X | X | NA |
| | 3.50 mm | X | X | X | X | X | X | NA |
| LV | 4.00 mm | X | X | X | X | X | X | NA |

## B. Drug Component Description

The PROMUS Element Stent coating consists of two layers, a primer layer and a drug matrix layer. The primer layer is composed of poly (n-butyl methacrylate) (PBMA). The drug matrix layer contains poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) blended with the anti-proliferative drug everolimus.

## B1. Everolimus

The active pharmaceutical ingredient in the PROMUS Element Stent is everolimus. The everolimus chemical name is 40-O-(2-hydroxyethyl)-rapamycin, and its chemical structure is provided in Figure 1. The nominal total loaded dose of everolimus per nominal stent length/diameter is shown in Table 3.

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Figure 1: Structure of Everolimus

Table 3: Nominal Total Loaded Dose of Everolimus (μg) per Nominal Stent Length and Diameter

| Stent Model | | Stent Length | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Design | Diameter | 8 mm | 12 mm | 16 mm | 20 mm | 24 mm | 28 mm | 32 mm |
| Total Loaded Dose Everolimus/Stent (μg) | SV | 38.2 | 57.3 | 72.7 | 91.8 | 107.2 | 126.3 | 145.5 |
| | SWH | 38.9 | 60.6 | 78.0 | 95.4 | 112.7 | 130.1 | N/A |
| | WH | 42.0 | 60.1 | 84.3 | 102.4 | 120.5 | 138.6 | N/A |
| | LV | 56.1 | 80.4 | 104.6 | 128.8 | 153.0 | 177.3 | N/A |

SV – Small Vessel (2.25 mm)
SWH – Small Workhorse (2.50 mm and 2.75 mm)
WH – Workhorse (3.00 mm and 3.50 mm)
LV – Large Vessel (4.00 mm)
N/A – size not available

## B2. Inactive Ingredients

### Primer Polymer and Drug Matrix Copolymer Carrier

The PROMUS Element Stent contains a primer polymer layer, PBMA, poly (n-butyl methacrylate), that functions as an adhesion promoter between the bare metal and the drug matrix layer. The chemical structure of PBMA is shown in Figure 2.

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Figure 2: Formula for Poly (n-butyl methacrylate) Polymer (PBMA)

The drug matrix layer contains a semi-crystalline random copolymer, PVDF-HFP, poly (vinylidene fluoride-co-hexafluoropropylene), blended with everolimus. The chemical structure of PVDF-HFP is shown in Figure 3.

Figure 3: Formula for Vinylidene Fluoride and Hexafluoropropylene Copolymer (PVDF-HFP)

## C. Mechanism of Action

The mechanism by which the PROMUS Element Stent inhibits neointimal growth as seen in preclinical and clinical studies has not been established. At the cellular level, everolimus inhibits growth factor-stimulated cell proliferation. At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12 (FK 506 Binding Protein). This complex binds to and interferes with FRAP (FKBP-12 Rapamycin Associated Protein), also known as mTOR (mammalian Target Of Rapamycin), leading to inhibition of cell metabolism, growth and proliferation by arresting the cell cycle at the late G1 stage.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

Treatment of patients with coronary artery disease 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.

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# VII. MARKET HISTORY

As of December 31, 2010, the PROMUS Element Everolimus-Eluting Coronary Stent System was commercially available in the following countries:

| Albania | Algeria | Andorra | Antigua/Barbuda |
| --- | --- | --- | --- |
| Argentina | Armenia | Aruba | Australia |
| Austria | Azerbaijan | Bahamas | Bahrain |
| Bangladesh | Barbados | Belgium | Belize |
| Belarus | Bermuda | Bolivia | Bosnia |
| Brazil | Brunei | Bulgaria | Chile |
| Colombia | Costa Rica | Croatia | Cyprus |
| Czech Republic | Denmark | Djibouti | Dominican Republic |
| Dutch Antilles | Ecuador | Egypt | El Salvador |
| Estonia | Finland | France | Georgia |
| Germany | Great Britain | Greece | Guatemala |
| Guyana | Haiti | Honduras | Hong Kong |
| Hungary | Iceland | India | Ireland |
| Indonesia | Israel | Iraq | Italy |
| Jamaica | Jordan | Kenya | Korea |
| Kuwait | Latvia | Lebanon | Libya |
| Liechtenstein | Lithuania | Luxembourg | Macedonia |
| Macau | Malaysia | Malta | Martinique |
| Moldavia | Morocco | Myanmar | Nepal |
| Netherlands | New Zealand | Nicaragua | Norway |
| Oman | Pakistan | Palestinian Territory | Panama |
| Paraguay | Peru | Philippines | Poland |
| Puerto Rico | Portugal | Qatar | Romania |
| Russia | Saudi Arabia | Serbia | Singapore |
| Slovakia | Sir Lanka | Slovenia | South Africa |
| Spain | Surinam | Sweden | Switzerland |
| Syria | Taiwan | Thailand | Trinidad/Tobago |
| Tunisia | Turkey | Ukraine | United Arab Emirates |
| Venezuela | Vietnam | Yemen | |

As of October 31, 2011, approximately 577,532 stents have been distributed outside the United States (OUS). No products have been withdrawn from the market in any country for any reason.

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# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Potential adverse events (in alphabetical order) which may be associated with the use of a coronary stent in native coronary arteries include 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
- Bleeding
- 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, which may require transfusion
- Hypotension/hypertension
- Infection, local or systemic
- Ischemia, myocardial
- Pain, access site
- Perforation or rupture of coronary artery
- Pericardial effusion
- Pseudoaneurysm, femoral
- Renal insufficiency or failure
- Respiratory failure
- Restenosis of stented segment
- Stent embolization or migration
- Stent fracture
- Stent thrombosis/occlusion
- Stroke/cerebrovascular accident/transient ischemic attack
- Total occlusion of coronary artery
- Vessel spasm
- Vessel trauma requiring surgical repair or reintervention

Zortress®, the oral formulation of everolimus developed by Novartis Pharmaceuticals Corporation, has been evaluated in clinical trials and is approved in the United States for the prevention of organ rejection in adult kidney transplant recipients at the dose of 1.5 mg/day.

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Outside the U.S., Zortress® is sold under the brand name, Certican®, in more than 70 countries. Everolimus is also approved in the United States under the name of Afinitor® for patients with advanced renal cell carcinoma (cancer), after failure of treatment with sunitinib or sorafenib, at doses of 5 to 20 mg/day when taken by mouth. The following list includes the known risks of everolimus at the oral doses listed above. The amount of drug that circulates in the bloodstream following implantation of a PROMUS Element stent is several folds lower than that obtained with oral doses (1.5 mg to 20 mg/day, see Section 7.2, Pharmacokinetics).

