SYNERGY EVEROLIMUS-ELUTING PLATINUM CHROMIUM CORONARY STENT SYSTEM

P150003 · Boston Scientific Corporation · NIQ · Oct 2, 2015 · Cardiovascular

Device Facts

• Record ID: P150003
• Device Name: SYNERGY EVEROLIMUS-ELUTING PLATINUM CHROMIUM CORONARY STENT SYSTEM
• Applicant: Boston Scientific Corporation
• Product Code: NIQ · Cardiovascular
• Decision Date: Oct 2, 2015
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent System is indicated for improving luminal diameter in patients with symptomatic heart disease, stable angina, unstable angina, non-ST elevation MI or documented silent ischemia due to atherosclerotic lesions in native coronary arteries ≥2.25 mm to ≤4.00 mm in diameter in lesions ≤34 mm in length.

Device Story

SYNERGY is a drug-eluting coronary stent system consisting of a platinum chromium alloy stent pre-mounted on a balloon-expandable delivery catheter (Monorail or Over-The-Wire). The stent features an abluminal coating of bioabsorbable PLGA polymer and the anti-proliferative drug everolimus. Used in the cardiac catheterization lab by interventional cardiologists to treat native coronary artery lesions. The device provides mechanical scaffolding to support the vessel lumen while everolimus is released to inhibit smooth muscle cell proliferation and reduce restenosis. The polymer is designed to be reabsorbed into the body over time. The physician uses fluoroscopic guidance to position and deploy the stent via balloon inflation. Successful deployment improves luminal diameter, reducing ischemia and associated symptoms. The device benefits patients by providing a temporary mechanical structure and localized drug delivery to maintain vessel patency.

Clinical Evidence

Evidence includes the EVOLVE II pivotal RCT (N=1684), a PK sub-study (N=21), a diabetic sub-study (N=203), and a QCA study (N=100). The RCT demonstrated non-inferiority to the PROMUS Element Plus control, with a 12-month TLF rate of 6.7% vs 6.5% (p=0.0005). Technical success was 98.3%. The QCA study showed an in-stent late loss of 0.23 ± 0.34 mm at 9 months, meeting the performance goal of 0.40 mm (p<0.0001). No longitudinal stent deformation was observed in the QCA cohort.

Technological Characteristics

Stent material: Platinum Chromium Alloy (PtCr). Coating: Abluminal bioabsorbable PLGA polymer with everolimus (1 μg/mm²). Stent strut thickness: 0.074-0.081 mm. Delivery system: Monorail or Over-The-Wire catheter. Sterilization: Ethylene oxide. MR Conditional (1.5T and 3.0T). Complies with ASTM F138-00, ASTM F2129-08, ASTM F746-04, and ISO 10993 standards.

Indications for Use

Indicated for patients ≥18 years with symptomatic heart disease, stable/unstable angina, non-ST elevation MI, or silent ischemia due to atherosclerotic lesions in native coronary arteries (2.25-4.00 mm diameter, ≤34 mm length). Contraindicated in patients with hypersensitivity to stent materials (316L stainless steel, platinum, chromium, iron, nickel, molybdenum), everolimus, or PLGA polymer; patients with uncorrected bleeding disorders; or patients unable to receive antiplatelet/anticoagulation therapy.

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

• PROMUS Element Plus Everolimus-Eluting Platinum Chromium Coronary Stent System (P150003)

Reference Devices

• Emerge PTCA Dilatation catheter (K113220)
• Promus PREMIER Everolimus-Eluting Platinum Chromium Coronary Stent System (NG PROMUS trial)
• XIENCE V Everolimus Eluting Coronary Stent System

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: SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent System (Monorail™)

SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent System (Over-The-Wire)

Device Procode: NIQ

Applicant’s Name and Address: Boston Scientific Corporation
300 Boston Scientific Way
Marlborough, MA 01752

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P150003

Date of FDA Notice of Approval: October 2, 2015

II. INDICATIONS FOR USE

The SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent System is indicated for improving luminal diameter in patients with symptomatic heart disease, stable angina, unstable angina, non-ST elevation MI or documented silent ischemia due to atherosclerotic lesions in native coronary arteries ≥2.25 mm to ≤4.00 mm in diameter in lesions ≤34 mm in length.

III. CONTRAINDICATIONS

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

- 316L stainless steel or, platinum, chromium, iron, nickel or molybdenum;
- everolimus or structurally-related compounds; and/or
- the polymer or their individual components.

Coronary Artery Stenting is contraindicated for use in:

- Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the stent or delivery device.
- Patients with uncorrected bleeding disorders or patients who cannot receive anticoagulation or antiplatelet aggregation therapy.

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent System labeling.

# V. DEVICE DESCRIPTION

The SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent System (SYNERGY) is a device/drug combination product that provides a mechanical structure for vascular lumen support (primary mode of action) and a pharmacological agent (everolimus) targeted towards reducing the injury response. The System consists 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 bioabsorbable polymer, poly (D,L-lactide-co-glycolide) (PLGA), and the active pharmaceutical ingredient, everolimus. The characteristics of the SYNERGY stent system are described in Table V-T1.

Table V-T1: SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent System Product Description

| | SYNERGY
Monorail Stent Delivery System | SYNERGY
Over-the-Wire Stent Delivery
System |
| --- | --- | --- |
| Available Stent
Lengths (mm) | 8, 12, 16, 20, 24, 28, 32, 38 | |
| Available Stent
Diameters (mm) | 2.25, 2.50, 2.75, 3.00, 3.50, 4.00 | |
| Stent Material | Platinum Chromium Alloy (PtCr) | |
| Stent Strut Thickness | 0.074 mm for diameters 2.25 mm to 2.75 mm
0.079 mm for diameters 3.00mm to 3.50 mm
0.081 mm for diameter of 4.00 mm | |
| Drug Product | An abluminal (outer surface of the stent) coating of a polymer carrier with
approximately 1 μg of everolimus per mm² of total stent surface area with a
maximum nominal drug content of 287.2 μg on the largest stent (4.00 x 38 mm). | |
| Delivery System | | |
| Effective Length | 144 cm | |
| Delivery System Y-Adapter Ports | Single access port to inflation lumen.
Guidewire exit port is located
approximately 25 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) | |

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| | SYNERGY Monorail Stent Delivery System | SYNERGY Over-the-Wire Stent Delivery System |
| --- | --- | --- |
| Catheter Shaft Outer Diameter | Proximal: 2.1 F (0.70 mm) Distal: 2.25 mm – 2.75 mm: 2.6F (0.90 mm) 3.00 mm (8 – 28 mm): 2.6F (0.90mm) 3.00 mm (32 – 38 mm): 2.7F (0.95 mm) 3.50 mm (8 – 20 mm): 2.6F (0.90 mm) 3.50 mm (24 – 38 mm): 2.7F( 0.95 mm) 4.00 mm: 2.7F (0.95 mm) | 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) |

# A. Device Component Description

The SYNERGY stent is comprised of a Platinum Chromium Alloy (PtCr). Similar to other metallic stents manufactured by BSC, the stent component is laser cut into a specific geometric pattern which consists of serpentine rings connected by links that are highly polished to a uniform rounded surface.

Three separate stent models were designed in specific size ranges. A stent model is defined as a variation of a specific geometry pattern designed for various vessel diameters. The three models are defined below:

- Small Vessel (SV): ${2.25}\mathrm{\;{mm}},{2.50}\mathrm{\;{mm}}$ ,and ${2.75}\mathrm{\;{mm}}$
- Workhorse (WH): ${3.00}\mathrm{\;{mm}}$ and ${3.50}\mathrm{\;{mm}}$
Large Vessel (LV): $4.00\mathrm{mm}$

The commercial matrix is shown in Table V.A-T2 below.

Table V.A-T2: SYNERGY U.S. Commercial Matrix (Monorail and Over-The-Wire)
Stent Length

| | | | 8 mm | 12 mm | 16 mm | 20 mm | 24 mm | 28 mm | 32 mm | 38 mm |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Stent Model / Balloon Diameter | SV | 2.25 mm | X | X | X | X | X | X | X | X |
| | | 2.50 mm | X | X | X | X | X | X | X | X |
| | | 2.75 mm | X | X | X | X | X | X | X | X |
| | WH | 3.00 mm | X | X | X | X | X | X | X | X |
| | | 3.50 mm | X | X | X | X | X | X | X | X |
| | LV | 4.00 mm | X | X | X | X | X | X | X | X |

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# B. Drug Component Description

The SYNERGY stent drug matrix is composed of the bioabsorbable polymer poly (D,L-lactide-co-glycolide) (PLGA) and the anti-proliferative drug everolimus. The drug to polymer formulation is 45:55 (w/w).

