Product Generic Name: Drug-Eluting Coronary Stent System (NIQ

Summary

of

Safety

and

Effectiveness

Data

I.

General

Information

Product

Generic

Name:

Drug-Eluting

Coronary

Stent

System

(NIQ)

Endeavor

Zotarolimus-Eluting

Coronary

Stent

on

Product

Trade

Name:

the

Over-the-Wire

(OTW),

Rapid

Exchange

(RX),

or

Multi-Exchange

II (MX

2

)

Stent

Delivery

Systems

Applicant's

Name

and

Medtronic

Vascular

Address:

3576

Unocal

Place

Santa

Rosa,

CA

95403

Premarket

Approval

Application

(PMA)

Number:

Date

of

Panel

Recommendation:

October

10,

2007

Date

of

Notice

of

Approval

February

1,

2008

to Applicant:

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.

SSED

P060033

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Page

1

of

59

c)

V.

Device

Description

The

Endeavor

Zotarolimus-Eluting

Coronary

Stent

System

is

a

device/drug

combination

product

comprised

of

device

components

(DriverTM

Coronary

Stent

and

Micro-DriverTM

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

Over-The-

Endeavor

i-

2

Endeavor38p

id

Exchan

(RJQ~f~e!ry

System:l

Available

Stent

lengths

(mm)*

lengths (mm)'

~~~~~~8,9,

12,

14, 15,

18,

24,

30

Available

Stent

25

.,.

2.5,

3.0,

3.5

A

cobalt-based

alloy

(MP35N)

-

the

Driver

and

Micro-Driver

stents

A

spray

coating

of

polymer

carrier

loaded

with

zotarolimus

is

applied

to

the

stent

Ougt

omplb~onbnght-

at

a

drug

loading

of

10

pg/mm

stent

length.

The

maximum

nominal

drug

content

on

the

longest

stent

(30

mm)

is

300

pg.

Delivery

Stem

Working

Lengh

135

138

(cm)

Y-Connector

(side

arm

for

access

to

Single

access

port

to

Single

access

port

to

inflation

balloon

inflation/

inflation

lumen.

Guidewire

exit

port

is

deflation

lumen.

Guidewire

exits

through

located

approximately

25

cm

Straight

arm

is

a

Z-component

located

from

tip.

Designed

for

continuous

with

shaft

on

the

proximal

shaft.

guidewire

<

0.014".

inner

lumen).

Designed

for

guidewire

Designed

for

<

0.014".

guidewire

•0.014".

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

Stelont

the

stent

which

aid

in

holding

the

stent

in

position.

Two

radiopaque

balloon

Deliver

markers

are

located

on

the

distal

section

of

the

inner

member

and

are

positioned

to

mark

the

working

length

of

the

balloon.

Balloon

Initation

Nominal

Inflation

Pressure:

9

ATM

Pressur&

Rated

Burst

Inflation

Pressure:

16

ATM

0.056"

minimum

(5 F)

0.056"

minimum

(5 F)

0.064"

minimum

(6 F)

Distal

=

2.7

F

Distal

2.7

F

Distal

=

2.7

F

Distal

Section

Outer

Middle

=

3.0

F

S metion

Outer

Proximal

=

3.0

F

Proximal

=

3.0

F

Diameter

~~~~~~~~~~~~~~~Proximal

3.8

F

=

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 S

and

14

mm

lengths

SSED

P060033

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Page

2

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59

to

A.

Device

Component

Description

The

device

component

consists

of

the

DriverTM

Coronary

Stent

or

Micro-DriverTM

Coronary

Stent

pre-mounted

onto

one

of

three

delivery

systems;

Over-The-Wire

(OTW),

Rapid

Exchange

(RX)

or

Multi-Exchange

II

(MX

2

)

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

MX

2

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

jtg

zotarolimus

per

millimeter

of

stent

length

for

all

diameters.

Because

an

identical

dose

(l0~tg/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*,I

OS*,

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-(

H-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]oxaazacyclohentriacontine-

1,5,11,28,29(4H,6H,31H)-pentone.

SSED

P060033

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Page

3

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59

tI

The

chemical

structure

of

zotarolimus

is

shown

below

(Figure

1).

N=N

/

\

3

CH·CH

O9

CH3

I

4

-

2H

26

0(,

0

'29k

2/T-%

25

24

Figure

1:

Chemical

Structure

of

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

C52H79N5012

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

carter

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.

SSED

P060033

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Page

4

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59

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.

-

-" /vv

,/vvwJ~

("--.

~)

2

3

~("

) I

I

-"

-)

2 5

I-~

0

o

0

H

ISi''CH

O

H

3

C0

~_IOCH

3

i

OCH

3

N

+

Figure

2:

Chemical

Structure

of

PC

Polymer*

PC

Technology

T

is

licensed

under

patents

or

patent

applications

owned

by

Biocompatibles.

SSED

P060033

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Page

S

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59

t3

Table

2:

Endeavor

Zotarolimus-Eluting

Coronary

Stent

System

Product

Matrix

and

Nominal

Zotarolimus

Doses

Product

P

uProdut.;pl

Number

E X

-a

nNumE

d

W

NM

:;,

.

Stent

ID

l

tConent

(mm)~

(mm)

(pg:

EN25008W

EN25008UX

EN25008MX

2.50

8*

84

The

8

mm

and

14 mm

stent

lengths

have

a

total

nominal

drug

content

of

84

pg

and

144

pg.

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.

OTW

MVR

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

EN3003OW

EN3003OUX

EN30030MX

3.00

30

300

EN35030W

EN3503OUX

EN35030MX

3.50

30

300

:

Note:

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

FKBP

12

(binding

protein).

The

suggested

mechanism

of

action

of

zotarolimus

is

to

bind

to

FKBP

12,

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

GI

to

the

S

phase.

SSED

P060033

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59

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

H

Trinidad

*

Aruba

*

Colombia

Hong

*

Malaysia

*

Portugal

and

*

Australia

*

Costa

Rica

·

Hungary

*

Malta

*

Qatar

Tobago

*

Tunisia

*

Austria

·

Cyprus

*

Iceland

*

Mauritius

·

Romania

*

Turkey

*

Bahamas

B

Czech

Republic

*

India

*

Mexico

*

Russia

·

Uganda

*

Bahrain

*

Denmark

·

Iran

*

Morocco

*

Saudi

Arabia

*United

Arab

Emirates

*Bangladesh

·

Dominican

Ban

h Republic

*Ireland

*

Mozambique

*

Senegal

*

United

Kingdom

*

Barbados

*

Ecuador

*

Israel

Nepal

·

*Serbia

&

Montenegro

*Uruguay

*

Belgium

*

Egypt

*

Italy

*

Netherlands

·

Singapore

*

Venezuela

*

Belize

*

-El

Belize

Salvador

·

Jamaica

*

New

Zealand

*

Slovakia

*

Virginia

Islands

,

Bermuda

a

Estonia

*

Jordan

*

Nicaragua

*

Slovenia

(British)

*

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.

SSED

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59

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

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-

30-times

the

estimated

Cma.

(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

Cmax

obtained

in

the

highest

IV

dose

tested

in

human

multiple

dose

study

for

safety

(800

jig

for

14

days).

Zotarolimus

did

not

reduce

hERG

current

at

concentration

up

to

181

ng/ml

(72

times

the

estimated

clinical

Cmax).

Zotarolimus

showed

minimal

prolongation

of

the

Purkinje

fiber

action

potential

duration

(by

6%)

at

concentration

up

to

21

ng/ml

(9

times

estimated

clinical

Cmax).

Zotarolimus

caused

in

vitro

inhibition

of

cell

proliferation

of

human

T

cell,

coronary

artery

smooth

muscle

and

endothelial

cells

at

IC

50

of

1.2,

2.9

and

2.6

nM,

respectively.

Zotarolimus

did

not

exhibit

receptor

interaction

when

tested

in

vitro

at

a

concentration

of

10

pM

for

binding

to

73

individual

assays.

At

levels

of

200

ng/ml

(100-fold

greater

than

a

typical

projected

Cmax

of

1.8

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

tg/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

SSED

P060033

-

Page

8

of

59

3

H-thymidine

incorporation

in

the

lymph

nodes

indicating

lack

of

skin

sensitizing

activity.

2.

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

jig/kg/day

and

above

(approximately

3

times

the

cumulative

blood

exposure

provided

by

Endeavor

stents

coated

with

300

jig

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

pg/kg/day

(approximately

13

times

the

cumulative

blood

exposure

provided

by

Endeavor

stents

coated

with

300

gg

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

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,

SSED

P060033

-

Page

9

of

59

(-7

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

ICs0

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

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

<

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.

SSED

P060033

-

Page

10

of

59

Table

3:

Pharmacokinetic

Parameters

(Mean

±

standard

deviation)

in

Patients

Following

Intravenous

Administration

of

Zotarolimus

meesUnlts

~

~;

6

Day

1

Day

14

Day

1

Day

14

Day

1

Day

14

Cmax

(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

Tmma

(h)

1.05

0.040

1.03

±

0.04

1.00

±

0.14

1.05

±

0.04

1.03

±

0.04

1.03

±

0.05

AUC

0

-

24

(ngoh/mL)

t

Wm$

(h)

34.19

±

4.39

*

47.70

±

6.68

32.9

±

6.8

68.43

±

15.41

100.47

±

18.02

37.6

±

4.5

123.48

±

13.34

174.43

±

19.88

36.0

±

4.7

CIL

(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

pg,

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

pg

drug

dose),

a

Cm.

of

4.0

ng/mL

and

AUCO-inf

(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

Cmax

and

AUCO-inf

values

calculated

from

the

IV

dosing

studies

conducted

on

zotarolimus.

Table

4:

