← Product Code NIQ · P060033

# ENDEAVOR ZOTAROLIMUS ELUTING CORONARY STENT SYSTEM (P060033)

_Medtronic, Inc. · NIQ · Feb 1, 2008 · Cardiovascular · APWD_

**Canonical URL:** https://fda.innolitics.com/device/P060033

## Device Facts

- **Applicant:** Medtronic, Inc.
- **Product Code:** NIQ
- **Decision Date:** Feb 1, 2008
- **Decision:** APWD
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic

## Intended Use

The Endeavor Zotarolimus-Eluting Coronary Stent System (hereafter referred to as the Endeavor stent system) is indicated for improving coronary luminal diameter in patients with ischemic heart disease due to de novo lesions of length ≤ 27 mm in native coronary arteries with reference vessel diameters of ≥ 2.5 mm to ≤ 3.5 mm.

## Device Story

The Endeavor Zotarolimus-Eluting Coronary Stent System is a drug-eluting stent (DES) used to treat coronary artery stenosis. It consists of a cobalt-alloy (MP35N) stent (Driver or Micro-Driver) coated with a Phosphorylcholine (PC) polymer carrier loaded with the immunosuppressant drug zotarolimus. The device is delivered via a balloon-expandable catheter (OTW, RX, or MX² systems) into the coronary vasculature. Upon inflation, the stent expands to hold the artery open, while the polymer coating releases zotarolimus to inhibit smooth muscle cell proliferation and reduce neointimal hyperplasia. The device is used by interventional cardiologists in a catheterization lab. The output is a mechanically supported, drug-treated vessel segment. Clinical benefit includes improved luminal diameter and reduced need for repeat revascularization compared to bare metal stents. The device is MR conditional.

## Clinical Evidence

Evidence from four prospective, multi-center clinical trials (ENDEAVOR I, II, III, IV) and a PK study. ENDEAVOR II (n=1197) demonstrated superiority of Endeavor over bare metal Driver stent (TVF 7.9% vs 15.1% at 9 months, p<0.001). ENDEAVOR III (n=436) and IV (n=1548) compared Endeavor to other DES (Cypher, Taxus). Pooled analysis (n=2133) showed Endeavor significantly reduced revascularization needs compared to Driver stents. Stent thrombosis rates were low and comparable to or lower than the Driver control. Primary endpoints included MACE, TVF, and in-segment late loss.

## Technological Characteristics

Stent material: Cobalt-based alloy (MP35N) per ASTM F562. Drug: Zotarolimus (10 μg/mm stent length). Polymer: Phosphorylcholine (PC) polymer. Delivery systems: OTW, RX, MX². Energy source: Balloon inflation (nominal 9 ATM, RBP 16 ATM). Sterilization: Ethylene oxide. Connectivity: None. Form factor: Modular sinusoidal pattern of crowns and struts.

## 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.

## Reference Devices

- Driver Coronary Stent ([P030009](/device/P030009.md))
- Driver MX² ([P030009](/device/P030009.md)/S001)
- Driver RX ([P030009](/device/P030009.md)/S003)
- Micro-Driver ([P030009](/device/P030009.md)/S002)
- Cypher Sirolimus-Eluting Coronary Stent
- Taxus Express 2 Paclitaxel-Eluting Coronary Stent

## Submission Summary (Full Text)

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# Summary of Safety and Effectiveness Data

## I. General Information

|  Product Generic Name: | Drug-Eluting Coronary Stent System (NIQ)  |
| --- | --- |
|  Product Trade Name: | Endeavor Zotarolimus-Eluting Coronary Stent on the Over-the-Wire (OTW), Rapid Exchange (RX), or Multi-Exchange II (MX²) Stent Delivery Systems  |
|  Applicant's Name and Address: | Medtronic Vascular
3576 Unocal Place
Santa Rosa, CA 95403  |
|  Premarket Approval Application (PMA) Number: | P060033  |
|  Date of Panel Recommendation: | October 10, 2007  |
|  Date of Notice of Approval to Applicant: | February 1, 2008  |

## II. Indications For Use

The Endeavor Zotarolimus-Eluting Coronary Stent System (hereafter referred to as the Endeavor stent system) is indicated for improving coronary luminal diameter in patients with ischemic heart disease due to *de novo* lesions of length ≤ 27 mm in native coronary arteries with reference vessel diameters of ≥ 2.5 mm to ≤ 3.5 mm.

## III. Contraindications

The Endeavor Zotarolimus-Eluting Coronary Stent System is contraindicated for use in patients with:

- Known hypersensitivity to zotarolimus or structurally-related compounds.
- Known hypersensitivity to the cobalt-based alloy (cobalt, nickel, chromium, and molybdenum).
- Known hypersensitivity to the Phosphorylcholine polymer or its individual components (see Section V. B – 2. Inactive Ingredients for details).

Coronary artery stenting is contraindicated for use in:

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

## IV. Warnings and Precautions

The warnings and precautions can be found in the Endeavor Zotarolimus-Eluting Coronary Stent System labeling.

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V. Device Description

The Endeavor Zotarolimus-Eluting Coronary Stent System is a device/drug combination product comprised of device components (Driver™ Coronary Stent and Micro-Driver™ Coronary Stent and the Endeavor delivery systems) and a drug component (a formulation of zotarolimus contained in a polymer coating). The characteristics of the Endeavor Zotarolimus-Eluting Coronary Stent System are described in Table 1.

Table 1: The Endeavor Zotarolimus-Eluting Coronary Stent System Product Description

|   | Endeavor Rapid Exchange (RX) Delivery System | Endeavor Over-The-Wire (OTW) Delivery System | Endeavor Multi-Exchange II (MX²) Delivery System  |
| --- | --- | --- | --- |
|  Available Stent lengths (mm)* | 8, 9, 12, 14, 15, 18, 24, 30  |   |   |
|  Available Stent diameters (mm)** | 2.5, 3.0, 3.5  |   |   |
|  Stent Material | A cobalt-based alloy (MP35N) – the Driver and Micro-Driver stents  |   |   |
|  Drug Component | A spray coating of polymer carrier loaded with zotarolimus is applied to the stent at a drug loading of 10 μg/mm stent length. The maximum nominal drug content on the longest stent (30 mm) is 300 μg.  |   |   |
|  Delivery System Working Length (cm) | 135 | 135 | 138  |
|  Delivery System Adapter Ports | Single access port to inflation lumen. Guidewire exit port is located approximately 25 cm from tip. Designed for guidewire ≤ 0.014". | Y-Connector (side arm for access to balloon inflation/deflation lumen. Straight arm is continuous with shaft inner lumen). Designed for guidewire ≤ 0.014". | Single access port to inflation lumen. Guidewire exits through a Z-component located on the proximal shaft. Designed for guidewire ≤ 0.014".  |
|  Stent Delivery Balloon | A semi-compliant balloon mounted on the distal end of the catheter to facilitate stent deployment. There are proximal and distal pillows formed on either side of the stent which aid in holding the stent in position. Two radiopaque balloon markers are located on the distal section of the inner member and are positioned to mark the working length of the balloon.  |   |   |
|  Balloon Inflation Pressure | Nominal Inflation Pressure: 9 ATM
Rated Burst Inflation Pressure: 16 ATM  |   |   |
|  Guiding Catheter Compatibility | 0.056" minimum (5 F) | 0.056" minimum (5 F) | 0.064" minimum (6 F)  |
|  Distal Section Outer Diameter | Distal = 2.7 F | Distal = 2.7 F | Distal = 2.7 F  |
|   |  Proximal = 3.0 F | Proximal = 3.0 F | Middle = 3.0 F  |
|   |   |   |  Proximal = 3.8 F  |
|  Proximal Outer Diameter | 2.2 F | 3.3 F | 2.3 F x 4.2 F (Oval)  |

* 2.5 mm diameter stents are not available in 9 and 15 mm lengths
** 3.0 and 3.5 mm diameter stents are not available in 8 and 14 mm lengths

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# A. Device Component Description

The device component consists of the Driver™ Coronary Stent or Micro-Driver™ Coronary Stent pre-mounted onto one of three delivery systems; Over-The-Wire (OTW), Rapid Exchange (RX) or Multi-Exchange II (MX²) Delivery Systems. Each delivery system provides a means for delivering the stent through the coronary vasculature and, once in the desired location, expands the stent through balloon inflation. The delivery systems utilized for the Endeavor product are similar in materials, design and construction to the approved Driver (P030009, approved October 1, 2003; Driver MX² P030009/S001, approved on August 4, 2004; Driver RX, P030009/S003, approved on December 22, 2005) and Micro-Driver (P030009/S002, approved on April 21, 2006) delivery systems.

The Endeavor stent is made of the cobalt alloy MP35N conforming to ASTM F562. The modular stent segments are created from a single ring formed into a repeating pattern of crowns and struts. The appropriate ring is formed into alternating upper and lower crowns with seven (2.5 mm diameters) or ten (3.0 – 3.5 mm diameters) crowns per end, connected by axial struts in a sinusoidal pattern. The stent is crimped onto various size delivery catheter balloons, with diameters of 2.5 mm, 3.0 mm or 3.5 mm.

The Endeavor stent contains 10 µg zotarolimus per millimeter of stent length for all diameters. Because an identical dose (10 µg/mm zotarolimus per mm stent length) is used for the entire Endeavor 2.5 mm – 3.5 mm diameter range, the total drug per stent is a function of stent length, irrespective of stent diameter.

# B. Drug Component Description

The drug component of the Endeavor Zotarolimus-Eluting Coronary Stent System consists of zotarolimus (the active ingredient) and Phosphorylcholine (PC) polymer (the inactive ingredient).

# A. 1. Zotarolimus

The active pharmaceutical ingredient utilized in the Endeavor stent is zotarolimus. It is a tetrazole-containing macrocyclic immunosuppressant. The chemical name of zotarolimus is: [3S-[3R*[S*(1R*,3S*,4R*)],6S*,7E,9S*,10S*,12S*,14R*,15E,17E, 19E,21R*,23R*, 26S*,27S*,34aR*]]-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[2-[3-methoxy-4-(1H-tetrazoyl-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c] [1,4]oxazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.

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The chemical structure of zotarolimus is shown below (Figure 1).