- Abdominal pain (including upper abdominal pain)
- Anemia
- Angioedema
- Anorexia
- Asthenia
- Constipation
- Cough
- Delayed wound healing/fluid accumulation
- Diarrhea
- Dyslipidemia (including hyperlipidemia and hypercholesterolemia)
- Dysgeusia
- Dyspepsia
- Dyspnea
- Dysuria
- Dry skin
- Edema (peripheral)
- Epistaxis
- Fatigue
- Headache
- Hematuria
- Hyperglycemia (may include new onset of diabetes)
- Hyperkalemia
- Hyperlipidemia
- Hypertension
- Hypokalemia
- Hypomagnesemia
- Hypophosphatemia
- Increased serum creatinine
- Infections and serious infections: bacterial, viral, fungal, and protozoal infections (may include herpes virus infection, polyoma virus infection which may be associated with BK virus associated nephropathy, and/or other opportunistic infections)
- Insomnia
- Interaction with strong inhibitors and inducers of CY3PA4
- Leukopenia
- Lymphoma and other malignancies (including skin cancer)
- Male infertility (azospermia and/or oligospermia)

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- Mucosal inflammation (including oral ulceration and oral mucositis)
- Nausea
- Neutropenia
- Non-infectious pneumonitis
- Pain: extremity, incision site and procedural, back, chest, musculoskeletal
- Proteinuria
- Pruritus
- Pyrexia
- Rash
- Stomatitis
- Thrombocytopenia
- Thrombotic microangiopathy (TMA)/Thrombotic thrombocytopenic purpura (TTP)/Hemolytic uremic syndrome (HUS)
- Tremor
- Upper respiratory tract infection
- Urinary tract infection
- Vomiting

Live vaccines should be avoided and close contact with those that have had live vaccines should be avoided. Fetal harm can occur when administered to a pregnant woman. There may be other potential adverse events that are unforeseen at this time.

Please refer to the observed events from the PLATINUM clinical study, which are presented in Section X – Summary of Primary Clinical Studies.

## IX. SUMMARY OF NONCLINICAL 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., PBMA and PVDF-HFP)
- The drug substance (i.e., everolimus)
- The finished combination product

These evaluations included biocompatibility studies, in vivo pharmacokinetics, in vitro engineering studies, coating characterization, chemistry manufacturing and controls testing, stability, sterilization, and animal studies.

## A. Biocompatibility Studies

A series of Good Laboratory Practice (GLP) biocompatibility tests were conducted to demonstrate that the components of the PROMUS Element Plus Everolimus-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, drug

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and polymer coated stents, and stent delivery systems. These test articles were processed in a manner similar to the finished PROMUS Element Plus product. There were some manufacturing differences that were determined not to impact the biocompatibility of the final device, as the surface treatment, coating processing, amount of drug/polymer coating, and sterilization processes were equivalent for both the finished PROMUS Element Stents and test articles utilized during testing.

All biocompatibility testing was conducted in accordance with:

- Guidance for Industry and FDA Staff: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, April 18, 2010
- ISO 10993-1, Biological Evaluation of Medical Devices: Evaluation and Testing (2003)
- Good Laboratory Practices Regulations (§21CFR 58)

The biocompatibility studies are summarized in Table 4.

Table 4.1: Biocompatibility Test Summary (Stent)

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

Sub-chronic toxicity, in vivo thrombogenicity, and implantation of the final PROMUS Element 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 G - Animal Studies, below.

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Carcinogenicity and Reproductive toxicity testing on the PROMUS Element 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 carcinogenicity.

- Everolimus has been extensively studied. The concentration of Everolimus (100μg/cm2) used in this application and the amounts used are equivalent to the concentrations used in the approved PROMUS® / Xience® V stents (P070015); therefore carcinogenicity and reproductive toxicity testing that was previously conducted on the Xience V product is applicable to the PROMUS Element Plus product. For more details, please refer to the SSED for PROMUS® / Xience® V stents located: http://www.accessdata.fda.gov/cdrh_docs/pdf7/P070015b.pdf

- The PVDF and PBMA polymer coating processes and amounts are equivalent to that used in the approved PROMUS® / Xience® V stents (P070015); therefore carcinogenicity and reproductive toxicity testing that was previously conducted on the Xience V product is applicable to the PROMUS Element Plus product. For more details, please refer to the SSED for PROMUS® / Xience® V stents located: http://www.accessdata.fda.gov/cdrh_docs/pdf7/P070015b.pdf

Table 4.2: Biocompatibility Test Summary (Delivery Systems)

| Test / Applicable ISO 10993 Part No. | Test Article | Test Result |
| --- | --- | --- |
| Cytotoxicity (L929 MEM Elution) / Part 5 | PROMUS Element Plus MR and OTW SDS
PROMUS Element MR SDS
ION OTW SDS + SIBS coated Element Stent | Pass |
| Cytotoxicity (Direct Contact) / Part 5 | PROMUS Element Plus MR and OTW SDS
PROMUS Element MR SDS
ION OTW SDS | Pass |
| Sensitization (Guinea Pig Maximization) / Part 10 | PROMUS Element Plus MR SDS
PROMUS Element MR SDS
ION OTW SDS+ SIBS coated Element Stent | Pass |

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| Test / Applicable ISO 10993 Part No. | Test Article | Test Result |
| --- | --- | --- |
| Intracutaneous Reactivity / Part 10 | PROMUS Element MR SDS
ION OTW SDS + SIBS coated Element Stent | Pass |
| Acute Systemic Injection / Part 11 | PROMUS Element MR SDS
ION OTW SDS + SIBS coated Element Stent | Pass |
| Material-Mediated Pyrogenicity (Rabbit) / Part 11 | PROMUS Element MR SDS
ION OTW SDS + SIBS coated Element Stent | Pass |
| Hemolysis (Direct Contact) / Part 4 | PROMUS Element Plus MR and OTW SDS
PROMUS Element MR SDS
ION OTW SDS+ SIBS coated Element Stent | Pass |
| Hemolysis (Extract) / Part 4 | PROMUS Element Plus MR and OTW SDS
PROMUS Element MR SDS
ION OTW SDS | Pass |
| | | Pass |
| Complement Activation (C3a and SC5b-9) / Part 4 | PROMUS Element MR SDS
ION OTW SDS + SIBS coated Element Stent | Pass |
| Supportive Analytical Chemistry Tests | | |
| USP Physicochemical Test for Plastics / Part 18 | PROMUS Element Plus MR and OTW SDS
PROMUS Element MR SDS
ION OTW SDS + SIBS coated Element Stent | Pass |

The commercial PROMUS Element Plus Monorail (MR) and Over-the-Wire (OTW) delivery systems are slightly different from those used in the PROMUS Element MR biocompatibility testing and the PLATINUM clinical trials. The commercial delivery systems consist of the identical materials and similar design and processing to that of PROMUS Element MR biocompatibility test samples and the ION Paclitaxel-Eluting Platinum Chromium Coronary Stent MR and OTW Systems (P100023). The data provided support that any differences between the commercial PROMUS Element Plus delivery systems and the PROMUS Element MR biocompatibility test samples and the

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approved ION MR and OTW delivery systems will not affect the biocompatibility of the final product. Therefore the data from the PROMUS Element MR biocompatibility testing and the ION stent MR and OTW delivery system testing are applicable to the PROMUS Element stent MR and OTW delivery systems.

The applicant did not conduct traditional in vivo thrombogenicity on the PROMUS Element 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 G – 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) and ION stent delivery system.

Based on the testing performed for the Element stent and delivery systems, as well as the established biocompatibility and safety data on everolimus, PBMA and PVDF-HFP, it can be concluded that the PROMUS Element Plus Everolimus–Eluting Platinum Chromium Coronary Stent System is biocompatible for its intended use.