Zotarolimus

Dose

Exposure

F

~

~~~1

~~480

~

Stent

>EbuEMultiples

I~E

Cmax

(n

Iml

4.0

27.69

¥

AUJCo~f

n

*h/mL162

15.06

#

¥

Calculated

based

on

the

mean

C

value

(110.78)

from

the

highest

dose

group

(900

pg)

from

human

single

escalation

IV

dose

study

conducted

on

zotarolimus

#

Based

on

the

mean

all

day

AUC,,,

(Day

1

to 14):

2440

ng-h/mL)

value

from

the

highest

dose

regimen

(800

pg

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.

SSED

P060033

-

Page

11

of

59

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

Term

in

the

Sti

nDose

Study

N8

(%/)~

.,N

=8(%/)

=

%

Headache

3

(15%)

0

(0%)

0

(0%)

0

(0%)

1

(13%)

0

(0%)

Body

as

a

whole

Injection

site

1(5%)

0

(0%)

0

(0%)

3

(38%)

0

(0%)

0

(0%)

Reaction

Pain

7(35%)

1

(13%)

0

(0%)

5

(63%)

5

(63%)

2

(25%)

Digestive

Diarrhea

2

(10%)

0

(0%)

0

(0%)

0

(0%)

0

(0%)

0

(0%)

System

Application

Skin

and

st

site

8

(40%)

1

(13%)

5

(63%)

2

(25%)

1

(13%)

5

(63%)

Appendage

Rato

Urogenmtal

Hematuria

1

(5%)

0

(0%)

System

I

1

(13%)

0

(0%)

1

(13%)

1

(13%)

I

__

_ __

I

_ __

_

__

_

I

I__

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

Tratment

b

Bod

S

stems

and

COSTART

Term

in

the

Multiple-dose

Study

~~td

OfA

TtCIAlTlaM21oo-

*S_

±4

pgdD

Term

.

(N)

_

_ _

_

_N_

(

)_

_

Headache

..

L

2

(13)

(4)

2

(13)

2

(13)

Pain

1

(4)

(13)

2

1

(6)

O

(0)

Injection

Site

Body

as

a

Ineto

ie2

(8)

O

(0)

0 (0)

2

(13)

Reaction

Injection

Site

Pain

2(8)

0(0)

Abdominal

Pain

1

(4)

1

0

(0)

Digestive

System

Diarrhea

1 (4)

0 (0)

1 (6)

0

(0)

Skin

and

Dry

Skin

0

(0)

2(13)

0

(0)

Appendage

Rash

0

01

61

0

(0)

SSED

P060033

-

Page

12

of

59

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

Group

G

Grop

V

Group

Pareter180

P

Un

: :'i

i

l

VI

2V

2240pg)(300

jig)

Vii

(360

g)

VIii

4

,

N=N

[]

6

N=7

N=

[

1

Cmax

(ng/mL)

0.847

2.176

1.513±

1.83

1.584

2.658±

2.539

3.133

0.616

0.210

0.998

Tmax

(h)

1.00

4.00

1.2

±

0.6

1.4

±

1.3

1.5

±

1.3

2.00

1.3

AUCo-iast

(ngeh/

46.51

71.73

57.02

±

63.83

±

125.18

90.77

±

95.21

87.45

mL)

13.46

15.27

19.51

#

AUCo-inf

(ngh/

56.57

78.28

66.61

±

72.84±

136.65

101.45±

113.85

99.82

mL)

14.86

19.96

23.48#

13

(1/h)

0.010

0.013

0.012

±

0.012

±

0.010

0.012

±

0.010

0.012

0.003

0.002

0.003

t4:l:

(h)

71.59

53.79

59.7

±

14.4

57.5

±

7.6

68.3

59.5

±

16.1

#

66.679

58.49

VdpIF

(L)

164.1

166.3

254,7

±

288.5

±

261.6

291.6

±

304.2

354.6

74.5

53.6

113.7#

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

Vdp/F

Apparent

volume

of

distribution

a.

Primary

dose

groups

Cm

Maximum

blood

concentration

t

Harmonic

mean

+

pseudo-standard

deviation

Tm.

Time

to

Cmax

t

No

SD

was

reported

when

N•

2

AUC-i.r

AUC

from

time

0

to

infinity

(AUConi

0

).

#

N

=

6

t'A

Harmonic

mean

half-life

CUF

Mean

apparent

clearance

AUCii.

Area

under

the blood

concentration-time

curve

(AUC)

from

time

0

to

time

of

last

measurable

concentration

§

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

>

2

(180,

240

and

300

pg),

following

the

implantation

of

Endeavor

stents

as

illustrated

by

dose

proportional

increases

in

Cmax,

AUCO-lat

and

AUCO-inf.

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

SSED

P060033

-

Page

13

of

59

to

59.7

hours,

respectively.

The

mean

time

to

reach

peak

systemic

concentration

(Tm.)

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

(FKBP

12)

may

interfere

with

the

efficacy

of

zotarolimus.

Zotarolimus

is

metabolized

by

CYP3A4,

a

human

cytochrome

P450

enzyme.

When

administered

concomitantly

with

200

mg

ketoconazole

bid,

a

strong

inhibitor

of

CYP3A4,

zotarolimus

produces

less

than

a

2-fold

increase

in

AUCO-inf

with

no

effect

on

Cmax.

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

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.

SSED

P060033

-

Page

14

of

59

Table

8:

Summary

of

Biocompatibility

Testing

Test

Name

Test

Descpti--

i--

Re8

ISO

10993-5:

In

Vitro

·

EndeaVor

stent

Cytotoxicity

.

Cytotoxicity

and

delivery

Pass

(non-cytotoxic)

([929

MEM

Elution)

systems

*

Endeavor

stent

ISO-10993-11:

Systemic

*

Endeavor

stent

Pyrogenicity

Toxicity

(Material

Mediated

and

delivery

Pass

(non-pyrogenic)

Rabbit,

Injection)

systems

ISO-1

0993-10:

Sensitization

*

Endeavor

stent

Sensitization

and

delivery

Pass

(non-sensitizing)

(Guinea

pig

Maximization)

systems

*

Endeavor

stent

Acute

Intracutaneous

ISO-10993-10:

Irritation

*

Endeavor

stent

and

delivery

Pass

(non-irritant)

Reactivity

(Injection)

systems

*

Endeavor

stent

*

Endeavor

stent

Acute

Systemic

Toxicity

ISO-i

0993-11:

Systemic

and

delivery

Pass

(non-toxic)

Toxicity

(Acute)

systems

*

Endeavor

stent

ISO-10993-4:

In

Vivo

·

Endeavor

stent

Pass

(non-

Thromboresistance

and

delivery

thrombogenic)

systems

ISQ0-10993-4:

*

Endeavor

stent

Pass

(non-

C3a

Complement

Activation

and

delivery

complement

(In

Vitro)

systems

activating)

ISO-10993-4:

*

Endeavor

stent

Pass

(non-

SC5b9

Complement

and

delivery

complement

Activation

(In

Vitro)

systems

activating)

Hemocompatability

ISO-10993-4:

·

Endeavor

stent

Pass

(no

significant

Plasma

Recalcification

and

delivery

change

in

coagulation

systems

time)

*

Endeavor

stent

ISO-10993-4:

and

delivery

In

Vitro

Hemolysis

Study

systems

Pass

(non-hemolytic)

*

Endeavor

stent

ISO-10993-4:

*

Endeavor

stent

Pass

(no

change

in

White

Blood

Cell

Morphology

and

delivery

WBC

morphologically)

systems

SSED

P060033

-

Page

15

of

59

J3

Table

8:

Summary

of

Biocompatibility

Testing

Test

Name

T

cription

Test

Article

Result

ISO-10993-3:

Bacterial

Reverse

Mutation

*

Endeavor

stent

Pass

(non-mutagenic)

(AMES)

ISO-10993-3:

Genotoxicity

In

Vitro

Chromosomal

Pass

(non-

Aberration

in

Mammalian

*

Endeavor

stent

clastogenic)

Cells

ISO-10993-3:

In

Vivo

Mouse

Bone

Marrow

*

Endeavor

stent

Pass

(non-mutagenic)

Micronucleus

Test

Material

Characterization

USP

Physicochemical

*

Balloon

Material

CUSP

Physicochemical

Extracts

<66>

*

Polyethylene

Sheath

Pass

Testing)

(Aqueous)

·

PC

Polymer-only

Coated

Coupons

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

MX

2

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

SSED

P060033

-

Page

16

of

59

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

on

of

Test

Conclus!o

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

Pass

ASTM

F562.

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

SSED

P060033

-

Page

17

of

59

Table

9:

Stent

and

De

ive

Catheter

Engineerin

Testing

Galvanic

Corrosion

Stent

Dimensional

Verification

Percent

Surface

Area

Foreshortening

Stent

Recoil

Stent

Integrity

Radial

Stiffness

and

Radial

Strength

Stent

Expansion/

Coating

Evaluation

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.

Stent

Dimensional

and

Functional

Attributes

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.

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.

The

length

of

the

stents

were

measured

prior

to

and

after

expansion

to

the

largest

nominal

diameter.

All

stents

met

product

specifications.

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.

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.

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.

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.

Pass

N/A

Characterization

only

Pass

N/A

Characterization

only

See

*

note

at

end

of

table.

SSED

P060033

-

Page

18

of

59

Table

9:

Stent

and

Del

ve

Catheter

Engineerin

Testing

__l

:tlonof

Test

Culuslon

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.

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.

Accelerated

Durability

This

testing

was

conducted

to

determine

the

fatigue

integrity

Testing

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.

Magnetic

Resonance

Non-clinical

testing

on

single

and

overlapped

stents

has

Imaging

(MRI)

Safety

demonstrated

the

Endeavor

stent

is

MR

Conditional.

It

can

be

and

Compatibility

scanned

safely

under

the

following

conditions:

Single

Stenting

Overlapped

(Stent

Length

30

mm)

Stenting

(Total

Length

55

mm)

Static

magnetic

field

of

3-

Static

magnetic

field

of

3-

Tesla

Spatial

gradient

field

of

525

Spatial

gradient

field

of

720

Gauss/cm

Maximum

whole-body-

Maximum

whole-body-

averaged

specific

absorption

averaged

specific

absorption

rate

(SAR)

of

2

W/kg

for

20

rate

(SAR)

of

3

W/kg

for

15

minutes

of

scanning

minutes

of

scanning

In

non-clinical

testing,

the

In

non-clinical

testing,

the

Endeavor

stent

produced

a

Endeavor

stent

produced

a

temperature

rise

of

less

than

temperature

rise

of

less

than

0.50C

at

a

maximum

whole

0.50C

at

a

maximum

whole

body

averaged

specific

body

averaged

specific

absorption

rate

(SAR)

of

2

absorption

rate

(SAR)

of

3

W/kg

for

20

minutes

of

MR

W/kg

for

15

minutes

of

MR

scanning

in

a

3-Tesla,

Signa,

scanning

in

a

3-Tesla,

Excite,

General

Electric

Medical

General

Electric

Healthcare

Systems

(software

version

(software

version

G3.0-052B)

9.0)

MR

scanner.

The

MR

scanner.

The

maximum

whole

body

whole

body

averaged

SAR

averaged

SAR

was

displayed

was

displayed

on

MR

on

MR

scanner

console.

scanner

console.

Pass

See

*

note

at

end

of

table.

N/A

SSED

P060033

-

Page

19

of

59

Table

9:

Stent

and

Delivery

Catheter

Engineering

Testing

Test

ption

Testo~~nclusI

t~~

C>

The

Endeavor

stent

should

not

move

or

migrate

when

exposed

to

MR

scanning

immediately

post-implantation.

The

image

artifact

extends

The

image

artifact

extends

approximately

9

mm

from

the

approximately

10

mm

from

device/lumen

centerline

the

device/lumen

centerline

when

scanned

in

nonclinical

when

scanned

in

nonclinical

testing

using

a

3-Tesla,

testing

using

a

3-Tesla,

Signa,

General

Electric

Excite,

General

Electric

Medical

Systems

(software

Healthcare

(software

version

9.0)

MR

system

with

G3.0-052B)

MR

system

with

a

send-receive

RF

body

coil.

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.

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.

Delivery

System

Dimensional

and

Functional

Attributes

Delivery,

Deployment,

In

vitro

testing

was

conducted

to

evaluate

delivery,

and

Retraction

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.

Balloon

Maximum

This

test

was

conducted

to

demonstrate

that

the

Endeavor

Pressure

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.

Balloon

Fatigue

Endeavor

stent

systems

were

required

to

complete

10

unconstrained

pressurization

cycles

to

rated

burst

pressure

(RSP).

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.

Stent

Diameter

vs.

Testing

was

performed

to

determine

how

the

stent

inner

Balloon

Pressure

diameter

varies

with

applied

inflation

pressures.

The

stent

(Compliance)

sizing

results

verify

that

the

stent

systems

meet

the labeled

compliance

curves.

Pass

N/A

Characterization

only

Pass

NA

Characterization

for

product

labeling

SSED

P060033

-

Page

20

of

59

Table

9:

Stent

and

Delivery

Catheter

Engineering

Testing

lon

frTest

ion

Catheter

Bond

Strength

Testing

was

performed

to

confirm

the

bond

strength

Pass

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.

Stent/Catheter

Crossing

Endeavor

stents

and

delivery

systems

were

tested

to

verify

Pass

Profile

the

crossing

profile

per

label

claims.

All

samples

met

product

specifications.

Balloon

Inflation

and

Endeavor

delivery

systems

were

tested

for

inflation/deflation

Pass

Deflation

Time

times.

All

samples

met

the

product

specification.

Stent

Securement

*

Testing

was

conducted

to

assess

the

force

required

to

Pass

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.

Balloon

Deflatability

This

test

was

performed

to

provide

assurance

that

the

Pass

deflated

delivery

system

balloons

will

release

from

the

expanded

stent

without

interference.

All

samples

met

specification.

Catheter

Body

Testing

was

conducted

on

the

Endeavor

stent

delivery

Pass

Maximum

Pressure

systems

to

determine

the

ability

of

the

catheter

shaft

to

withstand

inflation

to

balloon

rated

burst

pressure.

All

samples

met

the

product

specification.

·

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.

SSED

P060033

-

Page

21

of

59

Table

10:

Coatin

Characterization

Testing

.~-

~

escrt~~~~r

Pton

of

Test

Materials

Analysis

-

Polymer

components

were

tested

to

ensure

conformity

to

raw

materials

Polymer

specifications

and

incoming

inspection

procedures.

Chemical

Analysis

-

Assays

were

conducted

to

determine

residual

monomer

content,

residual

Polymer

solvent

levels

and

water

content.

Chemical

Analysis

-

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

Testing

was

conducted

to

characterize

the

uniformity

of

distribution

of

Length

drug

along

the

length

of

the

Endeavor

stent

system.

Total

Drug

were

conducted

to

quantitatively

determine

the

type

and

amount

Substances

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.

SSED

P060033

-

Page

22

of

59

30

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

:_

_

_ _

_

_ _

_

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

verity

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.,

drig

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

All

study

phases

(feasibility,

safety,

pharmacokinetic

and

SSED

P060033

-

Page

23

of

59

________

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

Stent

Design

Stento

)o!in

FS102

Test

Article:

Diameter:

Domestic

Swine

Test:

32

7

days

*Angiographic

patency

zotarolimus-eluting

*

3.0,

3.5,

4.0

Test

and

Control:

20

*Histologic

and

Endeavor

stent

mm

1

histomorphometric

system,

multiple

doses

Lengths:

evaluation

of

single

Control:

BMIS

*12,

18mm

(LAD,

LCX,

RCA)

and

overlapping

GLP:

Yes

One

stent/vessel

stents

GLP:

Yes

Cell

proliferation

!.~~~~~~~~~~~~~~~~~~~~

Animals

received

·

Acute

delivery

both

test

and

control

FS1

35

Test

Article:

Diameter:

Juvenile

Test:

24

28

days

*

Anglographic

patency

zotarolimus-eluting

·

2.25,

2.5

mm

Yorkshire

Swine

*

Histologic

and

Control:

20

hsoohmti

Endeavor

stent

Lengths:

Test

and

Control:ic

system,

multiple

doses

·

8

mm

21

Control

evaluation

of

Control:

BIMIS

and

(Polymer

exaggerated

dose

Polymer

only coated

(LAD,

LCX,

RCA)

Coated

and

Endeavor

stent

stents

One

stent

per

Stents):

12

systems

GLP:

Yes

vessel.

Animals

*Acute

Delivery

received

both

test

*Chronic

vascular

and

control.

response

at

28

days

FS99

Test

Article:

Diameter:

Domestic

Swine

Test:

99

28

days

*

Angiographic

patency

zotarolimus-eluting

·

2.5,

3.0,

3.5,

Test

and

Control:

64

*Histologic

and

Endeavor

stent

4.0

mm

histomorphometric

system,

multiple

doses

Lengths:

Control

evaluation

of

Control:

BMVIS

and

12,

18mm

(LAD,

LCX,

RCA)

(Polymer

exaggerated

dose,

Polymer

only

coated

One

stent

per

Coated

single

and

Stents):

13

overlapping

stents

vessel.

Animals

13

sents

*

Acute

Delivery

GLP:

Yes

received

both

test

and

control.

*

Chronic

vascular

response

at

28

days

FS100

Test

Article:

Diameter:

Yucatan

Test:

58

90

days

·

Angiographic

patency

zotarolimus-eluting

·

2.5,

3.0

3.5,

Miniswine

*

Histologic

and

Endeavor

stent

Endeavor

stent

~~~~~~~~Control:

4.0

mm

Test

&

Control:

31

43

histomorphometric

system,

multiple

doses

Lengths:

Control

evaluation

of

Control:

BMIS

and

*12

mm

(LAD,

LCX,

RCA)

(Polymer

exaggerated

dose,

Polymer

only

coated

One

stent

per

Coated

single

and

Stents):

overlapping

stents

vessel.

Animals

GLP:

Yes

received

both

test

9

Acute

Delivery

and

control.

*

Chronic

vascular

_________

_

______

________

_

______

________response

at

90

days

SSED

P060033

-

Page

24

of

59

3a

________

Table

12:

Summary

of

Major

Supportive

Animal

Studies

FS101

Test

Article:

Diameter:

Yucatan

Test:

55

180

days

*

Angiographic

patency

zotarolimus-eluting

*2.5,

3.0,

3.5,

Miniswine

Coto:4

Histologic

and

Endeavor

stent

4.0

mm

Test

&

Control:

30

Cnrl40histomorphometric

system,

multiple

doses

Legh:Cnrlevaluation

of

Control:

BMS

and

*12

mm

(LAD,

LCX,

RCA)

(Polymer

exaggerated

dose,

Polymer

only

coated

One

stent

per

~~Coated

single

and

stlyents

l

oae

vnessel.