![img-0.jpeg](img-0.jpeg)
Figure 1: Chemical Structure of Zotarolimus

Zotarolimus has extremely low water solubility and is a lipophilic compound that is freely soluble in propylene glycol, acetone, toluene, acetonitrile, ethanol, benzyl alcohol and dimethyl sulfoxide (DMSO). The molecular formula of zotarolimus is $\mathrm{C}_{52}\mathrm{H}_{79}\mathrm{N}_{5}\mathrm{O}_{12}$ and its molecular weight is 966.2.

Zotarolimus does not have any ionizable groups in the physiological pH range; therefore, its solubility is expected to be unaltered in this range.

## B. 2. Inactive Ingredients

The only inactive ingredient in the Endeavor stent is the Phosphorylcholine (PC) polymer, which acts as a carrier for zotarolimus. The PC polymer consists of 2-methacryloyloxyethyl phosphorylcholine that is synthesized and then used in the preparation of cross-linked polymer membranes with lauryl methacrylate, hydroxypropyl methacrylate and trimethoxysilylpropyl methacrylate (crosslinker) co-monomers.

The molecular weight of PC polymer was estimated using viscometry and resulted in values of Mw ranging from 160,000 to 270,000. These figures were supported by light scattering values of Mw (g/mol) ranging from 100,000 to 200,000.

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PC polymer in a solvent carrier (ethanol) is applied to the Driver stent to form the base layer coat of the Endeavor stent. The polymer is also mixed with the drug zotarolimus and then applied to the base layer-coated stents. Finally, a drug-free overspray of PC polymer is applied after the stent has been coated with the drug/polymer formulation and it has been crimped onto the balloon. The drug/polymer coating is applied to the entire surface (i.e., luminal and abluminal) of the stent. The structural formula of the polymer is shown in Figure 2.

Figure 2: Chemical Structure of PC Polymer*
![img-1.jpeg](img-1.jpeg)
* PC Technology™ is licensed under patents or patent applications owned by Biocompatibles.

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Table 2: Endeavor Zotarolimus-Eluting Coronary Stent System Product Matrix and Nominal Zotarolimus Doses

|  Product Number OTW | Product Number RX | Product Number MX² | Nominal Expanded Stent ID (mm) | Nominal Unexpanded Stent Length (mm) | Nominal Zotarolimus Content (μg)  |
| --- | --- | --- | --- | --- | --- |
|  EN25008W | EN25008UX | EN25008MX | 2.50 | 8* | 84  |
|  EN30009W | EN30009UX | EN30009MX | 3.00 | 9 | 90  |
|  EN35009W | EN35009UX | EN35009MX | 3.50 | 9 | 90  |
|  EN25012W | EN25012UX | EN25012MX | 2.50 | 12 | 120  |
|  EN30012W | EN30012UX | EN30012MX | 3.00 | 12 | 120  |
|  EN35012W | EN35012UX | EN35012MX | 3.50 | 12 | 120  |
|  EN25014W | EN25014UX | EN25014MX | 2.50 | 14* | 144  |
|  EN30015W | EN30015UX | EN30015MX | 3.00 | 15 | 150  |
|  EN35015W | EN35015UX | EN35015MX | 3.50 | 15 | 150  |
|  EN25018W | EN25018UX | EN25018MX | 2.50 | 18 | 180  |
|  EN30018W | EN30018UX | EN30018MX | 3.00 | 18 | 180  |
|  EN35018W | EN35018UX | EN35018MX | 3.50 | 18 | 180  |
|  EN25024W | EN25024UX | EN25024MX | 2.50 | 24 | 240  |
|  EN30024W | EN30024UX | EN30024MX | 3.00 | 24 | 240  |
|  EN35024W | EN35024UX | EN35024MX | 3.50 | 24 | 240  |
|  EN25030W | EN25030UX | EN25030MX | 2.50 | 30 | 300  |
|  EN30030W | EN30030UX | EN30030MX | 3.00 | 30 | 300  |
|  EN35030W | EN35030UX | EN35030MX | 3.50 | 30 | 300  |

*Note: The 8 mm and 14 mm stent lengths have a total nominal drug content of 84 μg and 144 μg, respectively, since the actual stent length for the 8 mm stent is 8.4 mm, and the actual stent length for the 14 mm stent is 14.4 mm.

## C. Mechanism of Action

The mechanism (or mechanisms) by which the Endeavor Zotarolimus-Eluting Coronary Stent System affects neointimal production as seen in clinical studies has not been established conclusively. In vitro, zotarolimus inhibited growth factor-induced proliferation of human coronary artery smooth muscle cells and also demonstrated binding affinity with FKBP12 (binding protein). The suggested mechanism of action of zotarolimus is to bind to FKBP12, leading to the formation of a trimeric complex with the protein kinase mTOR (mammalian target of rapamycin), inhibiting its activity. Inhibition of mTOR activity leads to inhibition of cell cycle progression from the G1 to the S phase.

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VI. Alternative Practices and Procedures

Treatment of patients with coronary artery disease may include exercise, diet, drug therapy, percutaneous coronary interventions (such as angioplasty, bare metal stents, coated stents, and other drug-eluting stents), and coronary artery bypass surgery (CABG).

VII. Marketing History

The Endeavor Zotarolimus-Eluting Coronary Stent System is commercially available in the following countries:

|  • Albania | • Brazil | • Germany | • Lebanon | • Pakistan | • Sudan  |
| --- | --- | --- | --- | --- | --- |
|  • Algeria | • Bulgaria | • Ghana | • Libya | • Panama | • Sweden  |
|  • Antigua and Barbuda | • Cayman Islands | • Greece | • Liechtenstein | • Paraguay | • Switzerland  |
|  • Argentina | • Chile | • Guatemala | • Lithuania | • Peru | • Syria  |
|  • Armenia | • China | • Honduras | • Luxembourg | • Poland | • Thailand  |
|  • Aruba | • Colombia | • Hong Kong | • Malaysia | • Portugal | • Trinidad and Tobago  |
|  • Australia | • Costa Rica | • Hungary | • Malta | • Qatar | • Tunisia  |
|  • Austria | • Cyprus | • Iceland | • Mauritius | • Romania | • Turkey  |
|  • Bahamas | • Czech Republic | • India | • Mexico | • Russia | • Uganda  |
|  • Bahrain | • Denmark | • Iran | • Morocco | • Saudi Arabia | • United Arab Emirates  |
|  • Bangladesh | • Dominican Republic | • Ireland | • Mozambique | • Senegal | • United Kingdom  |
|  • Barbados | • Ecuador | • Israel | • Nepal | • Serbia & Montenegro | • Uruguay  |
|  • Belgium | • Egypt | • Italy | • Netherlands | • Singapore | • Venezuela  |
|  • Belize | • El Salvador | • Jamaica | • New Zealand | • Slovakia | • Virginia Islands (British)  |
|  • Bermuda | • Estonia | • Jordan | • Nicaragua | • Slovenia | • Yemen  |
|  • Bolivia | • Finland | • Kenya | • Nigeria | • South Africa | • Zimbabwe  |
|  • Bosnia-Herzegovina | • France | • Kuwait | • Norway | • South Korea |   |
|  • Botswana | • Georgia | • Latvia | • Oman | • Spain |   |

As of December 31, 2007, approximately 392,000 Endeavor Zotarolimus-Eluting Coronary Stent Systems have been distributed outside of the United States (OUS). No products have been withdrawn from the market in any country for any reason.

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# VIII. Summary of Non-Clinical Studies

A series of non-clinical laboratory studies were performed, pertaining to the stent and the stent delivery system (i.e., the stent mounted on either the Endeavor OTW, RX and $\mathbf{MX}^2$ stent delivery system), the polymer substance (i.e., Phosphorylcholine), the drug substance (i.e., zotarolimus), and the finished combination product (i.e., Endeavor Zotarolimus-Eluting Coronary Stent System).

# A. Studies of the Drug Substance

Medtronic Vascular provided a letter from the drug substance manufacturer, Abbott Laboratories Inc., authorizing FDA access to a Drug Master File (DMF) in support of this application. *In vivo* and *in vitro* pharmacology and toxicology studies as well as animal and human pharmacokinetic studies were conducted on zotarolimus to provide information about systemic and regional toxicity, distribution profiles, end-organ disposition, drug metabolism and potential drug-drug interactions.

# 1. Safety Pharmacology

Safety pharmacology studies have been conducted to determine the effects of zotarolimus on the central nervous system and pulmonary function in rats, the cardiovascular system in conscious primates, hemodynamic and electrophysiologic function in conscious and anesthetized dogs, canine cardiac Purkinje fibers repolarization (*in vitro* assay), hERG current (*in vitro*), antigenicity in guinea pigs, and lymph nodes in mice.

IV administered zotarolimus has no effect on the CNS and respiratory system parameters in the rat at blood concentrations of $\sim 30$-times the estimated $C_{\mathrm{max}}$ (maximum blood concentration) from one stent. In the anesthetized dog model, IV doses of zotarolimus showed no significant effect on heart rate, QTc and PR interval. The blood concentration of zotarolimus is estimated to be about 5-fold higher than the $C_{\mathrm{max}}$ obtained in the highest IV dose tested in human multiple dose study for safety (800 $\mu$g for 14 days). Zotarolimus did not reduce hERG current at concentration up to 181 ng/ml (72 times the estimated clinical $C_{\mathrm{max}}$). Zotarolimus showed minimal prolongation of the Purkinje fiber action potential duration (by 6%) at concentration up to 21 ng/ml (9 times estimated clinical $C_{\mathrm{max}}$).

Zotarolimus caused *in vitro* inhibition of cell proliferation of human T cell, coronary artery smooth muscle and endothelial cells at $\mathrm{IC}_{50}$ of 1.2, 2.9 and $2.6\,\mathrm{nM}$, respectively. Zotarolimus did not exhibit receptor interaction when tested *in vitro* at a concentration of $10\,\mu\mathrm{M}$ for binding to 73 individual assays. At levels of $200\,\mathrm{ng/ml}$ (100-fold greater than a typical projected $C_{\mathrm{max}}$ of $1.8\,\mathrm{ng/ml}$), zotarolimus caused no direct aggregation of human platelets in whole blood or did not enhance aggregation to stimulation by platelet agonists.

In guinea pigs sensitized once per week for four weeks by subcutaneous administration of zotarolimus (30 $\mu$g/kg), showed no induced systemic anaphylactic or passive cutaneous anaphylactic reactions indicating that zotarolimus was non-antigenic. Topically applied zotarolimus (50% w/v) on the dorsal surface of both ears of mice showed no increase in

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³H-thymidine incorporation in the lymph nodes indicating lack of skin sensitizing activity.

