> SUMMARY OF SAFETY AND PROBABLE BENEFIT

I. General Information

Device Generic Name: Intravascular Intracranial Stent

Intracranial Dilatation Catheter

Device Trade Name: NEUROLINK® System, including:

NEUROLINK® Stent & Delivery Catheter

NEUROLINK® Balloon Dilatation Catheter

Applicant's Name and Address: Guidant Corporation

3200 Lakeside Drive

Santa Clara, CA 95052

Humanitarian Device Exemption (HDE) Number: H010004

Date of Humanitarian Use Device Designation: September 5, 2001

Date of Panel Recommendation: Not applicable. See Section XII.

Date of Good Manufacturing Practices (GMP) Inspection:

> Santa Clara, CA: April 26, 2001
>
> Temecula, CA: May 23, 2001

Date of notice of Approval to the Applicant: August 9, 2002

II. **Indications for Use**

The NEUROLINK® System is indicated for the treatment of patients with
recurrent intracranial stroke attributable to atherosclerotic disease
refractory to medical therapy in intracranial vessels ranging from 2.5
to 4.5 mm in diameter with [\>]{.underline} 50% stenosis and that are
accessible to the stent system.

# III. Contraindications 

# 

# NEUROLINK® Stent & Delivery Catheter and NEUROLINK® Balloon Dilatation Catheter are contraindicated for use in:

-   Lesions that are highly calcified or otherwise could prevent access
    or appropriate expansion of the Stent.

-   Patients in whom anticoagulant and/or antiplatelet therapy is
    contraindicated.

**IV. Warnings and Precautions**

See *Warnings and Precautions* in the final labeling (Instructions for
Use) for the NEUROLINK® Stent & Delivery Catheter and NEUROLINK® Balloon
Dilatation Catheter:

# V. Device Description

The NEUROLINK® System is comprised of two devices, the NEUROLINK® Stent
& Delivery Catheter and the NEUROLINK® Balloon Dilatation Catheter. The
NEUROLINK® Stent & Delivery Catheter consists of a balloon-expandable
stent that is pre-mounted on a balloon of the Delivery Catheter. The
NEUROLINK® Stent is fabricated from 316L stainless steel tubing and is
comprised of a series of cylindrically oriented rings aligned along a
common longitudinal axis.

The NEUROLINK® Stent & Delivery Catheter is an over-the-wire, co-axial
catheter design, with a balloon located at its distal end upon which the
Stent is mounted. Proximal and distal radiopaque markers are positioned
within the balloon to demarcate the proximal and distal edges of the
NEUROLINK® Stent, and are used to facilitate accurate positioning of the
stent within the target lesion. The NEUROLINK® Stent & Delivery Catheter
provides a means for safely carrying the stainless steel NEUROLINK®
Stent through the neurovasculature over a 0.014 inch guide wire to the
target lesion for deployment. A balloon located on the distal end of the
delivery catheter is designed to expand the stent to a specific diameter
at a specified pressure. The distal shaft of the NEUROLINK® Stent &
Delivery Catheter, excluding the NEUROLINK® Stent and the Balloon, is
coated with a hydrophilic coating. At the proximal end of the catheter,
a 2-port adaptation hub is incorporated to allow both guide wire
insertion and contrast medium injection.

The NEUROLINK® Balloon Dilatation Catheter is very similar in design to
the NEUROLINK® Stent & Delivery Catheter, except the NEUROLINK® Balloon
Dilatation Catheter does not include a NEUROLINK® Stent. The distal
shaft of the catheter is coated with a hydrophilic coating, which is
activated when hydrated. The balloon is designed to inflate to a
specific diameter and length at a specified pressure. Proximal and
distal radiopaque markers are positioned within the balloon on the
catheter to demarcate the proximal and distal shoulders of the balloon
to facilitate accurate positioning of the balloon within an artery. At
the proximal end of the catheter, a 2-port adaptation hub is
incorporated to allow both guide wire insertion and contrast medium
injection.

The NEUROLINK® Balloon Dilatation Catheter is used in patients who
require pre-dilatation of a symptomatic atherosclerotic lesion prior to
NEUROLINK® Stent placement to ensure a lumen of sufficient size for
access with the NEUROLINK® Stent & Delivery Catheter; or in patients who
require post-dilatation following placement of the NEUROLINK® Stent to
optimize placement and apposition of the NEUROLINK® Stent implanted in a
symptomatic atherosclerotic lesion.

Table 1 Device Specifications for the NEUROLINK® Stent & Delivery
Catheter

+----------------+-------------+----------+-------------+-------------+
| ## Product     | **Stent     | **Stent  | **Crossing  | **Expanded  |
|                | Di          | L        | Profile**   | Stent       |
|                | ameter(s)** | engths** |             | Length      |
|                |             |          | *           | (mm)**      |
|                | **(mm)**    | **(mm)** | *(inches)** |             |
+----------------+-------------+----------+-------------+-------------+
| NEUROLINK®     | 2.5         | 8        | 0.044" --   | 7.8         |
| Stent &        |             |          | 0.049"      |             |
| Delivery       | 3.0         |          |             | 7.5         |
| Catheter       |             |          |             |             |
|                | 3.5         |          |             | 7.3         |
| [Inflation     |             |          |             |             |
| Pressure       | 4.0         |          |             | 6.7         |
| s]{.underline} |             |          |             |             |
|                | 4.5         |          |             | 6.4         |
| RBP 10atm      |             |          |             |             |
|                |             |          |             |             |
| Nom.           |             |          |             |             |
| 5.5-7.0atm     |             |          |             |             |
| (8mm)          |             |          |             |             |
|                |             |          |             |             |
| Nom.           |             |          |             |             |
| 6.5-7.5atm     |             |          |             |             |
| (16mm)         |             |          |             |             |
+----------------+-------------+----------+-------------+-------------+
|                | 2.5         | 16       | 0.046" --   | 16.0        |
|                |             |          | 0.051"      |             |
|                | 3.0         |          |             | 15.9        |
|                |             |          |             |             |
|                | 3.5         |          |             | 15.9        |
|                |             |          |             |             |
|                | 4.0         |          |             | 15.3        |
|                |             |          |             |             |
|                | 4.5         |          |             | 14.6        |
+----------------+-------------+----------+-------------+-------------+

Table 2 Device Specifications for the NEUROLINK® Balloon Dilatation
Catheter

+-------------------+-------------------+--------------+---------------+
| **Product**       | Balloon           | **Balloon    | **Crossing    |
|                   | Diameter(s)       | Length       | Profile**     |
|                   |                   | (mm)**       |               |
|                   | **(mm)**          |              | **(inches)**  |
+-------------------+-------------------+--------------+---------------+
| NEUROLINK®        | 2.0               | 10           | 0.034"        |
| Balloon           |                   |              |               |
| Dilatation        | 2.5               |              | 0.038"        |
| Catheter          |                   |              |               |
|                   | 3.0               |              | 0.040"        |
| ### In            |                   |              |               |
| flation Pressures | 3.5               |              | 0.044"        |
|                   |                   |              |               |
| RBP 10atm         | 4.0               |              | 0.045"        |
|                   |                   |              |               |
| Nom.              | 4.5               |              | 0.049"        |
| 3.5atm--10atm     |                   |              |               |
|                   | 5.0               |              | 0.053"        |
+-------------------+-------------------+--------------+---------------+

#  

# [VI.]{.smallcaps} Alternative Practices and Procedures

Treatment of recurrent ischemic stroke resulting from intracranial
atherosclerosis currently includes medical therapy, percutaneous
transluminal angioplasty (PTA) and surgery. Medical therapy includes use
of antiplatelet and or anticoagulants and modification of
atherosclerotic risk factors. Antiplatelet drugs include aspirin, Plavix
(clopidogrel), or Aggrenox (dipyridamole and aspirin). Anticoagulants
include warfarin. Alternative treatments used to re-establish blood flow
to the brain are accomplished either by mechanically opening the
atherosclerotic blockage (for example, PTA) or by surgically bypassing
the affected artery.