Anial

Stents):

1 1

overlapping

stents

vessel.

Animals

~~~~~~~~~~~*

Acute

delivery

GLP:

Yes

received

both

test

and

control.

*

Chronic

vascular

__________________

at

180

days

~~~~~~~~~~~response

FS114

Test

Article:

Diameter:

Domestic

Swine

48

1,

2,

3,

5,7,

Evaluation

of

drug

zotarolimus-eluting

*

3.0

mm

(ALXRC)10,

14

and

release

rate,

arterial

Endeavor

stent

system

Lengths:

(ALXRC)28

days

drug

levels

&

systemic

GLP:

Yes

*12

mm

One

stent

per

drug

levels

over

time.

vessel.

FS161

Test

Article:

Diameter:

Juvenile

Test:

ACT

level:

0,

*

Microscopic

zotarolimus-eluting

*

3.0

mm

Yorkshire

Swine

3,

6,9

and

evaluation

of

the

Endeavor

stent

system

Legh:Endeavor

II

days

overall

subacute

Lengths:

~Test

and

Control:

RX:

6

Control:

BMS

*15

mm

22

divided

into

3

Angiography:

tissue

reaction

of

the

tes

1an

ontolEndeavor

1 1

days

vessel

and

the

GLP:

Yes

temst

an

otol

TW:

5

surrounding

(Arms

LXRC

Enevrmyocardium;

Endeavor

One

tentper

MX2:

6

thrombogenicity

of

Onesstent

pr

Control:

the

stent

and

delivery

vessel

~~~~~~~~~~device

(LAD,

LCX,

RCA)

examination

of

the

at

1

1-days

0riv:

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

I

~~~~~~~~~~~~~~~~~~~~~~explant

BMS

=

bare

metal

stent

-

Drnver

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,

FSlOO0,

FSlI

l,

FSlO

2,

FSllOI

,

FS124

and

FS

135).

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.

SSED

P060033

-

Page

25

of

59

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

pg/mm

or

10

jtg/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

(FS1

14).

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,

FS

I00,

FS

01,

FS

102,

FS

135)

and

rabbit

iliac

arteries

(Study

FS

107).

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

MX

2

delivery

systems)

is

sterilized

using

ethylene

oxide

sterilization,

and

has

been

validated

per

SSED

P060033

-

Page

26

of

59

AAMIIISO

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

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

SSED

P060033

-

Page

27

of

59

¢:5

_________

________

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-segmnent

late

loss

at

8

months,

measured

by

QCA.

Post-

procedure,

patients

received

aspirin

indefinitely

and

clopidogrel

for

a

minimum

of

6

months.

Table

13:

Clinicai

Trial

Comparisons

ENDEAVOR

I

EDA61EN

AVO

ENDEAVOR1V1

Il

.

Multi-center

(n=8)

Mult-center

(n=7

Multi-center

(n=29)

Multi-center

(n=80)

Study

Type

Prospective

Non-randomized

Randomized

Number

of

10

~

'

Tota:

117(ndeavor:

Total:

436

(Endeavor:

Total:

1548

(Endeavor:

Patients

Total:

1

(ndeavor)

598,

Driver:

599)

323,

Cypher:1

13)

773,

Taxus:

775)

Single

de

novo

lesion

Single

de

novo

lesion

Single

de

novo

lesion

Single

de

novo

lesion

Lesion

in

native

coronary

in

native

coronary

in

native

coronary

in

native

coronary

Critria

artery

<515

mm

in

artery

>

14

mm

and

<

Criteria

length

and

>

3.0

mm

to

27

mm

in

length

and

>

artery>14

mm

and

<

artey<2mmi

27

mm

in

length

and>

an

mm

2

.

2.Smm

to

<

3a5mm

i

leryt

27

5

in

35

~~~~

2

5

mm

to

<3.Smm

in

lngt

n~

m

t

35mm

in

diameter

3.5

mm

in

diameter

Product

Endeavor

Stent

on

the

Endeavor

Stent

on

the

Endeavor

Stent

on

the

Endeavor

Stent

on

the

Used

Rapid

Exchange

Stent

Rapid

Exchange

Stent

Over-The

-Wire

Stent

Over-The

-Wire

Stent

Delivery

System

Delivery

System

Delivery

System

Delivery

System

Aspirin

indTefi~nitely

and

~Aspirin

indefinitely

and-

Aspirin

indefinitely

and

Aspirin

indefinitely

and

Antiplatelet

clopidogrel

or

clopidogrel

or

clopidogrel

or

clopidogrel

or

Therapy

ticlopidine

for

~:

3

ticlopidine

for

Ž:

3

ticlopidine

for

>

3

ticlopidine

for

~:

6

months,

months

30

days:

clinical

30

days:

clinical

30

days:

clinical

30

days:

clinical

4

&

12

months:

clinical

8

months:

clinical

and

8

months:

clinical

and

8

months:

clinical

and

Follow

up

and

angiographic/IVUS

9

month:

clinical

9

month:

clinical

9

month:

clinical

9

month:

clinical

1-5

years:

telephone

6

month,

1-5

years:

6

month,

I-5

years:

6

month,

1-5

years:

telepon

telehn

telepon

48

month

follow-up

36

month

follow-up

is

24

month

follow-up

is

9

month

follow-up

is

Status

complete.

Yearly

follow

complete.

Yearly

follow

complete.

Yearly

follow

complete.

Yearly

follow

up

to

5

years

is

up

to

5

years

is

up

to

5

years

is

up

to

5

years

is

__________ongoing.

ongoing

.

oina

on

I

onaninn

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

pharmnacokinetic

profile

of

the

Endeavor

stent

(see

Section

VIII.

A

-

S

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)).

SSED

P060033

-

Page

28

of

59

The

Endeavor

MX

2

delivery

system

was

not

used

in

the

Endeavor

clinical

investigations

(ENDEAVOR

I

to

IV).

The

Endeavor

MX

2

utilizes

a

modified

shaft

to

facilitate

the

multi-exchange

feature

of

the

delivery

system.

The

distal

section

of

the

Endeavor

MX

2

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

MX

2

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.

SSED

P060033

-

Page

29

of

59

3-)

Table

14:

ENDEAVOR

IV,

III,

Ii

and

I

-

Principal

Adverse

Events

from

Post-procedure

to

Latest

Foi~ow-

p

~JbrAVORIV

yr

Taxcus

Ed>CpDriver,

.J4V

N=775

N

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%/

(1

7/596)

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

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)

DeathI

ml

0.8%

(6/773)

2.1%

(16/775)

0.6%

(21323)

3.5%

(4/113)

2.5%

(15/597)

2.7%

(16/596)

0.0%

(0/100)

0

wave

Ml

0.3%

(2/773)

0.1%

(1/775)

0.0%

(01323)

0.0%

(0/113)

0.2%

(1/597)

0.3%

(2/596)

0.0%

(0/100)

Non-Q

wave

Ml

0.5%

(4/773)

(15/775)

~(2/323)

3.5%

(4/113)

2.3%

(14/597)

2.3%

(14/596)

0.0%

(0/100)

1.9%9/

0T.6%

TVR

--

_0.4%

-(3/773)

0.6%

(51775)

0.0%

(0/323)

0.0%1

~(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%1

-(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

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)

ml

TVF

0.9%

(7/773)

2.6%(2-0/775)

0.6%

.(2/323)

3.5%

(4/113)

2.9%o_

2.5%

(15/597)

(1-7/5

96)

0.0%

(0/100)

Stent

thrombosis

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)

(protocol)

Data

at

9

Months

MACE

5.%(274)

57(4/3)

75%0(24/321)

7.1%

(8/113)

7.3%

(43/692)

14.4%

(85/591)

2.0%

(2/100)

Total

Death

(70.7%(5/740)

680/.8%(6/734)

0.6%/

~(2/321)

0.0%/

~(0/113)

-1.2%9

(7/5-92)

0.~5%/

~(3/591)

0.0%

(0/100)

Cardiac

Death

0.4%/(3/740)

0.3%2/734

0.%0/21

0.0%/

~(0/1113)

0.-8%/

(5/592)

50.5%(3/591)

0.0%

(0/100)

Non-Cardiac

0.3%

.(2/740)

05%

(4/734)

06%/

(2/321)

00(0/1

13)

03%~/(2/592)

.%(/9)

0.0%

(0/100)

Death

ml

1.5%

(11/740)

2.5%

(18/734)

_0.6%/6(2/321)

3.5%

(41113)

2.7%(16/592)

3.9%

(23/591)

1.0%

(1/100)

QOwaveMl

30.3%(2/740)

0.1%

(1/734)

0.0%(0/321)

0_O-.0(0/113)

06._3-%(2/592)

0_.~8%/(5/591)

0.0%

(0/100)

Non-0

wave

Ml

1.2%/

(9/740)

_2.3%/

(17/734)

0.6_6%

3.5%~(4/1

13)

/

(14/592)

3.0%

(18/591)

1.0%

(1/100)

(2/3-21)

24%

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%1

(20/32

1)

3.T5%/

(4/1-13)

4._~/6%(27/592)

171.8%

~(70/691-)

.0%(2/100)

2--

Norn-TLR

2.0%

(15/740)

2.9%

(21/734)

5.90%

(19/321)

5.3%

(6/1

13)

1.59%(9/592)

2.2%

(13/591)

0.0%

(0/100)

Cardiac

death

or

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)

ml

TVF

6.8%

(0/740)

7.4

(54/734)

11.8%

TVE

6.8%(50/740)

7.4%(54/734)

~~~~~(38/321)

7.9%

(47/592)

15.1%

(89/591)

2.0%

(2/100)

11.5%

(13/113)

Stent

thrombosis

0.8%

(6/740)

0.1%

(1/734)

0.0%

(0/321)

0.0%

(0/113)

0.5%

(3/592)

1.2%

(7/591)

1.0%

(1/100)

(protocol)

1-year

MACE

NA

7.8%

(25/320)

8.0%

(9/112)

88

(52/590)

15.6%

(92/589)

2.0%

(2/99)

2-erMACE

NAN

.%(933

1.%(312

.%(58/587)

18.1%

(10-6/586)

3.0%

(3/99)

_Y'

M

NA

~~~~~~~~~~~~~~~~12.0%

~3-year

M

A

rCE

N

AN

A(

9 5

7

0 7

1

0 5

9

. %

(

/ 8

SSED

P060033

-

Page

30

of

59

Table

14:

ENDEAVOR

IV,

Ill,

II

and

I

-

Princi

al

Adverse

Events

from

Post-procedure

to

Latest

Follow-up

VoRIR

m

...

.

ENDEAVOR.

4-year

MACE

NANA

NA

7.2%

(7/97)

Latest

Data

Available

9

Months

24

Months

36

Months

48

Months

MACE

5.7%

(42/740)

5.7% (42/734)

9.3%

(29/313)

11.6%

(13/112)

12.0%

(69/%577)

20.7%

(120/579)

7.2%

(7197)

Total

Death

0.7%

(5/740)

0.8%

(6/734)

1.6%

(5/313)

4.5%

(5/112)

3.3%

(19/577)

4.5%

(26/579)

4.1%

(4/97)

Cardiac

Death

0.4%

(3/740)

0.3%

(2/734)

0.0%

(0/313)

0.9%

(1/112)

1.6%

(9/577)

2.4%

(14/579)

0.0%

(0/97)

Non-Cardiac

Death

0.3%

(2/740)

0.5%

(4/734)

1.6%

(5/313)

3.6%

(4/112)

1.7%

(10/577)

2.1%

(12/579)

4.1%

(4/97)

MI

1.5%

(11/740)

2.5%

(18/734)

0.6%

(2/313)

3.6%

(4/112)

3.3%

(19/577)

4.3%

(25/579)

1.0%

(1/97)

Q

wave

MI

0.3%

(2/740)

0.1%

(1/734)

0.0%

(0/313)

0.0%

(0/112)

0.3%

(2/577)

1.0%

(6/579)

0.0%

(0/97)

Non-Q

wave

MI

1.2%

(9/740)

2.3%

(17/734)

0.6%

(2/313)

3.6%

(4/112)

2.9%

(17/577)

3.3%

(19/579)

1.0%

(1/97)

TVR

TV R

5.5%

(41/740)

5.5%

(41/740)

5.0%

(37/734)

~~~~13.7%

13)

9.8%

(11/112)

(43/313)

9.5%

(55/577)

17.6%

(102/579)

5.2%

(5/97)

TLR

4.2%

(31/740)

2.7%

(20/734)

7.0%

(22/313)

4.5%

(5/112)

7.3%

(42/577)

14.7%

(85/579)

3.1%

(3/97)

Non-TLR

2.0%

(15/740)

2.9%

(21/734)

8.3%

(26/313)

6.3%

(7/112)

2.9%

(17/577)

4.8%

(28/579)

2.1%

(2/97)

Cardiac

death

or

ml

1.9%

(14/740)

2.7%

(20/734)

0.6%

(2/313)

3.6%

(4/112)

4.5%

(26/577)

6.7%

(39/579)

0.0%

(0/0)

TVF

6.8%

(50/740)

7.4%

(54/734)

14.4%

(45/313)

13.4% (15/112)

(45/313)