## 2. Toxicology

Toxicology studies have been conducted to determine the general toxicological effects in various species and the potential for genetic, reproductive and developmental toxicology. These include single and 28 day repeat dose IV infusion toxicokinetic studies in the rat and cynomolgus monkey, fertility and teratology reproductive toxicity studies in the rat and rabbit, and genotoxicity studies *in vitro* and in the mouse.

Zotarolimus was embryo/feto-toxic in rats at IV dosages of 25 µg/kg/day and above (approximately 3 times the cumulative blood exposure provided by Endeavor stents coated with 300 µg zotarolimus). Embryotoxicity was manifested as reduced fetal body weights and fetal ossification delays, but no major fetal malformations, deaths, or minor fetal abnormalities were observed. No embryo-fetal effects were observed in pregnant rabbits at the maternally toxic dosage of 30 µg/kg/day (approximately 13 times the cumulative blood exposure provided by Endeavor stents coated with 300 µg zotarolimus). The Endeavor stent should be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo/fetus.

Zotarolimus was not genotoxic in the *in vitro* bacterial reverse mutation assay, the human peripheral lymphocyte chromosomal aberration assay, or the *in vivo* mouse micronucleus assay.

## 3. Absorption, Distribution, Metabolism, and Excretion (ADME) Studies

Studies were conducted to characterize the absorption, distribution, metabolism, and excretion profiles in various species.

Absorption studies included pharmacokinetic evaluations in the rat, rabbit, mouse, monkey, and pig following single IV or oral drug dosing.

Distribution studies included *in vitro* distribution in human whole blood, *in vitro* binding to plasma proteins in the mouse, rat, rabbit, dog, pig, monkey, and human plasma, and tracing of radioactivity-labeled drug in the rat, monkey, and pig following IV dosing. The results of the plasma protein binding study suggest that all clinically relevant concentrations, zotarolimus would be extensively protein bound in plasma and would undergo significant degradation. Results from the analysis of radioactive-labeled drug in the blood and plasma are consistent with zotarolimus undergoing rapid degradation within plasma while drug that is sequestered within blood cells is relatively more stable and is released slowly. All concentrations largely decreased in parallel with blood radioactivity with little evidence for accumulation.

Metabolism studies included analysis of metabolites after metabolism by human liver microsomes *in vitro*, analysis of metabolites in blood, plasma, feces, and urine in the rat, pig, monkey, and human following IV dosing, metabolism and excretion in rats,

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metabolism, excretion, and tissue distribution in rabbits, metabolism by hepatocytes from the rat, dog, monkey, and human, and the effect of ketoconazole on PK profile in the dog following IV dosing. Review of studies of the metabolism in the rat, dog, monkey, and human indicated that in all cases the presence of hepatocytes accelerated the loss of parent compound from the incubation mixture. Although no metabolites or breakdown products were formally identified in the present study, it is likely that many routes of metabolism will be shared.

In the studies of metabolites by human liver microsomes, the $\mathrm{IC}_{50}$ for zotarolimus determined as a competitive inhibitor was not significantly different from the potency determined after pre-incubation, suggesting that the compound is not a mechanism-based inhibitor of human CYP3A enzymes. The anticipated clinical plasma levels of zotarolimus are unlikely to exceed the $\mathrm{IC}_{50}$ values determined in this study, which would suggest that the compound is unlikely to be a source of clinical drug-drug interactions through inhibition of CYP3A.

In studies of the effects of zotarolimus on seven cytochrome P450-dependent monooxygenase activities in human liver microsomes, in all cases the extent of inhibition of each enzyme were largely the same, irrespective of the absence or presence of a pre-incubation step, suggesting that the compound is not a mechanism based inhibitor of any of the human P450 enzymes tested. Given the anticipated clinical plasma levels of zotarolimus, the compound is unlikely to be a source of clinical drug-drug interactions through inhibition of CYP3A or the other P450 enzymes tested. In common with other immunosuppressive macrolides, such as sirolimus, the metabolism of zotarolimus appears to be catalyzed by cytochromes P450 of the CYP3A subfamily, CYP3A4 in particular.

In a study of ketoconazole interaction with zotarolimus in the dog, the results indicated that oxidative metabolism of zotarolimus can be blocked by the CYP3A selective inhibitor ketoconazole. Co-dosing with ketoconazole produced a statistically significant $(p &lt; 0.05)$ increase in the zotarolimus area under the curve, with a significant decrease in the clearance values.

Excretion studies in male rats included assessment of physical and metabolic stability in excreta. The results indicated that elimination occurs primarily via the feces.

## 4. Intravenous Administration of Zotarolimus

- Pharmacokinetics

Zotarolimus pharmacokinetic activity has been determined following intravenous (IV) administration in healthy patients. Table 3 provides a summary of the pharmacokinetic analysis.

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Table 3: Pharmacokinetic Parameters (Mean ± standard deviation) in Patients Following Intravenous Administration of Zotarolimus

|  PK Parameters | Units | 200 μg QD (N = 15) |   | 400 μg QD (N = 16) |   | 800 μg QD (N = 16)  |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |  | Day 1 | Day 14 | Day 1 | Day 14 | Day 1 | Day 14  |
|  C_{max} | (ng/mL) | 11.41 ± 1.38^{#} | 11.93 ± 1.25 | 21.99 ± 3.79 | 23.31 ± 3.15 | 37.72 ± 7.00 | 41.79 ± 6.68  |
|  T_{max} | (h) | 1.05 ± 0.04^{#} | 1.03 ± 0.04 | 1.00 ± 0.14 | 1.05 ± 0.04 | 1.03 ± 0.04 | 1.03 ± 0.05  |
|  AUC_{0-24} | (ng•h/mL) | 34.19 ± 4.39^{#} | 47.70 ± 6.68 | 68.43 ± 15.41 | 100.47 ± 18.02 | 123.48 ± 13.34 | 174.43 ± 19.88  |
|  t_{1/2}^{#} | (h) |  | 32.9 ± 6.8 |  | 37.6 ± 4.5 |  | 36.0 ± 4.7  |
|  CL^{E} | (L/h) | 4.2 ± 0.6 | 4.2 ± 0.6 | 4.0 ± 0.9 | 4.0 ± 0.9 | 4.6 ± 0.4 | 4.6 ± 0.4  |

¥ N = 16
$ Harmonic mean ± pseudo-standard deviation
£ Clearance data is calculated using compartmental methods. All other data presented in Table 3 is calculated using non-compartmental methods.

When administered intravenously for 14 consecutive days, zotarolimus showed dose proportionality. Renal excretion is not a major route of elimination for zotarolimus, as approximately 0.1% of the dose was excreted as unchanged drug in the urine per day. In multiple doses of 200, 400, and 800 μg, zotarolimus was generally well tolerated by the patients. No clinically significant changes in physical examination, vital signs, or laboratory measurements were observed during the course of the study. For a total stent length of 48 mm (480 μg drug dose), a C<sub>max</sub> of 4.0 ng/mL and AUC<sub>0-inf</sub> (area under the blood concentration-time curve (AUC) from time 0 to infinity) of 162 ng•h/mL were estimated as seen in Table 4 below. These calculations are based on the mean C<sub>max</sub> and AUC<sub>0-inf</sub> values calculated from the IV dosing studies conducted on zotarolimus.

Table 4: Zotarolimus Dose Exposure

|  Units | 480μg Dose Stent | Exposure Multiples  |
| --- | --- | --- |
|  C_{max} (ng/ml) | 4.0 | 27.69^{#}  |
|  AUC_{0-inf} (ng•h/mL) | 162 | 15.06^{#}  |

* Calculated based on the mean C<sub>max</sub> value (110.78) from the highest dose group (900 μg) from human single escalation IV dose study conducted on zotarolimus
# Based on the mean all day AUC<sub>0-inf</sub> (Day 1 to 14); 2440 ng•h/mL) value from the highest dose regimen (800 μg QD x 14 days) from human multiple escalation IV dose study conducted on zotarolimus

- Adverse Event Profile

The incidence of adverse events attributed to the drug zotarolimus was determined in IV escalating and multiple-dose studies. In the single-escalating dose study, the proportion of patients reporting treatment-emergent adverse events was slightly lower among patients who received doses of zotarolimus than those who received placebo for zotarolimus. The most common treatment-emergent adverse events associated with zotarolimus were application site reaction, injection site reaction, pain, and hematuria. There were no deaths or other serious adverse events reported in this study. No clinically significant changes in physical examination, vital signs, or laboratory measurements were observed during the course of the study. Table 5 provides a summary of the analysis.

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Table 5: Summary of Treatment-Emergent Adverse Events Reported by Two or More Patients in Any One Treatment by Body Systems and Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART Term) in the Single-escalating Dose Study

|  BODY SYSTEMS | COSTART Term | All Placebo N = 20 (%) | Zotarolimus 100 μg N = 8 (%) | Zotarolimus 300 μg N = 8 (%) | Zotarolimus 500 μg N = 8 (%) | Zotarolimus 700 μg N = 8 (%) | Zotarolimus 900 μg N = 8 (%)  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  Body as a whole | Headache | 3 (15%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (13%) | 0 (0%)  |
|   |  Injection site Reaction | 1(5%) | 0 (0%) | 0 (0%) | 3 (38%) | 0 (0%) | 0 (0%)  |
|   |  Pain | 7 (35%) | 1 (13%) | 0 (0%) | 5 (63%) | 5 (63%) | 2 (25%)  |
|  Digestive System | Diarrhea | 2 (10%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%)  |
|  Skin and Appendage | Application site Reaction | 8 (40%) | 1 (13%) | 5 (63%) | 2 (25%) | 1 (13%) | 5 (63%)  |
|  Urogenital System | Hematuria | 1 (5%) | 0 (0%) | 1 (13%) | 0 (0%) | 1 (13%) | 1 (13%)  |

In the multiple-dose study, the proportion of patients reporting treatment-emergent adverse events was similar among patients who received doses of zotarolimus, and the most common treatment-emergent adverse events associated with zotarolimus were headache, pain, injection site reaction, dry skin, abdominal pain, diarrhea, and rash. There were no deaths or other serious adverse events. Results of other safety analyses including individual patient changes, changes over time and individual clinically significant values for vital signs, laboratory safety assessments and physical examinations were unremarkable for each treatment group. No clinically significant changes in physical examination, vital signs, or laboratory measurements were observed during the course of the study. No differences were seen among the doses with respect to adverse event profiles or overall drug safety. Table 6 provides a summary of the analysis.