**VII. Marketing History**

The NEUROLINK® System has not been marketed in the United States or any
foreign countries at the time of this submission.

**VIII. Potential Adverse Effects of the Device on Health**

***Potential adverse effects***

Potential adverse events listed below may be associated with the use of
the NEUROLINK® System in intracranial arteries:

Acute myocardial infarction

Death

Dissection

Drug reactions to anti-platelet or

anticoagulant agents or contrast medium

Distal emboli (air, tissue or thrombotic

emboli)

Fistula

Hemorrhage requiring transfusion

Hypotension/hypertension

Infection and pain at access site

Intracranial hemorrhage

Ischemia, cerebral

Pseudoaneurysm, femoral

Restenosis of stented segment

Spasm, vessel

Stent deformation

Stent embolization

Stent thrombosis/occlusion

Stroke/cerebrovascular accident

Total occlusion of an intracranial artery

Vessel perforation or rupture

Vessel spasm

***Reported adverse effects***

Table 3 identifies the adverse events observed in the clinical study
conducted to evaluate the safety and probable benefit of the NEUROLINK®
System. Sixty-one patients were enrolled in the study and information is
presented on all patients through 30 days and on 48 patients who have
reached the 6 month follow-up time point (see section X).

Table 3 Adverse Events

  --------------------- --------- ------------- --------- -------- -------------- ---------- --------------
  Event                 \# (%)    Time of                          Device /                  
                        (N=61)    Occurrence                       Procedure                 
                                                                   Related                   

                                  Proced^(1)^   \<30 days \>30     Yes            No         Pending^(2)^
                                                          days                               

  Stroke                8 (13.1%) 4^(3,\ 4)^    0         4^(5)^   5              2^(6,7)^   1

  Transient Ischemic    4 (6.6%)  0             1         3        3^(8)^         1^(9)^     0
  Attack (TIA)                                                                               

  Access Site Infection 1 (1.6%)  0             1         0        1              0          0

  Ankle Swelling        1 (1.6%)  0             0         1        0              1          0

  Arterial Dissection   2 (3.3%)  2             0         0        2              0          0

  Atrial Fibrillation   1 (1.6%)  0             0         1        0              1          0

  Bradycardia           1 (1.6%)  1             0         0        1              0          0

  Cancer (Pancreatic)   2 (3.3%)  0             0         2        0              0          2

  Carotid Cavernous     1 (1.6%)  1^(10)^       0         0        1              0          0
  Fistula                                                                                    

  Congestive Heart      2 (3.3%)  0             1^(11)^   1        0              2          0
  Failure                                                                                    

  Diabetes Mellitus     1 (1.6%)  0             0         1        0              1          0
  (new)                                                                                      

  Dysesthesia           2 (3.3%)  0             0         2        0              2          0

  Ecchymosis (eye)      1 (1.6%)  1             0         0        1              0          0

  Fractured Spine       1 (1.6%)  0             0         1        0              1          0

  Kidney Stones         1 (1.6%)  0             0         1        0              1          0

  Nerve Paresis (6^th^) 1 (1.6%)  1             0         0        1              0          0

  Neurologic Symptoms   2 (3.3%)  0             0         2        1^(12)^        0          1^(13)^

  Peripheral Vascular   1 (1.6%)  0             0         1        0              1          0
  Disease                                                                                    

  Rehospitalized for    2 (3.3%)  0             0         2        2^(14,\ 15)^   0          0
  revascularization of                                                                       
  asymptomatic stenosis                                                                      

  Stent Occlusion       1 (1.6%)  1^(16)^       0         0        1              0          0
  (Acute)                                                                                    

  Syncope               2 (3.3%)  0             0         2        0              1          1

  Thrombocytopenia      1 (1.6%)  0             1         0        0              1          0

  Vertebral Artery      1 (1.6%)  0             0         1        1              0          0
  Bypass                                                                                     

  Vertigo               3 (4.9%)  0             0         3        0              3          0
  --------------------- --------- ------------- --------- -------- -------------- ---------- --------------

^(1)^ Procedural' means that the event occurred at the time of the
procedure or within the same hospitalization but not in excess of 30
days within the same hospitalization

^(2)^ Event is pending adjudication by the Clinical Events Adjudication
Committee (CEAC)

^(3)^ Three strokes were adjudicated as major in severity, one as minor

^(4)^ Two of these patients later died

^(5)^ One of these patients later died

^(6)^ No Stent was implanted in one of these patients. Stroke occurred
five months post-procedure and is adjudicated as not related to the test
device or procedure

^(7)^ Adjudicated as not related to the test device or procedure, minor
and ipsilateral, due to local microvascular thrombosis

^(8)^ One of these TIAs was previously reported as, "possible
re-emergence of stroke symptoms". CEAC adjudicated event as "TIA,
probably related to test device and procedure".

^(9)^ Per investigator, symptoms occurred after six-month angiogram and
are not related to the test device, but are probably related to
pre-existing condition or may be reaction to contrast dye used for the
six-month angiogram.

^(10)^ Occurred at the time of the procedure, but did not require
treatment until after 30 days

^(11)^ Exacerbation of existing congestive heart failure at 20 days
post-procedure

^(12)^ Symptoms consistent with malperfusion syndrome related to
restenosis of the target lesion. Stroke and TIA ruled out. Target lesion
revascularization by balloon angioplasty.

^(13)^ Symptoms of facial droop and incontinence which resolved in 15
minutes. Ruled out stroke and TIA.

^(14)^ Six-month angiogram demonstrated 71% in-stent restenosis;
neurologic exam and stroke scale scores unchanged. Patient anxious and
requested treatment. Target lesion revascularization using PTA, with
residual stenosis of 46%. Follow-up unremarkable.

^(15)^ Patient asymptomatic but restenosis determined to be
"hemodynamically relevant" therefore target lesion revascularization
performed with PTA.

^(16)^ Lytic (10mg rt-PA) was administered and occlusion resolved with
no clinical sequelae.

**IX**. **Summary of Pre-Clinical Studies**

***Biocompatability Tests***

The NEUROLINK® System was subjected to biocompatibility testing in
accordance with the ANSI/AAMI//ISO 10993-1, "Biological Evaluation of
Medical Devices Part I: Evaluation and Testing" standard and the May
1994 FDA *Guidance for the Submission of Research and Marketing
Applications for Interventional Cardiology Devices: Intravascular
Stents*. All tests were conducted in compliance with Good Laboratory
Practices regulations (21 CFR § 58).