12.8%

(7/7)

~~~~~(74/577)

21.4% (124/579)

5.2%

(6/97)

Stent

thrombosis

0.8%

(6/740)

0.1%

(1/734)

0.0%

(0/313)

0.0%

(0/112)

0.5%

(3/577)

1.2%

(7/579)

1.0%

(1/97)

NA=

Not

Applicable;

variable

and/or

time

point

not

calculated

N

=

The

maximum

number

of eligible

patients.

The

numbers

are

%

(Count/Sample

Size).

Major

adverse

cardiac

events

(MACE)

is

defined

as

composite

of

death,

MI

(Q

wave

and

non-Q

wave),

emergent

bypass

surgery,

or

target

lesion

revascularization

(repeat

PTCA

or

CABG).

Q

wave

MI

(QMI)

defined

when

any

occurrence

of

chest

pain

or

other

acute

symptoms

consistent

with

myocardial

ischemia

and

new

pathological

Q

waves

in

two

or

more

contiguous

ECG

leads

as

determined

by

an

ECG

core

laboratory

or

independent

review

of

the

CEC,

in

the

absence

of

timely

cardiac

enzyme

data,

or

new

pathologic

Q

waves

in

two

or

more

contiguous

ECG

leads

as

determined

by

an

ECG

core

laboratory

or

independent

review

of

the

CEC

and

elevation

of

cardiac

enzymes.

In

the

absence

of

ECG

data

the

CEC

may

adjudicate

Q

wave

MI

based

on

the

clinical

scenario

and

appropriate

cardiac

enzyme

data.

Non-Q

Wave

MI

(NOMI)

is

defined

as

elevated

CK

Ž

2X

the

upper

laboratory

normal

with

the

presence

of

elevated

CK-

MB

(any

amount

above

the

institution's

upper

limit

of

normal)

in

the

absence

of

new

pathological

Q

waves.

Stent

Thrombosis:

See

section

XI.F1

for

the

per

protocol

stent

thrombosis

definition.

Target

vessel

failure

(TVF)

is

defined

as

a

composite

of

cardiac

death,

myocardial

infarction,

or

clinically-driven

target

vessel

revascularization.

Target

lesion

revascularization

(TLR)

is

defined

as

any

clinically-driven

repeat

intervention

of

the

target

lesion

by

PCI

or

CABG

of

the

target

vessel.

Target

vessel

revascularization

(TVR)

is

defined

as

any

clinically

driven

repeat

intervention

of

the

target

vessel

by

PCI

or

CABG.

SSED

P060033

-

Page

31

of59

B.

Potential

Adverse

Events

Adverse

events

associated

with

using

this

product

are

those

associated

with

percutaneous

coronary

diagnostic

(including

angiography

and

IVUS)

and

treatment

procedures.

These

risks

may

include,

but

are

not

limited

to,

the

following:

*

Abrupt

vessel

closure

*

Access

site

pain,

hematoma

or

hemorrhage

*

Allergic

reaction

(to

contrast,

antiplatelet

therapy,

stent

material,

or

drug

and

polymer

coating)

*

Aneurysm,

pseudoaneurysm,

or

arteriovenous

fistula

(AVF)

*

Arrhythmias

•

Balloon

rupture

*

Cardiac

tamponade

*

Coronary

artery

occlusion,

perforation,

rupture,

or

dissection

*

Coronary

artery

spasm

*

Death

*

Embolism

(air,

tissue,

device,

or

thrombus)

*

Emergency

surgery:

peripheral

vascular

or

coronary

bypass

*

Failure

to

deliver

the

stent

•

Hemorrhage

requiring

transfusion

·

Hypotension/hypertension

*

Incomplete

stent

apposition

*

Infection

or

fever

*

Late

or

very

late

thrombosis

*

Myocardial

infarction

(MI)

*

Myocardial

ischemia

*

Peripheral

ischemia/peripheral

nerve

injury

*

Renal

failure

*

Restenosis

of

the

stented

artery

*

Rupture

of

native

or

bypass

graft

*

Shock/pulmonary

edema

*

Stent

deformation,

collapse,

or

fracture

*

Stent

migration

*

Stent

misplacement

*

Stroke/transient

ischemic

attack

*

Thrombosis

(acute

and

subacute)

*

Unstable

angina

*

Ventricular

fibrillation

Patients'

exposure

to

zotarolimus

is

directly

the

total

amount

of

stent

length

implanted.

The

adverse

events

that

have

been

associated

with

the

intravenous

injection

of

zotarolimus

in

humans

include:

SSED

P060033

-

Page

34

of

59

'tO

*Anemia

*Application

site

reaction

*Diarrhea

*Dry

skin

*Headache

*Hematuria

*Infection

*Injection

site

reaction

*Pain

(abdominal,

arthralgia,

injection

site)

*Rash

In

addition,

thirty-day

adverse

event

information

was

provided

on

over

2000

patients

treated

with

the

Endeavor

Zotarolimus-Eluting

Coronary

Stent

System

to

support

the

safety

profile

of

zotarolimus.

There

may

be

other

potential

adverse

events

that

are

unforeseen

at

this

time.

XI.

Summary

of

Clinical

Studies

A.

Results

of

the

ENDEAVOR

IV

Trial

Primary

Objective:

To

demonstrate

the

non-inferiority

in

safety

and

efficacy

of

the

Endeavor

Zotarolimus-Eluting

Coronary

Stent

System

when

compared

to

the

Taxus

Express

2

Paclitaxel-Eluting

Coronary

Stent

System

for

the

treatment

of

single

de

novo

lesions

in

native

coronary

arteries

with

a

reference

vessel

diameter

of

2.5

mm

to

3.5

mm

and

lesion

length

of<~

27

mm.

Desi

n:

This

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

Taxus

stent).

A

total

of

1548

patients

were

enrolled

at 80

study

sites

in

the

United

States

who

presented

with

symptomatic

ischemic

heart

disease

attributable

to

stenotic

lesions

of

the

native

coronary

arteries

that

were

amenable

to

treatment

by

stenting.

Patients

were

stratified

by

diabetic

status

and

subsequently

randomized

to

receive

either

the

Endeavor

or

Taxus

stent

in

a

1:1I

ratio.

Multiple

stents

were

allowed

for

bailout

only.

Follow-up

was

performed

at

30

days,

6,

8,

and

9

months,

and

will

be

performed

at

12

months,

and

annually

thereafter

out

to

5

years.

The

first

328

consecutively

enrolled

patients

(across

all

sites)

were

scheduled

to

have

angiographic

and

IVUS

evaluations

at

8

months.

Following

the

index

procedure,

patients

were

treated

with

aspirin

indefinitely

and

clopidogrel

or

ticlopidine

for

a

minimum

of

6

months.

Demographics:

The

mean

age

was

63.5

years

for

patients

in

the

Endeavor

arm

and

63.6

years

for

patients

in

the

Taxus

arm.

The

Endeavor

arm

had

66.9%

(5

17/773)

males,

and

the

Taxus

arm

had

68.5%

(53

1/775)

males.

In

the

Endeavor

arm,

28.2%

(2

18/773)

of

patients

had

prior

percutaneous

coronary

revascularization,

compared

to

29.5%

(229/775)

of

patients

in

the

Taxus

arm.

In

the

Endeavor

arm,

3

1.2%

(241/773)

of

patients

had

a

history

of

diabetes

mellitus,

compared

to

30.5%

(236/775)

of

patients

in

the

Taxus

arm.

Patients

were

well-matched

for

baseline

demographics

with

no

statistically

significant

differences

between

treatment

arms.

SSED

P060033

-

Page

33

of

59

Results:

The

primary

and

secondary

endpoints,

protocol-defined

stent

thrombosis,

and

the

latest

available

follow-up

results

are

presented

below

(Table

15,

Table

16,

Table

17

and

Figure

3).

The

primary

endpoint

of

TVF

at

9

months

was

met

with

6.8%

(50/740)

for

the

Endeavor

arm

and

7.4%

(54/734)

for

the

Taxus

arm

(p <

0.001

for

non-inferiority).

The

pre-specified

secondary

endpoint

of

in-segment

late

loss

at

8

months

was

not

met

with

measurements

of

0.36

+

0.47

mm

(143)

for

the

Endeavor

arm

and

0.23

±

0.45

mm

(135)

for

the

Taxus

arm

(p

=

0.0890

for

non-inferiority)

Table

15:

ENDEAVOR

IV

Clinical

Results

PRIMARY

ENDPOINT

TVF

§

6.8%

(50/740)

7.4%

(54/734)

<

0.001*

§

9-month

primary

endpoint.

*

Test

for

non-inferiority.

EFFICACY

TVR

5.5%

(41/740)

5.0%

(37/734)

0.727**

TLR

4.2%

(31/740)

2.7%

(20/734)

0.154*t

TLR,

PCI

3.8%

(28/740)

1.9%

(14/734)

0.041**

TLR,

CABG

0.5%

(4/740)

0.8%

(6/734)

0.546**

Non-TLR

2.0%

(15/740)

2.9%

(21/734)

0.316**

Non-TLR,

PCI

1.8%

(13/740)

2.5%

(18/734)

0.370**

Non-TLR,

CABG

0.4%

(3/740)

0.4%

(3/734)

1.000**

SAFETY

Total

Death

0.7%

(5/740)

0.8%

(6/734)

0.773**

Cardiac

Death

0.4%

(3/740)

0.3%

(2/734)

1.000**

Non-Cardiac

Death

0.3%

(2/740)

0.5%

(4/734)

0.450**

Cardiac

Death

or

MI

1.9%

(14/740)

2.7%

(20/734)

0.303**

MI

1.5%

(11/740)

2.5%

(18/734)

0.194**

Q

wave

MI

0.3%

(2/740)

0.1%

(1/734)

1.000'*

Non-Q

wave

Mi

1.2%

(9/740)

2.3%

(17/734)

0.117**

Stent

Thrombosis

(protocol)

0.8%

(6/740)

0.1%

(1/734)

0.124**

**

P-values

for

outcome

differences

are

not

adjusted

for

multiple

comparisons.

Notes:

Fisher's

Exact

test

was

used

for

P-values.

This

trial

was

not

adequately

powered

to

compare

the

rate

of

low

frequency

events,

nor

was

it

sized

to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision.

Numbers

are

%

(Count/Sample

Size).

To

be

included

in

the

event

rate

calculation

for

a

given

interval,

a

patient

either

had

to

have

an

event

before

the

time

of

interest

or

they

had

to

be

event-free

before

the

lower

window

of

the

follow-up.

SSED

P060033

-

Page

34

of

59

0

1

00%'

E

'~

95%'

--

ENDEAVOR

--

TAXUS

90%

I

,

I

0

30

60

90

120

150

180

210

240

270

Time

after

Initial

Procedure

(days)

: 'TV

i

tree:

IENDEAVOR

93.3%96.7%6%

ITAXUS

1

92.8%

1

7.2%I

_

0.626

ILog-rank

P-value.

P-value

is

not

adjusted

for multiple

comparisons.

Figure

3:

Survival

Free

from

Target

Vessel

Failure

(at

270

days)

SSED

P060033

-

Page

35

of

59

'43

Table

16:

Endeavor

IV

8-Month

An

iographic

and

IVUS

Results

SECONDARY

ENDPOINT

Late

Loss,

In-segment

(mm)

¥

0.36

±

0.47

(143)

0.23

±

0.45

(135)

0.089*

¥

Powered

secondary

endpoint.

*

Test

for

non-inferiority.

OTHER

ANGIOGRAPHIC

RESULTS

MLD

(mm),

In-stent

Post-Procedure

2.62

±

0.43

(763)

2.61

±

0.44

(763)

0.703**

8-Month

1.95

±

0.61

(143)

2.25

±

0.61

(135)

<

0.001**

MLD

(mm),

In-segment

Post-Procedure

2.22

±

0.47

(770)

2.19

±

0.50

(772)

0.196*

8-Month

1.80

±

0.55

(144)

1.98

±

0.56 (135)

0.008**

%

DS,

In-stent

Post-Procedure

5.50

±

9.61

(763)

5.01

10.49(763)

0.348**

8-Month

26.41

±

19.74

(143)

16.09

±

17.99

(135)

<

0.001*

%

DS,

In-segment

Post-Procedure

20.47

9.54(770)

20.97

±11.12(772)

0.344**

8-Month

32.28

17.02

(144)

26.61

±

15.52

(135)

0.004**

Late

Loss, In-stent

(mm)

0.67

±

0.49

(142)

0.42

±

0.50

(135)

< 0.001*

Binary

Restenosis

In-stent

Restenosis

13.3% (19/143)

6.7%

(9/135)

0.075**

In-segment

Restenosis

15.3%

(22/144)

10.4%

(14/135)

0.284**

IVUS

RESULTS

Neointimal

Volume

(mm

3

)

24.14

±19.38

(74)

14.88

±16.62

(77)

0.002**

%

Volume

Obstruction

15.72

±10.40

(74)

9.88

±9.24

(77)

<

0.001'*

Incomplete

Apposition

Post-procedure

12.5%

(17/136)

11.8%

(15/127)

1.000'*

8-Month

10.0%

(12/120)

14.7%

(17/116)

0.324'

Resolved

3.8%

(4/106)

2.1%

(2/95)

0.686**

Persistent

8.5%

(9/106)

10.5%

(10/95)

0.638**

Late Acquired

0.9% (1/106)

3.2%

(3/95)

0.346**

**

P-values

for

outcome

differences

are

not

adjusted

for

multiple

comparisons.

Note:

Fisher's

Exact

test

or

Student's

t-test

was

used

for

P-values.

SSED P060033

-

Page

36

of

59

Table

17:

ENDEAVOR

IV

Protocol-Defined

Stent

Thrombosis*

Throu

h

9

Months

Cumulative

ST

through

9

Months

0.8%

(6/740)

0.1%

(1/734)

0.124**

Acute

ST

(<

24 hrs)

0.0%

(0/770)

0.0%

(0/771)

-

Subacute

ST

(>

24

hrs

and

•

30days)

0.4%

(3/770)

0.1%

(1/771)

0.374**

Late

ST

(>

30

days

and

•

9

months)

0.4%

(3/740)

0.0%

(0/734)

0.250**

*

See

section

XI.F1

for

the

per

protocol

stent

thrombosis

definition.

**

P-values

for

outcome

differences

are

not

adjusted

for

multiple

comparisons.

Notes:

Fisher's

Exact

test

was used

for

P-values.

This

trial

was

not

adequately

powered

to

compare

the

rate

of

low

frequency

events,

nor

was

it

sized

to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision,

To

be

included

in

the

event

rate

calculation

for

a

given

interval,

a

patient

either

had

to

have

an

event

before

the

time

of

interest

or

they

had

to

be event-free

before

the

lower

window

of

the

follow-up.

Numbers

are

%

(Count/Sample

Size).

B.

Results

of

the

ENDEAVOR

III

Clinical

Trial

Primary

Objective:

To

demonstrate

non-inferiority

in

in-segment

late

loss

at

8

months

between

the

Endeavor

Zotarolimus-Eluting

Coronary

Stent

System

and

the

Cypher

Sirolimus-Eluting

Coronary

Stent

System

for

the

treatment

of

single

de

novo

lesions

in

native

coronary

arteries

with

a

reference

vessel

diameter

of

2.5

mm

to

3.5

mm

and

lesion

lengths

ofŽ>

14

mm

and

<

27

mm.

Design:

This

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).

A

total

of

436

patients

were

enrolled

at

29

study

sites

in

the

United

States

who

presented

with

symptomatic

ischemic

heart

disease

attributable

to

stenotic

lesions

of

native

coronary

arteries

that

were

amenable

to

treatment

by

stenting.

Patients

were

randomized

to

receive

either

an

Endeavor

or

a

Cypher

stent

in

a

3:1

ratio.

Multiple

stents

were

allowed

for

bailout

only.

Follow-up

was

performed

at

30

days,

6, 8,

9,

12

months,

and

at

2

years,

and

will

be