Table 6: Summary of Treatment-Emergent Adverse Events Reported by Two or More Patients in Any One Treatment by Body Systems and COSTART Term in the Multiple-dose Study

|  BODY SYSTEM | COSTART Term | All Placebo (N = 16) N (%) | 200 μg QD (N = 16) N (%) | 400 μg QD (N = 16) N (%) | 800 μg QD (N = 16) N (%)  |
| --- | --- | --- | --- | --- | --- |
|  Body as a whole | Headache | 1 (4) | 2 (13) | 2 (13) | 2 (13)  |
|   |  Pain | 1 (4) | 2 (13) | 1 (6) | 0 (0)  |
|   |  Injection Site Reaction | 2 (8) | 0 (0) | 0 (0) | 2 (13)  |
|   |  Injection Site Pain | 2 (8) | 0 (0) | 0 (0) | 0 (0)  |
|   |  Abdominal Pain | 1 (4) | 1 (6) |  | 0 (0)  |
|  Digestive System | Diarrhea | 1 (4) | 0 (0) | 1 (6) | 0 (0)  |
|  Skin and Appendage | Dry Skin | 0 (0) | 0 (0) | 2 (13) | 0 (0)  |
|   |  Rash | 0 (0) | 1 (6) | 1 (6) | 0 (0)  |

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# 5. In Vivo Pharmacokinetics

The Endeavor US Pharmacokinetic (PK) study was conducted to evaluate the pharmacokinetic profile of the Endeavor Zotarolimus-Eluting Coronary Stent System in eligible patients. The Endeavor US PK Registry was a prospective, multi-center, single-arm, open-label study designed to assess the acute pharmacokinetics and safety of zotarolimus administered using the Endeavor Zotarolimus-Eluting Coronary Stent System for the treatment of single de novo lesions in native coronary arteries. Pharmacokinetic evaluation was conducted on all patients participating in the Endeavor US PK trial. Forty-three (43) patients received the Endeavor Zotarolimus-Eluting Coronary Stent System; six patients received overlapping stents.

Blood samples (5 mL) were collected at 30 days post-procedure. Selected pharmacokinetic parameters for the Endeavor US PK study analysis are provided in Table 7.

Table 7: Endeavor US PK Results

|  PK Parameter | Units | Group I (90 μg) N = 1† | Group II (168 μg) N = 1† | Group IIIa (180 μg) N = 24 | Group IVa (240 μg) N = 6 | Group V (270 μg) N = 2† | Group VIa (300 μg) N = 7 | Group VII (360 μg) N = 1† | Group VIII (420 μg) N = 1†  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  C_{max} | (ng/mL) | 0.847 | 2.176 | 1.513 ± 0.616 | 1.83 ± 0.210 | 1.584 | 2.658 ± 0.998 | 2.539 | 3.133  |
|  T_{max} | (h) | 1.00 | 4.00 | 1.2 ± 0.6 | 1.4 ± 1.3 | 1.5 | 1.5 ± 1.3 | 2.00 | 1.3  |
|  AUC_{0-last} | (ng·h/mL) | 46.51 | 71.73 | 57.02 ± 13.46 | 63.83 ± 15.27 | 125.18 | 90.77 ± 19.51# | 95.21 | 87.45  |
|  AUC_{0-inf} | (ng·h/mL) | 56.57 | 78.28 | 66.61 ± 14.86 | 72.84 ± 19.96 | 136.65 | 101.45 ± 23.48# | 113.85 | 99.82  |
|  β | (1/h) | 0.010 | 0.013 | 0.012 ± 0.003 | 0.012 ± 0.002 | 0.010 | 0.012 ± 0.003 | 0.010 | 0.012  |
|  t_{½}‡ | (h) | 71.5§ | 53.7§ | 59.7 ± 14.4 | 57.5 ± 7.6 | 68.3 | 59.5 ± 16.1# | 66.67§ | 58.4§  |
|  Vd_{β}/F | (L) | 164.1 | 166.3 | 254.7 ± 74.5 | 288.5 ± 53.6 | 261.6 | 291.6 ± 113.7# | 304.2 | 354.6  |
|  CL/F | (L/h) | 1.6 | 2.1 | 2.8 ± 0.7 | 3.5 ± 1.0 | 2.9 | 3.1 ± 0.8# | 3.2 | 4.2  |

Vdβ/F Apparent volume of distribution
Cmax Maximum blood concentration
Tmax Time to Cmax
AUC0-inf AUC from time 0 to infinity (AUC0-inf).
t½ Harmonic mean half-life
AUC0-last Area under the blood concentration-time curve (AUC) from time 0 to time of last measurable concentration

a. Primary dose groups
‡ Harmonic mean ± pseudo-standard deviation
† No SD was reported when N ≤ 2
# N = 6
CL/F Mean apparent clearance
§ Mean only

The results in Table 7 show that pharmacokinetics of zotarolimus were linear in the primary dose-proportionality evaluation, consisting of dose groups with N &gt; 2 (180, 240 and 300 μg), following the implantation of Endeavor stents as illustrated by dose proportional increases in C<sub>max</sub>, AUC<sub>0-last</sub> and AUC<sub>0-inf</sub>. Mean apparent clearance and harmonic mean half-life for the primary dose groups ranged from 2.8 to 3.5 L/h and 57.5

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to 59.7 hours, respectively. The mean time to reach peak systemic concentration $(T_{\max})$ ranged from 1.2 to 1.5 hours after stent implantation. Additionally, this study showed that zotarolimus is released gradually into the systemic circulation without any evidence of dose dumping.

## 6. Drug Interactions

The effect of potential drug interactions on the safety or efficacy of the Endeavor stent has not been investigated. While no specific clinical data are available, drugs, like sirolimus, that act through the same binding protein (FKBP12) may interfere with the efficacy of zotarolimus. Zotarolimus is metabolized by CYP3A4, a human cytochrome P450 enzyme. When administered concomitantly with $200\,\mathrm{mg}$ ketoconazole bid, a strong inhibitor of CYP3A4, zotarolimus produces less than a 2-fold increase in $\mathrm{AUC}_{0\text{-inf}}$ with no effect on $C_{\max}$. Therefore, consideration should be given to the potential for drug interactions when deciding to place an Endeavor stent in a patient who is taking drugs that are known substrates or inhibitors of the cytochrome P450 isoenzyme CYP3A4. Systemic exposure of zotarolimus should also be taken into consideration if the patient is treated concomitantly with systemic immunosuppressive therapy.

Formal drug interaction studies have not been conducted with the Endeavor stent.

## B. Biocompatibility Studies

A series of GLP biocompatibility tests and USP Physicochemical tests were conducted to demonstrate that the components of the Endeavor Zotarolimus-Eluting Coronary Stent System (OTW, RX and $\mathbf{MX}^2$) are non-toxic. Tests were conducted on ethylene oxide-sterilized Endeavor coated stents, stent delivery systems (finished product) and polymer-only coated stainless steel (SS) coupons. These test articles were processed in the same manner as the finished Endeavor product. The polymer-only coated coupons did not include drug substance but were manufactured to simulate the processing of Endeavor Zotarolimus-Eluting Coronary Stent System with equivalent surface treatment, cross-linking and sterilization processes utilized. In all of these test systems, the materials were non-reactive and met all acceptance criteria. The results of the biocompatibility studies indicated that the Endeavor Zotarolimus-Eluting Coronary Stent System was biologically safe and acceptable for clinical use.

All biocompatibility testing was conducted in accordance with Good Laboratory Practices Regulations (21 CFR § 58) and with consideration of the following guidances:

- Guidance for Industry and FDA Staff, Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems. Document issued on January 13, 2005.
- International Standard ISO 10993-1, Biological Evaluation of Medical Devices: Evaluation and Testing.

Table 8 provides a summary of the biocompatibility testing conducted in support of the Endeavor Zotarolimus-Eluting Coronary Stent System.

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Table 8: Summary of Biocompatibility Testing

|  Test Name | Test Description | Test Article | Result  |
| --- | --- | --- | --- |
|  Cytotoxicity | ISO 10993-5: In Vitro Cytotoxicity (L929 MEM Elution) | • Endeavor stent and delivery systems
• Endeavor stent | Pass (non-cytotoxic)  |
|  Pyrogenicity | ISO-10993-11: Systemic Toxicity (Material Mediated Rabbit, Injection) | • Endeavor stent and delivery systems | Pass (non-pyrogenic)  |
|  Sensitization | ISO-10993-10: Sensitization (Guinea pig Maximization) | • Endeavor stent and delivery systems
• Endeavor stent | Pass (non-sensitizing)  |
|  Acute Intracutaneous Reactivity | ISO-10993-10: Irritation (Injection) | • Endeavor stent and delivery systems
• Endeavor stent | Pass (non-irritant)  |
|  Acute Systemic Toxicity | ISO-10993-11: Systemic Toxicity (Acute) | • Endeavor stent and delivery systems
• Endeavor stent | Pass (non-toxic)  |
|  Hemocompatability | ISO-10993-4: In Vivo Thromboresistance | • Endeavor stent and delivery systems | Pass (non-thrombogenic)  |
|   |  ISO-10993-4: C3a Complement Activation (In Vitro) | • Endeavor stent and delivery systems | Pass (non-complement activating)  |
|   |  ISO-10993-4: SC5b9 Complement Activation (In Vitro) | • Endeavor stent and delivery systems | Pass (non-complement activating)  |
|   |  ISO-10993-4: Plasma Recalcification | • Endeavor stent and delivery systems | Pass (no significant change in coagulation time)  |
|   |  ISO-10993-4: In Vitro Hemolysis Study | • Endeavor stent and delivery systems
• Endeavor stent | Pass (non-hemolytic)  |
|   |  ISO-10993-4: White Blood Cell Morphology | • Endeavor stent and delivery systems | Pass (no change in WBC morphologically)  |

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Table 8: Summary of Biocompatibility Testing

|  Test Name | Test Description | Test Article | Result  |
| --- | --- | --- | --- |
|  Genotoxicity | ISO-10993-3: Bacterial Reverse Mutation (AMES) | • Endeavor stent | Pass (non-mutagenic)  |
|   |  ISO-10993-3: In Vitro Chromosomal Aberration in Mammalian Cells | • Endeavor stent | Pass (non-clastogenic)  |
|   |  ISO-10993-3: In Vivo Mouse Bone Marrow Micronucleus Test | • Endeavor stent | Pass (non-mutagenic)  |
|  Material Characterization (USP Physicochemical Testing) | USP Physicochemical Extracts <661> (Aqueous) | • Balloon Material
• Polyethylene Sheath
• PC Polymer-only Coated Coupons | Pass  |

In vivo animal testing conducted on the Endeavor Zotarolimus-Eluting Coronary Stent System evaluated the effects of multiple doses and device exposure in a porcine coronary or rabbit iliac artery model for up to 180 days, in lieu of ISO 10993 sub-chronic and muscle implantation testing. The in vivo results indicated that the Endeavor Zotarolimus-Eluting Coronary Stent System was biologically safe and acceptable for clinical use. The significant animal studies are summarized separately in Section VIII. F – Animal Studies.