***Useful Life (Shelf Life/Sterilization)***

The NEUROLINK® System is sterilized by ethylene oxide (EO) using an
overkill process resulting in a sterility assurance level (SAL) of
10^-6^. EO and ethylene chlorohydrin residuals do not exceed limits as
identified in the ANSI/AAMI//ISO 10993-7, "Biological Evaluation of
Medical Devices Part 7: Ethylene oxide sterilization residuals"
standard.

Product and package stability testing of the NEUROLINK® System was
performed following accelerated aging and extreme conditioning. Based
upon these results, an expiration date of 1 year has been established
for NEUROLINK® System.

Packaging integrity testing was performed to verify that the packaging
configuration for the NEUROLINK System has met all relevant guidelines
and current specifications for packaging materials.

***Pyrogens***

The endotoxin/pyrogen level for the NEUROLINK® System is \< 0.06EU/ml
per the *Guidelines for Validation of the Limulus Amebocyte Lysate Test
as End-Product Endotoxin Test for Human and Animal Parental Drug,
Biological Products and Medical Devices, 1987*.

***Magnetic Resonance Imaging Compatibility Evaluations***

The NEUROLINK® Stents are MR safe in MR systems operating at 1.5 Tesla
or less, and radiofrequency (RF) energy-induced heating at a whole body
averaged specific absorption rate (SAR) of 1.2 W/kg will not pose a risk
to the patient implanted with a NEUROLINK® Stent. The Stent will cause
image artifact.

***In Vitro Bench Testing***

*In vitro* bench testing was conducted on the NEUROLINK® System in
accordance with the *Guidance for the Submission of Research and
Marketing Applications for Interventional Cardiology Devices:
Intravascular Stents*. The relevant tests outlined in the guidance were
conducted to demonstrate the in vitro safety and effectiveness of the
NEUROLINK® System. All test units were sterilized by ethylene oxide
prior to *in vitro* bench testing. Summaries of testing conducted for
the NEUROLINK® Stents, NEUROLINK® Stent & Delivery Catheter, and
NEUROLINK® Balloon Dilatation Catheter follows:

**NEUROLINK® Stents**

> ***Material Specification Conformance Testing**:*
>
> [Chemical Analysis:]{.underline}
>
> The NEUROLINK® Stent is fabricated from medical grade 316L stainless
> steel tubing which conforms to ASTM F-138-92 Grade 2 in both the
> chemical analysis and the inclusion/ impurity content. ASTM E1086,
> E1019, and E112 were used to evaluate elemental composition and grain
> size. Scanning Electron Microscopy (SEM) analysis was performed to
> identify and analyze trace surface contaminants. Tensile strength and
> elongation evaluations determined that the NEUROLINK® Stent met the
> product specifications.
>
> [ASTM Conformance:]{.underline}
>
> The NEUROLINK® Stent 316L stainless steel tubing conforms to ASTM
> F-138-92 Grade 2 per the following ASTM Standards:
>
> **Table 4 NEUROLINK® Stent** **-- ASTM Conformance**

  -----------------------------------------------------------------------
  **ASTM         **Title**
  Standard**     
  -------------- --------------------------------------------------------
  ASTM A751-96   Practices and Terminology for Chemical Analysis of Steel
                 Products

  ASTM E1086-94  Standard Method for Optical Emission Vacuum
                 Spectrometric Analysis of Stainless Steel by the Point
                 to Plane Excitation Technique

  ASTM E112-96e1 Standard for Determining Average Grain Size

  ASTM A262-93a  Practices for Detecting Susceptibility to Inter‑granular
                 Attack in Austenitic Stainless Steel

  ASTM           Standard Test Method for Determination of Carbon,
  E1019-94e1     Sulfur, Nickel and Cobalt Alloys

  ASTM E345-97e2 Standard Test Methods for Determining the Inclusion
                 Content of Steel

  ASTM F86-91    Standard Practice for Surface Preparation and Marking of
                 Metallic Surgical Implants

  ASTM G102-89   Practice for Calculation of Corrosion Rates and related
  (1999)         Information from Electrochemical Measurements

  ASTM           Test Method for Making Potentiostatic and
  G5-94(1999)    Potentiodynamic Anodic Polarization Measurements

  ASTM G15-99b   Terminology Relating to Corrosion and Corrosion Testing
  -----------------------------------------------------------------------

***Stent Integrity Testing (8mm and 16mm length Stents):***

> NEUROLINK® Stent samples were measured under magnification for stent
> strut width, thickness, and length, stent free area percentage, length
> change due to expansion of the stent diameter, uniformity of expansion
> of the stent due to balloon inflation, percent recoil of the stent
> after balloon expansion, and radial hoop strength. The structural
> integrity of the NEUROLINK® Stents was evaluated using in vitro
> accelerated fatigue testing and finite element analysis modeling.