# B1. Everolimus

The active pharmaceutical ingredient in the SYNERGY stent is everolimus. The everolimus chemical name is 40-O-(2-hydroxyethyl)-rapamycin, and its chemical structure is provided in Figure V.B.1-F1. The nominal total loaded dose of everolimus per nominal stent length/diameter is shown in Table V.B.1-T1.

Figure V.B.1-F1: Structure of Everolimus

Table V.B.1-T1: Nominal Total Loaded Dose of Everolimus (μg) per Nominal Stent Length and Diameter

| | | Stent Length | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Design | Stent Model | 8 mm | 12 mm | 16 mm | 20 mm | 24 mm | 28 mm | 32 mm | 38 mm |
| Total Drug Content/Stent (μg) | SV | 38.9 | 58.3 | 77.6 | 96.9 | 121.1 | 140.5 | 159.8 | 188.9 |
| | WH | 46.5 | 66.3 | 92.7 | 112.5 | 132.3 | 158.7 | 178.5 | 211.6 |
| | LV | 67.5 | 96.2 | 124.8 | 153.5 | 182.2 | 210.8 | 239.5 | 287.2 |

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| | | Stent Length | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | | | | | | |
| Total Coat Weight/ Stent (μg) | SV | 87 | 132 | 174 | 218 | 273 | 316 | 360 | 426 |
| | WH | 104 | 149 | 209 | 254 | 298 | 358 | 403 | 477 |
| | LV | 152 | 217 | 281 | 346 | 411 | 475 | 539 | 647 |

SV – Small Vessel (2.25 mm, 2.50 mm, and 2.75 mm)
WH – Workhorse (3.00 mm and 3.50 mm)
LV – Large Vessel (4.00 mm)

## B2. Inactive Ingredient

Polymer—poly (DL-lactide-co-glycolide) (PLGA)

SYNERGY is abluminally coated with a bioabsorbable coating. The coating consists of bioabsorbable PLGA polymer and everolimus. The PLGA polymer provides controlled and sustained release of available everolimus through the intended time frame, during which the polymer is reabsorbed into the body. The chemical structure of PLGA is shown in Figure V.B.2-F1.

Figure V.B.2-F1: Structure of PLGA

## C. Mechanism of Action of Everolimus

On a cellular level, everolimus inhibits, in a reversible manner, growth factor-stimulated cell proliferation. On a molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus, the growth factor-stimulated phosphorylation of p70 S6 kinase and 4E-BP1 is inhibited. The latter proteins are key proteins involved in the initiation of protein synthesis. Since phosphorylation of both p70 S6 kinase and 4E-BP1 is under the control of FRAP (FKBP-12-rapamycin associated protein, also called mTOR, mammalian target of rapamycin) this finding suggests that, the everolimus-FKBP-12 complex binds to and thus interferes with the function of FRAP. FRAP is a key regulatory protein which governs cell metabolism, growth and proliferation. Disabling FRAP function explains the cell cycle arrest at the late G1 stage caused by everolimus.

## 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. MARKETING HISTORY

As of January 30, 2014, approximately 31,943 SYNERGY stents have been distributed outside the United States. Table VII-T1 lists countries where the product is currently commercially available. No products have been withdrawn from the market in any country for any reason.

Table VII-T1: Countries with SYNERGY Commercial Availability

| Algeria | Hungary | Norway |
| --- | --- | --- |
| Argentina | Iceland | Pakistan |
| Australia | India | Panama |
| Austria | Indonesia | Peru |
| Bahrain | Iraq | Philippines |
| Bangladesh | Ireland | Poland |
| Belgium | Italy | Portugal |
| Bosnia-Herz. | Kosovo | Romania |
| Brazil | Kuwait | Saudi Arabia |
| Bulgaria | Latvia | Singapore |
| Chile | Libya | Slovakia |
| Colombia | Liechtenstein | Slovenia |
| Cyprus | Lithuania | South Africa |
| Czech Republic | Luxembourg | Spain |
| Denmark | Macau | Sweden |
| Ecuador | Macedonia | Switzerland |
| Estonia | Malaysia | Thailand |
| Finland | Malta | Tunisia |
| France | Mexico | United Arab Emirates |
| Germany | Morocco | Uruguay |
| Great Britain | Nepal | Venezuela |
| Greece | Netherlands | White Russia |
| Hong Kong | New Zealand | |

# 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

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- 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 deformation, collapse, or fracture
- Stent thrombosis/occlusion
- Stroke/cerebrovascular accident/transient ischemic attack
- Total occlusion of coronary artery
- Vessel spasm
- Vessel trauma requiring surgical repair or re-intervention

Adverse events associated with daily oral administration of everolimus to organ transplant patients include but are not limited to:

- Abdominal pain
- Anemia
- Angioedema
- Anorexia
- Asthenia
- Constipation
- Cough
- Delayed wound healing/fluid accumulation
- Diarrhea
- Dyslipidemia (including hyperlipidemia and hypercholesterolemia)
- Dysgeusia
- Dyspepsia
- Dysuria
- Dry skin
- Edema (Peripheral)

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- Epistaxis
- Fatigue
- Headache
- Hematuria
- Hyperglycemia
- Hyperkalemia
- Hyperlipidemia
- Hypertension
- Hypokalemia
- Hypomagnesemia
- Increased serum creatinine
- Infections and serious infections: bacterial, viral, fungal, and protozoal infection (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 CYP3A4
- Leukopenia
- Lymphoma and other malignancies (including skin cancer)
- Male infertility (azospermia and/or oligospermia)
- 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)/Hemolytic uremic syndrome (HUS)
- Tremor
- Upper respiratory tract infection
- Urinary tract infection
- Venous thromboembolism
- Viral, bacterial, and fungal infections
- Vomiting

There may be other potential adverse events that are unforeseen at this time.

Please refer to the observed events for the EVOLVE II clinical study, which are presented in Section X: Summary of Clinical Studies.

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IX. SUMMARY OF PRECLINICAL STUDIES

A series of non-clinical laboratory studies were performed to evaluate:
- The stent and the stent delivery system [i.e., the stent on either the Monorail™ (MR) or Over-The-Wire (OTW) stent delivery system (SDS)];
- The PLGA polymer;
- The drug substance (i.e., everolimus); and
- 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 materials and components of the SYNERGY 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 drug and polymer coated stents, and stent delivery systems. These test articles were manufactured with the final proposed commercial process (i.e., surface treatment, coating processing, amount of drug/polymer coating, and sterilization). In all of these test systems, the materials were biocompatible and produced no greater response than the negative control employed in each test system.

All biocompatibility testing was conducted in accordance with:
- FDA Guidance for Industry: Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, April 18, 2010
- Draft FDA Guidance for Industry: Coronary Drug-Eluting Stents - Nonclinical and Clinical Studies, March 2008
- Draft FDA Guidance for Industry: Use of International Standard ISO 10993-1, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing, April 23, 2013
- Good Laboratory Practices Regulations (§21CFR 58)

The biocompatibility studies that have been conducted in support of the SYNERGY stent are summarized in Table IX.A-T1.