Formal carcinogenicity and reproductive toxicity testing was not conducted on the Endeavor Zotarolimus-Eluting Coronary Stent System. An appropriate rationale has been provided to demonstrate why the carcinogenic potential of the Endeavor stent is minimal based on the types and quantities of materials present and the limited period of zotarolimus release. The genotoxicity and reproductive toxicity of zotarolimus have been investigated in bacterial and mammalian cells in vitro and in laboratory animals in vivo.

There is no evidence to suggest that any chemical interactions occur between the PC polymer and zotarolimus drug under established processing and storage conditions that would lead to the formation of covalent bonds or that would alter the structure of the drug in any way to form a new intermediate or molecular entity.

Long term biocompatibility of the drug/polymer coating on the stent in humans is unknown.

## C. In Vitro Engineering Testing

In vitro engineering testing, in accordance with FDA’s “Guidance for Industry and FDA Staff: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems” (January 13, 2005), was conducted on the Endeavor stent mounted on the OTW, RX, and/or MX² delivery systems.

Some in vitro engineering tests were performed on the uncoated, bare metal version of the Endeavor stent since there was no change to the stent substrate. An appropriate rationale was provided where the testing of the bare metal stent provided a worst case or

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representative condition for the attributes evaluated. The effect of the coating is assumed to be negligible when evaluated against measurement and manufacturing tolerances.

Additional tests were conducted to support the integrity of the coating on the Endeavor Zotarolimus-Eluting Coronary Stent System and are summarized separately in Section VIII. D – Coating Characterization Testing.

The *in vitro* engineering studies conducted are summarized in Table 9. “Pass” denotes that the test results met product specifications and/or the recommendations in the referenced guidance documents.

Table 9: Stent and Delivery Catheter Engineering Testing

|  Test | Description of Test | Conclusion  |
| --- | --- | --- |
|  Stent Material Specification Conformance Testing  |   |   |
|  Material Characterization | Chemical analysis was conducted on the Co-Ni-Cr-Mo alloy provided by the material supplier to confirm chemical analysis and inclusion/impurity content as provided by ASTM F562 “Standard Specification for Wrought Cobalt-35 Nickel-20 Chromium-10 Molybdenum Alloy for Surgical Implant Applications.” | Pass  |
|  Surface Contamination | SEM analysis was conducted to detect evidence of surface contaminants or impurities. Results of SEM evaluation showed no evidence of contamination above the specified limits. | Pass  |
|  Mechanical Properties | Testing was conducted to characterize the following properties of the annealed Co-Ni-Cr-Mo alloy bars: 0.2% offset yield strength, ultimate tensile strength, percent elongation, and reduction of area. Bars were machined from barstock conforming to ASTM F562. The bars were tensile tested to failure while engineering stress and strain were continuously recorded. The results were in conformance with ASTM F562. | Pass  |
|  Stent Corrosion Resistance | Endeavor stents were tested according to ASTM F2129 “Standard Test Method for Conducting Cyclic Potentiodynamic Measurements to Determine the Corrosion Susceptibility of Small Implant Devices” to demonstrate that the finished stents exhibit corrosion and repassivation characteristics comparable to marketed Driver stents. Results were comparable to the control stents and met product specification requirements. Testing was also conducted to evaluate the relative susceptibility to pitting/crevice corrosion of the Endeavor stent utilizing the corrosion techniques outlined in ASTM F746 and using sample preparation techniques in accordance with ASTM F2129. Results were comparable to marketed Driver stents and met product specification requirements. | Pass  |
|  Fretting Corrosion | Overlapped bare metal Driver or Micro-Driver 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  |

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Table 9: Stent and Delivery Catheter Engineering Testing

|  Test | Description of Test | Conclusion  |
| --- | --- | --- |
|  Galvanic Corrosion | Testing was conducted on marketed Driver stents (MP35N) overlapped with marketed S7 (316L stainless steel) stents to determine the potential for galvanic corrosion. The results met all acceptance criteria and indicated a high resistance to galvanic corrosion. | Pass  |
|  Stent Dimensional and Functional Attributes  |   |   |
|  Stent Dimensional Verification | Testing was conducted to measure and optically inspect the stent to document that stent dimensional and visual specifications do not deviate from product specifications. All product met specifications. | Pass  |
|  Percent Surface Area | This value is calculated using stent nominal dimensional values and is based on the ratio of stent area to the area of the vessel. Metal to artery percentage ratios were calculated for all of the stent diameters recommended in the product labeling, with the highest surface to artery ratio (18.6%) occurring when the stent is deployed to the nominal diameter (2.5 mm) for the seven crown stent design and (19.9%) occurring when the stent is deployed to the nominal diameter (3.0 mm) for the ten crown stent design. | N/A
Characterization only  |
|  Foreshortening | The length of the stents were measured prior to and after expansion to the largest nominal diameter. All stents met product specifications. | Pass  |
|  Stent Recoil | Testing was conducted to quantify the amount of elastic recoil for the stent and correlate this parameter to the recommended sizing procedures. The stent delivery system was inflated to nominal pressure and the stent was removed allowing for recoil to occur. The inner diameter at each end of the stent was recorded. Recoil was calculated by subtracting the recoiled stent inner diameter from the pre-recoil inner diameter. All stents met the acceptance criteria after balloon inflation to nominal pressure. | Pass  |
|  Stent Integrity | Testing was conducted to determine if the plastic deformation experienced by the stent when expanded from the compressed profile to the final maximum deployed diameter can produce crack initiation for the stent. Samples were deployed to their largest possible diameters by inflating each delivery system to nominal plus 0.5 mm. Each stent was examined under magnification for potential cracks. All samples met the acceptance criteria with no visible cracks or notches. | Pass  |
|  Radial Stiffness and Radial Strength | Testing was conducted to determine stent resistance to radial load. The stents were deployed to nominal stent diameter and placed in a radial crush tester. All samples met the acceptance criteria. | Pass  |
|  Stent Expansion/ Coating Evaluation | Testing was conducted to provide a qualitative comparison of Endeavor coating in the pre-deployed, deployed to nominal and deployed to maximum diameter conditions using microscopy. A qualitative comparison of coating integrity was also performed pre- and post tracking through a tortuous anatomy using microscopy and SEM. | N/A
Characterization only
See * note at end of table.  |

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Table 9: Stent and Delivery Catheter Engineering Testing

|  Test | Description of Test |   | Conclusion  |
| --- | --- | --- | --- |
|  Coating Stress Analysis | A stress analysis, using a finite element analysis (FEA), demonstrated that the addition of a coating to a Driver or Micro-Driver stent will not change the critical location of stresses during expansion and during in vivo loading. Additionally, the coating stress analysis showed that the critical stress location within the coating is in the same location found on a bare stent. |   | Pass  |
|  Fatigue 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 Durability Testing | This testing was conducted to determine the fatigue integrity of a stent under accelerated cycling designed to model in vivo conditions. Stents were deployed up to the largest intended diameter and tested through a simulated 10 year life. After the completion of the ten year simulated durability testing, the stents were visually inspected using microscopy for cracking or breaks. All units tested were free of any cracks or breaks. There were no stent failures noted after 420 million cycles (equivalent to 10 years in vivo). Additionally, Endeavor stents were analyzed using SEM post accelerated durability testing. |   | Pass
See * note at end of table.  |
|  Magnetic Resonance Imaging (MRI) Safety and Compatibility | Non-clinical testing on single and overlapped stents has demonstrated the Endeavor stent is MR Conditional. It can be scanned safely under the following conditions: |   | N/A  |
|   |  Single Stenting (Stent Length 30 mm) | Overlapped Stenting (Total Length 55 mm)  |   |
|   |  Static magnetic field of 3-Tesla | Static magnetic field of 3-Tesla  |   |
|   |  Spatial gradient field of 525 Gauss/cm | Spatial gradient field of 720 Gauss/cm  |   |
|   |  Maximum whole-body-averaged specific absorption rate (SAR) of 2 W/kg for 20 minutes of scanning | Maximum whole-body-averaged specific absorption rate (SAR) of 3 W/kg for 15 minutes of scanning  |   |
|   |  In non-clinical testing, the Endeavor stent produced a temperature rise of less than 0.5°C at a maximum whole body averaged specific absorption rate (SAR) of 2 W/kg for 20 minutes of MR scanning in a 3-Tesla, Signa, General Electric Medical Systems (software version 9.0) MR scanner. The maximum whole body averaged SAR was displayed on MR scanner console. | In non-clinical testing, the Endeavor stent produced a temperature rise of less than 0.5°C at a maximum whole body averaged specific absorption rate (SAR) of 3 W/kg for 15 minutes of MR scanning in a 3-Tesla, Excite, General Electric Healthcare (software version G3.0-052B) MR scanner. The maximum whole body averaged SAR was displayed on MR scanner console.  |   |