**NEUROLINK® Stent & Delivery Catheter**

# Table 5 Summary of Functional Testing

+---------------+----------+---+-------------+--------+--------------+
| **Test**      | **S      |   | **Spec      | **Res  |              |
|               | amples** |   | ification** | ults** |              |
+===============+==========+===+=============+========+==============+
|               | **Size** | * |             | **     | **Outcome or |
|               |          | * |             | Size** | Mean ± SD**  |
|               |          | N |             |        |              |
|               |          | * |             |        |              |
|               |          | * |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
| Delivery      | All 8 mm | 1 | 0.052 mm    | All 8  | All samples  |
| System        | sizes    | 0 |             | mm     | met          |
| Profiles      |          | e |             | sixes  | s            |
|               | 2.5 x 16 | a |             |        | pecification |
| Crimped Stent | mm       | . |             | 2.5 x  |              |
| OD            |          |   |             | 16 mm  |              |
|               | 4.5 x 16 |   |             |        |              |
|               | mm       |   |             | 4.5 x  |              |
|               |          |   |             | 16 mm  |              |
+---------------+----------+---+-------------+--------+--------------+
| Catheter      | 2.5 x 8  | 1 | 3 double    | 2.5 x  | All samples  |
| Preparation   | mm       | 0 | negative    | 8 mm   | passed with  |
|               |          | e | preparation |        | 1 double     |
| Do            | 4.5 x 8  | a | cycles      | 4.5 x  | negative     |
| uble-negative | mm       | . |             | 8 mm   | cycle. One   |
| aspiration    |          |   |             |        | sample (4.5  |
| method with   | All 16   |   |             | All 16 | x 8 mm) did  |
| 60% contrast  | mm sizes |   |             | mm     | not pass     |
| diluted 1:1   |          |   |             | sizes  | (pin hole    |
| with water    |          |   |             |        | leak) and    |
|               |          |   |             |        | was          |
|               |          |   |             |        | replaced.    |
+---------------+----------+---+-------------+--------+--------------+
| Balloon       | All 8 mm | 1 | 30 seconds  | All 8  | All samples  |
| Deflation     | and 16   | 0 |             | mm and | met          |
| Times         | mm sizes | e |             | 16 mm  | s            |
|               |          | a |             | sizes  | pecification |
| at 10 atm     |          | . |             |        |              |
| (147 psi)     |          |   |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
| Stent         | All 8 mm | 3 | 2 mm after  | All 8  | All 8 mm and |
| Movement -    | sizes    | 0 | 2 cycles    | mm     | 16 mm        |
|               |          | e |             | sizes  | samples      |
| through       | 2.5 x 16 | a | with        |        | showed no    |
| rotating      | mm       | . | 95%/99%     | 2.5 x  |              |
| hemostatic    |          |   | confidence/ | 16 mm  | Movement.    |
| valve,        | 4.5 x 16 |   | reliability |        |              |
| guiding       | mm       |   |             | 4.5 x  | \(4\) 2.5 x  |
| catheter, and |          |   |             | 16 mm  | 16 mm units  |
| simulated 50% |          |   |             |        | replaced due |
| stenosis of   |          |   |             |        | to lesions   |
| 3.0mm ID      |          |   |             |        | set-up error |
| tubing,       |          |   |             |        |              |
| lesion ID of  |          |   |             |        | \(1\) 4.5 x  |
| \~1.5 mm      |          |   |             |        | 16 mm unit   |
| located at    |          |   |             |        | damaged      |
| radius of     |          |   |             |        | replaced     |
| curvature of  |          |   |             |        |              |
| 0.927\".      |          |   |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
| Guide         | 2.5x 8   | 1 | No movement | 2.5x 8 | All samples  |
| Catheter      | mm       | 5 | in 1 cycle  | mm     | showed no    |
| Stent         |          | e |             |        | movement     |
| Pullback --   | 4.5 x 8  | a | with        | 4.5 x  |              |
| retraction    | mm       | . | 95%/95%     | 8 mm   |              |
| through 6F    |          |   | confidence/ |        |              |
| guiding       | 2.5 x 16 |   | reliability | 2.5 x  |              |
| catheter      | mm       |   |             | 16 mm  |              |
|               |          |   |             |        |              |
|               | 4.5 x 16 |   |             | 4.5 x  |              |
|               | mm       |   |             | 16 mm  |              |
+---------------+----------+---+-------------+--------+--------------+
| In-Stent      | All 8 mm | 1 | 147 psi     | All 8  | All samples  |
| Catheter      | and 16   | 5 |             | mm and | met          |
| Rupture       | mm sizes | e | with        | 16 mm  | s            |
|               |          | a | 95%/99.9%   | sizes  | pecification |
| at 10 atm     |          | . | confidence/ |        | with         |
| (147 psi)     |          |   | reliability |        | confidence   |
|               |          |   |             |        | and          |
|               |          |   |             |        | reliability  |
+---------------+----------+---+-------------+--------+--------------+
| In-Stent      | All 8 mm | 1 | 40 cycles   | All 8  | All samples  |
| Balloon       | sizes    | 5 |             | mm     | passed with  |
| Inflation     |          | e | with 95%/90 | sizes  | confidence   |
| Fatigue       |          | a | confidence/ |        | and          |
|               |          | . | reliability |        | reliability  |
| at 10 atm     |          |   |             |        |              |
| (147 psi)     |          |   |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
|               | 2.5 x 16 | 3 | 20 cycles   | 2.5 x  | All samples  |
|               | mm       | 0 |             | 16 mm  | passed with  |
|               |          |   | with 95%/90 |        | confidence   |
|               | 4.5 x 16 | e | confidence/ | 4.5 x  | and          |
|               | mm       | a | reliability | 16 mm  | reliability  |
|               |          | . |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
| Stent         | 2.5x 8   | 1 | 2.65 mm     | 2.5x 8 | All samples  |
| Compliance    | mm       | 5 |             | mm     | met          |
|               |          | e | 3.24 mm     |        | s            |
| at 10 atm     | 3.0 x 8  | a |             | 3.0 x  | pecification |
| (147 psi)     | mm       | . | 3.72 mm     | 8 mm   |              |
|               |          |   |             |        |              |
|               | 3.5 x 8  |   | 4.34 mm     | 3.5 x  |              |
|               | mm       |   |             | 8 mm   |              |
|               |          |   | 4.86 mm     |        |              |
|               | 4.0 x 8  |   |             | 4.0 x  |              |
|               | mm       |   | 2.75 mm     | 8 mm   |              |
|               |          |   |             |        |              |
|               | 4.5 x 8  |   | 3.27 mm     | 4.5 x  |              |
|               | mm       |   |             | 8 mm   |              |
|               |          |   | 3.86 mm     |        |              |
|               | 2.5 x 16 |   |             | 2.5 x  |              |
|               | mm       |   | 4.31 mm     | 16 mm  |              |
|               |          |   |             |        |              |
|               | 3.0 x 16 |   | 4.81 mm     | 3.0 x  |              |
|               | mm       |   |             | 16 mm  |              |
|               |          |   |             |        |              |
|               | 3.5 x 16 |   |             | 3.5 x  |              |
|               | mm       |   |             | 16 mm  |              |
|               |          |   |             |        |              |
|               | 4.0 x 16 |   |             | 4.0 x  |              |
|               | mm       |   |             | 16 mm  |              |
|               |          |   |             |        |              |
|               | 4.5 x 16 |   |             | 4.5 x  |              |
|               | mm       |   |             | 16 mm  |              |
+---------------+----------+---+-------------+--------+--------------+
| Inner Member  | 2.5 x 16 | 3 | Reversible  | 2.5 x  | All samples  |
| Collapse      | mm       | 0 | at 10 atm   | 16 mm  | met          |
|               |          |   | (147 psi)   | 4.5 x  | s            |
|               | 4.5 x 16 | e |             | 16 mm  | pecification |
|               | mm       | a |             |        |              |
|               |          | . |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
| Shaft Tensile | 2.5 x 16 | 1 | 1.0 lbs.    | 2.5 x  | All samples  |
| Strength -    | mm       | 0 |             | 16 mm  | met          |
|               |          |   |             | 4.5 x  | s            |
| Proximal luer | 4.5 x 16 | e |             | 16 mm  | pecification |
| adaptor and   | mm       | a |             |        |              |
| distal        |          | . |             |        |              |
| catheter      |          |   |             |        |              |
| shaft         |          |   |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
| Proximal      | 2.5 x 16 | 1 | 1.0 lbs.    | 2.5 x  | All samples  |
| Adaption      | mm       | 0 |             | 16 mm  | met          |
| Tensile       |          |   |             | 4.5 x  | s            |
| Strength      | 4.5 x 16 | e |             | 16 mm  | pecification |
|               | mm       | a |             |        |              |
|               |          | . |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
| Proximal      | All 8 mm | 1 | 1.0 lbs     | All 8  | All samples  |
| Balloon Seal  | sizes    | 0 |             | mm     | met          |
| Tensile       |          | e |             | sizes  | s            |
| Strength -    | 2.5 x 16 | a |             |        | pecification |
|               | mm       | . |             | 2.5 x  |              |
| Proximal      |          |   |             | 16 mm  |              |
| balloon seal  | 4.5 x 16 |   |             | 4.5 x  |              |
| to the distal | mm       |   |             | 16 mm  |              |
| outer member  |          |   |             |        |              |
| junction      |          |   |             |        |              |
+---------------+----------+---+-------------+--------+--------------+
| Soft Tip      | 2.5 x 16 | 1 | 0.5 lbs     | 2.5 x  | All samples  |
| Tensile       | mm       | 0 |             | 16 mm  | met          |
| Strength -    |          |   |             | 4.5 x  | s            |
|               | 4.5 x 16 | e |             | 16 mm  | pecification |
| Distal        | mm       | a |             |        |              |
| balloon seal  |          | . |             |        |              |
| to soft tip   |          |   |             |        |              |
| junction      |          |   |             |        |              |
+---------------+----------+---+-------------+--------+--------------+