performed

annually

thereafter

out

to

5

years.

All

patients

were

scheduled

to

have

angiographic

and

IVUS

evaluations

at

8

months.

Following

the

index

procedure,

patients

were

treated

with

aspirin

indefinitely

and

clopidogrel

or

ticlopidine

for

a

minimum

of

3

months.

Demographics:

The

mean

age

was

61.4

years

for

patients

in

the

Endeavor

arm

and

61.7

years

for

patients

in

the

Cypher

arm.

The

Endeavor

arm

bad

65.3%

(211/323)

males

and

the

Cypher

arm

had

81.4%

(92/113)

males.

In

the

Endeavor

arm,

22.6%

(73/323)

of

patients

had

prior

percutaneous

coronary

revascularization

compared

to

16.8%

(19/113)

of

patients

in

the

Cypher

arm.

In

the

Endeavor

arm,

29.7%

(96/323)

of

patients

had

a

history

of

diabetes

mellitus

compared

to

28.3%

(32/113)

of

patients

in

the

Cypher

arm.

Patients

were

well

matched

for

baseline

demographics,

with

gender

being

the

only

significant

difference

between

treatment

arms.

Results:

The

primary

and

secondary

endpoints,

protocol-defined

stent

thrombosis,

and

the

latest

available

follow-up

results

are

presented

below

(Table

18,

Table

19,

and

Table

20).

SSED

P060033

-

Page

37

of

59

The

primary

endpoint

of

in-segment

late

loss

at

8

months

was

not

met

with

measurements

of

0.36

±

0.46

mm

(277)

for

the

Endeavor

arm

and

0.13

±

0.33

mm

(94)

for

the

Cypher

arm

(p

<

0.791

for

non-inferiority).

Differences

noted

in

baseline

demographics

(gender)

did

not

result

in

a

significant

impact

on

study

outcomes.

Table

18:

Endeavor

Iii

8-Month

Angao

raphic

and

IVUS

Results

*

i~~~:,;:

:Ende

7

PRIMARY

ENDPOINT

Late

Loss,

In-segment

(mm)

§

0.36

±

0.46

(277)

0.13

±

0.33

(94)

0.791*

§

8-month

primary

endpoint.

*

Test

for

non-inferiority.

OTHER

ANGIOGRAPHIC

RESULTS

MLD

(mm),

In-stent

Post-Procedure

2.67

±

0.42

(323)

2.67

±

0.40

(112)

0.993**

8-Month

2.06

±

0.57

(277)

2.52

±

0.56

(94)

<

0.001**

MLD

(mm),

In-segment

Post-Procedure

2.27

±

0.45

(323)

2.28

±

0.47

(113)

0.836**

8-Month

1.91

±

0.53 (277)

2.16

±

0.50

(94)

<

0.001*

%

DS,

In-stent

Post-Procedure

4.33

±

9.77

(323)

5.92

±

9.07

(112)

0.132**

8-Month

24.90

17.45(277)

11.01

+15.91

(94)

<0.001*

%

DS,

In-segment

Post-Procedure

19.38

±

9.25

(323)

20.17

±

11.74

(113)

0.522**

8-Month

30.42

±

15.57

(277)

23.86_+

13.87

(94)

<

0.001'*

Late

Loss,

In-stent

(mm)

0.62

±

0.49

(277)

0.15

±

0.34

(94)

<

0.001*

Binary

Restenosis

In-stent

Restenosis

9.7%

(27/277)

2.1%

(2/94)

0.014**

In-segment

Restenosis

12.3%

(34/277)

4.3%

(4/94)

0.029**

IVUS

RESULTS

Neointimal

Volume

(mm

3

)

24.09

±

21.16

(209)

3.74

±

5.20

(67)

<

0.001**

%

Volume

Obstruction

15.94

±

10.94

(187)

2.66

±

3.11

(61)

<

0.001'

Incomplete

Apposition

Post-procedure

12.4%

(31/251)

17.7%

(17/96)

0.224**

8-Month

7.5%

(17/226)

17.1%

(13/76)

0.025**

Resolved

5.8%

(11/189)

7.4%

(5/68)

0.770**

Persistent

7.9%

(15/189)

11.8%

(8/68)

0.332**

Late

Acquired

0.5%

(1/189)

5.9%

(4/68)

0.018*

P-values

for

outcome

differences

are

not

adjusted

for

multiple

comparisons.

Note:

Fisher's

Exact

test

or

Student's

t-test

was

used

for

P-values.

SSED

P060033

-

Page

38

of

59

Table

19:

ENDEAVOR

III

Clinical

Results

EFFICACY

TVF

11.8%(38/321)

11.5%(13/113)

1.000*

14.4%(45/313)

13.4%(15/112)

0.875*

TVR

11.2%

(36/321)

8.0%

(9/113)

0.375**

13.7%

(43/313)

9.8%

(11/112)

0.325*

TLR

6.2%

(20/321)

3.5%

(4/113)

0.346**

7.0%

(22/313)

4.5%

(5/112)

0.498**

TLR,

PCI

5.3%

(17/321)

3.5%

(4/113)

0.612'*

5.8%

(18/313)

4.5%

(5/112)

0.808*t

TLR,

CABG

0.9%

(3/321)

0.0%

(0/113)

0.571**

1.3%

(4/313)

0.0%

(0/112)

0.577`*

Non-TLR

5.9%

(19/321)

5.3%

(6/113)

1.000'*

8.3%

(26/313)

6.3%

(7/112)

0.545**

Non-TLR,

PCI

5.6%

(18/321)

5.3%

(6/113)

1.000'*

7.7%

(24/313)

6.3%

(7/112)

0.832**

Non-TLR,

CABG

0.3%

(1/321)

0.0%

(0/113)

1.000'*

1.0%

(3/313)

0.0%

(0/112)

0.570**

SAFETY

Total

Death

0.6%

(2/321)

0.0%

(0/113)

1.000*

1.6%

(5/313)

4.5%

(5/112)

0.138**

Cardiac

Death

0.0%

(0/321)

0.0%

(0/113)

-

0.0%

(0/313)

0.9%

(1/112)

0.264**

Non-Cardiac

Death

0.6%

(2/321)

0.0%

(0/113)

1.000**

1.6%

(5/313)

3.6%

(4/112)

0.252*`

Cardiac

Death

or

MI

0.6%

(2/321)

3.5%

(4/113)

0.042**

0.6%

(2/313)

3.6%

(4/112)

0.044**

Ml

0.6%

(2/321)

3.5%

(4/113)

0.042**

0.6%

(2/313)

3.6%

(4/112)

0.044**

Q

wave

MI

0.0%

(0/321)

0.0%

(0/113)

--

0.0%

(0/313)

0.0%

(0/112)

--

Non-Q

wave

MI

0.6%

(2/321)

3.5%

(4/113)

0.042**

0.6%

(2/313)

3.6%

(4/112)

0.044**

Stent

Thrombosis

(protocol)

0.0%

(0/321)

0.0%

(0/113)

--

0.0%

(0/313)

0.0%

(0/112)

--

**

P-values

for

outcome

differences

are not

adjusted

for

multiple

comparisons.

Notes:

Fisher's

Exact

test

was

used

for

P-values.

This

trial

was

not

adequately

powered

to

compare

the

rate

of

low

frequency

events,

nor

was

it

sized

to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision.

Numbers

are

%

(Count/Sample

Size).

To

be

included

in

the

event

rate

calculation

for

a

given

interval,

a

patient

either

had

to

have

an

event

before

the

time

of

interest

or

they

had

to

be

event-free

before

the

lower

window

of

the

follow-up.

SSED

P060033

-

Page

39

of

59

'-C7

Table

20:

ENDEAVOR

III

Protocol-Defined

Stent

Thrombosis*

Through

24

Months

Epdeavor

Cyhr

Cumulative

ST

through

24

Months

0.0%

(0/313)

0.0% (0/112)

-

Acute

ST

(•

24

hrs)

0.0%

(0/323)

0.0%

(0/113)

--

Subacute

ST

(>

24

hrs

and

•

30

days)

0.0%

(0/323)

0.0%

(0/113)

-

Late

ST

(>

30

days

and

<

12

months)

0.0%

(0/320)

0.0%

(0/112)

-

Very

late

ST

(>

12

months

and

_<

24

months)

0.0%

(0/313)

0.0%

(0/112)

-

See

section

XI.F1

for

the

per

protocol

stent

thrombosis

definition.

Notes:

This

trial

was

not

adequately

powered

to

compare

the

rate

of

low

frequency

events,

nor

was

it

sized

to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision.

To

be

included

in

the

event

rate

calculation

for

a

given

interval,

a

patient

either

had

to

have

an

event

before

the

time

of

interest

or

they

had

to

be

event-free

before

the

lower

window

of

the

follow-up.

Numbers

are

%

(Count/Sample

Size).

C.

Results

of

the

ENDEAVOR

II

Clinical

Trial

Primary

Objective:

To

demonstrate

superiority

in

the

safety

and

efficacy

of

the

Endeavor

Zotarolimus-Eluting

Coronary

Stent

System

when

compared

to

the

Driver

Coronary

Stent

System

for

the

treatment

of

single

de

novo

lesions

in

native

coronary

arteries

with

a

reference

vessel

diameter

of

2.25

mm

to

3.5

mm

in

diameter

and

lesion

lengths

of

>

14

mm

and

<

27

mm.

Design:

This

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

(BMS),

the

Driver

stent.

A

total

of

1197

patients

were

enrolled

at

72

study

sites

in

Asia,

Australia,

Europe,

Israel

and

New

Zealand

who

presented

with

symptomatic

ischemic

heart

disease

attributable

to

stenotic

lesions

of

native

coronary

arteries

that

were

amenable

to

treatment

by

stenting.

Patients

were

randomized

to

receive

either

an

Endeavor

or

a

Driver

stent

in

a

1:1

ratio.

Multiple

stents

were

allowed

for

bailout

only.

Follow-up

was

performed

at

30

days,

6,

8,

9,

12

months,

at

2

and

3

years,

and

will

be

performed

annually

thereafter

out

to

5

years.

The

first

600

consecutively

enrolled

patients

(across

all

sites)

were

scheduled

to

receive

angiographic

evaluation

at

8

months,

and

300

patients

were

scheduled

to

receive

IVUS

evaluation

at

8

months

at

pre-specified

sites.

Following

the

index

procedure,

patients

were

treated

with

aspirin

indefinitely

and

clopidogrel

or

ticlopidine

for

a

minimum

of

3

months.

Demographics:

The

mean

age

was

61.6

years

for

patients

in

the

Endeavor

arm

and

61.9

years

for

patients

in

the

Driver

arm.

The

Endeavor

arm

had

77.2%

(461/597)

males,

and

the

Driver

arm

had

75.3%

(449/596)

males.

In

the

Endeavor

arm,

21.7%

(129/595)

of

patients

had

prior

percutaneous

coronary

revascularization,

compared

to

18.0%

(107/594)

of

patients

in

the

Driver

arm.

In

the

Endeavor

arm,

18.2%

(108/595)

of

patients

had

a

history

of

diabetes

mellitus,

compared

to

22.2%

(132/595)

of

patients

in

the

Driver

arm.

Patients

were

well

matched

for

baseline

demographics,

with

no

statistically

significant

differences

between

treatment

arms.

SSED

P060033

-

Page

40

of

59

Results:

The

primary

and

secondary

endpoints,

protocol-defined

stent

thrombosis,

and

the

latest

available

follow-up

results

are

presented

below

(Table

21,

Table

22,

Table

23

and

Figure

4).

The

primary

endpoint

of

TVF

at

9

months

was

met

with

7.9%

(47/592)

for

the

Endeavor

arm

and

15.1%

(89/591)

for

the

Driver

arm

(p

< 0.001

for

superiority).

The

pre-specified

secondary

endpoint

of

in-segment

late

loss

at

8

months

was

met,

with

measurements

of

0.36

mm

±

0.46

mm

(264)

for

the

Endeavor

arm

and

0.72

mm

±

0.61

mm

(263)

for

the

Driver

arm

(p

<

0.001

for

superiority).

Table

21:

ENDEAVOR

II

Clinical

Results

ths

Endeava

river

PRIMARY

ENDPOINT

TVF

§

7.9%

(47/592)

15.1%

(89/591)

<0.001*

12.8%

21.4%

(124/579)

<0

0'01

(74/577)

§

9-month

primary

endpoint.

Test

for

superiority.

EFFICACY

TVR

5.6%

(33/592)

12.5%(74/591)

<0.001'*

9.5%

(55/577)

17.6%

(102/579)

<

0.001

TLR

4.6%

(27/592)

11.8%(70/591)

<0.001'*

7.3%

(42/577)

14.7%

(85/579)

<

0.001'*

TLR,

PCI

4.2%

(25/592)

11.3%

(67/591)

<

0.001**

6.9%

(40/577)

13.8%

(80/579)

<

0.001*

TLR, CABG

0.3% (2/592)

0.5%

(3/591)

0,687**

0.5%

(3/577)

1.0%

(6/579)

0.506**

Non-TLR

1.5%

(9/592)

2.2%

(13/591)

0.400**

2.9%

(17/577)

4.8%

(28/579)

0.128**

Non-TLR,

PCI

1.4%

(8/592)

2.2%

(13/591)

0.282**

2.8%

(16/577)

4.7%

(27/579)

0.119**

Non-TLR,

CABG

0.2%

(1/592)

0.0%

(0/591)

1.000**

0.2%

(1/577)

0.3% (2/579)

1.000'*

SAFETY

Total

Death

1.2%

(7/592)

0.5%

(3/591)

0.342**

3.3%

(19/577)

4.5%

(26/579)

0.362**

Cardiac

Death

0.8%

(5/592)

0.5%

(3/591)

0.726**

1.6%

(9/577)

2.4%

(14/579)

0.400**

Non-Cardiac

Death

0.3%

(2/592)

0.0%

(0/591)

0.500**

1.7%

(10/577)

2.1%

(12/579)

0.830**

Cardiac

Death

or

MI

3.4%

(20/592)

4.4%

(26/591)

0.372**

4.5%

(26/577)

6.7%

(39/579)

0.125-*

Ml

2.7%

(16/592)

3.9%

(23/591)

0.260**

3.3%

(19/577)

4.3%

(25/579)

0.443**

Q

wave

Ml

0.3%

(2/592)

0.8%

(5/591)

0.287**

0.3%

(2/577)

1.0%

(6/579)

0.287**

Non-Q

wave

MI

2.4%

(14/592)

3.0%

(18/591)

0.481**

2.9%

(17/577)

3.3%

(19/579)

0.866**

Stent

Thrombosis

0.5% (3/592)

1.2%

(7/591)

0.224**

0.5%

(3/577)

1.2%

(7/579)

0.342**

(protocol)

*'

P-values

for

outcome

differences

are

not

adjusted

for

multiple

comparisons.

Notes:

Fisher's

Exact

test

was

used

for

P-values.

This

trial

was

not

adequately

powered

to

compare

the

rate

of

low

frequency

events,

nor

was

it

sized

to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision.

Numbers

are

%

(Count/Sample

Size).

To

be

included

in

the

event

rate

calculation

for

a

given

interval,

a

patient

either

had

to

have

an

event

before

the

time

of

interest

or

they

had

to

be

event-free

before

the

lower

window

of

the

follow-up.

SSED

P060033

-

Page

41

of

59

1

00%-

I--

90%-

E

-'

85%-

80%-

75%.

,

0

90

180

II

270

-Endeavor

--

Driver

;

-

I I I

360

450

540

630

720

Time

after

Initial

Procedure

(days)

I

,_i

I

810

900

990

1080

Endeavo

87.4%

12.6%1

<0.001

Drv

78.9%

21.1%

*

Log-rank

P-value. P-value

is

not

adjusted

for

multiple

comparisons.

Figure

4:

Survival Free

from

Target

Vessel

Failure

(at

1080

days)

SSED

P060033

-

Page

42

of

59

5'0

Table

22:

Endeavor

II

8-Month

Angio

ra

hic

and

IVUS

Results

SECONDARY

ENDPOINT

Late

Loss, In-segment

(mm)

¥

0.36

±

0.46

(264)

0.72

±

0.61

(263)

<

0.001*

¥

Powered

secondary

endpoint.

*

test

for

superiority.

OTHER ANGIOGRAPHIC

RESULTS

MLD

(mm),

In-stent

Post-Procedure

2.59

±

0.43

(588)

2.61

±

0.44

(589)

0.436**

8-Month

1.99

±

0.56

(264)

1.62

±

0.70

(265)

<

0.001**

MLD

(mm),

In-segment

Post-Procedure

2.21

±

0.49 (589)

2.24

±

0.49

(590)

0.302**

8-Month 1.86

±

0.55

(264)

1.56

±

0.67

(265)

<

0.001'*

%

DS,

In-stent

Post-Procedure

6.04

±

10.43 (588)

6.23

±

10.03

(589)

0.757**

8-Month

27.91

±

17.30

(264) 42.24

±

21.73

(265)

< 0.001t*

%

DS,

In-segment

Post-Procedure

20.39

10.26

(589)

20.11

±9.38

(590)

0.622**

8-Month

32.67

±

16.27

(264)

44.33

±

20.45

(265)

<

0.001**

Late Loss, In-stent

(mm) 0.62

±

0.46 (264)

1.03

±

0.59 (263)

<