Table IX.A-T1: Biocompatibility Tests Summary

| Test Name | Test Description | Test Article and Results |
| --- | --- | --- |
| Cytotoxicity | ISO 10993-5: In Vitro Cytotoxicity (MEM Elution) | • Stent and delivery systems (MR and OTW): Pass (non-cytotoxic) |
| | ISO 10993-5: In Vitro Cytotoxicity (Direct Contact) | • Stent: Pass (non-cytotoxic) |

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| Test Name | Test Description | Test Article and Results |
| --- | --- | --- |
| Sensitization | ISO 10993-10: Sensitization (Guinea Pig Maximization) | • Stent and delivery systems (MR and OTW): Pass (non-sensitizing) |
| Intracutaneous Reactivity | ISO 10993-10: Irritation (Injection) | • Stent and delivery systems (MR and OTW): Pass (non-irritant) |
| Systemic Toxicity | ISO 10993-11: Systemic Toxicity (Acute) | • Stent and delivery systems (MR and OTW): Pass (non-toxic) |
| | ISO 10993-11: Systemic Toxicity (Material-Mediated Rabbit Pyrogen) | • Stent and delivery systems (MR and OTW): Pass (non-pyrogenic) |
| Genotoxicity | ISO 10993-3: Bacterial Reverse Mutation Assay (Ames Assay) | • Stent and delivery systems (MR and OTW): Pass (non-mutagenic) |
| | ISO 10993-3: Mouse Lymphoma | • Stent and delivery systems (MR and OTW): Pass (non-mutagenic, non-clastogenic) |
| | ISO 10993-3: In Vivo Mouse Micronucleus Test | • Stent: Pass (non-mutagenic) |

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| Test Name | Test Description | Test Article and Results |
| --- | --- | --- |
| Chemical Characterization – Extractables/ Leachables/ Corrosion | ISO 10993-9 and -18 Chemical Characterization Extractables: ICP-MS, GC-MS, LC-MS, Ion Chromatography | • Bare Metal Stent: Pass |
| | ISO 10993-9 and 18 Residues and Leachables Characterization | • Bare Metal Stent: Pass |
| | USP <661> Physiochemical Test for Plastics | • Delivery systems (MR and OTW): Pass |
| Latex | Latex Testing ASTM D6499-12 ELISA Assay | • Stent and delivery systems (MR and OTW): Below level of detection |
| Hemocompatibility | ISO 10993-4: Direct Hemolysis | • Stent and delivery systems (MR and OTW): Pass (non-hemolytic) |
| | ISO 10993-4: Indirect Hemolysis (Extract) | • Stent and delivery systems (MR and OTW): Pass (non-hemolytic) |
| | ISO 10993-4: In Vitro Hemocompatibility | • Stent and delivery systems (MR and OTW): Pass (comparable to control) |
| | ISO 10993-4: Partial Thromboplastin Time (PTT) | • Stent and delivery systems (MR and OTW): Pass (Results comparable to negative control) |
| | ISO 10993-4: Complement Activation C3a & SC5b-9 Assay | • Stent and delivery systems (MR and OTW): Pass (negative for C3a and SC5b-9 assays ) |
| | ISO 10993-4: In Vivo Thromboresistance (Porcine) | • Stent: Pass (no thrombus at 90 days) |
| Carcinogenicity | ISO 10993-3: Carcinogenicity (rasH2-Transgenic Mice) | • Not Directly Tested: See Justification below |
| Reproductive Toxicity | ISO 10993-3: Reproductive Toxicity Teratology (Rat) | • Not Directly Tested: See Justification below |
| Implantation/Chronic Toxicity | ISO 10993-11: Chronic Toxicity/ ISO 10993-6: Implantation (Rat) | • Stent: Pass (non-toxic, non-irritating) |
| Toxicokinetics | ISO 10993-16: Toxicokinetics (Porcine) | • Stent: Pass (non-toxic) |

Chronic toxicity, in vivo thrombogenicity, toxicokinetics, and implantation of a test article in the porcine model was provided to support the vascular safety and compatibility of the SYNERGY product. See Section IX.G: Animal Studies.

Carcinogenicity and Reproductive toxicity testing on the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System were omitted based on the following:

- SYNERGY was tested for genotoxicity (Ames mutagenicity, in vitro mouse lymphoma and in vivo mouse micronucleus assays); negative results of genotoxicity testing suggest that the likelihood of the stent material to cause a carcinogenic response is minimal.

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- In addition, the levels of ten elements (As, Co, Cr, Fe, Mo, Ni, Pb, Pt, Si, and V) were below the Quantitation Limit in a leachable study of the bare metal stent using Inductively Coupled Plasma analysis with Optical Emission Spectrometry (ICP-OES). No manufacturing residues could be found on bare metal stent using Pyrolysis GCMS and solvent extraction followed by GCMS. Chemical safety assessments conducted on the SS Pt-Cr material and potential manufacturing residues indicate that “the PERSS material as used in cardiovascular stents do not pose a health and safety concern to patients” As the SYNERGY bare metal stent is equivalent to the Element bare metal stent it can be concluded that the manufactured SYNERGY bare metal stent does not pose a carcinogenic risk to patients.

- The carcinogenic potential of everolimus has been addressed by Abbott Vascular in a previous study. The XIENCE stent coated with PBMA/PVDF-HFP was tested in transgenic mice (ras H-2) which showed no evidence of tumor formation. Also the SYNERGY stent containing everolimus has passed not only in vitro (Ames and Mouse Lymphoma) but also in vivo (Mouse Micronucleus) genotoxicity assays. The carcinogenic potential of everolimus does not appear to change in the presence of PLGA as all studies passed; therefore no additional carcinogenicity investigations were conducted. A GLP polymer safety study, literature safety assessment, and in vitro characterization of PLGA degradation products demonstrate that the polymer is non-carcinogenic.

The potential risk for vascular thrombosis due to use of the delivery system was deemed acceptable based upon an evaluation of a representative test article in the canine model. Use of the vascular study in the canine model was deemed acceptable because the materials of manufacture, design, and surface geometries for the delivery system are similar to the commercially available Emerge PTCA Dilatation catheter (K113220, cleared March 22, 2012).

Based upon the biocompatibility testing and safety data for everolimus, PLGA, product materials, it can be concluded that the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System is biocompatible for its intended use.

## B. In Vitro Engineering Testing

In vitro engineering testing on the SYNERGY 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, 18 April 2010
- FDA Draft Guidance for Industry and Staff: Coronary Drug-Eluting Stents-Nonclinical and Clinical Studies, March 2008
- FDA Guidance for Industry and Staff: Establishing Safety and Compatibility of Passive Implants in the Magnetic Resonance (MR) Environment, 21 August 2008

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- Draft FDA Guidance for Industry: Select Updates for Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, 30 August 2013

The in vitro engineering studies conducted are summarized in Table IX.B-T1. "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 SYNERGY Everolimus-Eluting Platinum Chromium stent as shown in Section IX.C: Coating Characterization Testing.

Table IX.B-T1: 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 SYNERGY stents were tested to determine the corrosion susceptibility using cyclic potentiodynamic polarization per ASTM F2129-08, “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 bare metal 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 Crevice Corrosion was assessed on “as manufactured” coated SYNERGY stents after pulsatile fatigue cycling. The corrosion series testing indicated that the corrosion resistance characteristics of the SYNERGY Everolimus-Eluting Platinum Chromium Coronary stent met product specification. | Pass |
| Nickel Elution | As outlined in Section IV.E of the FDA Draft Guidance for Industry “Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, the potential of nickel ion release is to be considered for devices containing nitinol. The SYNERGY combination product is comprised of a platinum chromium alloy stent and therefore is no subject to nickel ion release testing. Acceptable performance of SYNERGY in testing of potentiodynamic, crevice, galvanic and fretting corrosion demonstrates sufficient corrosion resistance and an adequate passivation layer to justify per the guidance therefore there is no need for additional nickel ion release testing. | N/A |
| Stent Dimensional and Functional Attributes | | |
| Dimensional Verification | To measure and inspect the stent to document that the stent dimensional specifications meet the product design requirements, including un-expanded stent dimensions, expanded diameter and length (see Stent Delivery System Dimensional and Functional Attributes testing). All product met specifications. | Pass |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| Percent Surface Area | Stent surface coverage as a function of stent diameter was measured for the SYNERGY 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 foreshortening test determined the change in length of the stent between the catheter-mounted condition and the condition in which the stent was expanded (deployed) to the nominal diameter and to stent over-expansion limits. All product met 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. | Pass |
| Stent Overexpansion | The purpose of this testing is to verify the stent integrity post-stent deployment when expanded above unconstrained diameter. No stent exhibited any strut fracture when visually examined at a minimum of 30X following overexpansion. | Pass |
| Radial Stiffness and Radial Strength (Compression Resistance) | Testing was conducted to determine the ability of the stent to resist deformation under radial loads. | Pass |
| Mechanical Properties | Ultimate tensile strength, yield strength and elongation testing was performed on tubing (pre-processing) used to fabricate the stents. Ultimate tensile strength, yield strength and elongation on pre-processed tubing met product specification. Analysis of SEM images on stent components at various process stages determined that mechanical properties were not altered by processing. | Pass |
| Magnetic Resonance Imaging (MRI) Safety and Compatibility | The SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent has shown to be MR Conditional (poses no known hazards under specified conditions) for single and overlapped conditions up to 75mm. A patient with this device can be safely scanned in a: Magnetic Resonance system meeting the following conditions: • Static magnetic field of 3.0 and 1.5 Tesla only • Maximum spatial gradient magnetic field of 2300 gauss/cm (23 T/m) • Maximum Magnetic Resonance system reported, whole body averaged specific absorption rate (SAR) of <2 W/kg (Normal Operating Mode) Under the scan conditions defined above, the SYNERGY Stent is expected to produce a maximum temperature rise of 3.1°C after 15 minutes of continuous scanning. In non-clinical testing, the image artifact caused by the device extends approximately 10mm from the SYNERGY Stent when imaged with a gradient echo pulse sequence and a 3.0 Tesla MRI system The SYNERGY stent should not migrate in this MRI environment. MR imaging within these conditions may be performed immediately following the implantation of the stent. This stent has not been evaluated to determine if it is MR Conditional beyond these conditions 3.0 Tesla Temperature Information Non-clinical testing of RF-induced heating was performed at 123 MHz in a 3 | Pass |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| | T General Electric Medical Systems MR system, Model Sigma Hdxt, software version 15.0 M4 0910.a. RF power was applied for 15 minutes and the measured conductivity of the phantom material was about 0.49 S/m. The phantom average SAR was calculated using calorimetry to be 2.3 W/kg. The maximal in vitro temperature rise was calculated as 2.6°C for a measured stent length up to 75 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.