**NEUROLINK® Balloon Dilatation Catheter**

> Table 6 Summary of Functional Testing

+----------------+---------+---+-------------+---------+--------------+
| **Test**       | **Sa    |   | **Spec      | **Re    |              |
|                | mples** |   | ification** | sults** |              |
+================+=========+===+=============+=========+==============+
|                | *       | * |             | *       | **Outcome or |
|                | *Size** | * |             | *Size** | Mean ± SD**  |
|                |         | N |             |         |              |
|                |         | * |             |         |              |
|                |         | * |             |         |              |
+----------------+---------+---+-------------+---------+--------------+
| Delivery       | All     | 1 | 0.053 mm    | All     | All samples  |
| System         | sizes   | 0 |             | sizes   | met          |
| Profile-       |         |   |             |         | s            |
|                |         | e |             |         | pecification |
| 2/3 Balloon    |         | a |             |         |              |
| Profile        |         | . |             |         |              |
+----------------+---------+---+-------------+---------+--------------+
| Catheter       | All     | 1 | 3 double    | All     | All samples  |
| Preparation:   | sizes   | 0 | negative    | sizes   | passed with  |
|                |         |   | preparation |         | 1 double     |
| D              |         | e | cycles      |         | negative     |
| ouble-negative |         | a |             |         | cycle.       |
| aspiration     |         | . |             |         |              |
| method with    |         |   |             |         |              |
| 60% contrast   |         |   |             |         |              |
| diluted 1:1    |         |   |             |         |              |
| with water     |         |   |             |         |              |
+----------------+---------+---+-------------+---------+--------------+
| Balloon        | All     | 1 | 30 seconds  | All     | All samples  |
| Deflation      | sizes   | 0 |             | sizes   | met          |
| Times          |         |   |             |         | sp           |
|                |         | e |             |         | ecification. |
| at 10 atm (147 |         | a |             |         |              |
| psi)           |         | . |             |         |              |
+----------------+---------+---+-------------+---------+--------------+
| Catheter       | 2.0x 10 | 1 | 186 psi     | 2.0x 10 | Each size    |
| Rupture (Out   | mm      | 5 |             | mm      | passed with  |
| of Stent)      |         |   | with        |         | confidence   |
|                | 4.0 x   | e | 95%/99.9%   | 4.0 x   | and          |
| at 10 atm (147 | 10 mm   | a | confidence/ | 10 mm   | reliability  |
| psi)           |         | . | reliability |         |              |
|                | 4.5 x   |   |             | 4.5 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 5.0 x   |   |             | 5.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
+----------------+---------+---+-------------+---------+--------------+
| Catheter       | 2.0x 10 | 1 | 147 psi     | 2.0x 10 | Each size    |
| Rupture        | mm      | 5 |             | mm      | passed with  |
| (In-Stent)     |         | e | with        |         | confidence   |
|                | 2.5x 10 | a | 95%/99.9%   | 2.5x 10 | and          |
| at 10 atm (147 | mm      | . | confidence/ | mm      | reliability  |
| psi)           |         |   | reliability |         |              |
|                | 3.0 x   | 1 |             | 3.0 x   |              |
|                | 10 mm   | 9 |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 3.5 x   |   |             | 3.5 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 4.0 x   |   |             | 4.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 4.5 x   |   |             | 4.5 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 5.0 x   |   |             | 5.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
+----------------+---------+---+-------------+---------+--------------+
| In-Stent       | 2.0x 10 | 3 | 20 cycles   | 2.0x 10 | Each size    |
| Balloon        | mm      | 0 |             | mm      | passed with  |
| Inflation      |         |   | with 95%/90 |         | confidence   |
| Fatigue        | 4.0 x   | e | confidence/ | 4.0 x   | and          |
|                | 10 mm   | a | reliability | 10 mm   | reliability  |
| at 10 atm (147 |         | . |             |         |              |
| psi)           | 4.5 x   |   |             | 4.5 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 5.0 x   |   |             | 5.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
+----------------+---------+---+-------------+---------+--------------+
| Balloon        | 2.0x 10 | 1 | 2.04 mm     | 2.0x 10 | All samples  |
| Compliance     | mm      | 5 |             | mm      | met          |
|                |         |   | 2.51 mm     |         | s            |
| at 10 atm (147 | 2.5x 10 | e |             | 2.5x 10 | pecification |
| psi)           | mm      | a | 3.06 mm     | mm      |              |
|                |         | . |             |         |              |
|                | 3.0 x   |   | 3.52 mm     | 3.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   | 4.14 mm     |         |              |
|                | 3.5 x   |   |             | 3.5 x   |              |
|                | 10 mm   |   | 4.61 mm     | 10 mm   |              |
|                |         |   |             |         |              |
|                | 4.0 x   |   | 5.17 mm     | 4.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 4.5 x   |   |             | 4.5 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 5.0 x   |   |             | 5.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
+----------------+---------+---+-------------+---------+--------------+
| Proximal       | 2.0x 10 | 1 | 1.0 lbs     | 2.0x 10 | All samples  |
| Balloon Seal   | mm      | 0 |             | mm      | met          |
| Tensile        |         | e |             |         | s            |
| Strength -     | 4.0 x   | a |             | 4.0 x   | pecification |
|                | 10 mm   | . |             | 10 mm   |              |
| Proximal       |         |   |             |         |              |
| balloon seal   | 4.5 x   |   |             | 4.5 x   |              |
| to the distal  | 10 mm   |   |             | 10 mm   |              |
| outer member   |         |   |             |         |              |
| junction       | 5.0 x   |   |             | 5.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
+----------------+---------+---+-------------+---------+--------------+
| Soft Tip       | 2.0x 10 | 1 | 0.5 lbs     | 2.0x 10 | All samples  |
| Tensile        | mm      | 0 |             | mm      | met          |
| Strength -     |         |   |             |         | s            |
|                | 4.0 x   | e |             | 4.0 x   | pecification |
| Distal balloon | 10 mm   | a |             | 10 mm   |              |
| seal to soft   |         | . |             |         |              |
| tip junction   | 4.5 x   |   |             | 4.5 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
|                |         |   |             |         |              |
|                | 5.0 x   |   |             | 5.0 x   |              |
|                | 10 mm   |   |             | 10 mm   |              |
+----------------+---------+---+-------------+---------+--------------+
| Coating        | 4.0 x   | 1 | 0.157       | 4.0 x   | All samples  |
| Friction       | 10 mm   | 0 |             | 10 mm   | met          |
|                |         |   | Coefficient |         | s            |
|                |         |   | of Friction |         | pecification |
+----------------+---------+---+-------------+---------+--------------+
| Coating Dry    | 4.0 x   | 1 | 0.20% Loss  | 4.0 x   | 1.  ± 0.0 %  |
| Adhesion       | 10 mm   | 0 |             | 10 mm   |     Loss     |
|                |         |   | [\>]{       |         |              |
|                |         |   | .underline} |         | 100 ± 0.0 %  |
|                |         |   | 80%         |         | Adhesion     |
|                |         |   | Adhesion    |         |              |
+----------------+---------+---+-------------+---------+--------------+
| Coating        | 4.0 x   | 1 | 200         | 4.0 x   | No           |
| Particulate    | 10 mm   | 0 | p           | 10 mm   | particulates |
|                |         |   | articulates |         | counted      |
|                | 5.0 x   | e |             | 5.0 x   |              |
|                | 10 mm   | a | \> 0.02 mm2 | 10 mm   | \> 0.02 mm2  |
|                |         | . |             |         |              |
+----------------+---------+---+-------------+---------+--------------+