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Table 9: Stent and Delivery Catheter Engineering Testing

|  Test | Description of Test |   | Conclusion  |
| --- | --- | --- | --- |
|   | The Endeavor stent should not move or migrate when exposed to MR scanning immediately post-implantation. |   |   |
|   |  The image artifact extends approximately 9 mm from the device/lumen centerline when scanned in nonclinical testing using a 3-Tesla, Signa, General Electric Medical Systems (software version 9.0) MR system with a send-receive RF body coil. | The image artifact extends approximately 10 mm from the device/lumen centerline when scanned in nonclinical testing using a 3-Tesla, Excite, General Electric Healthcare (software version G3.0-052B) MR system with a send-receive RF body coil.  |   |
|  Radiopacity | The radiopacity of the Endeavor stent system was evaluated at delivery, deployment and after implantation in an in vivo animal study and radiopacity characteristics were sufficiently comparable to marketed cobalt alloy stents. |   | Pass  |
|  Stent ID Uniformity | This test was conducted to demonstrate that the deployed internal diameter of the Endeavor stent system is consistent with labeling. Each stent was deployed to nominal pressure, and the stent inner diameter was measured at each end. The results indicated that the Endeavor stent system expands uniformly at all diameters and maintains this uniformity upon withdrawal of the balloon. |   | Pass  |
|  Delivery System Dimensional and Functional Attributes  |   |   |   |
|  Delivery, Deployment, and Retraction | In vitro testing was conducted to evaluate delivery, deployment, and retraction of the Endeavor stent delivery system through a simulated tortuous path according to the instructions for use. All results indicated that the system performed as intended and no damage to the stent was noted. |   | N/A
Characterization only  |
|  Balloon Maximum Pressure | This test was conducted to demonstrate that the Endeavor stent system (with mounted stent) will not experience balloon, shaft, proximal adaptation or proximal/distal seal loss of integrity at or below the pressure required to expand the stent to its labeled diameter. Stent delivery systems were initially pressurized to 90 psi. The cycle was then repeated, increasing inflation pressure by 15 psi each cycle until failure. The results demonstrate with 95% confidence that at least 99.9% of the delivery systems will not experience loss of integrity at or below the rated burst pressure. |   | Pass  |
|  Balloon Fatigue | Endeavor stent systems were required to complete 10 unconstrained pressurization cycles to rated burst pressure (RBP). The stent/balloon burst results show statistically that, with 95% confidence, 90% of the delivery systems will not experience balloon, shaft, or proximal/ distal seal loss of integrity at or below the maximum recommended RBP. |   | Pass  |
|  Stent Diameter vs. Balloon Pressure (Compliance) | Testing was performed to determine how the stent inner diameter varies with applied inflation pressures. The stent sizing results verify that the stent systems meet the labeled compliance curves. |   | N/A
Characterization for product labeling  |

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Table 9: Stent and Delivery Catheter Engineering Testing

|  Test | Description of Test | Conclusion  |
| --- | --- | --- |
|  Catheter Bond Strength | Testing was performed to confirm the bond strength specifications for the Endeavor stent delivery system. All bonds were loaded into the tensile tester and pulled to failure. All samples met the acceptance criteria. | Pass  |
|  Stent/Catheter Crossing Profile | Endeavor stents and delivery systems were tested to verify the crossing profile per label claims. All samples met product specifications. | Pass  |
|  Balloon Inflation and Deflation Time | Endeavor delivery systems were tested for inflation/deflation times. All samples met the product specification. | Pass  |
|  Stent Securement | • Testing was conducted to assess the force required to displace a crimped Endeavor stent from the Endeavor delivery system by both forward and reverse motion. All stent systems met the stent securement specification.
• Testing was performed to characterize the performance of the Endeavor stent system (undeployed) to cross a simulated lesion post tracking through a tortuous artery model. The Endeavor product performed as intended.
• To further characterize the performance of the Endeavor stent system undeployed stents were tracked through a tortuous artery model and withdrawn through the recommended guide catheter. The Endeavor product performed as intended. | Pass  |
|  Balloon Deflatability | This test was performed to provide assurance that the deflated delivery system balloons will release from the expanded stent without interference. All samples met specification. | Pass  |
|  Catheter Body Maximum Pressure | Testing was conducted on the Endeavor stent delivery systems to determine the ability of the catheter shaft to withstand inflation to balloon rated burst pressure. All samples met the product specification. | Pass  |

*Note:
Microcracks were observed in the drug/polymer coating layer of all samples both pre- and post simulated use and pre- and post durability testing. The location of microcracks did not appear to change from the pre- to the post deployed state. Microcracks were not observed in the cross-linked polymer base layer (i.e. the coating layer that remains implanted post drug exhaustion) after durability testing. Areas of apparent coating loss were observed on the inner and outer stent diameters; however areas of coating loss were predominantly on the ID surface of the stent.

D. Coating Characterization Testing

The following methods were developed to characterize and set initial specifications for the Endeavor Zotarolimus-Eluting Coronary Stent System. The coating characterization testing conducted on the Endeavor Zotarolimus-Eluting Coronary Stent System includes those tests summarized in Table 10.

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Table 10: Coating Characterization Testing

|  Test | Description of Test  |
| --- | --- |
|  Materials Analysis – Polymer | Polymer components were tested to ensure conformity to raw materials specifications and incoming inspection procedures.  |
|  Chemical Analysis – Polymer | Assays were conducted to determine residual monomer content, residual solvent levels and water content.  |
|  Chemical Analysis – Drug | Drug substance was tested to ensure conformity to incoming Certificate of Analysis.  |
|  Total Drug Content | Assay was conducted to quantitatively determine the total amount of drug substance, zotarolimus, on the Endeavor stent system.  |
|  Dose Density | Dose per mm was calculated.  |
|  Drug Content along Stent Length | Testing was conducted to characterize the uniformity of distribution of drug along the length of the Endeavor stent system.  |
|  Total Drug Related Substances | Assays were conducted to quantitatively determine the type and amount of impurities and degradation products on the Endeavor stent system.  |
|  Coating Thickness | Testing was conducted to describe the coating thickness along the length of the stent.  |
|  In Vitro Elution | Assay was developed to measure the in vitro release kinetics of zotarolimus from the Endeavor stent system.  |
|  Particulates | Particulate levels were determined for the Endeavor stent system post tracking and deployment. All samples met product specifications.  |

Medtronic Vascular provided a letter from the polymer manufacturer, Biocompatibles Ltd., authorizing access to a Master File (MAF) in support of this submission.

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# E. Chemistry Manufacturing and Controls (CMC) Testing

Where applicable, International Conference on Harmonization (ICH) Guidelines were followed for the testing routinely performed on Endeavor stents as part of CMC. This testing is summarized in Table 11. Information to support the stability of the Endeavor stent is summarized separately in Section VIII. G – Stability below.

Table 11: CMC Release Testing

|  Test | Description of Test  |
| --- | --- |
|  Material Analysis – Polymer | The polymer was tested to ensure conformity to specifications. The polymer met specifications prior to utilization in finished goods.  |
|  Drug Identity | Assay was conducted to verify the identity of the drug substance, zotarolimus, on the Endeavor Zotarolimus-Eluting Coronary Stent System. The product met specifications established for finished goods release.  |
|  Drug Content/Impurities | Assays were conducted to quantitatively verify the amount of drug and the type and amount of impurities on the Endeavor Zotarolimus-Eluting Coronary Stent System. The product met specifications established for finished goods release.  |
|  Drug Content Uniformity | Multiple stents were assayed to verify the uniformity of the drug content between the individual stents was within specifications established for finished good release.  |
|  Residual Solvents | Assay was conducted on the Endeavor stent system to verify that residual levels of solvents used in the manufacturing process were below acceptable limits established for finished goods release.  |
|  In Vitro Elution | The in vitro release profile for zotarolimus was measured on the Endeavor stent system. Specifications were based on the elution characteristics of stents evaluated in the clinical investigation. The product met specifications established for finished goods release.  |
|  Particulates | Particulate levels were monitored to verify that they remain below acceptable levels as established in the product specifications.  |

# F. Animal Studies

Detailed arterial histopathology and histomorphometry are not obtainable through human clinical trials. Consequently, a series of animal studies were conducted to evaluate safety, proof of concept and overall product performance.

Medtronic Vascular conducted a series of animal studies evaluating various zotarolimus-eluting stent formulations (e.g., drug dosages), polymer-coated control stents and/or bare metal control stents. These studies were conducted in coronary arteries of pigs, or iliac arteries of rabbits. Data from these studies served as the basis for the dose selection for the Endeavor Zotarolimus-Eluting Coronary Stent System used in the Endeavor clinical studies and provided an assessment of the safety of the product over a range of timepoints.

The intravascular safety and biocompatibility of zotarolimus-eluting stents were evaluated in a series of animal studies in a porcine model of stent-mediated vascular injury. Non-GLP studies were conducted in order to provide additional background data for non-safety related areas. All study phases (feasibility, safety, pharmacokinetic and

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acute) are represented by studies that were conducted in accordance with § 21CFR 58 (Good Laboratory Practices), except where noted. The results of these studies support the safety and biocompatibility of the Endeavor Zotarolimus-Eluting Coronary Stent System. Summaries of the major animal studies performed to support product safety are included in Table 12.

Table 12: Summary of Major Supportive Animal Studies

|  Study # | Stent Design | Stent Size (mm) | Type/ # of Animals | # of Stents | Follow-up Duration | Major Endpoints  |
| --- | --- | --- | --- | --- | --- | --- |
|  FS102 | Test Article: zotarolimus-eluting Endeavor stent system, multiple doses
Control: BMS
GLP: Yes | Diameter: • 3.0, 3.5, 4.0 mm
Lengths: • 12, 18 mm | Domestic Swine
Test and Control: 15
(LAD, LCX, RCA)
One stent/vessel
Animals received both test and control | Test: 32
Control: 20 | 7 days | • Angiographic patency
• Histologic and histomorphometric evaluation of single and overlapping stents
• Cell proliferation
• Acute delivery  |
|  FS135 | Test Article: zotarolimus-eluting Endeavor stent system, multiple doses
Control: BMS and Polymer only coated stents
GLP: Yes | Diameter: • 2.25, 2.5 mm
Lengths: • 8 mm | Juvenile Yorkshire Swine
Test and Control: 21
(LAD, LCX, RCA)
One stent per vessel. Animals received both test and control. | Test: 24
Control: 20
Control (Polymer Coated Stents): 12 | 28 days | • Angiographic patency
• Histologic and histomorphometric evaluation of exaggerated dose and Endeavor stent systems
• Acute Delivery
• Chronic vascular response at 28 days  |
|  FS99 | Test Article: zotarolimus-eluting Endeavor stent system, multiple doses
Control: BMS and Polymer only coated stents
GLP: Yes | Diameter: • 2.5, 3.0, 3.5, 4.0 mm
Lengths: • 12, 18 mm | Domestic Swine
Test and Control: 51
(LAD, LCX, RCA)
One stent per vessel. Animals received both test and control. | Test: 99
Control: 64
Control (Polymer Coated Stents): 13 | 28 days | • Angiographic patency
• Histologic and histomorphometric evaluation of exaggerated dose, single and overlapping stents
• Acute Delivery
• Chronic vascular response at 28 days  |
|  FS100 | Test Article: zotarolimus-eluting Endeavor stent system, multiple doses
Control: BMS and Polymer only coated stents
GLP: Yes | Diameter: • 2.5, 3.0, 3.5, 4.0 mm
Lengths: • 12 mm | Yucatan Miniswine
Test & Control: 31
(LAD, LCX, RCA)
One stent per vessel. Animals received both test and control. | Test: 58
Control: 43
Control (Polymer Coated Stents): 9 | 90 days | • Angiographic patency
• Histologic and histomorphometric evaluation of exaggerated dose, single and overlapping stents
• Acute Delivery
• Chronic vascular response at 90 days  |