**1.5 Tesla Temperature Information**
Non-clinical testing of RF-induced heating was performed at 64 MHz in a 1.5 T 64 MHz RF laboratory system, Medical Implant Test System (MITS) 1.5, Zurich Medtech AG (ZMT), Model Medical Implant Test Systems 1.5, software version MITS-DUAL BAND 1.2.5.2 whole body coil MR scanner. RF power was applied for 15 minutes and the measured conductivity of the phantom material was about 0.50 S/m. The phantom average SAR was calculated using calorimetry to be 2.3 W/kg. The maximal in vitro temperature rise was calculated as 3.1°C for a measured stent length up to 75 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.

The actual in vivo rise is expected to be less than these values as the calculations did not include the cooling effects due to blood flow in the lumen of the stent and blood perfusion in the tissue outside the stent.

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. No tests have been performed on possible nerve or other tissue stimulation possible to be activated by strong gradient magnetic fields and resulting induced voltages.

**Image Artifact Information**
The calculated image artifact extends approximately 8 mm from the perimeter of the device diameter and 6 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 10 mm beyond the perimeter of the diameter and 9 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 2.6.3.7 2101-11-2412 MR system.

**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. | |
| Radiopacity | The radiopacity of the stent was assessed through porcine model evaluations of stent positioning, expansion, and delivery system removal. The stent exhibits clinically acceptable radiopacity. | Pass |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| **Stent Dimensional and Functional Attributes, continued** | | |
| Stent Axial Strength | The ability of the stent to withstand length change after being subjected to a point-load force was tested. All product met specifications. | Pass |
| | The axial strength of the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent system was characterized in a constrained state with malapposition against commercially available Promus Premier and Resolute Integrity for force at work at 3 mm of displacement. The results demonstrate comparable performance to commercially marketed product. | Pass |
| **Delivery System Dimensional and Functional Attributes** | | |
| Delivery, Deployment and Retraction | The delivery, deployment and retraction of the delivery 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 stent system could be delivered to the target location, deployed, and retracted, thus meeting required acceptance criteria. | Pass |
| Balloon Rated Burst Pressure (RBP) | 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 | 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 |
| Balloon Inflation and Deflation Time | Stent systems across the range of balloon lengths and diameters were evaluated for deflation and inflation times. Results indicated that the product specifications were met. | Pass |
| Catheter Bond Strength | Representative sizes of the stent delivery system were tested to determine the balloon bond, tip bond, and full unit tensile strength of the delivery system. All stent systems met or exceeded the minimum specifications for full unit tensile strength and balloon bond. | Pass |
| Tip Tensile (Tip Pull) | Stent delivery systems were tested to determine the tip bond strength. All product met specifications. | Pass |
| Flexibility and Kink | Stent delivery systems were evaluated to determine the ability of the delivery system to withstand kinking. All product specifications were met. | Pass |
| Catheter Coating Integrity and Thickness | The acute coating integrity of the stent delivery system coating was evaluated via the results of a series of acute in vitro tests (baseline and simulated use). The test results demonstrated that the hydrophilic coating displays acceptable coating integrity. | Pass |
| Stent Securement for Unsheathed Stents | Stent systems were evaluated to assess the forces required to displace a 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. | Pass |
| Non-Coaxial Withdrawal into a Simulated Guiding Catheter | Stent systems were evaluated for performance during withdrawal of a catheter with a mounted stent non-coaxially into a simulated guide catheter tip following a repeated track conditioning step. Results indicated that the product specifications were met for stent securement. All samples met the specification. | Pass |

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| Test | Description of Test | Conclusion |
| --- | --- | --- |
| Stent/Balloon Catheter Withdrawal Resistance | Testing was conducted to verify that the 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 stent coating was assessed via a series of acute in vitro tests performed on the SYNERGY coated stent (baseline and simulated use). The test results demonstrate that the PLGA/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 SYNERGY stent coating. The 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 interface 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 stent fatigue failures will not occur over 400 million cycles (10-years) of loading. | Pass |
| Accelerated Durability Testing | Accelerated durability testing was performed on the SYNERGY 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 Overlapping Pulsatile Fatigue on a Curve. All tested stents were free from fatigue induced strut fracture. The coated stent met the 10 year accelerated fatigue resistance specification. | Pass |
| Particulate Evaluation (Simulated Use) | 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 until the point where particulation dropped to negligible levels with a plateau in the cumulative particulates observed from the biodegradable stent coating. | Pass |

# C. Coating Characterization Testing

The coating characterization testing conducted on the SYNERGY stent coating is summarized in Table IX.C-T1.

Table IX.C-T1: Coating Characterization Testing

| Test | Description of Test |
| --- | --- |
| Materials/Chemical Analysis – Polymer | Polymer components were tested to ensure conformity to raw material specifications. |
| Material/Chemical Analysis – Drug | Drug substance was tested to ensure conformity to raw material specifications. |

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| Drug Loading Density | Dose per unit area was calculated. |
| --- | --- |
| Coating Thickness Uniformity | Testing was conducted to verify the 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 stent coating. |
| Drug Content | Assay was conducted to quantitatively determine the total amount of the drug substance, everolimus, on the SYNERGY drug constituent part. |
| Impurities and Degradation Products | Assays were conducted to quantitatively determine the type and amount of impurities and degradation products on the SYNERGY drug constituent part. |
| Drug Release | Assay was developed to measure the in vitro drug release of everolimus from the SYNERGY drug constituent part. |
| Particulates | Particulate levels were evaluated for the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System post tracking, deployment, and fatigue. |

# D. Chemistry Manufacturing Control (CMC) Testing

Each batch of finished devices undergoes testing for release and distribution. This testing is summarized in Table IX.D-T1. Where applicable, the test methods follow International Conference on Harmonization (ICH) Guidelines. Information to support the stability of SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System is summarized separately in Section IX.E: Stability.