0.001'*

Binary

Restenosis

In-stent

Restenosis

9.5%

(25/264)

33.2%

(88/265)

<

0,001*

In-segment

Restenosis

13.3%

(35/264) 34.7%

(92/265)

<

0.001*

IVUS

RESULTS

Neointimal Volume (mm

3

)

30.15

±-21.66

(90)

53.51

±

39.80

(81)

<

0.001**

%

Volume

Obstruction 17.34

±

10.27 (90) 29.55

±

17.58

(81)

<

0.001**

Incomplete

Apposition

Post-procedure

24.8%

(36/145)

19.6%

(28/143)

0.322**

8-Month 16.8%

(21/125)

14.5%

(16/110)

0.721**

Resolved

7.0% (8/114)

6.7% (7/104)

1.000**

Persistent

17.5%

(20/114)

14.4%

(15/104)

0.583**

Late

Acquired 0.0%

(0/114)

0.0%

(0/104)

--

P-values

for

outcome

differences

are

not

adjusted

for

multiple

comparisons.

Note:

Fisher's

Exact

test

or

Student's

t-test

was

used

for

P-values.

SSED

P060033

-

Page

43

of

59

Table

23:

ENDEAVOR

II

Protocol-Defined

Stent

Thrombosis*

T

hrou

36

Months

j,,

aue

Cumulative

ST

through

36

Months

0.5%

(3/577)

1.2%

(7/579)

0.342**

Acute

ST

(•<

24

hrs)

0.2%

(1/596)

0.2%

(1/594)

1.000'*

Subacute

ST

(>

24

hrs

and

•

30

days)

0.3%

(2/596)

1.0%

(6/594)

0.178*t

Late

ST (>

30

days

and

<

12

months)

0.0%

(0/590)

0.0% (0/589)

-

Very

late

ST

(>

12

months

and

•

36

months)

0.0%

(0/577)

0.0%

(0/579)

--

*

See

section

XI.Flfor

the

per

protocol

stent

thrombosis

definition.

P-values

for

outcome

differences

are

not

adjusted

for

multiple

comparisons.

Notes:

Fisher's

Exact

test

was

used

for

P-values.

This

trial

was

not

adequately

powered

to

compare

the

rate

of

low

frequency

events,

nor

was

it

sized

to

determine

the rate

of

low

frequency

events

with

a

pre-specified

precision.

To

be

included

in

the

event

rate calculation

for

a

given

interval,

a

patient

either

had

to

have

an event

before

the

time

of

interest

or

they

had

to

be

event-free

before

the

lower

window

of

the

follow-up.

Numbers

are

%

(Count/Sample

Size).

D.

Results

of

the

ENDEAVOR

I

Clinical

Trial

Primary

Obiective:

To

demonstrate

the

safety

and

efficacy

of

the

Endeavor

Zotarolimus-

Eluting

Coronary

Stent

System

for

the

treatment

of

single

de

novo

lesions

in

native

coronary

arteries

with

a

reference

vessel

diameter

of

3.0

mm

to

3.5

mm

and

lesion

length

of•<

15

mm.

Design:

The

ENDEAVOR

I

trial

was

the

first-in-man

study

for

the

Endeavor

stent.

This

was

a

non-randomized,

prospective,

multi-center,

single-arm

trial.

A

total

of

100

patients

were

enrolled

at

8

study

sites

in

Australia

and

New Zealand

who

presented

with

symptomatic

ischemic

heart disease

attributable

to

stenotic

lesions

of

the

native

coronary

arteries

that

were

amenable

to

treatment

by

stenting.

Follow-up

was

performed

at

30

days,

4,

9,

12

months,

at

2,

3

and

4

years,

and

will

be

performed

at

5

years.

All

patients

were

scheduled

to

have

angiographic

follow-up

at

4

and

12

months.

Following

the

index

procedure,

patients

were

treated

with

aspirin

indefinitely

and

clopidogrel

for

a

minimum

of

3

months.

Demographics:

The

mean

age

was

59

years,

and

79%

were

male.

Diabetes

was

present

in

16%,

and

47%

had

a

prior

MI.

Results:

The

primary

and

secondary

endpoint,

protocol-defined

stent

thrombosis,

and

the

latest

available

follow-up

results

are

presented

below

(Table

24,

Table

25,

and

Table

26).

The

primary

endpoint

of

30-day

MACE

was

1.0%

(1/100),

and

the

co-primary

endpoint

of

in-segment

late

loss

at

4

months

was

0.22

±

0.43

mm

(98).

SSED

P060033

-

Page

44

of

59

Table

24:

ENDEAVOR

I

Clinical

Results

-

~

vor

::i'Endeavor

(N1=

00)

PRIMARY

ENDPOINT

MACE

at

30

days

§

1.0%

(1/100)

530

day

primary

endpoint.

Outcomes

at

48

Months

Outcomes

at

9

Months

(latest

available

follow-

up)

EFFICACY

TVF

2.0%

(2/100)

5.2%

(5/97)

TVR

2.0%

(2/100)

5.2%

(5/97)

TLR

2.0%

(2/100)

3.1%

(3/97)

TLR,

PCI

2.0%

(2/100)

3.1%

(3/97)

TLR,

CABG

1.0%

(1/100)

1.0%

(1/97)

Non-TLR

0.0%

(0/100)

2.1%

(2/97)

Non-TLR,

PCI

0.0%

(0/100)

1.0%

(1/97)

Non-TLR,

CABG

0.0% (0/100)

1.0%

(1/97)

SAFETY

Total

Death

0.0%

(0/100)

4.1%

(4/97)

Cardiac

Death

0.0%

(0/100)

0.0%

(0/97)

Non-Cardiac

Death

0.0%

(0/100)

4.1%

(4/97)

Cardiac

Death

or

MI

1.0%

(1/100)

1.0%

(1/97)

Ml

1.0%

(1/100)

1.0%

(1/97)

Q

wave

MI

0.0% (0/100)

0.0%

(0/97)

Non-Q

wave

MI

1.0%

(1/100)

1.0%

(1/97)

Stent

Thrombosis

(protocol)

1.0%

(1/100)

1.0%

(1/97)

Notes:

Numbers

are

%

(Count/Sample

Size).

This

trial

was

not

adequately

powered

to

compare

the

rate

of

low

frequency

events,

nor

was

it

sized

to

determine

the

rate

of

low

frequency

events

with

a

pre-specified

precision.

To

be

included

in

the event

rate

calculation

for

a

given

interval,

a

patient

either

had

to

have

an

event

before

the

time

of

interest

or

they

had

to

be

event-free

before

the

lower

window

of

the

follow-up.

SSED

P060033

-

Page

45

of

59

ss

________

___

______

Table

25:

ENDEAVOR

1

12-

Month

Angiographic

and

IVUS

Results

ANGIOGRAPHIC

RESULTS

MLD (mm),

In-stent

Post-Procedure

12-Month

MED

(mm),

In-segment

Post-Procedure

12-Month

%

DS,

In-stent

Post-Procedure

12-Month

%

DS,

In-segment

Post-Procedure

12-Month

Late

Loss,

In-stent

(mm)

Late

Loss,

In-segment

(mm)

Binary

Restenosis

In-stent

Restenosis

In-segment

Restenosis

IVUS

RESULTS

Neojntjmnal

Volume

(mm')

%

Volume

Obstruction

Incomplete

Apposition

Post-procedure

12-Month

Resolved

Persistent

Late

Acquired

2.84

±0.35

(100)

2.26

±0.49

(92)

2.52

±0.42

(100)

2.08

±0.47

(92)

5.37

±7.51

(1

00)_

21.75

±15.35

(92)

16.54±8.40

(100)

28.00

±13.41

(92)

0.58

±0.44

(92)

0.43

±0.44

(92)

4.3%

(4/92)

5.4% (5/92)

14.15

±11.82

(86)

9.73

±8.50

(86)

12.6%

(12/95)

4.7%

(4/86)

8.1%

(7/86)

4.7%

(4/86)

0.0%

(0/86)

SSED P060033

-

Page

46

of

59

Table

26:

ENDEAVOR

I

Protocol-Defined

Stent

Thrombosis*

Through

48

Months

Cumulative

ST

through

48

Months

1.0%

(1/97)

Acute

ST

(•

24

hrs)

0.0%

(0/100)

Subacute

ST

(>

24

hrs

and

<

30

days)

1.0%

(1/100)

Late

ST

(>

30

days

and

<

12

months)

0.0%

(0/99)

Very

Late

ST

(>

12

months

and

•

48

months)

0.0%

(0/97)

*

See

section

XI.Flfor

the

per

protocol

stent

thrombosis

definition.

Notes:

To

be

included

in

the

event

rate

calculation

for

a

given

interval,

a

patient

either

had

to

have

an

event

before

the

time

of

interest

or

they

had

to

be

event-free

before

the

lower

window

of

the

follow-up.

Numbers

are

%

(Count/Sample

Size).

E.

Gender

Bias

The

gender

selection

in

this

series

of

clinical

trials

was

completely

random,

and

solely

based

upon

exclusion

and

inclusion

criteria.

In

the

ENDEAVOR

IV

study

(conducted

in

the

US),

women

represented

32.3%

of

the

population.

In

the

ENDEAVOR

III

study

(conducted

in

the

US),

women

represented

30.5%

of

the

population.

In

the

ENDEAVOR

II

study

(conducted

OUS),

women

represented

23.7%

of

the

population.

In

the

ENDEAVOR

I

feasibility

trial

(conducted

OUS),

women

represented

21.0%

of

the

population.

According

to

the

American

Heart

Association

Heart

Disease

and

Stroke

Statistics

(2008

Update),

women

represent

approximately

40%

of

patients

age

60-79

with

coronary

heart

disease.

Although

the

ratio

of

men

to

women

in

the

ENDEAVOR

trials

does

not

match

the

prevalence

of

coronary

artery

disease

in

the

general

U.S.

population,

it

is

reflective

of

the

underlying

distribution

of

the

disease

for

the

types

of

patients

that

would

meet

the

study

inclusion/exclusion

criteria

(i.e.,

younger,

less

complex

disease).

No

selection

bias

on

the

basis

of

gender

was

identified

during

the

review.

In

addition,

data

were

analyzed

to

determine

if

gender

was

an

independent

predictor

of

clinical

outcomes

of

death,

cardiac

death,

all

MI,

QMI,

Non-Q

MI,

cardiac

death

or

MI,

TVF,

TVR,

TLR

and

stent

thrombosis

(all

definitions).

No

differences

in

safety

or

effectiveness

were

found,

with

respect

to

gender.

F.

Overall

Results

of

the

Endeavor

Clinical

Program

(ENDEAVOR

I,

II,

II-CA,

III,

IV

and

USPK)

In

order

to

better

estimate

the

incidence

of

low-frequency

events

or

outcomes

in

various

specific

patient

subgroups,

a

patient-level

pooled

analysis

was

conducted.

This

analysis

compared

pooled

Endeavor

stent

patients

(across

all

trials)

to

Driver

stent

patients

from

ENDEAVOR

II.

Although

ENDEAVOR

I

(100),

ENDEAVOR

1I-CA

(296)

and

ENDEAVOR

USPK

(43)

are

not

randomized

trials,

for

the

purpose

of

this

analysis,

they

are

pooled

with

the

randomized

trials

--

ENDEAVOR

11

(596),

ENDEAVOR

III

(323)

and

ENDEAVOR

IV

(770)

--

to

allow

the

broadest

comparison

of

the Endeavor

stent

(1287

patients)

vs.

the

Driver

stent

patients

(599)

to

2

years

of

follow-up.

Across

the

ENDEAVOR

program,

2133

patients

received

the

Endeavor

stent.

The

patient-level

data

SSED

P060033

-

Page

47

of

59

was

included

until

the

latest

available

time

point

depending

on

the

follow-up

status

for

each

trial

--

ENDEAVOR

1

(97%

complete

at

4

years),

ENDEAVOR

11

(97.8%

completed

at

3

years),

ENDEAVOR

I1-CA

(97.3%

complete

at

2

years),

ENDEAVOR

III

(96.9%

complete

at

2

years),

ENDEAVOR

IV

(96.1%

complete

at

9

months),

and

ENDEAVOR

USPK

(97.7%

complete

at

9

months).

Table

27:

Patient

Follow-up

"77'-tA~"o<'Wi7

1

2

24

48

nths

ii~~~~~~~

i~nhs:

2&onth

:i

ENDEAVOR

I

100

99

98

97

-

ENDEAVOR

II

596

593

592

590

587

577

ENDEAVOR

II

CA

296

295

293

292

288

-

ENDEAVOR

III

323

321

320

313

-

ENDEAVOR

IV

770

766

740

ENDEAVOR

PK

43

42

Total

2128

2118

2088

1301

1287

675

97

It

is

acknowledged

that

the

results

of

such

retrospective

pooled

analyses

are

hypothesis-

generating

in

nature.

Definitive

proof

of

the

presence

or

absence

of

any

differences

between

sub-groups

requires

prospectively

powered

assessment

in

dedicated

clinical

trials.

The

results

of

the

pooled

analysis

show

the

Endeavor

stent

significantly

reduces

the

need

for

repeat

revascularization

vs.

the

Driver

stent

that

is

maintained

throughout

long-term

follow-up

as

shown

in

Figure

5.

SSED

P060033

-

Page

48

of

59

100•

95%

-T

E

0

E

90%_~~~~~~

8s.s%

(D)

'.

85%'

p

=

<

0.001

-

Endeavor

--

Driver

80%

I

o

90

180

270

360

450

540

630 720

810

900

990

1080

Time

after

Initial

Procedure

(days)

100%~

_

95%-''-

89.4%

(E)

80%

-

u5_

--

Endeavor

--

Driver

0

980

180

270

360

450

540

630

720

610

900

990

080

Time

after

Initial

Procedure

(days)

Figure

5:

Efficacy-Target

Lesion

and

Target Vessel

Revascularization

in

ENDEAVOR

Pooled

Analysis

Kaplan-Meier

rates

%.

P-values

are

from

the

Log-rank

test

and

are

not

adjusted

for multiple

comparisons.

The

Endeavor

stent

is

more

effective

than

the

Driver

stent

in

reducing

the need

for

revascularization,

as

shown

in

Figure

5.

The analyses

shown

in

Figure

6

suggest

a

lower

rate

of

cardiac

death

in

pooled Endeavor

patients

compared

to

Driver patients

from

ENDEAVOR

II.

The

pooled

analysis

addressed

total

death

as

well

as

cardiac

death

and

non-cardiac

death

as

its

components.

There

were

no

differences

noted

in

non-cardiac

or

total death

between

groups.

SSED

P060033

-

Page

49

of

59

100%_

--

96.9%

(E)

96%-

-n~~~~~~

94)

95.5%

(D)

92%-

P

=

0.

199

-

Endeavor

--

Driver

90%

I

o

go

180

270

360

450

540

630

720

810

900

990

1080

Time

after

Initial

Procedure

(days)

99.0%

(E)

~98%_

97.6%

(D)

12

96%-

a

E

0

94%-

E

0)

P

92%-

92%-=

0.025

-

Endeavor

--

Driver

90%

1

,

I

--

,- - -

I

0

90

180

270

360

450

540

630

720

810

900

990

1080

Time

after

Initial

Procedure

(days)

lO%--

....

97.9%

....

(E)

....

98%-

97.8%

(D)

q)

96%.

0

z

92%

P

0.799

-Endeavor

--

Driver

90%

1

I

I I

I

o

90

180

270

360

450

540

630

720

810

900

990

1080

Time

after

Initial

Procedure

(days)

Figure

6:

Safety-Mortality

in

ENDEAVOR

Pooled

Analysis

Kaplan-Meier

rates

%.

P-values

are

from

the

Log-rank

test

and

are

not

adjusted

for

multiple

comparisons.

SSED

P060033

-

Page

50

of

59

5'g

The

MI

rates

in

patients

receiving

the

Endeavor

stent

vs.

the

Driver

control

stent

were

also

examined.

At

three

years,

any

differences

noted

favored

the

Endeavor

stent

as

shown

in

Figure

7.

100

E~~~~~~~~~~~~~~~~~~~~~~~E

0

94%-95.8%

(D)

=0.047

92%-

P

-Endeavor

-Driver

o

90

16~0

270

36~0

450

540

630

72'0

61'0

9010

990

1080

Time

after

Initial

Procedure

(days)

99.8%

(E)

96%