***Animal Studies***

Preclinical evaluations in swine were conducted with the NEUROLINK®
System and included acute and chronic studies. The acute performance
using angiography included the evaluation of the trackability,
accessibility, deployment accuracy, uniformity of stent expansion and
device compatibility of the NEUROLINK® Stent & Delivery Catheter, and
the NEUROLINK Balloon Dilatation Catheter. The acute performance of the
System was rated as above average when compared to the investigator's
experience with other balloon-expandable stent systems. Angiography at 3
and 28 days post-implant revealed patent lumens and TIMI 3 flow for both
the 8 mm and 16 mm NEUROLINK Stents (TIMI, or Thrombolysis In Myocardial
Infarction, is a grading system to describe blood perfusion, with Grade
0 representing no perfusion and Grade 3 representing complete
perfusion). At 28 days, all of the 20 implanted stents were fully patent
with two (2) of the 8 mm stents exhibiting mild to moderate stenosis and
four (4) of the 16 mm stents exhibiting mild stenosis. Histology
studies, including light microscopy, gross tissue evaluation, and
morphometry, was performed at 3 and 28 days in the chronic studies of
the 8 mm and 16 mm NEUROLINK Stents. With the exception of one (1)
stented vessel at the 28-day time point which showed \>50% stenosis,
vessels examined revealed mild stenosis, mild vessel injury, and mild to
mild/moderate medial compression. The vessels stented with the 16 mm
stent showed mild stenosis, mild vessel injury with the exception of two
(2) vessels with focal moderate injury, and mild to moderate medial
compression. Scanning electron microscope (SEM) analysis was performed
for one sample obtained from the 8 mm NEUROLINK Stent at 28 days. The
stent appeared equally expanded within the lumen and the struts were
well apposed to the wall. The stent was completely covered with a thin
layer of neointima comprised of spindle and polygonal shaped endothelial
cells.

## In separate studies, procedural performance of the device was evaluated in a total of forty-eight (48) NEUROLINK Stent and Delivery Catheters and six (6) NEUROLINK Balloon Dilatation Catheters. The devices were delivered and deployed in the left and right internal mammary arteries, left and right external carotid arteries, right coronary artery, lateral anterior descending artery, left anterior descending artery, right renal artery, and the right and left brachial arteries with a stent-to-artery ratio ranging between 1.0: 1 to 1.2: 1. A total of thirteen (13) pigs were used in five (5) separate studies. The safety and performance was evaluated angiographically for acute and long-term (28 days) studies and histologically for the long-term (28 days) implants. These studies revealed no complications during introduction of the devices through RHV (rotating hemostatic valves) and 6F guides, minimal resistance to contrast injection, ability to access distal anatomy, clinically acceptable radiopacity of the stent, good stent apposition to vessel walls, no angiographic evidence of vessel injury, and TIMI 3 flow.

X.  **Summary of Clinical Information**

## SSYLVIA: Stenting of SYmptomatic atherosclerotic Lesions in the Vertebral and Intracranial Arteries

The NEUROLINK® System was designed for the treatment of atherosclerotic
disease in the neurovasculature. The SSYLVIA clinical study is a
prospective, non-randomized, multi-center, international study and is
ongoing. The objective of the study is to evaluate the safety and
feasibility of the NEUROLINK System for the treatment of symptomatic
atherosclerotic lesions in the extracranial vertebral and intracranial
arteries. Patients were eligible for participation in the study if they
were symptomatic (previous stroke or TIA) due to an angiographically
demonstrated, discrete stenosis \>50% and 5mm in length in an
extracranial vertebral or intracranial artery between 2.5mm and 4.5mm in
diameter. The clinical study evaluated stent use in a broader patient
population than that characterized in the Humanitarian Use Device (HUD)
designation.

All patients were required to receive an antiplatelet regimen beginning
at least 48 hours prior to the procedure. This consisted of aspirin
(minimum 100mg twice daily) and Clopidogrel (75mg twice daily). Heparin
was administered during the Stent implantation procedure to maintain the
activated clotting time (ACT) at a therapeutic level of 200 to 300
seconds.

The NEUROLINK Balloon Dilatation Catheter could be used to predilate the
lesion to facilitate access by the NEUROLINK Stent and Delivery
Catheter. Both the Balloon and Stent were sized in a 1:1 ratio to the
smaller of the diameters of the vessel proximal or distal to the lesion.
Post-dilatation with either the Delivery Catheter or the Balloon
Dilatation Catheter could be used to optimize Stent apposition and
residual stenosis.

Post-procedure, dual antiplatelet therapy was required. This consisted
of aspirin daily for a minimum of one (1) year, plus Clopidogrel for a
minimum of four (4) weeks. Device and procedural safety were determined
by analyzing acute and 30-day individual endpoints, and all adverse
events. All primary endpoints were analyzed on an intent-to-treat basis.

The primary endpoints for safety are clinical outcome at 30 days
(composite stroke and death), and clinical and angiographic outcome at 6
months. Clinical outcome data is reported for the combined patient
population of extracranial vertebral and intracranial lesions.

All patients are required to have independent neurologic examinations
(performed by the non-operator stroke neurologist investigator) at one,
three, six, and 12 months. Angiographic assessment of the stented lesion
is required at six months. All procedure and follow-up angiograms are
analyzed by an independent Angiographic Core Laboratory. Major clinical
events are adjudicated by an independent Clinical Events Adjudication
Committee. The Data Safety Monitoring Board (DSMB) is responsible for
review of the cumulative safety data at scheduled intervals, to ensure
subject safety.

### 

### **Patient Data Available**

Sixty-one (61) patients were enrolled in the study. Results are
presented on all patients through 30 day follow-up. Data is presented
for the 48 patients who have reached 6 month follow-up. Adverse events
are reported for all patients in Table 3.

