← Product Code NIQ · P070015 # XIENCE AND PROMUS EVEROLIMUS ELUTING CORONARY STENT SYSTEMS (P070015) _Abbott Vascular, Inc. · NIQ · Jul 2, 2008 · Cardiovascular · APWD_ **Canonical URL:** https://fda.innolitics.com/device/P070015 ## Device Facts - **Applicant:** Abbott Vascular, Inc. - **Product Code:** NIQ - **Decision Date:** Jul 2, 2008 - **Decision:** APWD - **Device Class:** Class 3 - **Review Panel:** Cardiovascular - **Attributes:** Therapeutic ## Intended Use The XIENCE™ V Everolimus Eluting Coronary Stent System (XIENCE V stent) is indicated for improving coronary luminal diameter in patients with symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 28 mm) with reference vessel diameters of 2.5 mm to 4.25 mm. ## Device Story Drug-eluting coronary stent system; combines balloon-expandable L-605 cobalt-chromium alloy stent (MULTI-LINK VISION/MINI VISION) with everolimus drug coating in non-erodible polymer (PBMA/PVDF-HFP). Used in cardiac catheterization labs by interventional cardiologists to treat coronary artery disease. Stent delivered via RX or OTW catheter; balloon expansion deploys stent against vessel wall. Everolimus elutes from polymer to inhibit neointimal growth; reduces restenosis. Output is mechanical scaffolding of coronary artery. Benefits include improved luminal diameter and reduced target vessel failure compared to bare metal or other drug-eluting stents. Clinical decision-making informed by angiographic and IVUS imaging. ## Clinical Evidence Evidence from SPIRIT III (pivotal RCT, N=1002), SPIRIT II (N=300), and SPIRIT FIRST (N=60). Primary endpoints included in-segment/in-stent late loss at 180-240 days and ischemia-driven TVF. XIENCE V demonstrated non-inferiority to TAXUS in late loss and TVF; superior in-segment late loss (p=0.0037) in SPIRIT III. Stent thrombosis rates were low and consistent with literature. ## Technological Characteristics Stent: L-605 Cobalt Chromium alloy. Coating: Everolimus (100 μg/cm²) in PBMA/PVDF-HFP non-erodible polymer. Delivery: RX or OTW catheter, 143 cm length, compliant tapered balloon. MRI: MR Conditional (1.5T/3T). Sterilization: Ethylene Oxide (EtO). ## Regulatory 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 - MULTI-LINK VISION Coronary Stent System ([P020047](/device/P020047.md)) - MULTI-LINK MINI VISION Coronary Stent System ([P020047](/device/P020047.md)/S003) ## Reference Devices - TAXUS EXPRESS Paclitaxel Eluting Coronary Stent System ## Submission Summary (Full Text) > This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com. > > Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/). {0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Drug-Eluting Coronary Stent System (NIQ) Device Trade Name: XIENCE V Rapid Exchange (RX) Everolimus Eluting Coronary Stent System XIENCE V Over-the-Wire (OTW) Everolimus Eluting Coronary Stent System Device will also be distributed as: PROMUS Rapid Exchange (RX) Everolimus Eluting Coronary Stent System PROMUS Over-the-Wire (OTW) Everolimus Eluting Coronary Stent System Applicant's Name and Address: Abbott Vascular, Cardiac Therapies 3200 Lakeside Drive Santa Clara, CA 95054 Date of Panel Recommendation: November 29, 2007 Premarket Approval Application (PMA) Number: P070015 Date of FDA Notice of Approval: July 2, 2008 Expedited: Not Applicable II. INDICATIONS FOR USE The XIENCE™ V Everolimus Eluting Coronary Stent System (XIENCE V stent) is indicated for improving coronary luminal diameter in patients with symptomatic heart disease due to de novo native coronary artery lesions (length ≤ 28 mm) with reference vessel diameters of 2.5 mm to 4.25 mm. III. CONTRAINDICATIONS The XIENCE V stent is contraindicated for use in patients: - Who cannot receive anti-platelet and/or anti-coagulant therapy - With lesions that prevent complete angioplasty balloon inflation or proper placement of the stent or stent delivery system PMA P070015: FDA Summary of Safety and Effectiveness Data Page 1 of 67 {1} - With known hypersensitivity or contraindication to everolimus or structurally-related compounds, cobalt, chromium, nickel, tungsten, acrylic and fluoropolymers. ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the XIENCE V Everolimus Eluting Coronary Stent System labeling. ## V. DEVICE DESCRIPTION The XIENCE V Everolimus Eluting Coronary Stent System (XIENCE V EECSS or XIENCE V stent) is a device/drug combination product comprised of two regulated components: - A device (MULTI-LINK VISION® Coronary Stent System or MULTI-LINK MINI VISION® Coronary Stent System) - A drug coating (formulation of everolimus in a polymer coating) The characteristics of the XIENCE V EECSS are described in Table 1 below. Table 1 XIENCE V Stent System Product Description | | XIENCE V Rapid-Exchange (RX) EECSS | | XIENCE V Over-the-Wire (OTW) EECSS | | | | | --- | --- | --- | --- | --- | --- | --- | | Available Stent Lengths (mm) | 8, 12, 15, 18, 23, 28 | | 8, 12, 15, 18, 23, 28 | | | | | Available Stent Diameters (mm) | 2.5, 2.75, 3.0, 3.5, 4.0 | | 2.5, 2.75, 3.0, 3.5, 4.0 | | | | | Stent Material | A medical grade L-605 Cobalt Chromium (CoCr) alloy MULTI-LINK VISION or MULTI-LINK MINI VISION stent | | | | | | | Drug Component | A conformal coating of a non-erodible polymer loaded with 100 μg/cm² of everolimus with a maximum nominal drug content of 181 μg on the largest stent (4.0 x 28 mm) | | | | | | | Delivery System Working Length | 143 cm | | 143 cm | | | | | Delivery System Design | Single access port to inflation lumen. Guide wire exit notch is located 30 cm from tip. Designed for guide wires ≤ 0.014”. | | Sidearm adaptor provides access to balloon inflation/deflation lumen and guide wire lumen. Designed for guide wires ≤ 0.014”. | | | | | Stent Delivery System Balloon | A compliant, tapered balloon with two radiopaque markers to designate the stent placement on the balloon. | | | | | | | Balloon Inflation Pressure | Nominal inflation pressure: 8 atm for the 2.5 and 2.75 mm diameters; 9 atm for the 3.0, 3.5, and 4.0 mm diameters Rated Burst Pressure (RBP): 16 atm (1621 kPa) for all sizes | | | | | | | Guiding Catheter Inner Diameter | ≥ 5F (0.056”) | | | | | | | Catheter Shaft Outer Diameter (nominal) | 2.5-3.0 mm | 3.5-4.0 mm | | 2.5 mm | 2.75 x 8 - 3.5 x 18 | 3.5 x 23 - 4.0 x 28 | | | Distal: 0.032” | 0.035” | Distal: 0.032” 0.034” 0.036” | | | | | | Proximal: 0.026” | 0.026” | Proximal: 0.042” 0.042” 0.042” | | | | PMA P070015: FDA Summary of Safety and Effectiveness Data {2} # A. Device Component Description The device component is comprised of the balloon-expandable MULTI-LINK VISION or MULTI-LINK MINI VISION coronary stent pre-mounted onto either the MULTI-LINK VISION or MULTI-LINK MINI VISION delivery systems consisting of either the Rapid Exchange (RX) or the Over-the-Wire (OTW) platform. The MULTI-LINK VISION RX and OTW delivery systems were approved for deployment of the bare metal MULTI-LINK VISION stent in P020047 (approved July 16, 2003). The MULTI-LINK MINI-VISION RX and OTW delivery systems were approved for deployment of the bare metal MULTI-LINK MINI-VISION stent in P020047/S003 (approved September 10, 2004). The small XIENCE V stent design (2.5, 2.75, and 3.0 mm diameters) is identical to the MULTI-LINK MINI VISION stent for the 2.5 diameter, and the MULTI-LINK VISION stent for the 2.75 mm and 3.0 mm diameter. The medium XIENCE V stent design is identical to the medium MULTI-LINK VISION stent for the 3.5 mm and 4.0 mm diameters. All stent diameters will be available in 8-28 mm lengths. # B. Drug Component Description The XIENCE V Everolimus Eluting Coronary Stent (XIENCE V stent) is coated with everolimus (active ingredient), embedded in a non-erodible polymer (inactive ingredient). # B1. Everolimus Everolimus is the active pharmaceutical ingredient in the XIENCE V stent. It is a novel semi-synthetic macrolide immunosuppressant, synthesized by chemical modification of rapamycin (INN: sirolimus). The everolimus chemical name is 40-O-(2-hydroxyethyl)-rapamycin and the chemical structure is shown in Figure 1 below. ![img-0.jpeg](img-0.jpeg) Figure 1 Chemical Structure of Everolimus PMA P070015: FDA Summary of Safety and Effectiveness Data {3} # B2. Interactive Ingredients The XIENCE V stent contains inactive ingredients including poly n-butyl methacrylate (PBMA), a polymer that adheres to the stent and drug coating, and PVDF-HFP which is comprised of vinylidene fluoride and hexafluoropropylene monomers as the drug matrix layer containing everolimus. PBMA is a homopolymer with a molecular weight of 264,000 to 376,000 dalton. PVDF-HFP is a non-erodible semi-crystalline random copolymer with a molecular weight of 254,000 to 293,000 dalton. The drug matrix copolymer is mixed with everolimus (83%/17% w/w polymer / everolimus ratio) and applied to the entire PBMA coated stent surface. The drug load is $100~\mu \mathrm{g} / \mathrm{cm}^2$ for all product sizes. No topcoat layer is used. The chemical structure of the polymer components are shown in Figures 2a and 2b below. ![img-1.jpeg](img-1.jpeg) ![img-2.jpeg](img-2.jpeg) Figure 2a Chemical Structure of Poly (n-butyl methacrylate) (PBMA) Figure 2b Formula for Poly(Vinylidene Fluoride-Co-Hexafluoropropylene) (PVDF-HFP) The product matrix, including nominal dosages of everolimus in each XIENCE V stent is described in Table 2. The nominal everolimus content is based on stent design and length. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 4 of 67 {4} Table 2 XIENCE V EECSS Product Matrix and Everolimus Content | Model Number (RX) | Model Number (OTW) | Stent Diameter (mm) | Stent Length (mm) | Nominal Everolimus Content (μg) | | --- | --- | --- | --- | --- | | 1009539-08 | 1009545-08 | 2.5 | 8 | 37 | | 1009540-08 | 1009546-08 | 2.75 | 8 | 37 | | 1009541-08 | 1009547-08 | 3.0 | 8 | 37 | | 1009542-08 | 1009548-08 | 3.5 | 8 | 53 | | 1009543-08 | 1009549-08 | 4.0 | 8 | 53 | | 1009539-12 | 1009545-12 | 2.5 | 12 | 56 | | 1009540-12 | 1009546-12 | 2.75 | 12 | 56 | | 1009541-12 | 1009547-12 | 3.0 | 12 | 56 | | 1009542-12 | 1009548-12 | 3.5 | 12 | 75 | | 1009543-12 | 1009549-12 | 4.0 | 12 | 75 | | 1009539-15 | 1009545-15 | 2.5 | 15 | 75 | | 1009540-15 | 1009546-15 | 2.75 | 15 | 75 | | 1009541-15 | 1009547-15 | 3.0 | 15 | 75 | | 1009542-15 | 1009548-15 | 3.5 | 15 | 98 | | 1009543-15 | 1009549-15 | 4.0 | 15 | 98 | | 1009539-18 | 1009545-18 | 2.5 | 18 | 88 | | 1009540-18 | 1009546-18 | 2.75 | 18 | 88 | | 1009541-18 | 1009547-18 | 3.0 | 18 | 88 | | 1009542-18 | 1009548-18 | 3.5 | 18 | 113 | | 1009543-18 | 1009549-18 | 4.0 | 18 | 113 | | 1009539-23 | 1009545-23 | 2.5 | 23 | 113 | | 1009540-23 | 1009546-23 | 2.75 | 23 | 113 | | 1009541-23 | 1009547-23 | 3.0 | 23 | 113 | | 1009542-23 | 1009548-23 | 3.5 | 23 | 151 | | 1009543-23 | 1009549-23 | 4.0 | 23 | 151 | | 1009539-28 | 1009545-28 | 2.5 | 28 | 132 | | 1009540-28 | 1009546-28 | 2.75 | 28 | 132 | | 1009541-28 | 1009547-28 | 3.0 | 28 | 132 | | 1009542-28 | 1009548-28 | 3.5 | 28 | 181 | | 1009543-28 | 1009549-28 | 4.0 | 28 | 181 | C. Mechanism of Action The mechanism by which the XIENCE V 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 PMA P070015: FDA Summary of Safety and Effectiveness Data Page 5 of 67 13 {5} 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 There are several other alternatives for the treatment of patients with coronary artery disease including exercise, diet, drug therapy, percutaneous coronary interventions (i.e., balloon angioplasty, atherectomy, bare metal stents, coated stents, and other drug-eluting stents), and coronary artery bypass grafting (CABG) surgery. 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 XIENCE V Everolimus Eluting Coronary Stent System is commercially available in the following countries: | Argentina | France | Lithuania | Slovakia | | --- | --- | --- | --- | | Australia | Germany | Luxembourg | Slovenia | | Austria | Greece | Malaysia | Spain | | Bangladesh | Hong Kong | Macau | Sri Lanka | | Belgium | Hungary | Malta | Sweden | | Brazil | Iceland | Macedonia | Syria | | Bulgaria | India | Netherlands | Switzerland | | Colombia | Indonesia | New Zealand | Thailand | | Costa Rica | Ireland | Norway | Ukraine | | Croatia | Israel | Panama | United Arab Emirates | | Cyprus | Italy | Philippines | United Kingdom | | Czech Republic | Jordan | Poland | Uruguay | | Denmark | Kuwait | Portugal | Tunisia | | Egypt | Latvia | Romania | Turkey | | Estonia | Lebanon | Russian Federation | Venezuela | | Finland | Liechtenstein | Singapore | Vietnam | | Thailand | Serbia | Peru | Taiwan | | | | | South Korea | As of May 31, 2008, over 252,818 XIENCE V Stent systems have been distributed outside of the United States. The XIENCE V EECSS has not been withdrawn from marketing in any country for any reason. PMA P070015: FDA Summary of Safety and Effectiveness Data {6} # VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of the XIENCE V stent. Adverse events (in alphabetical order) which may be associated with coronary stent use in native coronary arteries include, but are not limited to: - Abrupt closure - Access site pain, hematoma or hemorrhage - Acute myocardial infarction - Allergic reaction or hypersensitivity to contrast agent or cobalt, chromium, nickel, tungsten, acrylic and fluoropolymers; and drug reactions to antiplatelet drugs or contrast agent - Aneurysm - Arterial perforation and injury to the coronary artery - Arterial rupture - Arteriovenous fistula - Arrhythmias, atrial and ventricular - Bleeding complications, which may require transfusion - Cardiac tamponade - Coronary artery spasm - Coronary or stent embolism - Coronary or stent thrombosis - Death - Dissection of the coronary artery - Distal emboli (air, tissue or thrombotic) - Emergent or non-emergent coronary artery bypass graft surgery - Fever - Hypotension and/or hypertension - Infection and pain at insertion site - Injury to the coronary artery - Ischemia (myocardial) - Myocardial infarction - Nausea and vomiting - Palpitations - Peripheral ischemia (due to vascular injury) - Pseudoaneurysm - Restenosis of the stented segment of the artery - Shock/pulmonary edema - Stroke/cerebrovascular accident (CVA) - Total occlusion of coronary artery - Unstable or stable angina pectoris - Vascular complications including at the entry site which may require vessel repair - Vessel dissection PMA P070015: FDA Summary of Safety and Effectiveness Data Page 7 of 67 {7} Adverse events associated with daily oral administration of everolimus to organ transplant patients include but are not limited to: - Abdominal pain - Acne - Anemia - Coagulopathy - Diarrhea - Edema - Hemolysis - Hypercholesterolemia - Hyperlipidemia - Hypertension - Hypertriglyceridemia - Hypogonadism male - Infections: wound infection, urinary tract infection, pneumonia, pyelonephritis, sepsis and other viral, bacterial and fungal infections - Leukopenia - Liver function test abnormality - Lymphocele - Myalgia - Nausea - Pain - Rash - Renal tubular necrosis - Surgical wound complication - Thrombocytopenia - Venous thromboembolism - Vomiting For the specific adverse events that occurred in the clinical studies, please see Section X, Summary of Primary Clinical Study, below. ## IX. SUMMARY OF PRECLINICAL STUDIES A series of non-clinical laboratory studies related to the XIENCE V product were performed. Studies included those performed on the bare metal stent system (MULTI-LINK VISION or MULTI-LINK MINI VISION stent mounted on the stent delivery system), the coated stent alone (the XIENCE V stent), the polymer-only coated stent alone (the MULTI-LINK VISION or MULTI-LINK MINI VISION with the PBMA primer layer and PVDF-HFP polymer layer), or the finished combination product (XIENCE V EECSS). PMA P070015: FDA Summary of Safety and Effectiveness Data {8} PMA P070015: FDA Summary of Safety and Effectiveness Data Page 9 of 67 # A. Laboratory Studies ## A1. Biocompatibility Testing A series of Good Laboratory Practices (GLP) biocompatibility tests were conducted to demonstrate the components of the XIENCE V EECSS are non-toxic. Tests were conducted on ethylene oxide-sterilized XIENCE V RX EECSSs, XIENCE V coated stents, or polymer-only coated stents. These test articles were processed in a similar manner as the finished XIENCE V product, except in the case of the polymer-only coated stent that did not contain the active pharmaceutical ingredient. Some portion of biocompatibility testing was conducted on the XIENCE V EECSS contained a drug dose approximately 2.6 times (2.6X) the amount of the commercial product. Additional testing of the XIENCE V stent was evaluated at appropriate extract dosing levels near the toxicity threshold of everolimus as confirmed through cell culture testing. Testing was also performed on polymer-only coated stents with the same total coating weight as the drug eluting stents. All biocompatibility testing was conducted in accordance with one or more of the following general regulations and guidance documents: - Guidance for Industry and FDA Staff, Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems; published by the Interventional Cardiology Devices Branch, Division of Cardiovascular Devices, Office of Device Evaluation on January 13, 2005. - Draft Guidance for Industry, Coronary Drug-Eluting Stents- Nonclinical and Clinical Studies; published by the Interventional Cardiology Devices Branch, Division of Cardiovascular Devices, Office of Device Evaluation on March 2008. - Good Laboratory Practices Regulations (21 CFR § 58) - ISO 10993, Biological Evaluation of Medical Devices - USP <85> Bacterial Endotoxin Test - USP <87/88> Biological Reactivity Tests - USP <161> Transfusion and Infusion Assemblies and Similar Medical Devices Table 3 describes the biocompatibility testing. {9} Table 3 Biocompatibility Test Summary | Test Name | Description of Test | Test Article and Results | | --- | --- | --- | | Cytotoxicity | ISO 10993-5: In Vitro Cytotoxicity (I.929 MEM Elution) | • XIENCE V Stent and OTW delivery system: Pass (non-cytotoxic) • 2.6X Stent and RX delivery system: Pass (non-cytotoxic) • XIENCE V Stent: Pass (non-cytotoxic below toxicity threshold of everolimus) • Polymer-only coated stent: Pass (non-cytotoxic) | | Sensitization | ISO 10993-10: Sensitization (Guinea Pig Maximization) | • XIENCE V Stent and OTW delivery system: Pass (non-sensitizing) • 2.6X Stent and RX delivery system: Pass (non-sensitizing) • XIENCE V Stent: Pass (non-sensitizing below toxicity threshold of everolimus) • Polymer-only coated stent: Pass (non-sensitizing) | | Intracutaneous Reactivity | ISO 10993-10: Irritation (Rabbit Injection) | • XIENCE V Stent and OTW delivery system: Pass (non-irritating) • 2.6X Stent and RX delivery system: Pass (non-irritating) • XIENCE V Stent: Pass (non-irritating below toxicity threshold of everolimus) • Polymer-only coated stent: Pass (non-irritating) | | Systemic Toxicity | ISO 10993-11: Systemic Toxicity, Acute (Mouse Injection) | • XIENCE V Stent and OTW delivery system: Pass (non-toxic) • 2.6X Stent and RX delivery system: Pass (non-toxic) | | | USP <88>: Systemic Injection Test (Mouse Injection) | • Polymer-only coated stent: Pass (non-toxic) | | Pyrogenicity | Bacterial Endotoxin (LAL) | • XIENCE V Stent and OTW delivery system: Pass (non-pyrogenic) • 2.6X Stent and RX delivery system: Pass (non-pyrogenic) | | | ISO 10993-11: Systemic Toxicity (Material Mediated Rabbit) | • XIENCE V Stent and OTW delivery system: Pass (non-pyrogenic) • 2.6X Stent and RX delivery system: Pass (non-pyrogenic) | | Hemocompatibility/Hemolysis* | ISO 10993-4: Hemolysis, Direct Contact (Rabbit Red Blood Cells) | • 2.6X Stent and RX delivery system: Pass (non-hemolytic) • XIENCE V stent: Pass (non-hemolytic) | | | Thrombosis (fulfilled through Hemolysis and in vivo animal testing) | • XIENCE V Stent and OTW delivery system: Pass (non-hemolytic) • 2.6X Stent and RX delivery system: Pass (non-hemolytic) | | | ISO 10993-4: Hemolysis, Indirect Contact (Rabbit Red Blood Cells) | • XIENCE V Stent and OTW delivery system: Pass (non-hemolytic) • XIENCE V stent: Pass (non-hemolytic) | | | ISO 10993-4: Clotting, PT (Human Plasma) | • 2.6X Stent and RX delivery system: Pass (non-hemolytic) | | | ISO 10993-4: Partial Thromboplastin Time, PTT (Human Plasma) | • 2.6X Stent and RX delivery system: Pass (non-hemolytic) | * See discussion of hemocompatibility testing below. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 10 of 67 {10} Table 3 Biocompatibility Test Summary (cont'd) | Test Name | Description of Test | Test Article and Results | | --- | --- | --- | | Implantation | ISO 10993-6: 90-day (Rabbit, Intramuscular) | • 2.6X XIENCE V stent: Pass | | | Sub-chronic Toxicity (fulfilled through 90-day implant) | | | | USP <88> 7-day (Rabbit, Intramuscular) | • Polymer-only coated stent: Pass | | Genotoxicity | ISO 10993-3: Bacterial Reverse Mutation Assay (Ames test) | • 2.6X XIENCE V stent: Pass (non-mutagenic) | | | ISO 10993-3: In Vitro Chromosomal Aberration (Chinese Hamster Ovary cells) | • 2.6X XIENCE V stent: Pass (non-mutagenic) | | | ISO 10993-3: Clastogenicity in Mammalian Cells (CHO/HGPRT forward mutation) | • 2.6X XIENCE V stent: Pass (non-mutagenic) | | | ISO 10993-3: Mammalian Erythrocyte Micronucleus Test | • 2.6X XIENCE V stent: Pass (non-mutagenic) | | Reproductive Toxicity (Teratology) | ISO 10993-3: Reproductive and Developmental Toxicity | • XIENCE V stent: Pass (non-teratogenic) | | Carcinogenicity | ISO 10993-3: Carcinogenicity | • XIENCE V stent: Pass (non-carcinogenic) | The applicant completed multiple tests to assess hemocompatibility, with the exception of complement activation testing. The applicant provided a scientific rationale for the omission of this testing. Although complement activation was not specifically studied in the SPIRIT III clinical trial, adverse cardiac events were reviewed through the first 37 days (30 day clinical follow-up ± 7 days) to assess any potential for complement activation in the adverse cardiac event profile of the XIENCE V product. No differences between treatment groups were observed and no manifestations of complement activation were revealed. In addition to adverse cardiac events, immediate hypersensitivity, a potential manifestation of complement activation, was evaluated through 37 days. Using the list of adverse events suggested by Nebeker et al.¹ to be manifestations of hypersensitivity, a search of the SPIRIT III subject database revealed no reports of allergy or hypersensitivity reactions to the stent in either study arm, and a comparable incidence of hypersensitivity reactions without an identified etiology between the two arms. Given these analyses, the omission of complement activation testing is acceptable. A 26-week carcinogenicity study was conducted to evaluate the carcinogenic potential of XIENCE V Stents following subcutaneous implantation in transgenic mice. During the course of the study, there were no abnormal clinical observations that suggested a carcinogenic effect of the test group (XIENCE V ¹ Nebeker JR, Barach P, Samore M. Clarifying Adverse Drug Events: A Clinician’s Guide to Terminology, Documentation, and Reporting. Ann Intern Med 2004; 140: 795-801. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 11 of 67 19 {11} Stent). The test group did not demonstrate an increased incidence of neoplastic lesions when compared to the negative control group. The positive control and the experimental positive control groups demonstrated notable increases in the incidence of neoplastic lesions compared to either the test or the negative control group. Based on the results of this study, the XIENCE V Stent does not appear to be carcinogenic when implanted in transgenic mice for 26 weeks. In addition, a teratology (reproductive toxicity) study was conducted to demonstrate that implantation of XIENCE V Stents in female Sprague-Dawley rats does not affect their fertility or reproductive capability as well as to show a lack of any teratology effect on their offspring. The XIENCE V Stent did not affect the fertility or reproductive capability of female Sprague-Dawley rats. There was no statistical difference between the test article (XIENCE V Stent) and the control system in terms of any of the evaluated parameters. The test article had no effect on litter size and caused no increase of in-utero mortality. Additionally, the XIENCE V Stent did not cause any teratologic effects in the offspring in this study. *In vivo* animal and pharmacology studies have been completed on the XIENCE V stent to provide information about systemic, regional and local toxicity, and dose-related toxicity. Abbott Vascular completed a series of *in vivo* pharmacokinetic studies of the XIENCE V stent. The animal PK studies are summarized in Section IX.B1. *In Vivo* Pharmacokinetics below. In addition, clinical pharmacokinetic studies have been performed on the XIENCE V stent. The human PK studies are described in Section X.D. Global Pharmacokinetics. There is no evidence to suggest that any chemical interactions, which would result in the formation of a new intermediate or molecular entity, occur between everolimus or the polymers used in the XIENCE V stents. Long term biocompatibility of the drug/polymer coating on the stent in humans is unknown. ## A2. In Vitro Engineering Testing *In vitro* engineering testing, in accordance with the FDA “Guidance for Industry and FDA Staff – Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems,” January 2005 and “Draft Guidance for Industry, Coronary Drug-Eluting Stents- Nonclinical and Clinical Studies,” March 2008, was conducted on the XIENCE V Stent except where the testing could be leveraged from the MULTI-LINK VISION or MULTI-LINK MINI VISION Stent, which were approved in P020047 and P020047/S003, respectively. Supplementary *in vitro* engineering tests were also performed on the XIENCE V delivery systems containing the XIENCE V stent mounted on a delivery catheter. This testing is summarized in Table 4. "Pass" denotes that the test results met product specifications and/or the recommendations in the above referenced guidance document. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 12 of 67 {12} Additional tests were conducted to support the integrity of the coating on the XIENCE V Stent and are summarized separately in Section IX.A3. Coating Characterization Testing. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 13 of 67 21 {13} Table 4 In Vitro Engineering Studies | Test | Test Description | Results | | --- | --- | --- | | Material Characterization Testing | | | | Material Analysis | Evaluations were conducted on the stent tubing provided by the material supplier prior to any processing to confirm chemical analysis, grain size, and inclusion content per relevant ASTMs (F90, A751, E1086, E1479, E1019, F138, E112, F2527, E45). In addition, SEM analysis was conducted on bare metal stents to identify and analyze trace contaminants which may be present on the stent. | PASS | | Mechanical Properties: Tensile Strength and Elongation | Tensile strength and elongation testing was performed on the stent tubing prior to any processing. The tensile strength and elongation met acceptance criteria. | PASS | | Corrosion Testing | Both bare metal and polymer-only coated stents were tested according to ASTM F2129-01 “Standard Test Method for Conducting Cyclic Potentiodynamic Measurements to Determine the Corrosion Susceptibility of Small Implant Devices” to demonstrate that the finished stents exhibit acceptable corrosion resistance. Testing was also conducted to evaluate the relative susceptibility to pitting/crevice corrosion. Results were comparable to the marketed MULTI-LINK VISION stents and met the specifications requirements. | PASS | | Fretting Corrosion | Overlapped XIENCE V Stents and overlapped MULTI-LINK VISION stents were evaluated post fatigue testing to determine the potential for fretting corrosion. The results met all acceptance criteria and indicated that the stents possess a high resistance to fretting corrosion.* | PASS | | Galvanic Corrosion | Testing was conducted on marketed stainless steel (MULTI-LINK TETRA) and CoCr (MULTI-LINK VISION) overlapped in a passive manner, and overlapped in an active manner (with disruption of the oxide layer) to determine the potential for galvanic corrosion. The results met the acceptance criteria and indicated a high resistance to galvanic corrosion. | PASS | | Stent Dimensional and Functional Attributes | | | | Stent Dimensional Inspection | Measurements were taken of the bare metal stent strut width, thickness, and length. All stents met product specifications. | PASS | | Stent Percent Surface Area | Determines the metal-to-artery ratio of the nominal XIENCE V stent using a theoretical calculation that divides the total vessel contact metal surface area of the stent by the theoretical surface area of the vessel at the desired diameter. Metal to artery percentage ratios were calculated for each stent diameter, with the highest surface to artery ratio (14.89%) occurring at the smallest stent diameter (2.5 mm). | Descriptive only | | Stent Uniformity of Expansion Test | Determines the uniformity of expansion along the stent length. Units were inflated to either nominal or post-dilated inner diameters, deflated, and diameter measurements were taken at various points along the stent length. Measurements were averaged and all stents met product specifications. | PASS | * The applicant has agreed to provide additional fretting corrosion testing out to 400 million cycles on overlapped stents placed in a 15 mm bend configuration postapproval. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 14 of 67 {14} Table 4 In vitro Engineering Studies (cont'd) | Test | Test Description | Results | | --- | --- | --- | | Stent Dimensional and Functional Attributes (cont'd) | | | | Stent Percent Length Change (Foreshortening) Test | Determines the difference in stent length pre-and post-expansion to either nominal or post-dilated inner diameters. All stents met product specifications. | PASS | | Stent Percent Recoil Test | Quantifies the amount of recoil of the stent after balloon expansion. The system was inflated to either nominal or post-dilated diameters and measurements were taken of the stent diameter at various locations along the stent length. The system was then deflated and the same measurements taken. The percent recoil is calculated by subtracting the average stent inner diameter (ID) without the balloon from the average stent ID with the balloon, dividing by the average stent ID with the balloon and multiplying by 100. All stents met product specifications. | PASS | | Stent Radial (Hoop) Strength Test | Testing was conducted to determine the radial strength of the stent under compression force. Stents were expanded to either nominal or post-dilated diameters, placed in an Instron tester, and subjected to incrementally increasing compression forces. The pressure at which deformation is no longer completely reversible was recorded. All stents met product specifications. | PASS | | Radial Stiffness | Radial stiffness was evaluated on the XIENCE V stent compared to the MULTI-LINK VISION stent | Descriptive only | | Finite Element Analysis (FEA) | An in-depth analysis of the stent was conducted to ensure that the implant conditions to which the stent will be subjected would not result in failure due to fatigue. The FEA evaluated the structural integrity of the stent 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 likely occur. | PASS | | Accelerated Fatigue Testing | Determines that the system can adequately withstand expected in vivo cyclic loading conditions. Accelerated fatigue testing was conducted on the following configurations: • Radial Fatigue Testing: Single Configuration • Radial Fatigue Testing: Overlapped Configuration • Radial Fatigue Testing: Overlapped Configuration on Static 20 mm Bend (to 400 million cycles) • Radial Fatigue Testing: Overlapped Configuration on Static 15 mm Bend (to 30 million cycles)** to ensure that the stent, when expanded to its largest intended diameter, will not show fatigue failure during simulated 10 year testing. The stents were dynamically cycled in a simulated vessel for 400 million cycles. Following cycling, stents were visually inspected under 40X magnification. No signs of strut cracking or breaking were detected. | PASS | ** The applicant has agreed to provide structural cyclic fatigue testing out to 400 million cycles on overlapped stents placed in a 15 mm bend configuration postapproval. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 15 of 67 {15} Table 4 In vitro Engineering Studies (cont'd) | Test | Test Description | Results | | --- | --- | --- | | Magnetic Resonance Imaging (MRI) | Non-clinical testing has demonstrated that the XIENCE V stent, in single and in overlapped configurations up to 68 mm in length, is MR Conditional. It can be scanned safely under the following conditions: • Static magnetic field of 1.5 or 3 Tesla • Spatial gradient field of 720 Gauss/cm or less • Maximum whole-body-averaged specific absorption rate (SAR) of 2.0 W/kg (normal operating mode) for 15 minutes of scanning or less The XIENCE V stent should not migrate in this MRI environment. Non-clinical testing at field strengths greater than 3 Tesla has not been performed to evaluate stent migration or heating. MRI at 1.5 or 3 Tesla may be performed immediately following the implantation of the XIENCE V stent. Stent heating was derived by relating the measured non-clinical, in vitro temperature rises in a GE Excite 3 Tesla scanner and in a GE 1.5 Tesla coil to the local specific absorption rates (SARs) in a digitized human heart model. The maximum whole body averaged SAR was determined by validated calculation. At overlapped lengths up to 68 mm, the XIENCE V stent produced a non-clinical maximum local temperature rise of 3°C at a maximum whole body averaged SAR of 2.0 W/kg (normal operating mode) for 15 minutes. These calculations do not take into consideration the cooling effects of blood flow. The effects of MRI on overlapped stents greater than 68 mm in length or stents with fractured struts is unknown. As demonstrated in non-clinical testing, an image artifact can be present when scanning the XIENCE V stent. MR image quality may be compromised if the area of interest is in the exact same area, or relatively close to, the position of the XIENCE V stent. Therefore, it may be necessary to optimize the MR imaging parameters for the presence of this implant. | PASS | | Radiopacity | Confirms that the XIENCE V stent is adequately visible under fluoroscopic imaging equipment. The XIENCE V stent is comparable to that of the MULTI-LINK VISION and MULTI-LINK MINI VISION under fluoroscopy. | PASS | | Delivery System Dimensional and Functional Attributes | | | | Balloon Rated Burst Pressure | Statistically demonstrates with 95% confidence, at least 99.9% of the XIENCE V systems will not rupture below the rated burst pressure (RBP) and to demonstrate that at a 95% confidence level, at least 99% of the XIENCE V systems will not rupture below the maximum labeled compliance (MLC) pressure. All systems met product specifications and confidence/reliability limits. | PASS | PMA P070015: FDA Summary of Safety and Effectiveness Data Page 16 of 67 {16} Table 4 In vitro Engineering Studies (cont'd) | Test | Test Description | Results | | --- | --- | --- | | Unconstrained Balloon Fatigue | Statistically demonstrates with 95% confidence, at least 90% of the XIENCE V systems will sustain 10 repeated inflations to the rated burst pressure inside the stent. All systems met product specifications. | PASS | | Stent Diameter vs. Balloon Pressure (Compliance) | Determines how the diameter of a deployed balloon varies with applied balloon pressures. All systems met product specifications. | PASS | | Soft Tip Tensile | Determines the tensile strength of the soft tip. All systems met product specifications. | PASS | | Distal Delivery System Tensile | Determines the tensile strength of the distal portion of the delivery system. All systems met product specifications. | PASS | | Proximal Delivery System Tensile | Determines the tensile strength of the proximal portion of the delivery system. All systems met product specifications. | PASS | | Delivery System Crossing Profile Crimped Stent Outer Diameter | Determines the crimped stent outer diameter. Measurements were taken at various locations along the length of the stent and averaged to calculate the mean outer diameter. All systems met product specifications. | PASS | | Delivery System Balloon Inflation/Deflation Times | Determines the amount of time required to inflate or deflate the delivery catheter balloon. All systems met product specifications for deflation times. Inflation times were tested for information only. | PASS | | Stent Dislodgement | Determines the amount of force required to displace a stent in both distal and proximal direction from its original, crimped position on the delivery system balloon after a pre-conditioning step where the system is tracked through a tortuous artery model. All systems met product specifications. | PASS | | Delivery System Guiding Catheter Pullback | Statistically demonstrates that with 95% confidence, at least 99% of the XIENCE V systems can be successfully retracted back into a 5F guiding catheter after tracking through a simulated tortuous model prior to the deployment of the stent. All systems met product specifications and confidence/reliability limits. | PASS | | Delivery, Deployment, and Retraction | Design validations demonstrate that the XIENCE V system meets the user needs. | PASS | | Delivery System Preparation | Evaluates the ease of preparing the XIENCE V system using the aspiration method. All systems met product specifications. | PASS | | Delivery System Shaft Pressure | Determines the pressure integrity of the XIENCE V catheter shaft proximal to the delivery system balloon. All systems met product specifications. | PASS | | Delivery System Inner Member Collapse | Verifies that irreversible collapse of the inner member does not occur at or below 300 psi. All systems met product specifications. | PASS | PMA P070015: FDA Summary of Safety and Effectiveness Data Page 17 of 67 {17} Table 4 In vitro Engineering Studies (cont'd) | Test | Test Description | Results | | --- | --- | --- | | Delivery System Dimensional and Functional Attributes (cont'd) | | | | Delivery System Coating Friction (Hydrophilic) | Determines the coefficient of friction along the hydrophilic coated portion of the XIENCE V catheter using an aorta lined fixture. All systems met product specifications. | PASS | | Delivery System Coating Dry Adhesion (Hydrophilic) | Determines the percent adhesion of the hydrophilic coating to the XIENCE V catheter. The percent coating adhesion is determined by subtracting the percent coating removed from 100. All systems met product specifications. | PASS | ## A3. Coating Characterization Testing The following methods were developed to characterize and set initial specifications for the XIENCE V stent. The coating characterization