Table IX.D-T1: CMC Release Testing

| Test | Description of Test |
| --- | --- |
| Material Analysis – Polymer | The polymer is tested at incoming inspection to ensure conformity to specifications. The polymer 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 finished combination product. |

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| Test | Description of Test |
| --- | --- |
| Drug Content/Content Uniformity | Multiple stents are assayed to verify the uniformity of the drug content between individual stents is within the specifications established for the finished combination product. |
| Impurities and Degradation Products | Testing is conducted to quantitatively verify the amount of impurities and degradation products in the finished product are within the specifications established for the finished combination product. |
| Drug Release | The in vitro drug release profile of everolimus is measured to verify that the drug release is within the specifications established for the finished combination product. |
| Particulates | Particulate counts are measured to verify that they remain below acceptable levels established for the finished combination product. |
| Residual Solvents | Testing is conducted to quantitatively verify the amount of N,N-Dimethylformamide and Tetrahydrofuran remain below acceptable levels established for the finished combination product. |
| BHT Content | Assay is conducted to verify the amount of butylated hydroxytoluene is within the specifications established for the finished combination product. |
| Molecular Weight and PDI | Assay to quantitatively verify the weight average molecular weight and Polydispersity Index of polymer in the drug constituent part. |
| Endotoxin | Testing is conducted to quantitatively verify endotoxin levels of the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System are within the specifications established for the finished combination product. |

## E. Stability and Shelf Life

Stability studies were conducted to establish a shelf life for the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System. The stability testing evaluation included appearance, drug content assay, impurities and degradants, drug release, particulates, sterility, butylated hydroxytoluene (BHT) content, molecular weight, polydispersity index, and endotoxin. Appropriate mechanical engineering tests were also performed on aged product and packaging to ensure that finished combination product continues to meet specification throughout its expiration dating. The data generated supports a shelf life of 12 months.

In addition, the stability of the drug substance has been independently verified. The PLGA polymer expiration date is supported by the vendor’s drug master file.

## F. Sterilization

The SYNERGY stent system (Monorail™ and Over-The-Wire) is sterilized using ethylene oxide sterilization and has been validated per AAMI/ISO 11135-1: 2007 “Sterilization of health care products – Ethylene Oxide—Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices.”

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 for the finished combination product.

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# G. Animal Studies

Boston Scientific conducted multiple animal studies in the non-injured porcine model to assess the safety, vascular compatibility, and acute performance of the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System. These nonclinical animal tests assessed the comparability between SYNERGY, PROMUS Element, polymer only coated SYNERGY stents, and bare metal stents (OMEGA and SYNERGY). The results of these tests demonstrated acceptable safety and vascular compatibility of the SYNERGY stent in single and overlap-stent implant configurations in the non-injured porcine coronary artery. In addition, comparable results were obtained for early and late in-stent healing. The endothelial response of the SYNERGY stent was comparable to that observed in a bare metal stent at 90 days.

Similar in vitro and in vivo drug release profiles and local arterial tissue concentration profiles) were demonstrated through the nonclinical pharmacokinetic study. Furthermore, fast and slow drug release formulations of SYNERGY™ were evaluated 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 SYNERGY product. Summaries of all animal studies are included in Table IX.G-T1. Studies were conducted in accordance with §21 CFR 58 (Good Laboratory Practices).

Table IX.G-T1: Summary of the Major Supportive Animal Studies

| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/ No. of Animals | Vessel Location | Evaluation Time Points | Results |
| --- | --- | --- | --- | --- | --- | --- |
| GLP Safety Overlap Study 11-009G
GLP: Yes | SYNERGY 3.00 x 8 mm
3.50 x 8 mm
(40 Single, 16 overlap pairs, 3 SEM) | 1 / 45:55 | Swine, 90 | RCA, LAD, and/or LCX | 5,28, 60, 90, 120, 180, 270 Days | Demonstrated safety. No device related mortality or morbidity. Vascular response showed early and late healing, vessel stability and patency over 5, 28, 60, 90, 120, 180, and 270 days. |
| | SYNERGY 3x Polymer Only
3.00 x 8 mm
3.50 x 8 mm
(55 single) | N/A/171 PLGA only | | | | |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/ No. of Animals | Vessel Location | Evaluation Time Points | Results |
| --- | --- | --- | --- | --- | --- | --- |
| | SYNERGY 1x Polymer Only
3.00 x 8 mm
3.50 x 8 mm
(56 single, 17 overlap pairs, 3 SEM pairs) | N/A/57
PLGA only | | | | |
| | Bare Metal SYNERGY 3.00 x 8 mm
3.50 x 8 mm
(17 Single) | N/A | | | | |
| | Bare Metal OMEGA
3.00 x 8 mm
3.50 x 8 mm
(56 Single, 16 overlap pairs) | N/A | | | | |
| Endothelial Cell Study 13-100G
GLP: Yes | SYNERGY
3.00 X 8 mm
3.50 X 8 mm
(13) | 1 / 45:55 | Swine, 9 | RCA, LAD, and/or LCX | 90 days | The presence and relative function of the endothelial cells, as determined by SEM and IHC in SYNERGY drug-eluting stents was comparable to Bare Metal Stent (OMEGA) response, with no discernable differences between groups. |
| | Bare Metal OMEGA
3.00 X 8 mm
3.00 X 8 mm
(13) | N/A-
Bare Stent | | | | |
| Long Stent Safety Study 11-052G
GLP: Yes | SYNERGY
3.00 x 20 mm
3.50 x 20 mm
(26, 3 SEM) | 1 / 45:55 | Swine,28 | RCA, LAD, and/or LCX | 28, 90, and 180 days | Demonstrated safety. No device related mortality or morbidity. Vascular response showed early and late healing, vessel stability and patency over 28, 90, and 180 days. |
| | Bare Metal OMEGA
3.00 x 20 mm
3.50 x 20 mm
(24, 3 SEM) | N/A –
Bare Stent | | | | |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/ No. of Animals | Vessel Location | Evaluation Time Points | Results |
| --- | --- | --- | --- | --- | --- | --- |
| | PROMUS Element 3.00 x 20 mm 3.50 x 20 mm (26, 3 SEM) | 1 / 16:84 | | | | |
| Safety Study 09-006N GLP: Yes | High Dose Element (PROMUS Dose) 3.00 x 12 mm 3.50 x 12 mm (46, 6 SEM) | 1 / 45:55 | Swine, 14 | RCA, LAD, and/or LCX | 30,90, 180, and 360 days | Demonstrated safety. No device related mortality or morbidity. Vascular response showed early and late healing, vessel stability and patency over 30, 90, 180, and 360 days. |
| | Low Dose Element (1/2 PROMUS Dose) 3.00 x 12 mm 3.50 x 12 mm (29, 7 SEM) | 1 / 45:55 | | | | |
| | Polymer Only Element 3.00 x 12 mm 3.50 x 12 mm (31, 5 SEM) | N/A – PLGA Polymer Only | | | | |
| | Bare Metal Element + Plasma Treatment 3.00 x 12 mm 3.50 x 12 mm (11, 4 SEM) | N/A- Bare Stent | | | | |
| | Bare Metal Element 3.00 x 12 mm 3.50 x 12 mm (28, 4 SEM) | N/A- Bare Stent | | | | |
| | PROMUS (XIENCE V) 3.00 x 12 mm 3.50 x 12 mm (31, 6 SEM) | 1 / 16:84 | | | | |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/ No. of Animals | Vessel Location | Evaluation Time Points | Results |
| --- | --- | --- | --- | --- | --- | --- |
| Pharmacokinetic (PK) Study 11-019G
GLP: Yes | SYNERGY Maple Grove
3.00 x 8 mm
3.50 x 8 mm
(100) | 1 / 45:55 | Swine, 134 | RCA, LAD, RCA LAD, and/or LCX | 3h ,6h, 1,3,7,14,28, 45,60,90, and120 days | Comparable in vivo performance between SYNERGY FHU, MG, GAL stents supported by in vivo drug release profiles and arterial tissue concentration. PK analysis of arterial tissue concentrations shows all test devices have similar C_{max} and total drug exposure as quantified by AUC. Blood, myocardium, and distal organ everolimus concentrations all are low |
| | SYNERGY Galway
3.00 x 8 mm
3.50 x 8 mm
(105) | 1 / 45:55 | | | | |
| | SYNERGY FHU
3.00 x 8 mm
3.50 x 8 mm
(102) | 1 / 45:55 | | | | |
| Max Dose Study R051503-DMH (Histology)
GLP: Yes | PROMUS (XIENCE V)
3.00 x12 mm
(11 histology, 1 SEM) | 100 / 1:4.9 | Swine, 14 | RCA LAD, and/or LCX | 180 days | Met angiographic criteria. Met vascular response safety criteria for both max dose and bulk polymer systems |
| | Vision Bare (Polymer Only)
3.00 x 12 mm
(11 histology, 1 SEM) | N/A – Bare stent | | | | |
| | Vision Bare
3.00 x 12 mm
(11 histology, 1 SEM) | N/A – Bare stent | | | | |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/ No. of Animals | Vessel Location | Evaluation Time Points | Results |
| --- | --- | --- | --- | --- | --- | --- |
| Max Dose Study R050503-DMH (Histology) GLP: Yes | PROMUS (XIENCE V) 3.00 x12 mm (11 histology, 1 SEM) | 100 / 1:4.9 | Swine,14 | RCA LAD, and/or LCX | 90 days | Met angiographic criteria. Met vascular response safety criteria for both max dose and bulk polymer systems |
| | Vision Bare (Polymer Only) 3.00 x 12 mm (11 histology, 1 SEM) | N/A /89 – Polymer Only | | | | |
| | Vision Bare 3.00 x 12 mm (11 histology, 1 SEM) | N/A – Bare stent | | | | |
| Max Dose Study R032204-PDD (Histology) GLP: Yes | PROMUS (XIENCE V) 3.00 x12 mm (11 histology, 1 SEM) | 100 / 1:4.9 | Swine, 13 | RCA, LAD, and/or LCX | 120 days | Met angiographic criteria. Met vascular response safety criteria for both max dose and bulk polymer systems |
| | Vision Bare (Polymer Only) 3.00 x 12 mm (11 histology, 1 SEM) | N/A/89 – Polymer Only | | | | |
| | Vision Bare 3.00 x 12 mm (11 histology, 1 SEM) | N/A – Bare stent | | | | |