## B. In Vivo Pharmacokinetics

### B1. PROMUS Element Plus Everolimus–Eluting Platinum Chromium Coronary Stent

Boston Scientific has provided a letter from the drug substance manufacturer authorizing access to the drug substance section of their everolimus New Drug Applications (NDAs) in support of this application. The drug substance manufacturer produces tablet forms of everolimus, Certican and Zortress, approved for organ transplant rejection prophylaxis indications and Afinitor for renal carcinoma treatment indications. In vivo animal and in vitro pharmacology and toxicology studies, as well as in vivo animal and human pharmacokinetic studies, were conducted on everolimus 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 matrix layer components of PROMUS Element Plus are identical to that of the PROMUS® (Xience® V) Everolimus Eluting Coronary Stent System (P070015), the evaluation of PROMUS® (Xience® V) is also applicable to PROMUS Element Plus.

The pharmacokinetics (PK) of everolimus eluted from the PROMUS Element stent post-implantation have been evaluated in patients from two different geographies (the United States of America [USA] and Japan) in a non-randomized sub-study of the PLATINUM clinical trial. The design of the sub-study is described in Section X - Summary of Primary Clinical Studies. Whole blood everolimus PK parameters are provided in Table 5 for groups with 3 or more patients receiving the PROMUS Element Stent.

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Table 5: Whole Blood Everolimus Pharmacokinetic Parameters (Mean ± SD) for PLATINUM Groups with Three or More Patients Following PROMUS Element Stent Implantation

| Region | USA | Japan | | Combined | | |
| --- | --- | --- | --- | --- | --- | --- |
| Dose (μg) | 102.4 μg | 102.4 μg | 138.6 μg | 95.4 μg | 102.4 μg | 138.6 μg |
| n | 3 | 4^{b} | 3^{b} | 4^{c} | 7^{b} | 3^{b} |
| t_{max}:
(h) | 0.66
± 0.27 | 0.60
± 0.22 | 0.52
± 0.09 | 0.47
± 0.03 | 0.62
± 0.23 | 0.52
± 0.09 |
| C_{max}:
(ng/mL) | 0.58
± 0.078 | 0.73
± 0.17 | 0.91
± 0.20 | 0.71
± 0.09 | 0.67
± 0.15 | 0.91
± 0.20 |
| AUC_{0-t}:
(ng.h/mL) | 4.77
± 1.70 | 7.71
± 6.97 | 10.87
± 7.36 | 7.27
± 4.97 | 6.45
± 5.26 | 10.87
± 7.36 |
| AUC_{0-24h}:
(ng.h/mL) | 5.76
± 0.85 | 6.42
± 1.30 | 9.51
± 0.64 | 6.83
± 2.03 | 6.14
± 1.10 | 9.51
± 0.64 |
| AUC_{0-∞}:^{a}
(ng.h/mL) | NA | 11.91
± 1.39 | 60.74
± 25.95 | 19.26
± 11.69 | 12.95
± 2.05 | 60.74
± 25.95 |
| t_{1/2}:^{a}
(h) | NA | 18.77
± 2.11 | 136.06
± 62.08 | 34.19
± 20.81 | 22.83
± 7.20 | 136.06
± 62.08 |
| CL:^{a}
(L/h) | NA | 8656
± 1005 | 2511
± 1073 | 6445
± 3924 | 8044
± 1276 | 2511
± 1073 |
| NA: Not assessable
a: Accurate determination not possible
b: n=2 for AUC_{0-∞}, t_{1/2term} and CL
c: n=3 for AUC_{0-∞}, t_{1/2term} and CL
t_{max}(h)= time to maximum concentration.
C_{max}= maximum observed blood concentration.
t_{1/2}(h)= terminal phase half-life.
AUC_{0-t}= the area beneath the blood concentration versus time curve: time zero to the final quantifiable concentration
AUC_{0-24h} = the area beneath the blood concentration versus time curve: time zero to 24 hours post-implant
AUC_{0-∞} = the area beneath the blood concentration versus time curve: time zero to the extrapolated infinite time
CL= total blood clearance | | | | | | |

The results show that individual whole blood concentrations of everolimus tended to increase in proportion to the total dose. Individual $t_{\max}$ values ranged from 0.42 to 1.17 hours. Individual $C_{\max}$ values ranged from 0.25 to 1.10 ng/mL. $AUC_{0-24h}$ values ranged from 0.64 to 9.96 ng.h/mL, while $AUC_{0-t}$ values ranged from 0.24 to 18.15 ng.h/mL. The concentration of everolimus was below the limit of quantification in all patients except for one at 72 hours. The $C_{\max}$ value never reached the minimum therapeutic value of 3.0 ng/mL necessary for effective systemic administration to prevent organ rejection. The PK parameters representing elimination, $t_{1/2}$, $AUC_{0-t}$, $AUC_{last}$, $AUC_{0-∞}$, and total blood clearance (CL) could also not be determined accurately due to rapid everolimus

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disappearance from the blood. These types of results have been seen with other drug-eluting stents.

In summary, in the PLATINUM PK study, everolimus levels were below the detection limit at 72 hrs after stent implantation using an analytical method with a lower limit of quantification (LLOQ) of 0.20 ng/mL, except in one patient. These findings were confirmed in preclinical studies using multiple stents with total loaded doses above the clinically available stent system, where levels were undetectable after 72 hrs post implantation. Hence, in the absence of systemically detectable levels, standard pharmacokinetic parameters were not established.

Everolimus disappearance from circulation following PROMUS Element Stent implantation should further limit systemic exposure and adverse events associated with long-term systemic administration at therapeutic levels. Despite limited systemic exposure to everolimus, consistent local arterial delivery of everolimus from the stent has been demonstrated in pre-clinical studies.

## B2. Drug Interactions

Everolimus is extensively metabolized by the cytochrome P4503A4 (CYP3A4) in the gut wall and liver and is a substrate for the countertransporter P-glycoprotein. Therefore, absorption and subsequent elimination of everolimus may be influenced by drugs that also affect this pathway. Everolimus has also been shown to reduce the clearance of some prescription medications when it was administered orally along with a cyclosporine (CsA). Formal drug interaction studies have not been performed with the PROMUS Element Stent because of limited systemic exposure to everolimus eluted from the stent. However, consideration should be given to the potential for both systemic and local drug interactions in the vessel wall when deciding to place the PROMUS Element Stent in a patient taking a drug with known interaction with everolimus.

Everolimus, when prescribed as an oral medication, may interact with the drugs/foods listed below. Medications that are strong inhibitors of CYP3A4 might reduce everolimus metabolism in vivo. Hence, co-administration of strong inhibitors of CYP3A4 may increase the blood concentrations of everolimus.

- CYP3A4 isozyme inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, erythromycin, clarithromycin, fluconazole, calcium channel blockers [verapamil and diltiazem], aprepitant, atazanavir, nefazodone, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, saquinavir and telithromycin
- Inducers of CYP3A4 isozyme (rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort, efavirenz, nevirapine, and dexamethasone)
- Antibiotics (ciprofloxacin, ofloxacin)
- Glucocorticoids
- HMGCoA reductase inhibitors (simvastatin, lovastatin)
- PgP inhibitors (digoxin, cyclosporine)
- Cisapride (theoretical potential interaction)

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- Sildenafil (Viagra®) (theoretical potential interaction)
- Antihistaminics (terfenadine, astemizole)
- Grapefruit/grapefruit juice

## C. In Vitro Engineering Testing

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

- FDA Guidance for Industry: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, April 18, 2010, and
- FDA Guidance for Industry and Staff: Establishing Safety and Compatibility of Passive Implants in the Magnetic Resonance (MR) Environment, August 2008.