testing conducted on the XIENCE V stent is summarized in Table 5. Table 5 Coating Characterization Testing | Test | Test Description | Results | | --- | --- | --- | | Stent Coating Durability | | | | Coating Physical Structure and Chemical Properties | Characterizes various aspects of the coated stent including: • the coating thickness along the length of the stent and the drug density and its distribution in the stent coating • the cross section of the coated stent struts • the content uniformity along the length of the stent • adhesion of the coating to the delivery system balloon • physical microstructure. | PASS | | Coating Adhesion | Evaluates adhesion properties between the coating and the metal stent with shear stress analysis using a Nano-Scratch Tester. | PASS | | Coating Surface Integrity | Determines the stent coating surface integrity of the XIENCE V stent after tracking through a tortuosity fixture, expansion, and post-dilated to RBP. Defect quantities and sizes were recorded. The compromised coating area was calculated as a percentage of entire coated stent surface. All stents met product specifications. | PASS | | Coating Integrity after Balloon Rupture | Evaluates the stent coating surface integrity of the XIENCE V stent after balloon rupture within the stent. The stents were compared to control stents expanded to nominal diameter. | PASS | PMA P070015: FDA Summary of Safety and Effectiveness Data Page 18 of 67 {18} Table 5 Coating Characterization Testing (cont'd) | Test | Test Description | Results | | --- | --- | --- | | Stent Coating Durability (cont'd) | | | | Accelerated Coating Fatigue | Demonstrates the coating durability of the XIENCE V stent under expected in vivo cyclic loading conditions for an equivalence of 10 years (~400 million cycles). Accelerated coating fatigue testing was conducted on the following configurations: • Coating Fatigue Testing: Single Configuration • Coating Fatigue Testing: Overlapped Configuration • Coating Fatigue Testing: Overlapped Configuration on Static 20 mm Bend (to 400 million cycles) • Coating Fatigue Testing: Overlapped Configuration on Static 15 mm Bend (to 30 million cycles)* | PASS | | | The stents were deployed and post-dilated to the largest intended diameter. The drug was eluted from the coating. The stents were evaluated under SEM and then loaded into tubing and the fatigue tester. The stents were dynamically cycled within simulated vessel conditions for 400 million cycles. The stents were removed and visually inspected under SEM for changes to coating morphology in the documented anomalies that were captured prior to fatigue testing. All stents met product specifications and confidence/reliability limits. | | | Particulate - Beaker Method (Over-expansion) | Determines the particulate matter generated during deployment and over expansion of the XIENCE V stent in a beaker of water. The distal end (balloon and stent) was inserted into glassware filled with clean water. The stents were deployed and post-dilated to the maximum stent diameter. After agitation, aliquots of the water were withdrawn and the particles quantities and sizes were counted and recorded. All stents met product specifications. | PASS | | Particulate – Tracking Method (Simulated Use) | Determines the particulate matter after navigating simulated, challenging vasculature followed by deployment. The XIENCE V system was tracked through a simulated tortuous artery model and the stent was deployed unconstrained to RBP inside simulated vasculature. Water was drawn through the vasculature and the particle quantities and sizes were counted and recorded. All stents met product specifications. | PASS | * The applicant has agreed to provide coating integrity testing out to 400 million cycles on overlapped stents placed in a 15 mm bend configuration. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 19 of 67 {19} Table 5 Coating Characterization Testing (cont'd) | Test | Test Description | Results | | --- | --- | --- | | Stent Coating Durability (cont'd) | | | | Embolic Fatigue (Overlap Configuration) | Investigates the embolic particle size and count from the XIENCE V stent during an accelerated radial fatigue test through multiple time points. Pre-condition units and deploy into tubing with a 4 mm overlap. Particle quantities and sizes were recorded from each pair of stents through the testing duration. Testing was done for the following configurations and time points: • Overlapped Straight Configuration through 9.3 million cycles • Overlapped Configuration on 20 mm Bend through 37.8 million cycles • Overlapped Configuration on 15 mm Bend through 30 million cycles** | PASS | ** The applicant has agreed to provide additional embolic fatigue data for overlapped stents placed in a 15 mm bend configuration. This new testing will be carried out to 10 years equivalent or at a minimum two years equivalent if the test data demonstrates a clear plateau. ## A4. Chemistry, Manufacturing & Controls (CMC) Testing Where applicable, International Conference on Harmonization (ICH) Guidelines were followed for the testing routinely performed on the XIENCE V stent as part of CMC. This testing is summarized in Table 6. Information to support the stability of the XIENCE V stent is summarized separately in Section IX.A5 Stability. Table 6 XIENCE V Stent Release Testing | Test | Description of Test | | --- | --- | | Appearance | A visual inspection was conducted to verify that the XIENCE V meets product appearance specifications. | | Identity | Assays were conducted to verify the identity of the drug substance, everolimus, on the XIENCE V stent using two different methods. | | Content Uniformity | Multiple stents were tested to verify that the uniformity of the drug content between individual stents was within specifications established for finished good release. | | Total Content | Assay was conducted to quantitatively verify that the total amount of drug on the XIENCE V stent met specification for finished good release. | | Drug Release | The in vitro drug release profile of everolimus was measured on the XIENCE V stent. The product met specifications established for finished good release. | | Degradation Products | Assays were conducted to quantitatively verify the amount and type of degradation products on the XIENCE V stent. | | USP <85> Bacterial Endotoxins Test | The amount of bacterial endotoxins was verified to be within the specification limits established for finished good release. | | Particulate | Particulate levels were verified to meet product specifications. | PMA P070015: FDA Summary of Safety and Effectiveness Data Page 20 of 67 {20} PMA P070015: FDA Summary of Safety and Effectiveness Data Page 21 of 67 # A5. Stability/Shelf Life Manufacturing site-specific stability studies were conducted to establish a shelf life/expiration date for the XIENCE V stent system. Testing included appearance, total content, drug release, degradation products, and butylated hydroxytoluene (BHT) content. Testing to establish container closure integrity was conducted to ensure sterility was maintained during the shelf life of the product. Functional testing of the stent system was conducted on aged product. The data generated to-date support a shelf life of 1 year. # A6. Sterilization The XIENCE V stent system is sterilized using ethylene oxide (EtO) 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 $10^{-6}$. In addition, the amount of bacterial endotoxins was verified to be within the specification limits. # B. In Vivo Animal Studies ## B1. In Vivo Pharmacokinetic Studies *In vivo* preclinical pharmacokinetic studies were performed in the porcine coronary artery model to determine: the percent drug release of everolimus from the XIENCE V stent over time, the tissue concentrations of everolimus over time, and the impact, if any, of systemic maximum dose of everolimus on platelet function. The pharmacokinetic data demonstrate that everolimus is delivered to the arterial wall in a controlled and reproducible manner. Also, blood and tissue levels were within safe levels when compared to therapeutic levels achieved in organ rejection therapy. Platelet function was not adversely affected at maximum doses of everolimus eluted from the XIENCE V stent. In summary, the XIENCE V EECSS has a safe pharmacokinetic profile as demonstrated in the porcine animal model. ## B2. Drug Interactions Formal drug interaction studies have not been conducted with the XIENCE V stent. Everolimus is extensively metabolized by cytochrome P450 3A4 (CYP3A) isozyme 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 affect these pathways. Coadministration of strong CYP3A inhibitors (such as ketoconazole, itraconazole, ritonavir) and inducers (such as rifampicin, rifabutin) should be avoided. Coadministration of moderate CYP3A inhibitors (such as erythromycin, fluconazole, calcium channel blockers) and inducers (such as carbamazepine, phenobarbital, phenytoin) should be accompanied by everolimus therapeutic drug monitoring. The {21} pharmacokinetic interaction between orally administered everolimus and concomitantly administered drugs is described in the XIENCE V stent system. Instructions for Use. ## B3. Animal Safety Studies Detailed arterial histopathology and histomorphometry are not obtainable through human clinical trials, so a series of animal studies were conducted to evaluate safety, efficacy (proof of concept dosing), and overall product performance. Twenty four (24) major supportive studies were carried out in a porcine non-atherosclerotic coronary artery model and rabbit iliac artery model at time points out to 2 years to determine the clinical dose of everolimus to incorporate into the XIENCE V stent, to determine the pharmacokinetics of the XIENCE V stent, and to evaluate the safety of and vascular response to the XIENCE V stent. Additionally, animal studies were conducted to evaluate the safety of overlapping two XIENCE V stents. To establish a drug safety margin, a maximum dose (~8X) XIENCE V stent was also assessed. Studies were also performed to evaluate the safety of the polymer alone at both an equivalent loading to that in the XIENCE V stent and a bulk polymer system. Supportive safety data and overlapping stent safety data have also been generated in a rabbit non-atherosclerotic iliac artery model. The results of these tests support the safety of the XIENCE V stent. A majority of these studies were conducted in accordance with 21 CFR 58 (Good Laboratory Practices). A rationale was provided for the non-GLP animal studies to demonstrate that appropriate animal care procedures were followed and data integrity were maintained. Summaries of the major supportive animal studies performed to support product safety are included in Table 7. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 22 of 67 30 {22} Table 7 Summary of Major Supportive Animal Studies | Study # | Stent Design | Animal Model (n) | # of Stents | Follow-up Duration | Endpoints | | --- | --- | --- | --- | --- | --- | | R040703-CW | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) • XIENCE (3.0 x 12 mm, 200 μg/cm²) • XIENCE (3.0 x 12 mm, 260 μg/cm²) Control: BMS GLP: no | Farm Swine (19) (LAD, LCX, RCA) 1 stent/vessel; 3 stents/animal | Test: 34 (100 =11, 200 =11, 260 =12) Control: 8 | 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) | | R051004-MJL | Test Article: XIENCE (3.0 x 12 mm, 100 μg/cm²) GLP: yes | Farm Swine (18) (LAD, LCX, RCA) 1 stent/vessel; 3 stents/animal | Test: 52 (Target: 6/time point) | 15, 30, 45, 60, 90, 120, 150, 180 minutes and 12 hours (blood levels only) 3 and 6 hours, 3, 14, 28, 60, 90, and 120 days (other evaluations) | Evaluation of % drug released, arterial and other tissue drug levels & systemic blood levels over time | | R050503-PDD | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) • XIENCE (3.0 x 12 mm, 200 μg/cm²) • XIENCE (3.0 x 12 mm, 260 μg/cm²) Controls: • Polymer (3.0 x 12 mm) 515μg • BMS (3.0 x 12 mm) GLP: yes | Farm Swine (24) (LAD, LCX, RCA) 1 stent/vessel; 3 stents/animal | Test: 37 (100 =12, 200 =12, 260 =13) Control: 32 (BMS =21, Polymer = 11) | 28 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R081704-KHB | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) Controls: • BMS (3.0 x 12 mm) GLP: yes | Farm Swine (12) (LAD, LCX, RCA) 1 stent/vessel; 2 stents/animal | Test: 12 Control: 12 | 28 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R100704-KHB | Test Article: • XIENCE (2.5 x 8 mm, 100 μg/cm²) Controls: • BMS (2.5 x 8 mm) GLP: yes | New Zealand White Rabbit (7) (Left & Right Iliac) 1 stent/vessel 2 stents/animal | Test: 7 Control: 7 | 28 days | • Histological & histomorphometric evaluations • Acute delivery • Chronic vascular response | PMA P070015: FDA Summary of Safety and Effectiveness Data Page 23 of 67 {23} Table 7 Summary of Major Supportive Animal Studies (cont'd) | Study # | Stent Design | Animal Model (n) | # of Stents | Follow-up Duration | Endpoints | | --- | --- | --- | --- | --- | --- | | R042403-PDD | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) • XIENCE (3.0 x 12 mm, 200 μg/cm²) • XIENCE (3.0 x 12 mm, 260 μg/cm²) Controls: • Polymer (3.0 x 12 mm) 515μg • BMS (3.0 x 12 mm) GLP: yes | Farm Swine (24) (LAD, LCX, RCA) 1 stent/vessel; 3 stents/animal | Test: 36 (100 =12, 200 =12, 260 =12) Control: 34 (BMS =22, Polymer ≈ 12) | 90 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R042204-PDD | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) Controls: • BMS (3.0 x 12 mm) GLP: yes | Farm Swine (12) (LAD, LCX, RCA) 1 stent/vessel; 2 stents/animal | Test: 12 Control: 12 | 90 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R081103-PDD | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) • XIENCE (3.0 x 12 mm, 200 μg/cm²) • XIENCE (3.0 x 12 mm, 260 μg/cm²) Controls: • Polymer (3.0 x 12 mm) 836μg • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (24) (LAD, LCX, RCA) 1 stent/vessel; 3 stents/animal | Test: 35 (100 =11, 200 =12, 260 =12) Control: 33 (BMS =21, Polymer = 12) | 180 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R041504-PDD | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) Controls: • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (13) (LAD, LCX, RCA) 1 stent/vessel; 2 stents/animal | Test: 12 Control: 12 | 180 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R042904-KHB | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) Controls: • BMS (3.0 x 12 mm) GLP: yes | Farm Swine (12) (LAD, LCX, RCA) 2 stents/vessel; 2 stent pairs/animal | Test: 24 (12 stent pairs) Control: 24 (12 stent pairs) | 28 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | PMA P070015: FDA Summary of Safety and Effectiveness Data Page 24 of 67 32 {24} Table 7 Summary of Major Supportive Animal Studies (cont'd) | Study # | Stent Design | Animal Model (n) | # of Stents | Follow-up Duration | Endpoints | | --- | --- | --- | --- | --- | --- | | R100604-KHB | Test Article: • XIENCE (2.5 x 8 mm, 100 μg/cm²) Controls: • BMS (2.5 x 8 mm) GLP: yes | New Zealand White Rabbit (8) (Left & Right Iliac) 2 stents/vessel; 2 stent pairs/animal | Test: 16 (8 stent pairs) Control: 16 (8 stent pairs) | 28 days | • Histological & histomorphometric evaluations • Acute delivery • Chronic vascular response | | R042604-KHB | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) Controls: • BMS (3.0 x 12 mm) GLP: yes | Farm Swine (12) (LAD, LCX, RCA) 2 stents/vessel; 2 stent pairs/animal | Test: 24 (12 stent pairs) Control: 24 (12 stent pairs) | 90 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R041904-KHB-01 | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) Controls: • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (12) (LAD, LCX, RCA) 2 stents/vessel; 2 stent pairs/animal | Test: 24 (12 stent pairs) Control: 24 (12 stent pairs) | 180 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R051503-DMH | Test Article: • XIENCE (3.0 x 12 mm, 803 μg/cm²) Controls: • Polymer (3.0 x 12 mm) 905μg • BMS (3.0 x 12 mm) GLP: yes | Farm Swine (14) (LAD, LCX, RCA) 1 stent/vessel; 3 stents/animal | Test: 13 Control: 25 (BMS = 12, bulk polymer = 13) | 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 | | R050503-DMH | Test Article: • XIENCE (3.0 x 12 mm, 803 μg/cm²) Controls: • Polymer (3.0 x 12 mm) 905μg • BMS (3.0 x 12 mm) GLP: yes | Farm Swine (14) (LAD, LCX, RCA) 1 stent/vessel; 3 stents/animal | Test: 12 Control: 21 (BMS = 9, bulk polymer = 12) | 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 | PMA P070015: FDA Summary of Safety and Effectiveness Data Page 25 of 67 {25} Table 7 Summary of Major Supportive Animal Studies (cont'd) | Study # | Stent Design | Animal Model (n) | # of Stents | Follow-up Duration | Endpoints | | --- | --- | --- | --- | --- | --- | | R032204-PDD | Test Article: • XIENCE (3.0 x 12 mm, 803 μg/cm²) Controls: • Polymer (3.0 x 12 mm) 891 μg • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (13) (LAD, LCX, RCA) 1 stent/vessel; 3 stents/animal | Test: 10 Control: 25 (BMS = 13, bulk polymer = 12) | 180 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 | | R041904-KHB-02 | Test Article: • Polymer (3.0 x 12 mm) 329 μg Controls: • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (12) (LAD, LCX, RCA) 1 stent/vessel; 2 stents/animal | Test: 12 Control: 12 | 180 days | • Angiography • Histological & histomorphometric evaluations • Evaluation of degree of endothelialization by SEM • Acute delivery • Chronic vascular response | | R093004-KHB-01 | Test Article: • XIENCE (2.5 x 8 mm, 100 μg/cm²) Controls: • BMS (2.5 x 8 mm) GLP: yes | New Zealand White Rabbit (6) (Left & Right Iliac) 1 stent/vessel 2 stents/animal | Test: 6 Control: 6 | 90 days | • Histological & histomorphometric evaluations • Acute delivery • Chronic vascular response | | R093004-KHB | Test Article: • XIENCE (2.5 x 8 mm, 100 μg/cm²) Controls: • BMS (2.5 x 8 mm) GLP: yes | New Zealand White Rabbit (8) (Left & Right Iliac) 2 stents/vessel; 2 stent pairs/animal | Test: #16 (8 stent pairs) Control: 16 (8 stent pairs) | 90 days | • Histological & histomorphometric evaluations • Acute delivery • Chronic vascular response | | R050304-PDD Part I | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) Controls: • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (6) (LAD, LCX, RCA) 1 stent/vessel; 2 stents/animal | Test: 6 Control: 6 | 1 year | • Angiography • Histological & histomorphometric evaluations • Acute delivery • Chronic vascular response | | R050504-KHB Part I | Test Article: • Polymer (3.0 x 12 mm) 329 μg Controls: • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (6) (LAD, LCX, RCA) 1 stent/vessel; 2 stents/animal | Test: 6 Control: 6 | 1 year | Evaluation of polymer safety. • Angiography • Histological & histomorphometric evaluations • Acute delivery • Chronic vascular response | PMA P070015: FDA Summary of Safety and Effectiveness Data Page 26 of 67 {26} Table 7 Summary of Major Supportive Animal Studies (cont'd) | Study # | Stent Design | Animal Model (n) | # of Stents | Follow-up Duration | Endpoints | | --- | --- | --- | --- | --- | --- | | R050304-PDD Part II | Test Article: • XIENCE (3.0 x 12 mm, 100 μg/cm²) Controls: • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (6) (LAD, LCX, RCA) 1 stent/vessel; 2 stents/animal | Test: 6 Control: 6 | 2 years | • Angiography • Histological & histomorphometric evaluations • Acute delivery • Chronic vascular response | | R050504-KHB Part II | Test Article: • Polymer (3.0 x 12 mm) 329 μg Controls: • BMS (3.0 x 12 mm) GLP: yes | Yucatan Swine (5) (LAD, LCX, RCA) 