Table 7. Summary of Patient Data Available

  --------------------------------------- -------------- -----------------
  Visit Type                              Patient Data   Percent of Total
                                          Available\*    (N=61)

  Pre-procedure                           61             100%

  Procedure                               61             100%

  Discharge                               61             100%

  30-day Follow-up                        61             100%

  3-month Follow-up                       54             88.5%

  6-month Clinical Follow-up              48             78.7%

  6-month Angiogram                       42             68.9%
  --------------------------------------- -------------- -----------------

Table 8. Patient Demographics: Age Sex, and Neurological History

+----------------------------------------------+-----------------------+
| Patient Characteristics                      |                       |
+----------------------------------------------+-----------------------+
| Age (years) ^1^                              | 63.4 9.8              |
|                                              |                       |
| Mean SD                                      | 64                    |
|                                              |                       |
| Median                                       | (37, 80)              |
|                                              |                       |
| Range (min, max)                             |                       |
+----------------------------------------------+-----------------------+
| Male                                         | 80.3%                 |
+----------------------------------------------+-----------------------+
| Transient Ischemic Attack                    | 68.9% (42/61)         |
+----------------------------------------------+-----------------------+
| Stroke                                       | 60.7% (37/61)         |
+----------------------------------------------+-----------------------+
| Other Neurological Disease currently being   | 3.3% ( 2/61)          |
| treated or requiring treatment ^2^           |                       |
+----------------------------------------------+-----------------------+

> ^1^ Data available through Age statistics based on 58 patients
>
> ^2^ Back injury in one patient causing back and right leg pain.
> Bladder dysfunction,
>
> described by the investigational site as attributable to neurologic
> deficit in one patient.

Table 9 Medical History: Cardiac

  ------------------------------------------- ---------------------------
  Cardiac Risk Factor                         Percent with Risk Factor

  Hypertension                                63.9% (39/61)

  Coronary Artery Disease (CAD) Intervention  13.1% ( 8/61)

  Angina                                      11.5.% ( 7/61)

  Myocardial Infarction                       11.5% ( 7/61)

  Arrhythmia                                  3.3% ( 2/61)

  Atrial Fibrillation                         3.3% ( 2/61)

  Other Cardiac^1^                            3.3% ( 2/61)

  Patent Foramen Ovale                        3.3% ( 2/61)

  Congestive Heart Failure                    1.6% ( 1/61)

  Surgical Intervention Planned^2^            1.6% ( 1/61)
  ------------------------------------------- ---------------------------

^1^ Aortic valve replacement in one patient, mild mitral valve
insufficiency

^2^ Cardiac catheterization

Table 10 Medical History: Other

  --------------------------------------- -------------------------------
  Risk Factors                            Percent with Risk Factor

  Hypercholesterolemia                    54.1% (33/61)

  Smoking (current or former)             52.5% (32/61)

  Diabetes                                32.8% (20/61)

  Hereditary or Racial Risk               18.0% (11/61)

  Pulmonary Disease: Other\*              13.1% ( 8/61)

  Cancer                                  6.6% ( 4/61)

  Other Significant Risk Factors          4.9% ( 3/61)

  Pulmonary Disease: COPD                 4.9% ( 3/61)

  Substance Abuse                         4.9% ( 3/61)

  GI Bleed                                1.6% ( 1/61)
  --------------------------------------- -------------------------------

\*pulmonary cancer, asbestos exposure, sleep apnea, emphysema, possible

tuberculosis, dyspnea and asthma (two)

Baseline lesion locations are listed in Table 11. Of the 61 subjects,
six (6) lesions were in the vertebral ostium and 12 in the pre-posterior
inferior cerebellar artery (PICA) region of the vertebral artery. These
two lesion types were classified as extracranial. Thus, there were 43/61
(70.5%) intracranial lesions, and 18/61 (29.5%) extracranial vertebral
lesions.

Table 11. Primary Lesion Location

  ---------------------------------------- ------------- ----------------
  Primary Lesion Location                  \# Patients   \% of Total
                                                         (N=61)

  Intracranial                                           

  Basilar -- proximal                      11            18.0%

  Basilar -- mid                           6             9.8%

  Internal Carotid -- Cavernous            7             11.5%

  Intracranial Vertebral -- post PICA      5             8.2%

  Internal Carotid -- Supraclinoid         6             9.8%

  Middle Cerebral                          5             8.2%

  Internal Carotid -- Petrous              2             3.3%

  Posterior Cerebral                       1             1.6%

  Total Intracranial                       43            70.5%

  Extracranial                                           

  Extracranial Vertebral -- pre PICA       12            19.7%

  Extracranial Vertebral Ostium            6             9.8%

  Total Extracranial                       18            29.5%
  ---------------------------------------- ------------- ----------------

###  

### **Primary Endpoints**

The primary endpoints for safety are clinical outcome at 30 days
(composite stroke and death), and clinical and angiographic outcome at 6
months. Clinical outcome data is reported for the combined patient
population of extracranial vertebral and intracranial lesions.

> Table 12. Primary Endpoints

  -------------------------------------------- ----------- --------------
  Primary Endpoints                            (N=61)      

                                               \# Patients \% Incidence

  Death and Stroke (composite) at 30 days      4           6.6%

  Non-Fatal Stroke at 30 days^(1)^             4           6.6%

  Major stroke                                 3           4.9%

  Minor stroke                                 1           1.7%

  Death at 30 days                             0           0%

  Death and Stroke (composite) \> 30 days      8           13.2%

  Non-Fatal Stroke \> 30 days                  4           6.6%

  Major stroke                                 1^(4)^      1.7%

  Minor stroke                                 3           4.9%

  Death \> 30 days                             4^(5)^      6.6%

  Acute Success Measures                                   

  Stent Success^(2)^                           58          95.1%

  Procedure Success^(3)^                       54          88.5%
  -------------------------------------------- ----------- --------------

> ^(1)^The CEAC determined that three of the four strokes were major and
> one stroke was minor. The distinction of Major stroke and Minor stroke
> is based on the NIHSS and/or Modified Rankin Score and/or Barthel
> Index score at 30 days post-stroke.
>
> ^(2)^ Stent Success is defined as achieving a final residual stenosis
> \<50% covering an area no longer than the original lesion. Results are
> based on Core Lab measurements for fifty-three (53) patients and on
> investigator measurements for the patients for whom data is not
> available.

^(3)^ Procedure Success is achieved if there was Stent Success and no
death or stroke prior to discharge.

^(4)^ This patient later died

^(5^ Two (2) patients had non-fatal major strokes within 30 days of
treatment, one (1) patient died of metastatic pancreatic cancer at one
year post procedure, one (1) patient suffered a major stroke at one year
post-procedure.

### 

### **Secondary Endpoints**

The secondary endpoints include access site complications requiring
treatment, angiographic evaluation of the treated segment at six months,
and ipsilateral (same territory) stroke at 12 months.

[Access Site Complications]{.underline}: There was one access site
infection that required treatment, for an incidence rate of 1.6% (1/61).

[Angiographic Evaluation at 6 months]{.underline}: Forty-eight (48)
patients have completed their six month follow-up. The minimum lumen
diameter increased from a mean of 1.00mm at pre-procedure, to a mean of
1.64mm. The percent stenosis decreased from a mean of 69.9%
pre-procedure, to a mean of 50.6% at six months. Eighteen (18) patients
had stenoses \>50% at 6 months and seven of these (38.9%) were
symptomatic, while 11 (61.1%) were asymptomatic.