The in vitro engineering studies conducted are summarized in Table 6. “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 PROMUS Element Stent as shown in Section IX – D. Drug Coating Characterization Testing.

For delivery system characterization testing, test articles used were devices identical to the commercial product for balloon characterization and Delivery, Deployment and Retraction testing, while delivery systems identical to those used in the clinical study were used for the other tests. Note that the only differences between the delivery systems used in the clinical study and the commercial devices are in the balloon.

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Table 6: Stent and Delivery Catheter Engineering Testing

| Test | Description of Test | Conclusion |
| --- | --- | --- |
| Material Characterization | | |
| Material Composition | Chemical analysis was conducted on the platinum chromium alloy (PtCr) and is 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).” | Pass |
| Stent Corrosion Resistance | Uncoated Element stents were tested to determine the corrosion susceptibility using cyclic potentiodynamic polarization per ASTM F2129-06,”Conducting Cyclic Potentiodynamic Polarization Measurements.” Characterization of the crevice corrosion behavior of coated stents was performed similar to that described in ASTM F746-04, “Pitting or Crevice Corrosion of Metallic Surgical Implant Materials.” Galvanic Corrosion characterization was performed when the Uncoated Element stent was overlapped with a stent of different metal/metal alloy per ASTM G71-81, “Conducting and Evaluation Galvanic Corrosion Tests in Electrolytes.” Fretting Corrosion and Pitting and Crevice Corrosion was assessed on uncoated Element stents after pulsatile fatigue cycling. The corrosion series testing indicated that the corrosion resistance characteristics of the PROMUS Element Stent met product specification. | Pass |
| Dimensional Verification | To measure and inspect the Element stent to document that the stent dimensional specifications meet the product design requirements, including un-expanded stent dimensions, expanded diameter and length (see also Stent Delivery System Dimensional and Functional Attributes testing). All product met specifications. | Pass |
| Percent Surface Area | Stent surface coverage as a function of stent diameter was measured for the PROMUS Element Stent. The percent surface area is determined by 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. | Pass |
| 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. Results indicated that product specifications were met for recoil of the stent. | Pass |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| 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 when visually examined at 30X following overexpansion. | Pass |
| Radial Stiffness and Radial Strength | Testing was conducted to determine the ability of the PROMUS Element Stent to resist deformation under radial loads. | Pass |
| Compression Resistance | Testing was conducted to determine the radial resistance of the PROMUS Element 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 |
| Radiopacity | In vivo radiopacity of PROMUS Element Plus was performed using fluoroscopy in a porcine model during stent positioning, expansion and after the stent delivery system removal. Radiopacity of PROMUS Element Plus was found to be clinically acceptable in the swine model based on a blinded subjective assessment by the study Interventionalist. | Pass |
| Longitudinal Stiffness | Testing was conducted to determine the ability of the PROMUS Element Stent to resist deformation under axial compressive loads. | Characterization test / no acceptance criteria |
| Magnetic Resonance Imaging (MRI) Safety and Compatibility | The PROMUS Element 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. The conditions are as follows:
• Field strengths of 1.5 and 3 Tesla
• Static magnetic field gradient <900 gauss/cm (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 PROMUS Element 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 | Pass |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| | MR Conditional beyond these conditions.

3.0 Tesla Temperature Information
Non-clinical testing of RF-induced heating was performed at 123 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 39 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. | |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| | Medical Registration
It is recommended that patients register the conditions under which the implant can be scanned safely with the MedicAlert Foundation (www.medicalert.org) or equivalent organization. | |
| **Stent Delivery System Dimensional and Functional Attributes** | | |
| Delivery, Deployment and Retraction | The delivery, deployment and retraction of the PROMUS Element Plus Stent System was assessed by testing system track, crossing profile, deflated balloon profile, stent deployment, flexibility/kink, guidewire movement, torque strength, and balloon withdrawal from a stent and into the guide catheter. Testing demonstrated that the PROMUS Element Plus stent system could be delivered to the target location, deployed, and retracted, thus meeting required acceptance criteria. | Pass |
| Balloon Rated Burst Pressure (RBP) | PROMUS Element Plus 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 | PROMUS Element Plus 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 PROMUS Element Plus stent delivery system were tested to determine the balloon bond, tip 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 | PROMUS Element Plus delivery systems across the range of balloon lengths and diameters were tested for deflation times, and all stent systems met specifications. | Pass |
| Stent | Testing was conducted to assess the forces required to | Pass |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| Securement for Unsheathed Stents | displace a crimped PROMUS Element Stent from the delivery systems (1) directly from the delivery catheters, (2) after tracking through a simulated tortuous artery model and then through a simulated lesion. All stent systems met the stent securement specification. | |
| 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 following a track conditioning step in which the PROMUS Element Plus Stent Delivery Systems were challenged by repeatedly tracking the crimped stent system through a tortuous artery model. The unit was then assessed for stent movement. All samples met the specification. | Pass |
| Stent/Balloon Catheter Withdrawal Resistance | Testing was conducted to verify that the PROMUS Element Stent and deflated balloon 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 |
| **Stent, System and Coating Durability Testing** | | |
| Acute Coating Integrity | The acute coating integrity of the PROMUS Element Stent coating was assessed via a series of acute in vitro tests performed on the coated stent (baseline and simulated use). The test results demonstrate that the PVDF-HFP/everolimus coating displays acceptable acute coating integrity. | Pass |
| Coating Adhesion and Cohesion | Coating adhesion and coating cohesion testing has been performed to assess the adhesive and cohesive properties of the PROMUS Element Stent coating. The PROMUS Element Plus 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 | Accelerated durability testing was performed on the | Pass |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| Durability Testing | PROMUS Element 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. All tested stents were free from fatigue induced strut fracture, and there was no evidence of coating integrity impact. The coated stent met the 10 year accelerated fatigue resistance specification. | |
| Particulate Testing | Particulate testing included assessment of Baseline Particulate (including Overexpansion), Simulated Use Particulate on the stent and delivery system, and Chronic Particulate overlapped on a curve following exposure to the pulsatile stresses and strains exceeding those typically experienced by a human coronary artery for 10 years (400 million cycles). The results demonstrate that the particulate counts are similar between PROMUS Element and ION stents, which in turn was similar to bare Element stents. Given comparable particulate counts, and that there is no evident increase in counts on PROMUS Element coated stent product, no chemical identification of particulates was warranted. | Pass |

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# D. Drug Coating Characterization Testing

The coating characterization testing conducted on the PROMUS Element Stent coating is summarized in Table 7.