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Table 12: Summary of Major Supportive Animal Studies

|  Study # | Stent Design | Stent Size (mm) | Type/ # of Animals | # of Stents | Follow-up Duration | Major Endpoints  |
| --- | --- | --- | --- | --- | --- | --- |
|  FS101 | Test Article: zotarolimus-eluting Endeavor stent system, multiple doses
Control: BMS and Polymer only coated stents
GLP: Yes | Diameter: • 2.5, 3.0, 3.5, 4.0 mm
Lengths: • 12 mm | Yucatan Miniswine
Test & Control: 30 (LAD, LCX, RCA)
One stent per vessel. Animals received both test and control. | Test: 55
Control: 40
Control (Polymer Coated Stents): 11 | 180 days | • Angiographic patency
• Histologic and histomorphometric evaluation of exaggerated dose, single and overlapping stents
• Acute delivery
• Chronic vascular response at 180 days  |
|  FS114 | Test Article: zotarolimus-eluting Endeavor stent system
GLP: Yes | Diameter: • 3.0 mm
Lengths: • 12 mm | Domestic Swine (LAD, LCX, RCA)
One stent per vessel. | 48 | 1, 2, 3, 5, 7, 10, 14 and 28 days | Evaluation of drug release rate, arterial drug levels & systemic drug levels over time.  |
|  FS161 | Test Article: zotarolimus-eluting Endeavor stent system
Control: BMS
GLP: Yes | Diameter: • 3.0 mm
Lengths: • 15 mm | Juvenile Yorkshire Swine
Test and Control: 22 divided into 3 test and 1 control arms (LAD, LCX, RCA)
One stent per vessel | Test: Endeavor RX: 6
Endeavor OTW: 5
Endeavor MX2: 6
Control: Driver OTW: 5 | ACT level: 0, 3, 6, 9 and 11 days
Angiography: 11 days | • Microscopic evaluation of the overall subacute tissue reaction of the vessel and the surrounding myocardium; examination of the thrombogenicity of the stent and delivery device at 11-days post-stenting
• Acute delivery
• Angiographic patency
• Histologic and histomorphometric evaluation of test and controls
• ACT levels at time of implant, 3, 6, and 9 days post-implant, at explant  |

BMS = bare metal stent – Driver for these studies.

The systemic toxicity of the intact Endeavor Zotarolimus-Eluting Coronary Stent System has been investigated in a number of studies that were intended principally to define the local tolerance and healing response to the implanted Endeavor Zotarolimus-Eluting Coronary Stent System (Studies FS97, FS99, FS100, FS101, FS102, FS110, FS124 and FS135). In these studies, body weight data, clinical laboratory measurements, necropsies, and histopathological examination of selected tissues from the animals implanted with stents demonstrated only infrequent adverse systemic effects and no systemic effects that could be attributed to stent implantation.

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The efficacy of the zotarolimus incorporated into the coating of the Endeavor Zotarolimus-Eluting Coronary Stent System in inhibiting smooth muscle proliferation at the site of implantation has been examined in studies FS102 and FS107. In both studies, there were significantly fewer proliferating cells found in sections of stented tissue at 7 days post-implantation when zotarolimus was incorporated into the stent coating at 5 µg/mm or 10 µg/mm than when bare Driver stents were implanted.

The rate of elution of zotarolimus from the implanted Endeavor Zotarolimus-Eluting Coronary Stent System and the distribution of zotarolimus from the stent to surrounding arterial tissues, plasma, and distant organs has been measured using the rabbit iliac artery model (FS97) and the swine coronary artery model (FS114). These studies demonstrate that the drug rapidly elutes from the stent, with less than 50% of the drug remaining on the stent at 24 hours after implantation and less than 6% remaining at 7 days. Blood levels rapidly decline to undetectable levels by 7 days after implantation and peripheral tissues have highly limited exposures. Thus, while systemic exposure is limited, drug remains at the implantation site for at least 28 days.

The local tolerance and healing of coronary vessels after implantation of the Endeavor stent have been evaluated at various times (i.e., 7, 28, 90, and 180 days) after stent implantation into swine coronary arteries (Studies FS99, FS100, FS101, FS102, FS135) and rabbit iliac arteries (Study FS107). These studies demonstrate that initially the stent produced a slightly greater level of inflammation surrounding stents than the bare control Driver stents. This effect was observed early after implantation but did not persist. Also, a slight delay in endothelialization and fibrin removal between overlapped bare and overlapped drug-coated stents was observed. However, no differences in long-term healing attributable to the presence of the drug coating on the stents were observed. The slightly greater inflammation observed with the Endeavor stent did not result in greater levels of restenosis.

The effect of the stents on vascular healing after stent placement was also evaluated in both swine and rabbits. All of the stents exhibited complete endothelialization at both the 90 and 180 day timepoints.

## G. Stability

Manufacturing site-specific stability studies were conducted to establish a shelf-life/expiration date for the Endeavor Zotarolimus-Eluting Coronary Stent System. Testing to establish package integrity and functional testing of the stent system were conducted on aged product. Testing evaluation included drug identity, assay, degradants, *in vitro* elution, particulates, sterility, drug content uniformity, residual solvents, and endotoxins. Appropriate engineering tests were also performed on aged product and compared to baseline to ensure that the Endeavor Zotarolimus-Eluting Coronary Stent System performed acceptably. The data generated support a shelf life of one year.

## H. Sterilization

The Endeavor Zotarolimus-Eluting Coronary Stent System (OTW, RX, and MX² delivery systems) is sterilized using ethylene oxide sterilization, and has been validated per

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AAMI/ISO 11135:1994 “Medical Devices – Validation and Routine Control of Ethylene Oxide Sterilization.”

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

The amount of bacterial endotoxins was verified to be within the specification limit for the Endeavor Zotarolimus-Eluting Coronary Stent System.

## IX. Overview of Clinical Studies

The principal safety and efficacy information for the Endeavor stent is presented from the following clinical studies – the ENDEAVOR I trial, the ENDEAVOR II trial, the ENDEAVOR III trial and the ENDEAVOR IV trial. These studies have evaluated the performance of the Endeavor Stent in patients with symptomatic ischemic heart disease in single de novo lesions of native coronary arteries.

The ENDEAVOR I trial was the first-in-man study for the Endeavor stent. ENDEAVOR I was a non-randomized, prospective, multi-center, single-arm trial. The purpose of the trial was to assess the initial safety of the Endeavor stent. The primary endpoints in this trial were the rate of major adverse cardiac events (MACE) defined as composite of death, myocardial infarction (MI), emergent bypass surgery, or target lesion revascularization (TLR) at 30 days and in-segment late loss at 4 months as measured by quantitative coronary angiography (QCA). Post-procedure, patients received aspirin indefinitely and clopidogrel or ticlopidine for a minimum of 3 months.

The ENDEAVOR II trial was a prospective, multi-center, double-blind, two-arm randomized and controlled, superiority trial that compared the Endeavor stent to a control bare metal stent (the Driver stent). Eligibility was based on assessments of lesion reference vessel diameter and lesion length. The primary endpoint in this trial was the target vessel failure (TVF) rate, defined as the composite of cardiac death, MI, or clinically-driven target vessel revascularization (TVR) of the treated vessel at 9 months post-procedure. The powered secondary endpoint was in-segment late loss at 8 months measured by QCA. Post-procedure, patients received aspirin indefinitely and clopidogrel or ticlopidine for a minimum of 3 months.

The ENDEAVOR III trial was a prospective, multi-center, single-blind, two-arm randomized and controlled, non-inferiority trial that compared the Endeavor stent to a control DES (the Cypher stent). Eligibility was based on the assessments of a lesion reference vessel diameter and lesion length. The primary endpoint of this study was in-segment late loss at 8 months as measured by QCA and defined as the difference between post-procedure minimum lumen diameter (MLD) and the MLD at time of follow-up within the stented region and $5\mathrm{mm}$ proximal and distal to the edges of the stent. Post-procedure, patients received aspirin indefinitely and clopidogrel or ticlopidine for a minimum of 3 months.

The ENDEAVOR IV trial was a prospective, multi-center, single-blind, two-arm randomized and controlled, non-inferiority trial that compared the Endeavor stent to a

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control DES (the Taxus stent). Eligibility was based on the assessments of a lesion reference vessel diameter and lesion length. The primary clinical endpoint in this non-inferiority study was the TVF rate, defined as the composite of cardiac death, MI, or clinically-driven TVR of the treated vessel at 9 months post-procedure. The powered secondary endpoint was in-segment late loss at 8 months, measured by QCA. Post-procedure, patients received aspirin indefinitely and clopidogrel for a minimum of 6 months.