1 stent/vessel; 2 stents/animal | Test: 5 Control: 5 | 2 years | Evaluation of polymer safety. • Angiography • Histological & histomorphometric evaluations • Acute delivery • Chronic vascular response | | R0060228-MJL | Test Article: XIENCE (3.0 x 12 mm, 800 μg/cm²) GLP: yes | Farm Swine (32) (LAD, LCX, RCA) 1 stent/vessel; 2-3 stents/animal | Test: 70 (Target: 10/time point) | 1, 3, 7, and 14 days (platelet function), 15,30,45,60, 90,120, 150,180 minutes, 6 and 12 hours (blood levels only) 3, 6 and 24 hours, 3,14,28, 60 days (all other evaluations) | 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. | ## X. SUMMARY OF PRIMARY CLINICAL STUDIES Principal XIENCE V safety and effectiveness information is derived from the SPIRIT III clinical trial and is supported by the SPIRIT FIRST and SPIRIT II clinical trials. These studies evaluated XIENCE V EECSS performance in subjects with symptomatic ischemic heart disease due to de novo lesions in native coronary arteries. Major study characteristics are summarized below and listed in Table 8. SPIRIT III, a pivotal clinical trial, was designed to demonstrate the non-inferiority of the XIENCE V stent to the TAXUS EXPRESS™ Paclitaxel Eluting Coronary Stent System (TAXUS stent) and was conducted in the United States (US) and Japan. The SPIRIT III clinical trial consisted of a US randomized clinical trial (RCT), a non-randomized 4.0 mm diameter stent arm in the US, and a non-randomized arm in Japan, which included a pharmacokinetic substudy (see Section D - Global Pharmacokinetics). Enrollment is complete in the RCT and the Japan arm. The SPIRIT III RCT was a prospective, randomized (2:1; XIENCE V:TAXUS), active-controlled, single-blinded, multi-center, clinical trial in the US designed to evaluate the safety and efficacy of the XIENCE V stent in the treatment of up to two de novo lesions ≤ 28 mm in length in native coronary arteries with RVD ≥ 2.5 mm to ≤ 3.75 mm. The PMA P070015: FDA Summary of Safety and Effectiveness Data {27} RCT study was designed to enroll 1,002 subjects at up to 80 sites in the US. The primary endpoint in the RCT was in-segment late loss at 240 days and the co-primary endpoint was ischemia-driven target vessel failure (TVF, defined as the composite of cardiac death, MI, or clinically-driven TVR) at 270 days. Other secondary endpoints included clinical outcomes of all the subjects (30, 180, 270 days and annually from 1 to 5 years), as well as angiographic results and intravascular ultrasound (IVUS) results at 240 days. Follow-up through 1 year is currently available, and yearly follow-up for clinical parameters through 5 years is ongoing. The SPIRIT III 4.0 mm arm was a prospective, multi-center, single-arm registry designed to evaluate XIENCE V stent in the treatment of up to two de novo lesions ≤ 28 mm in length in native coronary arteries with RVD > 3.75 mm to ≤ 4.25 mm. This study was designed to enroll up to 80 subjects at up to 80 sites in the US. Enrolled subjects were scheduled for clinical follow up at 30, 180, 240, and 270 days and annually from 1 to 5 years, with angiographic follow-up at 240 days. The primary endpoint was in-segment late loss at 240 days compared to the TAXUS arm from the SPIRIT III RCT. Follow-up through 1 year is currently available, and yearly follow-up for clinical parameters through 5 years is ongoing. The SPIRIT III clinical trial included a pharmacokinetic substudy in a subset derived from the RCT² and the Japan non-randomized arm. Eleven sites in the US and 9 sites in Japan participated in this substudy and have enrolled 34 subjects (17 subjects in the US and 17 subjects in Japan). The SPIRIT II clinical trial was a randomized, single-blind, active-control, multi-center clinical evaluation. Subject eligibility criteria were similar to the SPIRIT III clinical trial and enrollment duration overlapped between studies. In this study, 300 subjects (3:1 randomization XIENCE V:TAXUS) were enrolled at 28 sites outside the United States. The primary endpoint was in-stent late loss at 6 months. Secondary endpoints included clinical outcomes at 30, 180, 270 days and annually from 1 to 5 years; angiographic results at 180 days and 2 years; and IVUS results at 180 days and 2 years. Follow-up through 2 years is currently available, and yearly follow-up for clinical parameters through 5 years is ongoing. The SPIRIT FIRST clinical trial was a randomized, single-blind, control, multi-center first-in-man study. This trial was the first human study to evaluate the safety and performance of the XIENCE V stent. Sixty (60) subjects [XIENCE V stent (n=28) and MULTI-LINK VISION bare metal control stent (n=32)] were enrolled at 9 sites in Europe. The primary endpoint was in-stent late loss at 6 months assessed in the per-treatment evaluable population, and the major secondary endpoint was the percent in-stent volume obstruction (% VO) at 180 days based on IVUS analysis of the per-treatment evaluable population. Follow-up through 3 years is currently available, and yearly follow-up for clinical parameters through 5 years is ongoing. Table 8 summarizes the clinical trial designs for the SPIRIT family of trials. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 28 of 67 36 {28} Table 8 XIENCE V SPIRIT Clinical Trial Designs | | SPIRIT III clinical trial | | SPIRIT II clinical trial | SPIRIT FIRST clinical trial | | --- | --- | --- | --- | --- | | | RCT | Registries | | | | Study Type/Design | • Multi-center • Randomized • Single-blinded • Active-Control | • Multi-center • Single-arm • Open-label | • Multi-center • Randomized • Single-blinded • Active-Control | • Multi-center • Randomized • Single-blinded • Control | | Planned Number of Subjects | Total: 1,002 XIENCE V: 668 TAXUS Control: 334 | Total: 168 4.0 mm: 80 Japan: 88* | Total: 300 XIENCE V: 225 TAXUS Control: 75 | Total: 60 XIENCE V: 30 VISION Control: 30 | | Treatment | Up to two de novo lesions in different epicardial vessels | Up to two de novo lesions in different epicardial vessels | Up to two de novo lesions in different epicardial vessels | Single de novo lesion | | Lesion Size | RVD: ≥ 2.5 ≤ 3.75 mm Length: ≤ 28 mm | 4.0 mm RVD: > 3.75 ≤ 4.25 mm Length: ≤ 28 mm Japan RVD: ≥ 2.5 ≤ 4.25 mm Length: ≤ 28 mm | RVD: ≥ 2.5 ≤ 4.25 mm Length: ≤ 28 mm | RVD: 3 mm Length: ≤ 12 mm | | Stent Sizes (XIENCE V) | D: 2.5, 3.0, 3.5 mm L: 8, 18, 28 mm | 4.0 mm D: 4.0 mm L: 8, 18, 28 mm Japan D: 2.5, 3.0, 3.5, 4.0 mm L: 8, 18, 28 mm | D: 2.5, 3.0, 3.5, 4.0 mm L: 8, 18, 28 mm | D: 3.0 mm L: 18 mm | | Post-procedure Antiplatelet Therapy | Clopidogrel 6 months minimum (or ticlopidine per site standard), Aspirin 5 years | 4.0 mm: same as RCT Japan: Ticlopidine 3 months, Aspirin 5 years | Clopidogrel 6 months minimum (or ticlopidine per site standard), Aspirin 1 year | Clopidogrel 3 months minimum (or ticlopidine per site standard), Aspirin 1 year | | Primary Endpoint | In-segment late loss at 240-days | In-segment late loss at 240-days | In-stent late loss at 180-days | In-stent late loss at 180-days | | Co-Primary Endpoint | TVF at 270-days | None | None | None | | Clinical Follow-up | 30, 180, 240, 270 days, 1 to 5 years | 30, 180, 240, 270 days, 1 to 5 years | 30, 180, 270 days, 1 to 5 years | 30, 180, 270 days, 1 to 5 years | | Angiographic Follow-up | 240 days (N=564) | 240 days (All registry) | 180-day (all), 2-years (N=152) | 180-days, 1-year (all) | | IVUS Follow-up | 240 days (N=240) | 240 days (Japan only) | 180-day, 2-years (N=152) | 180-days, 1-year (all) | | PK Study | US: Minimum 15 subjects with single lesion, maximum 20 with dual lesions Japan: Minimum 10 subjects with single lesion, maximum 20 with dual lesions | | Minimum 15 subjects with single lesion, maximum 20 with dual lesions | None | | Status | One year reported; 2, 3, 4 and 5 years planned | | One and 2 years reported; 3, 4 and 5 years planned | One, 2, and 3 years reported; 4 and 5 years planned | * Only pharmacokinetic substudy results included (see Section D - Global Pharmacokinetics) PMA P070015: FDA Summary of Safety and Effectiveness Data {29} PMA P070015: FDA Summary of Safety and Effectiveness Data Page 30 of 67 38 # A. SPIRIT III Pivotal Clinical Trial SPIRIT III, a pivotal clinical trial, was designed to demonstrate the non-inferiority of the XIENCE V stent to the TAXUS EXPRESS™ stent and was conducted in the United States (US) and Japan. The SPIRIT III clinical trial consists of a US randomized clinical trial (RCT), a non-randomized 4.0 mm diameter stent arm in the US, and a non-randomized arm in Japan, which included a pharmacokinetic substudy. Enrollment is complete in the RCT and the Japan arm. The SPIRIT III clinical trial included a pharmacokinetic sub-study in a subject subset derived from the RCT³ and Japan non-randomized arm (see Section D Global Pharmacokinetics). Eleven sites in the US and 9 sites in Japan participated in this substudy and have enrolled 34 subjects (17 subjects in the US and 17 subjects in Japan). Venous blood was drawn at regular intervals for pharmacokinetics analysis of total blood everolimus level at pre-determined sites. ## Study Design ### SPIRIT III Randomized Clinical Trial (RCT) The SPIRIT III RCT was a prospective, 2:1 (XIENCE V:TAXUS) randomized, active-controlled, single-blinded, parallel, multi-center non-inferiority evaluation of the XIENCE V stent compared to the TAXUS stent in the treatment of up to two *de novo* lesions ≤ 28 mm in length in native coronary arteries with RVD ≥ 2.5 mm to ≤ 3.75 mm. Given the available XIENCE V stent lengths of 8, 18 and 28 mm for this trial, in the XIENCE V arm, treatment of a target lesion > 22 mm and ≤ 28 mm in length was accomplished by planned overlap of either two 18 mm stents or a 28 mm and an 8 mm stent. In the TAXUS arm, overlap was only permitted