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| Study Number | Stent Design | Drug Loading Density (μg/cm²) / (Drug: Polymer w/w)ᵃ | Type/ No. of Animals | Vessel Location | Evaluation Time Points | Results |
| --- | --- | --- | --- | --- | --- | --- |
| In Vivo/In Vitro Correlation Study 13-005G
GLP: Yes | SYNERGY
(Nominal Release)
3.00 x 8 mm
3.50 x 8 mm
(102 stents tissue and 18 stents coating integrity) | 1 / 45:55 | Swine, 71 | RCA, LAD, and/or LCX | 3, 6 hours, 1, 3, 7, 14, 28, 45, 60, 90, and 120 days | The average everolimus remaining on the three formulations was essentially 0% at 120 days. The regional stented arterial concentration of everolimus tended to decrease from the 3 hour survival time point through 1 to 7 days for nominal and low formulations, and decreased from the 3 hour through 1 day for the fast formulation. All formulations increased again through 28 days, and then steadily diminished through 120 days. |
| | SYNERGY
(Fast Release)
3.00 x 8 mm
3.50 x 8 mm
(67 total stents) | 1 / 50:50 | | | | |
| | PROMUS Element
(Slow Release)
3.00 x 8 mm
3.50 x 8 mm
(66 total stents) | 1 / 37.5:62.5 | | | | |
| SYNERGY Acute Performance Study 13-163G
GLP: Yes | SYNERGY
2.25 x 16 mm
2.50 x 16 mm
2.75 x 16 mm
3.00 x 16 mm
3.50 x 16 mm
4.00 x 16 mm
(19) | 1 / 45:55 | Swine, 3 | RCA, LAD, and/or LCX | 0.25, 1, 3, 7, 14, 28, 60 days | All acute performance criteria for the SYNERGY stent and stent delivery system were rated Acceptable |

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| Study Number | Stent Design | Drug Loading Density (μg/cm2)/ (Drug: Polymer w/w)a | Type/ No. of Animals | Vessel Location | Evaluation Time Points | Results |
| --- | --- | --- | --- | --- | --- | --- |
| Acute Performance Study 11-175G GLP: Yes | SYNERGY 2.25 x 16 mm 2.50 x 16 mm 2.75 x 16 mm 3.00 x 16 mm 3.50 x 16 mm 4.00 x 16 mm (16) | 1 / 45:55 | Swine, 2 | 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 | All acute performance criteria for the SYNERGY stent and stent delivery system with Bioslide coating were rated Acceptable or higher. |

# H. In Vivo Pharmacokinetics

The pharmacokinetics (PK) of Everolimus released from the SYNERGY™ 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 EVOLVE II clinical trial. The design of the sub-study is described in Section X: Summary of Clinical Studies. Whole blood everolimus PK parameters are provided in Table IX.H-T1 for groups with 3 or more patients receiving the SYNERGY™ stent.

Table IX.H-T1: Whole Blood Everolimus Pharmacokinetic Parameters (Mean ± SD) for EVOLVE II Groups with Three or More Patients Following SYNERGY Stent Implantation

| Region | USA* | Japan* | Combined | | |
| --- | --- | --- | --- | --- | --- |
| Dose (μg) | NA | NA | 58 μgb | 113 μgc | 189 μg |
| n | | | 3c | 3b | 4b |
| tmax: (h) | | | 0.90 ± 0.36 | 0.48 ± 0.08 | 0.48 ± 0.03 |
| Cmax: (ng/mL) | | | 0.31 ± 0.07 | 0.35 ± 0.04 | 0.84 ± 0.41 |
| AUC0-t: (ng.h/mL) | | | 0.32 ± 0.25 | 0.56 ± 0.47 | 8.50 ± 3.91 |
| AUC0-24h: (ng.h/mL) | | | 0.32 ± 0.25 | 0.56 ± 0.47 | 6.73 ± 2.10 |
| AUC0-∞:a (ng.h/mL) | | | NA | NA | 47.81 ± 61.50 |

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| Region | USA* | Japan* | Combined | | |
| --- | --- | --- | --- | --- | --- |
| t_{1/2}:^{a}
(h) | | | NA | NA | 105.79
± 149.33 |
| CL:^{a}
(L/h) | | | NA | NA | 0.0545
± 0.0436 |

Data are presented as n or mean ±SD

Abbreviation: NA=not assessable

*: Do not meet requirement of 3 or more subjects at any 1 dose level

a: Accurate determination not possible

b: n=0 for AUC_0-∞, t_1/2term and CL

c: n=1 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 tmax values ranged from 0.42 to 1.18 hours. Individual Cmax values ranged from 0.26 to 1.35 ng/mL. AUC0-24h values ranged from 0.069 to 11.22 ng·h/mL, while AUC0-t values ranged from 0.07 to 19.42 ng·h/mL. The concentration of everolimus was below the limit of quantification in all patients except 3 at 48 hours. The Cmax 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, t½ and AUC0-∞ could also not be determined accurately due to rapid everolimus disappearance from blood. These types of results have been seen with other drug-eluting stents. Everolimus disappearance from circulation following SYNERGY 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.

## H1. SYNERGY™ Everolimus-Eluting Platinum Chromium Coronary Stent

Boston Scientific Corporation has provided a letter from the drug substance manufacturer authorizing use of drug substance information in support of this application. 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 active pharmaceutical ingredient of SYNERGY is identical to that of the PROMUS (XIENCE® V) Everolimus Eluting Coronary Stent System, the evaluation of PROMUS (XIENCE® V) is applicable to SYNERGY.

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# H2. 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™ Plus 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™ Plus 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 (ketaconazole, itraconazole, voriconazole, ritonavir, erythromycin, clarithromycin, fluconazole, calcium channel blockers)
- Inducers of CYP3A4 isozyme (rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin)
- Antibiotics (ciprofloxacin, ofloxacin)
- Glucocorticoids
- HMGCoA reductase inhibitors (simvastatin, lovastatin)
- Digoxin
- Cisapride (theoretical potential reaction)
- Sildenafil (Viagra®) (theoretical potential reaction)
- Antihistaminics (terfenadine, astemizole)
- Grapefruit juice

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# X. SUMMARY OF CLINICAL STUDIES

The EVOLVE II Clinical Program evaluates the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System for the treatment of atherosclerotic lesions in 3 studies. The Program includes the EVOLVE II trial, (randomized controlled trial (RCT) with a parallel single-arm pharmacokinetics (PK) sub-study, and consecutive single arm diabetic (DM) sub-study). Additionally, EVOLVE II QCA, a quantitative coronary angiography (QCA) study was conducted. A summary of the RCT, PK, diabetic, and QCA trial designs is presented in Table X-T1.