Table 13: Clinical Trial Comparisons

|   | ENDEAVOR I | ENDEAVOR II | ENDEAVOR III | ENDEAVOR IV  |
| --- | --- | --- | --- | --- |
|  Study Type | Multi-center (n=8)
Prospective
Non-randomized | Multi-center (n=72)
Prospective
Randomized | Multi-center (n=29)
Prospective
Randomized | Multi-center (n=80)
Prospective
Randomized  |
|  Number of Patients | Total: 100 (Endeavor) | Total: 1197 (Endeavor: 598, Driver: 599) | Total: 436 (Endeavor: 323, Cypher:113) | Total: 1548 (Endeavor: 773, Taxus: 775)  |
|  Lesion Criteria | Single de novo lesion in native coronary artery ≤ 15 mm in length and ≥ 3.0 mm to ≤ 3.5 mm in diameter | Single de novo lesion in native coronary artery ≥ 14 mm and ≤ 27 mm in length and ≥ 2.25 mm to ≤ 3.5 mm in diameter | Single de novo lesion in native coronary artery ≥ 14 mm and ≤ 27 mm in length and ≥ 2.5 mm to ≤ 3.5 mm in diameter | Single de novo lesion in native coronary artery ≤ 27 mm in length and ≥ 2.5 mm to ≤ 3.5 mm in diameter  |
|  Product Used | Endeavor Stent on the Rapid Exchange Stent Delivery System | Endeavor Stent on the Rapid Exchange Stent Delivery System | Endeavor Stent on the Over-The -Wire Stent Delivery System | Endeavor Stent on the Over-The -Wire Stent Delivery System  |
|  Antiplatelet Therapy | Aspirin indefinitely and clopidogrel or ticlopidine for ≥ 3 months. | Aspirin indefinitely and clopidogrel or ticlopidine for ≥ 3 months. | Aspirin indefinitely and clopidogrel or ticlopidine for ≥ 3 months. | Aspirin indefinitely and clopidogrel or ticlopidine for ≥ 6 months  |
|  Follow up | 30 days: clinical
4 & 12 months: clinical and angiographic/IVUS
9 month: clinical
1-5 years: telephone | 30 days: clinical
8 months: clinical and angiographic/IVUS
9 month: clinical
6 month, 1-5 years: telephone | 30 days: clinical
8 months: clinical and angiographic/IVUS
9 month: clinical
6 month, 1-5 years: telephone | 30 days: clinical
8 months: clinical and angiographic/IVUS
9 month: clinical
6 month, 1-5 years: telephone  |
|  Status | 48 month follow-up complete. Yearly follow up to 5 years is ongoing. | 36 month follow-up is complete. Yearly follow up to 5 years is ongoing. | 24 month follow-up is complete. Yearly follow up to 5 years is ongoing. | 9 month follow-up is complete. Yearly follow up to 5 years is ongoing.  |

Two additional single-arm non-randomized trials were reviewed by FDA: the ENDEAVOR II Continued Access study and the ENDEAVOR PK study. The objective of the ENDEAVOR II Continued Access registry was to collect additional acute safety information and performance data of the Endeavor stent. The primary endpoint was MACE at 30 days. The objective of the ENDEAVOR PK study was to assess the pharmacokinetic profile of the Endeavor stent (see Section VIII. A - 5 In Vivo Pharmacokinetics). These trials provide additional data on Endeavor stent use. Results of these studies have been pooled with the patients treated with Endeavor stents in Endeavor I, II, III, and IV studies described above in a post-hoc patient-level analysis to provide an enhanced estimate of the incidence of low-frequency events and outcomes in specific patient subgroups (see Section XI. F Overall Results of the ENDEAVOR Clinical Program (ENDEAVOR I, II, II-CA, III, IV and USPK)).

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The Endeavor MX² delivery system was not used in the Endeavor clinical investigations (ENDEAVOR I to IV). The Endeavor MX² utilizes a modified shaft to facilitate the multi-exchange feature of the delivery system.

The distal section of the Endeavor MX² Zotarolimus-Eluting Coronary Stent System, including the stent, balloon, drug coating and stent interfaces are identical to that of the Endeavor RX and OTW delivery systems which were studied clinically. Appropriate pre-clinical testing was provided to support the Endeavor MX² delivery system. Acute and long term safety and performance data is provided in the PMA application (ENDEAVOR I to IV clinical investigations, over 2000 patients) to support the clinical safety and efficacy of the Endeavor stent mounted on the Endeavor delivery systems.

## X. Adverse Events

### A. Observed Adverse Events

Observed adverse event experience with the Endeavor stent comes from four clinical studies: the ENDEAVOR IV, the ENDEAVOR III, the ENDEAVOR II, and the ENDEAVOR I trials.

The ENDEAVOR IV, III, II, and I trials have evaluated the performance of the Endeavor stent in patients with symptomatic ischemic heart disease in single de novo lesions of native coronary arteries. Principal adverse events are shown in Table 14.

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Table 14: ENDEAVOR IV, III, II and I - Principal Adverse Events from Post-procedure to Latest Follow-up

|   | ENDEAVOR IV |   | ENDEAVOR III |   | ENDEAVOR II |   | ENDEAVOR I  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   | Endeavor N = 773 | Taxus N = 775 | Endeavor N = 323 | Cypher N = 113 | Endeavor N = 598 | Driver N = 599 | Endeavor N = 100  |
|  In-Hospital |  |  |  |  |  |  |   |
|  MACE | 0.9% (7/773) | 2.6% (20/775) | 0.6% (2/323) | 3.5% (4/113) | 2.5% (15/597) | 2.9% (17/596) | 0% (0/100)  |
|  Total Death | 0% (0/773) | 0% (0/775) | 0.0% (0/323) | 0.0% (0/113) | 0.2% (1/597) | 0.0% (0/596) | 0.0% (0/100)  |
|  Cardiac Death | 0.0% (0/773) | 0.0% (0/775) | 0.0% (0/323) | 0.0% (0/113) | 0.2% (1/597) | 0.0% (0/596) | 0.0% (0/100)  |
|  Non-Cardiac Death | 0.0% (0/773) | 0.0% (0/775) | 0.0% (0/323) | 0.0% (0/113) | 0.0% (0/597) | 0.0% (0/596) | 0.0% (0/100)  |
|  MI | 0.8% (6/773) | 2.1% (16/775) | 0.6% (2/323) | 3.5% (4/113) | 2.5% (15/597) | 2.7% (16/596) | 0.0% (0/100)  |
|  Q wave MI | 0.3% (2/773) | 0.1% (1/775) | 0.0% (0/323) | 0.0% (0/113) | 0.2% (1/597) | 0.3% (2/596) | 0.0% (0/100)  |
|  Non-Q wave MI | 0.5% (4/773) | 1.9% (15/775) | 0.6% (2/323) | 3.5% (4/113) | 2.3% (14/597) | 2.3% (14/596) | 0.0% (0/100)  |
|  TVR | 0.4% (3/773) | 0.6% (5/775) | 0.0% (0/323) | 0.0% (0/113) | 0.5% (3/597) | 0.3% (2/596) | 0.0% (0/100)  |
|  TLR | 0.4% (3/773) | 0.5% (4/775) | 0.0% (0/323) | 0.0% (0/113) | 0.5% (3/597) | 0.3% (2/596) | 0.0% (0/100)  |
|  Non-TLR | 0.0% (0/773) | 0.3% (2/775) | 0.0% (0/323) | 0.0% (0/113) | 0.0% (0/597) | 0.0% (0/596) | 0.0% (0/100)  |
|  Cardiac death or MI | 0.8% (6/773) | 2.1% (16/775) | 0.6% (2/323) | 3.5% (4/113) | 2.5% (15/597) | 2.7% (16/596) | 0.0% (0/100)  |
|  TVF | 0.9% (7/773) | 2.6% (20/775) | 0.6% (2/323) | 3.5% (4/113) | 2.5% (15/597) | 2.9% (17/596) | 0.0% (0/100)  |
|  Stent thrombosis (protocol) | 0.3% (2/773) | 0.0% (0/775) | 0.0% (0/323) | 0.0% (0/113) | 0.3% (2/597) | 0.3% (2/596) | 0.0% (0/100)  |
|  Data at 9 Months |  |  |  |  |  |  |   |
|  MACE | 5.7% (42/740) | 5.7% (42/734) | 7.5% (24/321) | 7.1% (8/113) | 7.3% (43/592) | 14.4% (85/591) | 2.0% (2/100)  |
|  Total Death | 0.7% (5/740) | 0.8% (6/734) | 0.6% (2/321) | 0.0% (0/113) | 1.2% (7/592) | 0.5% (3/591) | 0.0% (0/100)  |
|  Cardiac Death | 0.4% (3/740) | 0.3% (2/734) | 0.0% (0/321) | 0.0% (0/113) | 0.8% (5/592) | 0.5% (3/591) | 0.0% (0/100)  |
|  Non-Cardiac Death | 0.3% (2/740) | 0.5% (4/734) | 0.6% (2/321) | 0.0% (0/113) | 0.3% (2/592) | 0.0% (0/591) | 0.0% (0/100)  |
|  MI | 1.5% (11/740) | 2.5% (18/734) | 0.6% (2/321) | 3.5% (4/113) | 2.7% (16/592) | 3.9% (23/591) | 1.0% (1/100)  |
|  Q wave MI | 0.3% (2/740) | 0.1% (1/734) | 0.0% (0/321) | 0.0% (0/113) | 0.3% (2/592) | 0.8% (5/591) | 0.0% (0/100)  |
|  Non-Q wave MI | 1.2% (9/740) | 2.3% (17/734) | 0.6% (2/321) | 3.5% (4/113) | 2.4% (14/592) | 3.0% (18/591) | 1.0% (1/100)  |
|  TVR | 5.5% (41/740) | 5.0% (37/734) | 11.2% (36/321) | 8.0% (9/113) | 5.6% (33/592) | 12.5% (74/591) | 2.0% (2/100)  |
|  TLR | 4.2% (31/740) | 2.7% (20/734) | 6.2% (20/321) | 3.5% (4/113) | 4.6% (27/592) | 11.8% (70/591) | 2.0% (2/100)  |
|  Non-TLR | 2.0% (15/740) | 2.9% (21/734) | 5.9% (19/321) | 5.3% (6/113) | 1.5% (9/592) | 2.2% (13/591) | 0.0% (0/100)  |
|  Cardiac death or MI | 1.9% (14/740) | 2.7% (20/734) | 0.6% (2/321) | 3.5% (4/113) | 3.4% (20/592) | 4.4% (26/591) | 1.0% (1/100)  |
|  TVF | 6.8% (50/740) | 7.4% (54/734) | 11.8% (38/321) | 11.5% (13/113) | 7.9% (47/592) | 15.1% (89/591) | 2.0% (2/100)  |
|  Stent thrombosis (protocol)…

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**Source:** [https://fda.innolitics.com/device/P060033](https://fda.innolitics.com/device/P060033)

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