~~~~~~~~~~~~~~~~~99.0%

(D)

E

98%-

ci

E

S

4%-

U-

92%-

P

0.016

-Endeavor

-

-Driver

0

90

180

270

360

4

50

540

630

72'0

810

900

990

10O80

Time

after

Initial

Procedure

(days)

o

~~~~~~~~~~~~~~~~~~~~96.5%(D)

0 9%

92%-

P

=0.256

-

Endeavor

-

-Driver

0

90

180

270

360

450

540

630 720

810

900

990

1080

Time

after

Initial

Procedure

(days)

Figure

7:

Safety-MI

in

ENDEAVOR

Pooled

Analysis

Kaplan-Meier

rates

%.

P-values

are

from

the

Log-rank

test

and are

not

adjusted for

multiple

comparisons.

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51

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59

1.

Stent

Thrombosis

in

Endeavor

Pooled

Analysis

For

the

critical

safety

endpoint

of

stent

thrombosis,

Endeavor

rates

have

been

reported

using

two

different

reporting

mechanisms:

the

pre-specified

protocol

definition

and

the

retrospective

Academic

Research

Consortium

(ARC)'

definition.

Stent

thrombosis

was

defined

(per

protocol)

in

the

ENDEAVOR

clinical

trials

as

the

occurrence

of

any

of

the

following:

*

Angiographic

thrombus

or

subacute

closure

within

the

stented

vessel

at

the

time

of

the

clinically-driven

angiographic

restudy

for

documented

ischemia

(chest

pain

and

ECG

changes).

*

Any death

not

attributed

to

a

non-cardiac

cause

within

the

first

30

days.

·

Late stent

thrombosis

is

reported

according

to

the

following

criteria:

MI

>

30

days

after

index

and

attributable

to

the

target

vessel,

angiographic

documentation

(site-reported

or

by

QCA)

of

thrombus

or

total

occlusion

at

the

target

site

and

freedom

from

interim

revascularization

of

the

target

vessel.

All

events

were

re-adjudicated

based

on

FDA

recommendation

using

the

ST

definitions

proposed

by

ARC.

This

was

performed

by

an

independent

events

committee

blinded

to

the

treatment

groups

of

the

individual

patients.

According

to

ARC,

each

incident

of

ST

is

categorized

by

timing,

level

of

evidence,

and

relationship

to

TLR

as

follows:

Timing:

Acute

stent

thrombosis

2

:

0-24

hours

post

stent

implantation

Subacute

stent

thrombosis

2

:

>

24

hours-30

days

post

stent

implantation

Late

stent

thrombosis:

>

30

days-l

year

post

stent

implantation

Very

late

stent

thrombosis:

>

1

year

post

stent

implantation

Level

of

Evidence:

*

Definite

stent

thrombosis:

Definite

stent

thrombosis

is

considered

to

have

occurred

by

either

angiographic

or

pathologic

confirmation.

*

Probable

stent

thrombosis:

Clinical

definition

of

probable

stent

thrombosis

is

considered

to

have

occurred

after

intracoronary

stenting

in the

following

cases:

*

Any

unexplained

death

within

the

first

30

days

*

Irrespective

of

the

time

after

the

index

procedure,

any

MI

that

is

documented

acute

ischemia

in

the

territory

of

the

implanted

stent

without

angiographic

confirmation

of

stent

thrombosis

and

in

the

absence

of

any

other

obvious

cause

*

Possible

stent

thrombosis:

Clinical

definition

of

possible

stent

thrombosis

is

considered

to

have

occurred

with

any

unexplained

death

from

30

days

following

intracoronary

stenting

until

end

of

trial

follow-up.

SSED

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52

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59

GOO

Stent

Thrombosis

After

TLR:

Censored

vs.

Non-Censored:

Censoring

stent

thrombosis

events

that

occur

post-TLR

performed

for

stent

restenosis

may

be

appropriate,

as

the

thrombosis

may

be

the

treatment

chosen

to

treat

restenosis

(e.g.,

brachytherapy)

rather

than

the

type

of

stent

used

in

the

index

procedure.

Alternatively,

censoring

stent

thrombosis

events

that

occur

after

TLR

may

bias

results

in

favor

of

devices

with

higher

restenosis

risks.

Therefore,

stent

thrombosis

data

presented

in

this

review

will

report

both

TLR-censored

and

TLR-

uncensored

rates

as

follows:

*

ARC

Definite

+

probable

(TLR-censored):

Adjudicated

stent

thrombosis

meeting

the

definite

or

probable

ARC

definition

with

censoring

of

any

definite

or

probable

stent

thrombosis

events

that

may

have

occurred

after

a

TLR.

*

ARC

Definite

+

probable

(TLR-uncensored):

Adjudicated

stent

thrombosis

meeting

the

definite

or

probable

ARC

definition

including

any

definite

or

probable

stent

thrombosis

events

that

may

have

occurred

after

a

TLR.

In

the

ENDEAVOR

clinical

program

comprised

of

six

multi-center

trials,

2133

patients

were

assigned

to

receive

the

Endeavor

Stent

(1287

patients

were

followed

out

to

two

years

and

675

patients

out

to

three

years).

When

all

patients

who

received

the

Endeavor

stent

across

trials

were

pooled

and

compared

to

the

patients

who

received

the

Driver

stent

in

ENDEAVOR

II,

the

Endeavor

stent

did

not

appear

to

pose

an

increased

stent

thrombosis

risk.

Regardless

of

the

method

for

reporting

the

pre-specified

protocol

definition

or

the

retrospective

ARC

definition,

in

the

randomized

ENDEAVOR

II

trial

and

the

FDA-requested

pooled

analysis,

the

Endeavor

stent

exhibited

low

event

rates

that

were

similar

to

or

lower

than

the

Driver

stent.

The

cumulative

rates

of

stent

thrombosis

(per

protocol

and

per

the

ARC

definite

+

probable

definitions)

in

patients

treated

with

Endeavor

stents

from

the

pooled

ENDEAVOR

trials

are

shown

in

Table

28

below.

(Stent

thrombosis

rates

observed

in

patients

treated

with

Driver

stents

in

ENDEAVOR

II

are

shown

for

reference.)

ARC

definite

+

probable

stent

thrombosis

is

reported

both

as

TLR-censored

and

uncensored.

SSED

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53

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59

Table

28:

Stent

Thrombosis

Protocol

and

Definite

+

Probable

Stent

Thrombosis

(ARC

I

Thrombosis

(0-30

Days)

Stent

Thrombosis

(Protocol)

0.3%

(7/2128)

[0.1%,

0.7%]

1.2%

(7/594)

[0.5%,

2.4%]

ARC

Definite

+

Probable

(TLR-censored)

0.3%

(7/2128)

[0.1%,

0.7%]

1.2%

(7/594)

[0.5%,

2.4%]

[0.5%,

2.4%]

ARC

Definite

+

Probable

(TLR-uncensored)

0.3%

(7/2128)

[0.1%,

0.7%]

1.2%

(7/594)

Thrombosis

(0-6

Months)

Stent

Thrombosis

(Protocol)

0.5%

(10/2118)

[0.2%,

0.9%]

1.2%

(7/593)

[0.5%,

2.4%]

[0.5%,2.4%]

ARC

Definite

+

Probable

(TLR-censored)

0.5%(11/2118)

[0.3%,00.9%]

1.2%(7/593)

[0.3%,

0.9%]

1.2%

(7/593)

[0.5%,

2.4%]

ARC

definite

+

probable

(TLR-uncensored)

0.5%

(11/2118)

Thrombosis

(0-12

Months)

Stent

Thrombosis

(Protocol)

0.3%

(4/1301)

[0.1%,

0.8%]

1.2%

(7/589)

[0.5%,

2.4%]

ARC

Definite

+

Probable

(TLR-censored)

0.4%

(5/1301)

[0.1%,

0.9%]

1.4%

(8/589)

[0.6%,

2.7%]

ARC

Definite

+

Probable

(TLR-uncensored)

0.5%

(6/1301)

[0.2%,

1.0%]

1.4%

(8/589)

[0.6%,

2.7%]

Thrombosis

(0-24

Months)

Stent

Thrombosis

(Protocol)

0.3%

(4/1287)

[0.1%,

0.8%]

1.2%

(7/586)

[0.5%,

2.4%]

ARC

Definite

+

Probable

(TLR-censored)

0.5%

(6/1287)

[0.2%,

1.0%]

1.4%

(8/586)

[0.6%,

2.7%]

[0.2%,

1.1%]

1.4%

(8/586)

[0.6%,2.7%]

ARC

Definite

+

Probable

(TLR-uncensored)

0.5%

(7/1287)

Thrombosis

(0-36

Months)

Stent

Thrombosis

(Protocol)

0.6%

(4/675)

[0.2%,

1.5%]

1.2%

(7/579)

[0.5%,

2.5%]

ARC

Definite

+

Probable

(TLR-censored)

0.9%

(6/675)

[0.3%,

1.9%]

1.4%

(8/579)

[0.6%,

2.7%]

ARC

Definite

+

Probable

(TLR-uncensored)

0.9%

(6/675)

[0.3%,

1.9%]

1.6%

(9/579)

[0.7%,

2.9%]

Beyond

one

year,

the

Endeavor

stent

showed

zero

stent

thrombosis

by

the

pre-specified

protocol

definition

and

one

stent

thrombosis

event

by

the

post

hoc

ARC

definition

(definite

+

probable).

SSED

P060033

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54

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59

IS

100.0%

(E)

10

-~98%-

g

96%-

E

94%

I-.

E

92%

P =

n/a

~~-Endeavor

-Driver

E

0

o,

90%]

2?

360

450

540

630

720

810

900

§90

1090

Time

after

Initial

Procedure

(days)

99.9%

(E)

100%-

----

r-

---

99.8%

(D)

~98%-

4

E

96%_

94%-

0E

92%-

P

0.737

-Endeavor

--

Driver

0

90%-

360

4605

0

630

720

81,0

g00

990

1080

Time

after

Initial

Procedure

(days)

Figure

8:

Freedom

from

Stent

Thrombosis

(Protocol)

and

Definite/Probable

Thrombosis

(ARC)

Kaplan-Meier

rates

%.

P-values

are

from

the

Log-rank

test

and

are

not

adjusted

for

multiple

comparisons.

2.

Diabetic

Patients

in

ENDEAVOR

Pooled

Analysis

Diabetic

patients

comprise

an

important

patient

subgroup

that

is

at

increased

risk

for

cardiovascular

morbidity

and

mortality.

Although

diabetic

patients

were

included

in

the

Endeavor

clinical

trials,

there

were

no

pre-specifled

hypotheses

or

trial

design

features

to

warrant

a

specific

labeled

indication

for

the

use

of

the

Endeavor

stent

in

diabetic

individuals.

Table

29

shows

clinical

outcomes

through

9

months

in

patients

pooled

from

the

ENDEAVOR

trials

and

stratified

by

non-diabetics,

all

diabetics,

insulin-dependent

diabetics,

and

non-insulin

dependent

diabetics.

As

expected,

TLR

and

TVR

rates

were

numerically

increased

in

diabetics

vs.

non-diabetics,

with

no

observed

safety

signals

with

respect

to

the

rates

of

death,

cardiac

death,

MI,

or

stent

thrombosis.

SSED

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55

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59

Table

29:

Clinical

Events

Through

9

Months

Death

0.8%

0.7%

0.8%

Cardiac

Death

0.5

0.6

0.0%

0.8%

~MI

2.4%

1.5%

2.0%

1.4%

Cardiac

Death

or

MI

2.0%

1.9%

Protocol

ST

0.5%

0.6%

0.7%

0.5%

Definite

and

Probable

ST

ARC

(TLR.

censored)

~