Table 7: Coating Characterization Testing

| Test | Description of Test |
| --- | --- |
| Materials Analysis – Polymer | Polymer components were tested to ensure conformity to raw material specifications. The analysis confirmed the material met specifications. |
| Chemical Analysis–Polymer | Assays were conducted to determine Mw, polydispersity, and monomer content. 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 Loading Density | Dose per unit area was calculated. |
| Coating Thickness Uniformity | Testing was conducted to verify the adluminal/abluminal/sidewall coating thickness uniformity along the stent, from stent to stent and batch to batch. |
| Coating Adhesion/Cohesion | Coating Adhesion and Cohesion testing was conducted to assess the adhesive and cohesive properties of the PROMUS Element Stent coating. |
| Drug Content | Assay was conducted to quantitatively determine the total amount of the drug substance, everolimus, on the PROMUS Element Stent. |
| Impurities and Degradation Products | Assays were conducted to quantitatively determine the type and amount of impurities and degradation products on the PROMUS Element Stent. |
| In Vitro Elution | Assay was developed to measure the in vitro release kinetics of everolimus from the PROMUS Element Stent. |
| Particulates | Particulate levels were evaluated for the PROMUS Element Plus stent system under simulated use conditions, including tracking and deployment (see Table 5 above). |

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# Chemistry Manufacturing and Controls (CMC) Testing

Each batch of finished devices undergoes CMC testing. This testing is summarized in Table 8. Where applicable, the test methods follow International Conference on Harmonization (ICH) Guidelines. Information to support the stability of PROMUS Element Plus is summarized separately in Section IX – E. Stability.

Table 8: CMC Release Testing

| Test | Description of Test |
| --- | --- |
| Material Analysis - Polymer | The polymers are tested to ensure conformity to specifications. The polymers must meet specifications prior to utilization in finished goods. |
| Drug Identity | Assay is conducted to verify the identity of the drug substance, everolimus, in the PROMUS Element Stent. |
| Drug Content/Content Uniformity | Multiple stents are assayed to verify the uniformity of the drug content between individual stents is within specifications established for the PROMUS Element Stent. |
| Impurities and Degradation Products | Testing is conducted to quantitatively verify amount of impurities and degradation products on the PROMUS Element Stent are within the specifications established for the PROMUS Element Stent. |
| In Vitro Drug Elution | The in vitro release profile of everolimus is measured to verify that the drug release is within the specifications established for the PROMUS Element Stent. |
| Particulates | Particulate counts are measured to verify that they remain below acceptable levels established for the PROMUS Element Stent. |
| Endotoxin | Testing is conducted to quantitatively verify endotoxin on the PROMUS Element Stent are within the specifications established for the PROMUS Element Stent. |

## E. Stability

Stability studies were conducted to establish a shelf life/expiration date for PROMUS Element Plus. The stability testing evaluation included appearance, drug content assay, drug content uniformity, drug identity, residual solvents, impurities and degradants, in vitro elution, particulates, sterility, and endotoxin. Appropriate mechanical engineering tests were also performed on aged product and packaging to ensure that PROMUS Element Plus continues to meet specification throughout its shelf life. The data generated supports a shelf life of 12 months. In addition, the stability of the drug substance and inactive polymers has been independently verified.

## F. Sterilization

The PROMUS Element Plus Everolimus-Eluting Platinum Chromium Coronary Stent System (Monorail and Over-The-Wire) is sterilized using ethylene oxide sterilization and has been validated per AAMI/ISO 11135-1: 2007 “Medical Devices – Validation and Routine Control of Ethylene Oxide Sterilization.”

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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 specification limit of 20EU/device for PROMUS Element Plus stent delivery systems.

Packaging shelf-life testing supports a shelf life of up to 19 months.

## G. 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 PROMUS Element Everolimus-Eluting Stent were evaluated in the non-injured porcine coronary artery model in Study 07-032G. This nonclinical animal testing also assessed comparability between PROMUS Element and PROMUS® (Xience® V), Polymer Only coated Element stents, and Uncoated Element stents. The results of these tests support the safety and vascular compatibility of the PROMUS Element stent in single and overlap-stent implant configurations in the non-injured porcine coronary artery. The early and late tissue responses were similar to PROMUS® (Xience® V). In addition, acute performance of PROMUS Element was found to be the same as or better than PROMUS® (Xience® V), supporting the safety of the PROMUS Element stent system.

Additionally, similar in vitro and in vivo drug release profiles and local arterial tissue concentration profiles between PROMUS Element and PROMUS® (Xience® V) were demonstrated through the nonclinical pharmacokinetic study, Study 07-036G. PROMUS Element in vivo everolimus release and tissue everolimus levels were evaluated and compared with PROMUS® (Xience® V) using the porcine coronary artery model. Furthermore, fast and slow drug release formulations of PROMUS Element were included in this study for the development and validation of in vitro-in vivo correlation (IVIVC) models.

In addition to conducting these GLP studies, previous studies completed for the PROMUS® (Xience® V) Everolimus Eluting Coronary Stent System also support the PROMUS Element Plus product. For more details on these studies, please refer to the SSED for PROMUS® / Xience® V stents located: http://www.accessdata.fda.gov/cdrh_docs/pdf7/P070015b.pdf Summaries of all animal studies are included in Table 9. Studies were conducted in accordance with §21 CFR 58 (Good Laboratory Practices), except one study on PROMUS® (Xience® V) where a rationale was provided to demonstrate that appropriate animal care procedures were followed and data integrity was maintained.

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Table 9: Summary of the Major Supportive Animal Studies

| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/# of Animals | Vessel Location | Evaluation Time Points | Endpoints |
| --- | --- | --- | --- | --- | --- | --- |
| GLP Safety Overlap Study 07-032G
GLP: Yes | Test Article: PROMUS Element 3.00 x 8 mm 3.50 x 8 mm (53 pairs histology, 9 pairs SEM) | 100 / 1:4.9 | Swine, 79 | LAD, RCA, and/or LCX | 7, 30, 90, 180, 270 Days | • Morbidity, mortality, stent thrombosis, Myocardial Infarction (MI)
• Angiographic vessel patency
• Visual analysis of fracture
• Histological vascular response
• SEM
• Morphological and morphometric parameters
• Acute device handling and deliverability |
| | Control Articles: Polymer Only Element 3.00 x 8 mm 3.50 x 8 mm (46 pairs histology, 9 pairs SEM) | N/A | | | | |
| | Element Bare 3.00 x 8 mm 3.50 x 8 mm (45 pairs histology, 9 pairs SEM) | N/A | | | | |
| | PROMUS (Xience V) 3.00 x 8 mm 3.50 x 8 mm (47 pairs histology, 9 pairs SEM) | 100 / 1:4.9 | | | | |
| Dosing Study R-040703-CW-02
GLP: No | Test Articles: PROMUS (Xience V) 3.00 X 12 mm 3.00 X 12 mm (11 histology) | 100 / 1:4.9 | Swine, 19 | RCA, LAD, and/or LCX | 28 days | Evaluation of dose response of various everolimus formulations.
• Angiography
• Histological & histomorphometric evaluations
• Evaluation of degree of endothelialization by SEM
• Acute delivery
• Chronic vascular response
• Dosing study (B;A=1.3:1.0) |
| | PROMUS (Xience V) 3.00 X 12 mm 3.00 X 12 mm (11 histology) | 200 / 1:3 | | | | |
| | PROMUS (Xience V) 3.00 X 12 mm (11 histology) | 260 / 1:4 | | | | |
| | Control Article: Vision Bare (11 histology) | N/A – Bare stent | | | | |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/# of Animals | Vessel Location | Evaluation Time Points | Endpoints |
| --- | --- | --- | --- | --- | --- | --- |
| Max Dose Study R051503-DMH GLP: Yes | Test Article: PROMUS (Xience V) 3.00 x 12 mm (11 histology, 1 SEM) | 803 / 1:1.42 | Swine, 14 | RCA, LAD, and/or LCX | 28 days | Evaluation of maximum dose everolimus and bulk polymer.
• Angiography
• Histological & histomorphometric evaluations
• Evaluation of degree of endothelialization by SEM
• Acute delivery
• Chronic vascular response |
| | Control Articles: Polymer Only Vision stent 3.00 x 12 mm (11 histology, 1 SEM) | N/A – Polymer Only | | | | |
| | Vision Bare 3.00 x 12 mm (11 histology) | N/A – Bare stent | | | | |
| Max Dose Study R050503-DMH GLP: Yes | Test Articles: PROMUS (Xience V) 3.00 x 12 mm (11 histology, 1 SEM) | 803 / 1:1.42 | Swine, 14 | RCA, LAD, and/or LCX | 90 days | Evaluation of maximum dose everolimus and bulk polymer.
• Angiography
• Histological & histomorphometric evaluations
• Evaluation of degree of endothelialization by SEM
• Acute delivery
• Chronic vascular response |
| | Control Articles: Polymer Only Vision stent 3.00 x 12 mm (11 histology, 1 SEM) | N/A – Polymer only | | | | |
| | Vision Bare 3.00 x 12 mm (11 histology, 1 SEM) | N/A – Bare stent | | | | |
| Max Dose Study R032204-PDD GLP: Yes | Test Article: PROMUS (Xience V) 3.00 x 12 mm (11 histology, 1 SEM) | 803 / 1:1.42 | Swine, 13 | RCA, LAD, RCA LAD, and/or LCX | 180 days | Evaluation of maximum dose everolimus and bulk polymer.
• Angiography
• Histological & histomorphometric |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/# of Animals | Vessel Location | Evaluation Time Points | Endpoints |
| --- | --- | --- | --- | --- | --- | --- |
| | Control Articles: Polymer Only Vision stent 3.00 x 12 mm (11 histology, 1 SEM) | N/A – Polymer only | | | | evaluations
• Evaluation of degree of endothelialization by SEM
• Acute delivery
• Chronic vascular response |
| | Vision Bare 3.00 x 12 mm (11 histology, 1 SEM) | N/A – Bare stent | | | | |
| Safety Study R050304-PDD Part II
GLP: Yes | Test Article: PROMUS (Xience V) 3.00 x12 mm (11 histology, 1 SEM) | 100 / 1:4.9 | Swine, 6 | RCA LAD, RCA LAD, and/or LCX | 2 years | • Angiography
• Histological & histomorphometric evaluations
• Acute delivery
• Chronic vascular response |
| | Control Article: Vision Bare 3.00 x 12 mm (11 histology, 1 SEM) | N/A – Bare stent | | | | |
| Polymer Safety Study R050504-KHB Part II
GLP: Yes | Test Article: Polymer Only Vision stent 3.00 x 12 mm (5 histology) | N/A – Polymer only | Swine, 5 | RCA LAD, RCA LAD, and/or LCX | 2 years | Evaluation of polymer safety
• Angiography
• Histological & histomorphometric evaluations
• Acute delivery
• Chronic vascular response |
| | Control Article: Vision Bare 3.00 x 12 mm (5 histology) | N/A – Bare stent | | | | |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)* | Type/# of Animals | Vessel Location | Evaluation Time Points | Endpoints |
| --- | --- | --- | --- | --- | --- | --- |
| R051004-MJL
GLP: Yes | Test Article: PROMUS (Xience V) 3.00 x 12 mm (54, 6 per time point) | 100 / 1:4.9 | Swine, 18 | RCA, LAD, and/or LCX | Blood: 15, 30, 45, 60, 90, 120, 150, 180 min, 6 and 12 hours
Others: 3, 6 and 24 hours, 3,14,28, 60,90,120 days | Evaluation of % drug released, arterial and other tissue drug levels & systemic blood levels over time. |
| In Vivo PK Study 07-036G
GLP: Yes | Test Articles: PROMUS Element (Nominal Release) 3.00 x 8 mm 3.50 x 8 mm (107 stents tissue and 18 stents coating integrity) | 100 / 1:4.9 | Swine, 147 | LAD, RCA, LCX | 3, 6 hours, 1, 3, 7, 10, 14, 28, 60, 90 days | Arterial tissue levels of Everolimus + residual stent content
• 3 hrs, 6 hrs, 1, 3, 7, 10, 14, 28, 60, 90 days time pts
Tissues sampled:
• Proximal unstented coronary artery
• Stented coronary artery
• Distal unstented coronary artery
• Control - uninjured carotid artery
• Kidney, liver, myocardium, spleen, and lung
Blood levels (everolimus) at:
• 15 min, 30 min, and 1, 2, 4, 6, 8, 24, 48 and 72 hours |
| | PROMUS Element (Slow Release) 3.00 x 8 mm 3.50 x 8 mm (105 total stents) | 100 / 1:5.5 | | | | |
| | PROMUS Element (Fast Release) 3.00 x 8 mm 3.50 x 8 mm (105 total stents) | 100 / 1:4.3 | | | | |
| | Control Article: PROMUS (Xience V) 3.00 x 8 mm (105 total stents) | 100 / 1:4.9 | | | | |
| R050203-MJL
GLP: Yes | Test Articles: PROMUS (Xience V) 3.00 x 12 mm (42, 6 per time point) | 100 / 1:4.9 | Swine, 51 | RCA, LAD, and/or LCX | 0.25, 1, 3, 7, 14, 28, 60 days | Determination of everolimus in:
• coronary/ carotid artery
• kidney
• liver |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)* | Type/# of Animals | Vessel Location | Evaluation Time Points | Endpoints |
| --- | --- | --- | --- | --- | --- | --- |
| | PROMUS (Xience V) 3.00 x 12 mm (54, 6 per time point) | 200 / 1:3 | | | 0.25, 1, 3, 7, 14, 28, 60, 90, 120 days | • lung
• myocardium
• spleen
System characterized in terms of drug release and tissue concentration levels. |
| | PROMUS (Xience V) 3.00 x 12 mm (54, 6 per time point) | 260 / 1:4 | | | 0.25, 1, 3, 7, 14, 28, 60, 90, 120 days | |
| R0060228-MJL (Platelet Function, Max Dose PK)
GLP: Yes | Test Article: PROMUS (Xience V) 3.00 x 12 mm (36, 4-6 per time point) | 803 / 1:1.42 | Swine, 32 | RCA, LAD, and/or LCX | Blood Levels: 15, 30, 45, 60, 90, 120, 150, 180 min, 6 and 12 hours
Others: 3, 6 and 24 hours, 3, 14, 28, 60 days
Platelet Function: 1, 3, 7, and 14 days | Evaluate the effect of high dose everolimus eluting stents on platelet function and to evaluate the systemic exposure of everolimus following stent-based delivery of >700 μg of everolimus by determining the concentration of everolimus in blood and selected key organs. |

Note: The stent delivery system used in these animal studies was identical to the devices used in the PLATINUM series of clinical trials, but is slightly different from commercial product. The commercial product utilizes a stent delivery system that consists of the identical materials and similar design and processing to that of the ION Paclitaxel-Eluting Platinum Chromium Coronary Stent System (P100023).