for bailout or to ensure adequate lesion coverage. The RCT was designed to enroll 1,002 subjects at up to 80 sites in the United States. All subjects had clinical follow-up at 30, 180, and 270 days, and annually from 1 to 5 years. A pre-specified subgroup of 564 subjects had angiographic follow-up at 240 days. Of these 564, 240 subjects had IVUS at baseline and at 240 days. Subjects that received a bailout stent also had IVUS at baseline and angiographic and IVUS follow-up at 240 days. Following the index procedure, all subjects were to be maintained on clopidogrel bisulfate daily for a minimum of 6 months and aspirin daily to be taken throughout the length of the trial (5 years). SPIRIT III RCT patients were randomized into follow-up coronary imaging subgroups: ### Group A: (N=240) Follow-up angiography at 240 days during their office/hospital visit follow-up was specified for 160 subjects enrolled in the XIENCE V arm and 80 subjects enrolled in the TAXUS arm. These subjects were also to be enrolled in the IVUS group (N=240) ³ Includes one subject from the 4.0 mm non-randomized arm {30} at fixed number of pre-determined clinical sites and were to have follow-up IVUS at 240 days. ## Group B: (N=324) Follow-up angiography at 240 days during their office/hospital visit without follow-up IVUS at 240 days was specified for approximately 216 subjects enrolled in the XIENCE V arm and 108 subjects in the TAXUS arm. ## Group C: (N=438) No follow-up angiography or IVUS at 240 days was specified for 292 subjects in the XIENCE V arm and 146 subjects in the TAXUS arm. ## SPIRIT III US 4.0 Arm This was a prospective, single-arm, multi-center, clinical trial in the United States evaluating the 4.0 mm diameter XIENCE V stent compared to the TAXUS stent arm in the SPIRIT III Randomized Control Trial (RCT). At the time of database lock on June 14, 2007, a total of 69 of the 73 subjects that were enrolled into the SPIRIT III 4.0 mm arm had reached their primary endpoint. Therefore, 69 subjects were included in the interim analysis. All subjects had clinical follow-up at 30, 180, 240, and 270 days, and annually from 1 to 5 years. In addition, all subjects had angiographic follow-up at 240 days. IVUS was performed in subjects who received a bailout stent at baseline and at 240 days. Following the index procedure, all subjects were to be maintained on clopidogrel bisulfate daily for a minimum of 6 months and aspirin daily to be taken throughout the length of the trial (5 years). ## Clinical Inclusion and Exclusion Criteria Enrollment in the SPIRIT III RCT and 4.0 mm arms was limited to subjects who met the eligibility criteria and who provided a signed informed consent form prior to enrollment. Subjects had to be at least 18 years old, with evidence of myocardial ischemia based on the presence of angina, silent ischemia, a positive functional study or reversible ECG changes consistent with ischemia. Female subjects with childbearing potential had to have a negative pregnancy test within 7 days of the index procedure. Key angiographic inclusion criteria included a maximum of two de novo native coronary artery lesions, each within a different epicardial vessel. For the SPIRIT III RCT arm, the reference vessel diameter (RVD) had to be ≥ 2.5 mm and ≤ 3.75 mm, and for the SPIRIT III 4.0 mm arm, the RVD had to be > 3.75 mm and ≤ 4.25 mm. For both the RCT and the 4.0 mm arm, lesion length had to be ≤ 28 mm by visual estimation, percent diameter stenosis (%DS) ≥ 50% and < 100%, and TIMI flow ≥ 1. Subjects were not permitted to enroll in the SPIRIT III RCT and 4.0 mm arms if their lesions met any of the following key angiographic exclusion criteria: aorto-ostial location, left main location, excessive tortuosity, extreme angulation (≥ 90°), heavy PMA P070015: FDA Summary of Safety and Effectiveness Data Page 31 of 67 {31} calcification, target vessel containing thrombus, and other significant lesions (> 40 %DS) in the target vessel or side branch for which intervention was required within 9 months. If two target lesions were treated, each of these lesions had to meet all angiographic inclusion/exclusion criteria. ## Follow-up Schedule All subjects were scheduled to return postoperatively for a follow-up office/hospital visit at 30 days, telephone call/office visit follow-up at 180 and 270 days, an office/hospital visit at 240 days for angiographic follow-up, and an office/hospital visit or telephone call/office visit at 1, 2, 3, 4, and 5 years. ## Stent Thrombosis Definitions Protocol defined stent thrombosis (ST) was categorized as acute (< 1 day), subacute (1 - 30 days) and late (> 30 days) and was defined as any of the following⁴: - Clinical presentation of acute coronary syndrome with angiographic evidence of stent thrombosis (angiographic appearance of thrombus within or adjacent to a previously treated target lesion) - In the absence of angiography, any unexplained death, or acute MI (ST segment elevation or new Q-wave)⁵ in the distribution of the target lesion within 30 days. All stent thrombosis events were also classified using the ST definitions proposed by the Academic Research Consortium (ARC)⁶. This was performed by an independent event committee blinded to the treatment group of the individual subject. The committee categorized each incident of ST by timing and level of probability (definite, probable, possible), and relation to the original index procedure (primary, secondary after revascularization). These categories are defined as follows: ## Timing: - Early ST: 0 to 30 days post stent implantation - Late ST: 31 days to 1 year post stent implantation - Very late ST: > 1 year post stent implantation ## Level of probability: - Definite ST - considered to have occurred by either angiographic or pathologic confirmation. - Probable ST - considered to have occurred after intracoronary stenting in the following cases: 1. Any unexplained death within the first 30 days. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 32 of 67 40 {32} 2. Irrespective of the time after the index procedure, any MI which is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of ST and in the absence of any other obvious cause. - Possible ST - considered to have occurred with any unexplained death following 30 days after the intracoronary stenting until the end of trial follow-up.⁷ ## Clinical Endpoints ### SPIRIT III Randomized Clinical Trial (RCT) The objective of the SPIRIT III RCT was to demonstrate the non-inferiority in in-segment late loss at 240 days and target vessel failure at 270 days of the XIENCE V stent compared to the TAXUS stent in the treatment of up to two *de novo* lesions ≤ 28 mm in length in native coronary arteries with RVD ≥ 2.5 mm to ≤ 3.75 mm. If non-inferiority was demonstrated, it was pre-specified that testing for superiority could be conducted. ### SPIRIT III US 4.0 Arm The objective of the SPIRIT III 4.0 mm arm was to demonstrate the non-inferiority in in-segment late loss at 240 days compared to the TAXUS arm of the RCT. ## Accountability of Subjects ### SPIRIT III Randomized Clinical Trial (RCT) A total of 1002 subjects (intent-to-treat) were randomized and enrolled into the SPIRIT III RCT. At the time of database lock on June 14, 2007, 997 subjects (99.5%) completed the 30-day follow-up; 987 subjects (98.5%) completed the 180-day follow-up; 972 subjects (97.0%) completed the 270-day follow-up, and 962 (96.0%) subjects completed the one-year follow-up. It should be noted that 973 subjects completed the 270-day follow-up. This result is based on the database which was locked on March 10, 2007 for the 270-day report. One TAXUS subject had the 270-day follow-up completed, but the study completion form for this subject was not updated in the database until it was locked on June 14, 2007 for the one-year report. Therefore, this subject was considered to be lost to follow-up at Day 214 post index procedure. Thus, the 270-day follow-up is reduced to 972 subjects (97.0%). A total of 947 subjects were included in the per-treatment evaluable population. As of June 14, 2007, 945 subjects (99.8%) completed the 30-day follow-up; 937 subjects (98.9%) completed the 180-day follow-up; 923 subjects (97.5%) completed the 270-day follow-up, and 913 (96.4%) subjects completed the one-year follow-up. ⁷ All data within this Instructions for Use is presented as definite + probable only. PMA P070015: FDA Summary of Safety and Effectiveness Data Page 33 of 67 41 {33} # SPIRIT III US 4.0 Arm At the time of database lock on June 14, 2007, a total of 69 of the 73 subjects that were enrolled into the SPIRIT III 4.0 mm arm had reached their primary endpoint. Therefore, 69 subjects were included in the interim analysis. As of June 14, 2007, 69 subjects (100%) completed the 30-day follow-up; 67 subjects (97.1%) completed the 180-day, 270-day and one-year follow-ups. ![img-3.jpeg](img-3.jpeg) Figure 3 SPIRIT III 1-Year Clinical Follow-Up Subject Disposition (Intent-to-Treat) PMA P070015: FDA Summary of Safety and Effectiveness Data Page 34 of 67 {34} ![img-4.jpeg](img-4.jpeg) Figure 4 SPIRIT III 1-Year Clinical Follow-Up Subject Disposition (Per-Treatment Evaluable) ## Study Population Demographics and Baseline Parameters ## SPIRIT III Randomized Clinical Trial (RCT) The mean age was 63.2 years for the XIENCE V arm and 62.8 for the TAXUS arm. The XIENCE V had 70.1% (469/669) males and the TAXUS arm had 65.7% (218/332) males. The XIENCE V arm had 32.… --- **Source:** [https://fda.innolitics.com/device/P070015](https://fda.innolitics.com/device/P070015) **Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. If you're preparing [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/), [get in touch](https://innolitics.com/contact). **Cite:** Innolitics at https://innolitics.com