~~~0,5%

censored)

0,8%

1,3%

0,5%

Definite

and

Probable

ST

ARC

(TLR

0

uncensored)

~

~~0,5%

0.8%

1.3%

uncensored)

0.5%

TLR

4.1%

6.3%

6.0%

6.5%

TVR

5.8%

9,4%

8.0%

9.8%

From

the

pooled

ENDEAVOR

studies,

clinical

outcomes

through

9

months

are

shown

in

Table

30

stratified

by

all

diabetics,

insulin-dependent

diabetics,

and

non-insulin

dependent

diabetics.

Event

rates

for

the

Driver

patients

in

the

ENDEAVOR

II

study

are

shown

for

reference.

These

data

show

no

observed

safety

signals

with

respect

to

the

rates

of

death,

cardiac

death,

MI,

or

stent

thrombosis

with

the

Endeavor

stent

compared

to

the

Driver

stent.

Table

30:

Clinical

Events

in

Diabetics

Endeavor

Compared

to

Driver

BMS

uh

9

Months

Death~~~~~~~~~~~~~~~~~~~~~~

0

.

'.......

Death

~~~~~0.8%

Cardiac

Death

0.6%

MI

1.5%

Cardiac

Death

or

Ml

1.9%

Protocol

ST

0.6%

Definite

and

Probable

ST

ARC

(TLR-

0.8%

1.5%

3.8%

5.3%

2.3%

0.7%

0.0%

2.0%

0.7%

1.3%

2.3%

4.5%

0.0%

0.8%

1.4%

1.9%

0.5%

1.1

%

1.1%

4.5%

5.7%

3.4%

censored)

Definite

and

Probable

ST

ARC

(TLR-

0.8%

2.3%

1.3%

0.0%

0.5%

3.4%

uncensored)

TLR

TVR

6.3%

9.4%

15.2%

15.9%

6.0%

8.0%

13.6%

6.5%

9.8%

15.9%

17.0%

SSED

P060033

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Page

56

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59

XII.

Conclusions

Drawn

from

the

Studies

The

safety

and

effectiveness

of

the

Endeavor

Zotarolimus-Eluting

Coronary

Stent

System

are

based

on

the

results

obtained

from:

biocompatibility;

in

vivo

pharmacokinetics;

in

vitro

engineering

testing;

coating

characterization;

chemistry,

manufacturing

and

controls

information;

in

vivo

animal

testing;

sterilization

and

stability

testing;

and

clinical

studies.

These

test

results

revealed

the

following:

The

biocompatibility,

in

vivo

pharmacokinetics,

and

in

vivo

animal

testing

that

were

conducted

demonstrated

that

the

acute

and

chronic

in

vivo

performance

characteristics

of

the

product

provide

reasonable

assurance

of

safety

and

are

acceptable

for

clinical

use.

The

in

vitro

engineering

testing

conducted

on

the

stent

and

delivery

system(s)

demonstrated

that

the

performance

characteristics

met

the

product

specifications

and

the

coating

characterization

testing

adequately

described

the

important

attributes

of

the

zotarolimus/polymer

coating.

The

chemistry,

manufacturing,

and

controls

information

ensures

that

product

meeting

specifications

will

be

released.

The

test

results

obtained

from

the

sterilization

testing

demonstrated

that

the

product

can

be

adequately

sterilized

and

is

acceptable

for

clinical

use.

The

stability

testing

demonstrated

that

the

product

can

be

labeled

with

a

shelf

life

of

12

months.

The

clinical

testing

conducted

demonstrated

that

the

product

provides

a

reasonable

assurance

of

safety

and

effectiveness

when

used

as

indicated

in

accordance

with

the

instructions

for

use.

Specifically,

the

Endeavor

stent

was

shown

to

be

superior

to

an

approved

bare

metal

stent

with

respect

to

both

clinical

outcomes

and

angiographic

data.

In

addition,

clinical

outcomes

with

the

Endeavor

stent

were

non-inferior

to

those

obtained

using

an

approved

drug-eluting

stent.

Although

the

Endeavor

stent

did

not

demonstrate

non-inferiority

to

two

approved

drug-eluting

stents

based

on

angiographic

data,

the

aggregate

of

clinically

relevant

safety

and

effectiveness

data

outweighed

the

results

of

surrogate

angiographic

measurements.

XIII.

Panel

Recommendation

At

an

advisory

meeting

held

on

October

10,

2007,

the

Circulatory

Systems

Devices

Panel

unanimously

recommended

that

Medtronic's

PMA

for

the

Endeavor

Zotarolimus

Drug-

Eluting

Coronary

Stent

System

&

Over-the-Wire

(OTW),

Rapid

Exchange

(RX),

and

Multi-Exchange

II

(MX

2

)

Stent

Delivery

Systems

be

approved

subject

to

submission,

and

approval

by,

the

Center

for

Devices

and

Radiological

Health

(CDRH)

of

the

following:

1.

The

sponsor

should

conduct

a

>

5,000

patient

single-arm

post-approval

study

with

endpoints

of

very

late

stent

thrombosis

and

cardiac

death

+

myocardial

infarction,

rigorous

monitoring,

and

follow-up

through

at

least

5

years.

2.

The

labeling

regarding

antiplatelet

therapy

use

should

be

consistent

with

current

ACC/AHA

Guidelines

as

FDA

has

proposed

for

currently

approved

drug-eluting

stents

following

the

December

2006

panel

meeting.

Specifically,

the

labeling

should

describe

the

use

of

antiplatelet

therapy

in

the

clinical

trials

and

suggest

that

use

through

1

year

may

be

beneficial

per

the

published

consensus

guidelines.

SSED

P060033

-

Page

57

of

59

XIV.

CDRH

Decision

CDRH

concurred

with

the

Panel's

recommendations

of

October

10,

2007.

Medtronic's

post-approval

study

proposal

developed

with

FDA

and

presented

to

the

Panel

addresses

the

Panel's

first

recommendation.

Specifically,

data

from

5,300

Endeavor

patients

(2,000

from

the

US

registry

and

3,300

OUS

from

the

Endeavor

arm

of

the

PROTECT

study)

will

be

collected

and

pooled

for

an

analysis

of

rates

of

stent

thrombosis

and

cardiac

death

plus

myocardial

infarction.

Data

will

be

analyzed

separately

for

the

patients

enrolled

in

accordance

with

the

labeled

indication

and

collectively

for

all

patients

enrolled

in

the

studies.

Medtronic

expects

the

PROTECT

trial

and

the

U.S.

Post

Approval

Registry

will

include

a

sufficient

number

of

patients

who

have

received

the

Endeavor

stent

in

accordance

with

the

approved

indication

to

allow

evaluation

of

both

endpoints

noted

above.

Data

from

at

least

2000

patients

will

be

available

to

provide

80%

power

to

demonstrate

that

the

rate

of

stent

thrombosis

per

year

is

<

1.0%

in

Endeavor

patients

who

receive

the

Endeavor

stent

in

accordance

with

the

approved

indication.

This

sample

size

also

provides

>

80%

power

to

demonstrate

that

the

rate

of

cardiac

death

+

myocardial

infarction

at

annual

timepoints

through

5

years

in

Endeavor-stented

patients

is

less

than

the

incidence

in

patients

who

received

the

Driver

stent

in

the

ENDEAVOR

II

trial

plus

a

50%

non-inferiority

margin.

To

address

the

Panel's

second

recommendation,

Medtronic

provided

revised

labeling

in

a

PMA

amendment.

The

final

labeling

describes

the

use

of

dual

antiplatelet

therapy

in

the

ENDEAVOR

trials

and

further

states

that

"Current

guidelines

recommend

that

patients

receive

aspirin

indefinitely

and

that

clopidogrel

therapy

be

extended

to

12

months

in

patients

at

low

risk

of

bleeding

(ref:

ACC/AHA/SCAI

PCI

Practice

Guidelines3,

4

)."

Additionally,

Medtronic

has

agreed

to

conduct

or

participate

in

a

study

that

will

develop

clinical

data

to

identify

the

optimal

duration

of

dual

antiplatelet

therapy

following

percutaneous

intervention

with

the

Endeavor

drug-eluting

stent.

The

applicant's

manufacturing

and

sterilization

facilities

were

inspected

and

found

to

be

in

compliance

with

relevant

Quality

System

Regulations

(21

CFR

820)

and

pharmaceutical

current

Good

Manufacturing

Practice

(cGMP)

regulations.

FDA

issued

an

approval

order

on

February

1,

2008.

XV.

Approved

Specifications

Directions

for

Use:

See

product

labeling.

Hazard

to

Health

from

Use

of

the

Product:

See

Indications,

Contraindications,

Warnings,

Precautions,

and

Adverse

Events

in

the

labeling.

Post

Approval

Requirements

and

Restrictions:

See

Approval

Order.

SSED

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-

Page

58

of

59

66

XVI.

References

ICutlip

DE,

Windecker

S,

Mehran

R,

et

al.

Clinical

end

points

in

coronary

stent

trials:

a

case

for

standardized

definitions.

Circ

2007;

115:2344-51.

2Acute

or

subacute

can

also

be

replaced

by

the

term

early

stent

thrombosis.

Early

stent

thrombosis

(0

-

30

days)

will

be

used

in

the

remainder

of

this

document.

3Smith

et

al.

ACC/AHA/SCAI

2005

Guideline

Update

for

Percutaneous

Coronary

Intervention.

JACC,

2006;

47:

el-121.

4King

III

et

al.

2007

Focused

Update

of

the

ACC/AHA/SCAI

2005

Guideline

Update

for

Percutaneous

Coronary

Intervention.

JACC,

2008;

51:172-209.

SSED

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59

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59