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant collected clinical data through the PLATINUM Clinical Trial Program, to establish a reasonable assurance of safety and effectiveness of coronary artery stenting with the PROMUS Element stent for improving luminal diameter in patients with symptomatic heart disease due to de novo lesions in native coronary arteries. The PLATINUM Trial program consisted of a workhorse (WH) randomized controlled trial (RCT) with single-arm small vessel (SV), long lesion (LL), and pharmacokinetics (PK) sub-studies, and the PLATINUM quantitative coronary angiography (QCA) study. Note that the LL study data were not included in this

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submission. The PLATINUM WH trial included sites in the United States, Europe, Japan, and the Asia-Pacific region excluding Japan. The PLATINUM SV trial included sites in Australia, Belgium, France, Japan, and New Zealand. Both trials were evaluated under IDE G080202. The intent of the PK sub-study was to confirm that the PK parameters measured following implantation of the PROMUS Element device were consistent with prior studies conducted with the PROMUS® (Xience® V) device. Refer to Section IX – B. In Vivo Pharmacokinetics for results.

The PLATINUM QCA study was conducted at clinical sites in Australia, Malaysia, New Zealand, and Singapore. A summary of the trial design and results are provided in Section X - C. PLATINUM QCA.

Data from the PLATINUM Clinical Trial Program were the basis for the PMA approval decision. A summary of the WH, SV, PK and QCA trial designs is presented in Table 10.

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Table 10: Comparison of PLATINUM Clinical Studies

| | PLATINUM | | | PLATINUM QCA |
| --- | --- | --- | --- | --- |
| | Workhorse RCT | Small Vessel | PK | |
| Purpose | Evaluation of safety and effectiveness in workhorse lesions | Evaluation of safety and effectiveness in small vessel lesions | Evaluation of everolimus blood levels | Evaluation of angiographic and IVUS outcomes |
| Study Design | Prospective, randomized, controlled, multi-center, single-blind non-inferiority to PROMUS | Prospective, single arm, multicenter, comparison to performance goal | Prospective, single arm, multicenter, observational | Prospective, single arm, multicenter, observational; comparisons of two efficacy endpoints to performance goals |
| Primary Endpoint | 12M TLF | 12M TLF | N/A, observational | 30D composite rate (cardiac death, MI, TLR, ST) |
| Number of Patients (ITT) | 1530 enrolled; PROMUS Element: 768 PROMUS: 762 | 94 PROMUS Element | 22 PROMUS Element | 100 PROMUS Element |
| Polymer | PBMA, PVDF-HFP | | | |
| Everolimus Dose Density | 100 μg/cm² | | | |
| Lesion Criteria: Vessel Diameter (by visual estimate), mm | ≥2.50 to ≤4.25 | ≥2.25 to <2.50 | ≥2.50 to ≤4.25 | ≥2.25 to ≤4.25 |
| Lesion Criteria: Lesion Length (by visual estimate), mm | ≤24 | ≤28 | ≤24 | ≤34 |
| Total Target Lesions | Up to 2 | 1 | Up to 2 | 1 |
| Stent Matrix | 2.50-4.00 mm diameter 12, 18/20¹, 28 mm length | 2.25 mm diameter 12, 20, 28, 32 mm length | 2.50-4.00 mm diameter 12, 20, 28 mm length | 2.25-4.00 mm diameter 12, 20, 28, 32, 38² mm length |
| Post-Procedure Antiplatelet Therapy | Thienopyridine: at least 6 months, ideally for 12 months in patients not at high risk of bleeding; ASA: indefinitely | | | |
| Follow-Up | Clinical: 30 days, 6 months, 1 year, 18 months, annually 2-5 years | | | Clinical: 30 day, 9 month, 1 year; |

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Table 10: Comparison of PLATINUM Clinical Studies

| | PLATINUM | | | PLATINUM QCA |
| --- | --- | --- | --- | --- |
| | Workhorse RCT | Small Vessel | PK | |
| | | | | Angiographic: 9 month; IVUS: 9 month |
| 1PROMUS available in 18 mm length; PROMUS Element available in 20 mm length.
22.25 mm stent not available in 38 mm length.
Abbreviations: ASA=aspirin; ITT=intent-to-treat; IVUS=intravascular ultrasound; MI=myocardial infarction; PK=pharmacokinetics; PBMA=poly (n-butyl methacrylate); PVDF-HFP=poly (vinylidene fluoride-co-hexafluoropropylene); QCA=quantitative coronary angiography; RCT=randomized controlled trial; ST=stent thrombosis; TLF=target lesion failure; TLR=target lesion revascularization | | | | |

## A. PLATINUM Workhorse

Primary Objective: The objective of the study is to evaluate the safety and effectiveness of the PROMUS Element Everolimus-Eluting Coronary Stent for the treatment of patients with up to two de novo atherosclerotic coronary artery lesions.

## Design

The PLATINUM Workhorse (WH) study is a prospective, randomized, controlled, single-blind, multi-center non-inferiority trial designed to evaluate the PROMUS Element Everolimus-Eluting Platinum Chromium Coronary Stent System in the treatment of de novo coronary lesions. The trial employs a 1:1 randomization to the PROMUS Element (test) or the PROMUS® (control) everolimus-eluting stent. The primary endpoint is 12-month target lesion failure (TLF), defined as any ischemia-driven revascularization of the target lesion (TLR), MI (Q-wave and non-Q-wave) related to the target vessel, or cardiac death related to the target vessel.

Eligible patients were those ≥18 years old with left ventricular ejection fraction (LVEF) ≥30% and with documented stable angina pectoris, silent ischemia, or unstable angina pectoris. De novo target lesions in a native coronary artery with diameter stenosis ≥50% and &lt;100% with Thrombolysis in Myocardial Infarction (TIMI) flow &gt;1, reference vessel diameter (RVD) ≥2.50 mm and ≤4.25 mm (visual estimate), and lesion length ≤24 mm (visual estimate) were eligible. Patients could be treated for 1 or 2 target lesions. Patients treated for a single target lesion could also have 1 de novo native coronary artery lesion within a different epicardial vessel (non-target lesion) treated with a commercial treatment (e.g., stent, balloon angioplasty, excluding brachytherapy) during the index procedure. The non-target lesion had to be treated before the target lesion and the treatment had to be a clinical angiographic success (defined as visually assessed &lt;50% [&lt;30% for stents] with TIMI 3 flow without prolonged chest pain or electrocardiogram [ECG] changes consistent with myocardial infarction [MI]) before the patient could be enrolled. Patients were to have provided written informed consent. Randomization was stratified by the presence or absence of diabetes mellitus treated with medication(s), by the intent to treat 1 versus 2 target lesions, and by study site. A complete list of inclusion and exclusion criteria follows. This list is applicable to the SV sub-study as well, which is summarized in

Section X (B1) – PLATINUM Small Vessel, Clinical Study Design.