Additionally NG PROMUS data is presented in Table X.E4-T1 to support the minor stent design changes that took place to the SYNERGY stent platform after the EVOLVE II trial was underway. The design changes assessed in the NG PROMUS trial are comparable to those incorporated in the final SYNERGY design. A summary of the NG PROMUS trial design is presented in Section E.

Table X-T1: Comparison of EVOLVE II Clinical Studies

| | EVOLVE II | | | EVOLVE II QCA |
| --- | --- | --- | --- | --- |
| | RCT | PK | Diabetic | |
| Purpose | Evaluation of safety and effectiveness in native coronary lesions | Evaluation of everolimus blood levels | Evaluation of safety and effectiveness in native coronary lesions in patients with medically treated diabetes mellitus | Evaluation of angiographic and IVUS outcomes in native coronary lesions |
| Study Design | Prospective, randomized, controlled, multicenter, single-blind non-inferiority to PROMUS Element Plus | Prospective, single arm, multicenter, observational study | Prospective, single arm, multicenter, comparison to performance goal | Prospective, single arm, multicenter, observational; study |
| Primary Endpoint | 12M TLF | N/A, observational | 12M TLF | 9 month in-stent late loss |
| Number of Patients (ITT) | 1684 enrolled; SYNERGY: 846 PROMUS Element Plus: 838 | 21 SYNERGY | 203 SYNERGY | 100 SYNERGY |
| Polymer | PLGA | | | |
| Everolimus Dose Density | 58 to 257 μg | | | |
| Lesion Criteria: Vessel Diameter (by visual estimate), mm | ≥2.25to ≤4.00 | | | |
| Lesion Criteria: Lesion Length (by visual estimate), mm | ≤34 | | | |
| Total Target Lesions | Up to 3 in 2 epicardial vessels | | | |

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| | EVOLVE II | | | EVOLVE II
QCA |
| --- | --- | --- | --- | --- |
| | RCT | PK | Diabetic | |
| Stent Matrix
Diameter | Diameter: 2.25, 2.50, 3.00, 3.50, 4.00 Length: 8, 12, 20, 28, 32/38* | | | |
| Post-Procedure
Antiplatelet Therapy | A P2Y12 inhibitor for at least 6 months, ideally for 12 months in patients who were 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; Angiographic: 9 month; IVUS: 9 month |

Abbreviations: ASA=aspirin; IVUS=intravascular ultrasound; PK=pharmacokinetics; QCA=quantitative coronary angiography; RCT=randomized controlled trial; TLF=target lesion failure

## A. EVOLVE II Pivotal Clinical Trial

### A1. Study Design

The EVOLVE II RCT is a prospective, randomized (1:1), controlled, single-blind, multicenter, non-inferiority trial designed to evaluate the safety and effectiveness of the SYNERGY Everolimus-Eluting Platinum Chromium Coronary Stent System compared to the PROMUS Element Plus Everolimus-Eluting Platinum Chromium Coronary Stent System for the treatment of native coronary lesions. Patients with a maximum of 3 lesions in 2 epicardial vessels ≤34 mm in length (visual estimate) in native coronary arteries ≥2.25 mm to ≤4.00mm (visual estimate) in diameter were considered for enrollment.

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# Clinical Inclusion and Exclusion Criteria

Table X.A1-T1: EVOLVE II Clinical Inclusion and Exclusion Criteria

| Clinical Inclusion Criteria | CI1. | Subject must be at least 18 years of age |
| --- | --- | --- |
| | CI2. | Subject (or legal guardian) understands the trial requirements and the treatment procedures and provides written informed consent before any trial-specific tests or procedures are performed |
| | CI3. | For subjects less than 20 years of age enrolled at a Japanese site, the subject and the subject’s legal representative must provide written informed consent before any study-specific tests or procedures are performed |
| | CI4. | Subject is eligible for percutaneous coronary intervention (PCI) |
| | CI5. | Subject has symptomatic coronary artery disease with objective evidence of ischemia or silent ischemia |
| | CI6. | Subject is an acceptable candidate for coronary artery bypass grafting (CABG) |
| | CI7. | Subject is willing to comply with all protocol-required follow-up evaluation |
| Angiographic Inclusion Criteria (visual estimate) | AI1. | Target lesion(s) must be located in a native coronary artery with a visually estimated reference vessel diameter (RVD) ≥2.25 mm and ≤4.0 mm |
| | AI2. | Target lesion(s) length must be ≤34 mm (by visual estimate) |
| | AI3. | Target lesion(s) must have visually estimated stenosis ≥50% and <100% with thrombolysis in Myocardial Infarction (TIMI) flow >1 and one of the following: stenosis ≥70%, abnormal fractional flow reserve (FFR), abnormal stress or imaging stress test, or elevated biomarkers prior to the procedure |
| | AI4. | Coronary anatomy is likely to allow delivery of a study device to the target lesions(s) |
| | AI5. | The first lesion treated must be successfully predilated/pretreated Note: Successful predilatation/pretreatment refers to dilatation with a balloon catheter of appropriate length and diameter, or pretreatment with directional or rotational coronary atherectomy, laser or cutting/scoring balloon with no greater than 50% residual stenosis and no dissection greater than National Heart, Lung, Blood Institute (NHLBI) type C. |

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| Clinical Exclusion Criteria | CE1. Subject has clinical symptoms and/or electrocardiogram (ECG) changes consistent with acute ST elevation MI (STEMI)CE2. Subject has cardiogenic shock, hemodynamic instability requiring inotropic or mechanical circulatory support, intractable ventricular arrhythmias, or ongoing intractable anginaCE3. Subject has received an organ transplant or is on a waiting list for an organ transplantCE4. Subject is receiving or scheduled to receive chemotherapy within 30 days before or after the index procedureCE5. Planned PCI (including staged procedures) or CABG after the index procedureCE6. Subject previously treated at any time with intravascular brachytherapyCE7. Subject has a known allergy to contrast (that cannot be adequately pre-medicated) and/or the trial stent system or protocol-required concomitant medications (e.g., platinum, platinum-chromium alloy, stainless steel, everolimus or structurally related compounds, polymer or individual components, all P2Y12 inhibitors, or aspirin)CE8. Subject has one of the following (as assessed prior to the index procedure):○ Other serious medical illness (e.g., cancer, congestive heart failure) with estimated life expectancy of 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 interpretationCE9. Subject is receiving chronic (≥72 hours) anticoagulation therapy (i.e., heparin, coumadin) for indications other than acute coronary syndromeCE10. Subject has a platelet count <100,000 cells/mm3or >700,000 cells/mm3CE11. Subject has a white blood cell (WBC) count < 3,000 cells/mm3CE12. Subject has documented or suspected liver disease, including laboratory evidence of hepatitisCE13. Subject is on dialysis or has baseline serum creatinine level >2.0 mg/dL (177μmol/L)CE14. Subject has a history of bleeding diathesis or coagulopathy or will refuse blood transfusionsCE15. Subject has had a history of cerebrovascular accident (CVA) or transient ischemic attack (TIA) within the past 6 monthsCE16. Subject has an active peptic ulcer or active gastrointestinal (GI) bleedingCE17. Subject has signs or symptoms of active heart failure (i.e., NYHA class IV) at the time of the index procedureCE18. Subject is participating in another investigational drug or device clinical trial that has not reached its primary endpointCE19. Subject intends to participate in another investigational drug or device clinical trial within 12 months after the index procedureCE20. Subject 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)CE21. Subject 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) |
| --- | --- |