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| Clinical Inclusion Criteria | • Patient must be at least 18 years of age
• Patient (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
• For patients less than 20 years of age enrolled at a Japanese site, the patient and the patient’s legal representative must provide written informed consent before any study-specific tests or procedures are performed
• Patient is eligible for percutaneous coronary intervention (PCI)
• Patient has documented stable angina pectoris or documented silent ischemia; or unstable angina pectoris
• Patient is an acceptable candidate for coronary artery bypass grafting (CABG)
• Patient has a left ventricular ejection fraction (LVEF) ≥30% as measured within 30 days prior to enrollment
• Patient is willing to comply with all protocol-required follow-up evaluations |
| --- | --- |
| Angiographic Inclusion Criteria (visual estimate) | • Target lesion must be a de novo lesion located in a native coronary artery with a visually estimated RVD as follows:
○ ≥2.50 mm and ≤4.25 mm for the RCT (WH selection criteria)
○ ≥2.25 mm and <2.50 mm for the non-randomized SV subtrial (SV selection criteria)
• Target lesion length must measure (by visual estimate) as follows.
○ ≤24 mm for the RCT (WH selection criteria)
○ ≤28 mm for the non-randomized SV subtrial (SV selection criteria)
• Target lesion must be in a major coronary artery or branch with visually estimated stenosis ≥50% and <100% with TIMI flow >1 |
| Clinical Exclusion Criteria | • Patient has clinical symptoms and/or electrocardiogram (ECG) changes consistent with acute MI
• Patient has had a known diagnosis of recent MI (i.e., within 72 hours prior to the index procedure) and has elevated enzymes at the time of the index procedure as follows:
○ Patients are excluded if any of the following criteria are met at the time of the index procedure:
○ If CK-MB >2× upper limit of normal (ULN), the patient is excluded regardless of the CK Total
○ If CK-MB is 1-2× ULN, the patient is excluded if the CK Total is >2× ULN
○ If CK Total/CK-MB are not used and Troponin is, patients are excluded if the following criterion is met at the time of the index procedure.
○ Troponin >1× ULN with at least one of the following:
○ Patient has ischemic symptoms and ECG changes indicative of ongoing ischemia (e.g., >1 mm ST segment |

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elevation or depression in consecutive leads or new left bundle branch block [LBBB]);
- Development of pathological Q-waves in the ECG; or
- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

**Note:** For patients with unstable angina or patients who have had a recent MI, CK Total/CK-MB (or Troponin if CK Total/CK-MB are not used) must be documented prior to enrolling/randomizing the patient

- Patient has received an organ transplant or is on a waiting list for an organ transplant
- Patient is receiving or scheduled to receive chemotherapy within 30 days before or after the index procedure
- Patient is receiving oral or intravenous immunosuppressive therapy (i.e., inhaled steroids are not excluded) or has known life-limiting immunosuppressive or autoimmune disease (e.g., human immunodeficiency virus, systemic lupus erythematosus, but not including diabetes mellitus)
- Patient is receiving chronic (≥72 hours) anticoagulation therapy (e.g., heparin, coumadin) for indications other than acute coronary syndrome
- Patient has a platelet count &lt;100,000 cells/mm³ or &gt;700,000 cells/mm³
- Patient has a white blood cell (WBC) count &lt;3,000 cells/mm³
- Patient has documented or suspected liver disease, including laboratory evidence of hepatitis
- Patient is on dialysis or has known renal insufficiency (i.e., estimated creatinine clearance &lt;50 ml/min by the Cockcroft Gault formula: [(140-age)*lean body weight (in kg)]/[plasma creatinine (mg/dl)*72])
- Patient has a history of bleeding diathesis or coagulopathy or will refuse blood transfusions
- Patient has had a cerebrovascular accident (CVA) or transient ischemic attack (TIA) within the past 6 months, or has any permanent neurologic defect that may cause non-compliance with the protocol
- Target vessel(s) or side branch has been treated with any type of PCI (e.g., balloon angioplasty, stent, cutting balloon, atherectomy) within 12 months prior to the index procedure
- Target vessel(s) has been treated within 10 mm proximal or distal to the target lesion (by visual estimate) with any type of PCI (e.g., balloon angioplasty, stent, cutting balloon, atherectomy) at any time prior to the index procedure
- Non-target vessel or side branch has been treated with any type of PCI (e.g., balloon angioplasty, stent, cutting balloon, atherectomy) within 24 hours prior to the index procedure
- Planned or actual target vessel(s) treatment with an unapproved device, directional or rotational coronary atherectomy, laser, cutting

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| | balloon, or transluminal extraction catheter immediately prior to stent placement
• Planned PCI or CABG after the index procedure
• Patient previously treated at any time with coronary intravascular brachytherapy
• Patient has a known allergy to the study stent system or protocol-required concomitant medications (e.g., stainless steel, platinum, cobalt, chromium, nickel, tungsten, acrylic, fluoropolymers, everolimus, thienopyridines, aspirin, contrast) that cannot be adequately premedicated
• Patient has an active peptic ulcer or active gastrointestinal (GI) bleeding
• Patient has one of the following.
○ Other serious medical illness (e.g., cancer, congestive heart failure) that may reduce life expectancy to less than 24 months
○ Current problems with substance abuse (e.g., alcohol, cocaine, heroin, etc.)
○ Planned procedure that may cause non-compliance with the protocol or confound data interpretation
• Patient is participating in another investigational drug or device clinical trial that has not reached its primary endpoint
• Patient intends to participate in another investigational drug or device clinical trial within 12 months after the index procedure
• Patient with known intention to procreate within 12 months after the index procedure (Women of child-bearing potential who are sexually active must agree to use a reliable method of contraception from the time of screening through 12 months after the index procedure.)
• Patient is a woman who is pregnant or nursing (A pregnancy test must be performed within 7 days prior to the index procedure in women of child-bearing potential.)
• WH patient has more than 2 target lesions, or more than 1 target lesion and 1 non-target lesion, which will be treated during the index procedure
• SV patient has more than 1 target lesion, or more than 1 target lesion and 1 non-target lesion, which will be treated during the index procedure |
| --- | --- |
| Angiographic Exclusion Criteria (visual estimate) | • Target lesion meets any of the following criteria:
○ Aorto-ostial location (i.e., lesion located within 5 mm of the ostium by visual estimate)
○ Left main location
○ Located within 5 mm of the origin of the left anterior descending (LAD) coronary artery or left circumflex (LCX) coronary artery by visual estimate
○ Located within a saphenous vein graft or an arterial graft
○ Will be accessed via a saphenous vein graft or an arterial graft
○ Involves a side branch ≥2.0 mm in diameter by visual estimate |

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- Involves a clinically significant side branch &lt;2.0 mm in diameter by visual estimate that has a clinically significant stenosis at the ostium
- TIMI flow 0 (total occlusion) or TIMI flow 1 prior to wire crossing
- Excessive tortuosity proximal to or within the lesion
- Extreme angulation proximal to or within the lesion
- Target lesion and/or target vessel proximal to the target lesion is moderately to severely calcified by visual estimate
- Restenotic from previous intervention
- Thrombus, or possible thrombus, present in the target vessel

- Non-target lesion to be treated during the index procedure meets any of the following criteria:
- Located within the target vessel
- Located within a bypass graft (venous or arterial)
- Left main location
- Chronic total occlusion
- Involves a complex bifurcation (e.g., bifurcations requiring treatment with more than 1 stent)
- Restenotic from previous intervention

- Patient has unprotected left main coronary artery disease (&gt;50% diameter stenosis)
- Patient has protected left main coronary artery disease and a target lesion in the LAD or LCX
- Patient has an additional clinically significant lesion(s) in the target vessel for which an intervention within 12 months after the index procedure is likely to be required
- Patient has 2 target lesions in the same vessel that are separated…