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| Angiographic Exclusion Criteria (visual estimate) | AE1. Planned treatment of more than 3 lesions |
| --- | --- |
| | AE2. Planned treatment of lesions in more than 2 major epicardial vessels |
| | AE3. Planned treatment of a single lesion with more than 1 stent |
| | Note: Planned use of 2 overlapping stents will be allowed in subjects randomized to PROMUS Element Plus where lesion length is ≥28 mm and 2.25 mm stents are used. |
| | AE4. Subject has 2 target lesions in the same vessel that are separated by less than 15 mm (by visual estimate) |
| | AE5. Target lesion(s) is located in the left main |
| | AE6. Target lesion(s) is located within 3 mm of the origin of the left anterior descending (LAD) coronary artery or left circumflex (LCx) coronary artery by visual estimate |
| | AE7. Target lesion(s) is located within a saphenous vein graft or an arterial graft |
| | AE8. Target lesion(s) will be accessed via a saphenous vein graft or arterial graft |
| | AE9. Target lesion(s) with a TIMI flow 0 (total occlusion) or TIMI flow 1 prior to guide wire crossing |
| | AE10. Target lesion(s) treated during the index procedure that involves a complex bifurcation (e.g., bifurcation lesion requiring treatment with more than 1 stent) |
| | AE11. Target lesion(s) is restenotic from a previous stent implantation or study stent would overlap with a previous stent |
| | AE12. Subject has unprotected left main coronary artery disease (>50% diameter stenosis) |
| | AE13. Subject has been treated with any type of PCI (i.e., balloon angioplasty, stent, cutting balloon atherectomy) within 24 hours prior to the index procedure |
| | AE14. Thrombus, or possible thrombus, present in the target vessel (by visual estimate) |

# Follow-up Schedule

Clinical follow-up was required at the following time points for the RCT: in hospital, 30 days, 6 months, 12 months, 18 months and then annually between 2 and 5 years after the index procedure. Subjects who were enrolled but who did not receive a study stent will be followed through 12 months only. Starting with the 18 month follow-up, only the Safety Population (i.e., those subjects who receive a study stent) will be followed.

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

# Clinical Endpoints

The primary endpoint was the rate of target lesion failure (TLF), defined as any ischemia-driven revascularization of the target lesion (TLR), myocardial infarction (MI) (Q-wave and non-Q-wave) related to the target vessel, or cardiac death, at 12 months post-index procedure. EVOLVE II RCT was designed to test the hypothesis that the rate of 12-month TLF in patients treated with the SYNERGY is non-inferior to the rate of 12-month TLF in patients treated with the PROMUS Element Plus.

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## Additional Endpoints

Clinical endpoints measured in-hospital and at 30 days, 6 months, 12 months, 18 months, 2 years, 3 years, 4 years, and 5 years in the RCT are:

- TLR rate
- TLF rate (primary endpoint at 12 months for the RCT)
- TVR rate
- All revascularization rate
- Target vessel failure (TVF) rate
- MI* (Q-wave and non-Q-wave) rate
- Cardiac death rate
- Non-cardiac death rate
- All death rate
- Cardiac death or MI rate
- All death or MI rate
- All death/MI/TVR rate
- Stent thrombosis rates (by Academic Research Consortium [ARC] definitions)
- Stroke rate (ischemic and hemorrhagic)
- Longitudinal stent deformation rate assessed by an independent angiographic core laboratory

## Peri-procedural endpoints:

- Technical success rate
- Clinical procedural success rate
- Longitudinal stent deformation assessed by an independent angiographic core laboratory

## A2. Accountability of PMA Cohort: EVOLVE II RCT Study

A total of 1684 patients (846 SYNERGY and 838 PROMUS Element Plus) were randomized at 125 centers in the United States (US), Canada, Europe, Australia, New Zealand, Japan and Singapore from November 26, 2012 to August 29, 2013 (GMT -4). Of the 1,684 patients included in the intent-to-treat analysis set, a total of 1630 patients (826 SYNERGY and 804 PROMUS Element Plus) were evaluable for the 12 month primary endpoint.

Table X.A2-T1: EVOLVE II RCT Subject Disposition, ITT Analysis Set

| | PROMUS Element Plus | SYNERGY | Total |
| --- | --- | --- | --- |
| Intent-to-Treat Analysis Set | 838 | 846 | 1684 |
| Death ≤395 days with no 12-Month Clinical Follow-up Performed | 9 | 9 | 18 |
| Eligible for 12-Month Clinical Follow-up^{a} | 829 | 837 | 1666 |
| 12-Month Clinical Follow-up Performed^{b} | 96.1% (797/829) | 98.2% (822/837) | 97.2% (1619/1666) |

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| No 12-Month Clinical Follow-up Performed | 32 | 15 | 47 |
| --- | --- | --- | --- |
| Prematurely Discontinued | 9 | 7 | 16 |
| Death > 395 days | 0 | 0 | 0 |
| Withdrew Consent | 3 | 5 | 8 |
| Lost to Follow-up | 0 | 0 | 0 |
| Adverse Event | 0 | 0 | 0 |
| Investigator Discretion | 6 | 2 | 8 |
| Other | 0 | 0 | 0 |
| Missed 12-Month Visit | 23 | 8 | 31 |
| With Later Follow-up Visit Performed | 0 | 0 | 0 |
| No Later Follow-up Visit Performed | 23 | 8 | 31 |
| 12-Month Clinical Follow-up or Deathc | 96.2% (806/838) | 98.2% (831/846) | 97.2% (1637/1684) |
| 12-Month Clinical Follow-up Subject Accountabilityd | 95.1% (797/838) | 97.2% (822/846) | 96.1% (1619/1684) |

Numbers are n or % (count/sample size).
a: Subjects who died prior to completion of the follow-up window and prior to completing a 12-month clinical follow-up visit were considered censored and were excluded from calculation of proportion of subjects who completed clinical follow-up visit.
b: Based on subjects eligible for 12-month clinical follow-up (excludes subjects who died within 395 days with no 12-month follow-up).
c: Includes subjects who have died in both the numerator and the denominator; based on the Intent-to-Treat analysis set.
d: Includes subjects who have died in the denominator only; based on the Intent-to-Treat analysis set.

# A3. Study Population Demographics and Baseline Parameters

Table X.A3-T1 and Table X.A3-T2 present demographics and baseline clinical characteristics for the ITT analysis set (N=846 SYNERGY and N=838 PROMUS Element Plus (Control). The ITT population was predominantly male (70.6%/72.7%) with a history of medically treated hyperlipidemia (74%/74.5%) and hypertension (77.3%/75.1%). Medically treated diabetic subjects accounted for 31.1%/30.8% of ITT subjects. Unstable angina was reported for 33.9%/34.8% of subjects and 25.9%/29.2% had a history of MI.

Table X.A3-T1: Baseline Demographic and Clinical Characteristics, ITT Analysis Set

| Variable | PROMUS Element Plus (N=838 Subjects) | SYNERGY (N=846 Subjects) | Difference [95% CI] | P valuea |
| --- | --- | --- | --- | --- |
| Male | 72.7% (609/838) | 70.6% (597/846) | -2.1% [-6.4%, 2.2%] | 0.3379 |
| Age (yr) | 63.92±10.50 (838) (32, 93) | 63.48±10.44 (846) (26, 88) | -0.43 [-1.43, 0.57] | 0.3975 |
| Ethnicity and Raceb | | | | |
| American Indian or Alaska native | 0.2% (2/838) | 0.1% (1/846) | -0.1% [NA] | 0.6230* |
| Asian | 11.9% (100/838) | 11.8% (100/846) | -0.1% [-3.2%, 3.0%] | 0.9429 |
| Japanese | 9.9% (83/838) | 8.7% (74/846) | -1.2% [-3.9%, 1.6%] | 0.4140 |
| Chinese | 1.3% (11/838) | 2.0% (17/846) | 0.7% [-0.5%, 1.9%] | 0.2635 |
| Korean | 0.0% (0/838) | 0.0% (0/846) | 0.0% [NA, NA] | Undef |
| Other Asian | 0.7% (6/838) | 1.1% (9/846) | 0.3% [-0.5%, 1.2%] | 0.4475 |

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| Variable | PROMUS Element Plus (N=838 Subjects) | SYNERGY (N=846 Subjects) | Difference [95% CI] | P valuea |
| --- | --- | --- | --- | --- |
| Black, of African heritage | 4.4% (37/838) | 6.1% (52/846) | 1.7% [-0.4%, 3.9%] | 0.1123 |
| Caucasian | 79.2% (664/838) | 77.4% (655/846) | -1.8% [-5.7%, 2.1%] | 0.3666 |
| Hispanic or Latino | 1.9% (16/838) | 1.8% (15/846) | -0.1% [-1.4%, 1.1%] | 0.8352 |
| Native Hawaiian or other Pacific Islander | 0.2% (2/838) | 0.4% (3/846) | 0.1% [NA] | 1.0000* |
| Other | 0…