[Ipsilateral stroke at 12 months:]{.underline}The mean follow-up was 216
days , with a minimum and maximum follow-up of 2 and 367 days,
respectively. Within this follow-up period, there were four (4) strokes.
Four (4) procedure-related strokes occurred; three of these strokes were
major and ipsilateral, and one was minor and contralateral. Four (4)
strokes occurred after 30 days. Three of these strokes were adjudicated
as ipsilateral and minor. The fourth stroke is pending adjudication, and
will be assumed to be ipsilateral for the purpose of this analysis.
Therefore, the lower limit of the rate of ipsilateral stroke at 12
months for this patient population is 11.5% (7/61).

**Table 13. Lesion Characteristics**

This data compares independent angiographic core laboratory measurements
of lesion characteristics pre-procedure, post-procedure, and at 180 days
(6 months) for the combined patient group with extracranial vertebral
and intracranial lesions. Subgroup analysis is provided for intracranial
lesions only.

+-----------+--------+--------+--------+--------+---------+----------+
| Parameter | Ba     |        | Po     |        | 6       |          |
|           | seline |        | st-Pro |        | Months  |          |
|           | ^(1)^  |        | cedure |        |         |          |
|           |        |        | ^(1)^  |        |         |          |
+-----------+--------+--------+--------+--------+---------+----------+
|           | All    | Intrac | All    | Intrac | All     | Intr     |
|           | V      | ranial | V      | ranial | Vessels | acranial |
|           | essels | Only   | essels | Only   |         | Only     |
|           |        | (N=42) |        | (N=42) | (N=42)  | (N=27)   |
|           | (N=60) |        | (N=60) |        | ^(7)^   |          |
+-----------+--------+--------+--------+--------+---------+----------+
| Lesion    | 5.10   | 5.15   |        |        |         |          |
| Length    | 1.91   | 1.91   |        |        |         |          |
| (mm)      |        |        |        |        |         |          |
| ^(2)^     | 4.80   | 4.85   |        |        |         |          |
|           |        |        |        |        |         |          |
| Mean SD   | (1.5,  | (1.5,  |        |        |         |          |
|           | 9.9)   | 9.9)   |        |        |         |          |
| Median    |        |        |        |        |         |          |
|           |        |        |        |        |         |          |
| Range     |        |        |        |        |         |          |
| (min,     |        |        |        |        |         |          |
| max)      |        |        |        |        |         |          |
+-----------+--------+--------+--------+--------+---------+----------+
| Reference | 3.29   | 3.29   | 3.32   | 3.30   | 3.30    | 3.29     |
| Vessel    | 0.70   | 0.74   | 0.68   | 0.71   | 0.61    | 0.65     |
| Diameter  |        |        |        |        |         |          |
| (mm)      | 3.30   | 3.35   | 3.35   | 3.40   | 3.35    | 3.30     |
|           |        |        |        |        |         |          |
| Mean SD   | (1.7,  | (1.7,  | (1.9,  | (1.9,  | (2.0,   | (2.0,    |
|           | 4.7)   | 4.6)   | 5.0)   | 4.7)   | 4.4)    | 4.4)     |
| Median    |        |        |        |        |         |          |
|           |        |        |        |        |         |          |
| Range     |        |        |        |        |         |          |
| (min,     |        |        |        |        |         |          |
| max)      |        |        |        |        |         |          |
+-----------+--------+--------+--------+--------+---------+----------+
| MLD at    | 1.00   | 0.95   | 2.63   | 2.62   | 1.64    | 1.90     |
| Stenosis  | 0.46   | 0.45   | 0.72   | 0.69   | 0.94    | 0.98     |
| (mm)      |        |        |        |        |         |          |
|           | 1.00   | 0.90   | 2.50   | 2.50   | 1.65    | 1.80     |
| Mean SD   |        |        |        |        |         |          |
|           | (0.0,  | (0.0,  | (1.4,  | (1.5,  | (0.0,   | (0.4,    |
| Median    | 2.3)   | 2.0)   | 5.1)   | 4.2)   | 4.2)    | 4.2)     |
|           |        |        |        |        |         |          |
| Range     |        |        |        |        |         |          |
| (min,     |        |        |        |        |         |          |
| max)      |        |        |        |        |         |          |
+-----------+--------+--------+--------+--------+---------+----------+
| Gain in   |        |        | 1.62   | 1.68   | #       | #  {#se  |
| MLD from  |        |        | 0.75   | 0.72   |   {#sec | ction-10 |
| Baseline  |        |        |        |        | tion-5  |  .TOC-1} |
| (mm)      |        |        | 1.60   | 1.75   | .TOC-1} |          |
| ^(3)(6)^  |        |        |        |        |         | #  {#se  |
|           |        |        | (0.1,  | (0.5,  | #       | ction-11 |
| Mean SD   |        |        | 3.7)   | 3.7)   |   {#sec |  .TOC-1} |
|           |        |        |        |        | tion-6  |          |
| Median    |        |        |        |        | .TOC-1} | # 1.89   |
|           |        |        |        |        |         | 0.1 {#se |
| Range     |        |        |        |        | #       | ction-12 |
| (min,     |        |        |        |        |  1.5 0. |  .TOC-1} |
| max)      |        |        |        |        | 9 {#sec |          |
|           |        |        |        |        | tion-7  | #        |
|           |        |        |        |        | .TOC-1} | 1.8 {#se |
|           |        |        |        |        |         | ction-13 |
|           |        |        |        |        | # 1.    |  .TOC-1} |
|           |        |        |        |        | 4 {#sec |          |
|           |        |        |        |        | tion-8  | #        |
|           |        |        |        |        | .TOC-1} | (-0.5, 3 |
|           |        |        |        |        |         | .7) {#se |
|           |        |        |        |        | # (-1   | ction-14 |
|           |        |        |        |        | .3, 2.5 |  .TOC-1} |
|           |        |        |        |        | ) {#sec |          |
|           |        |        |        |        | tion-9  |          |
|           |        |        |        |        | .TOC-1} |          |
+-----------+--------+--------+--------+--------+---------+----------+
| Percent   | 69.9%  | 71.1%  | 20.3%  | 19.7%  | 50.6%   | 43.4%    |
| Stenosis  | 12.41  | 13.08  | 15.38  | 15.66  | 25.6    | 24.1     |
|           |        |        |        |        |         |          |
| Mean SD   | 70.2%  | 70.7%  | 16.67% | 16.24% | 44.8%   | 42.4%    |
|           |        |        |        |        |         |          |
| Median    | (42%   | (42%   | (      | (      | (0%,    | (0.0%,   |
|           | ^(4)^, | ^(4)^, | -9.1%, | -9.1%, | 100%)   | 84.4%)   |
| Range     | 100%)  | 100%)  | 56.3%) | 50.0%) |         |          |
| (min,     |        |        |        |        |         |          |
| max)      |        |        |        |        |         |          |
+-----------+--------+--------+--------+--------+---------+----------+
| Change in |        |        | +49.6% | +51.3% | +17.1%  | #  {#se  |
| %         |        |        | 20.44  | 19.79  | 28.0    | ction-16 |
| Stenosis  |        |        |        |        |         |  .TOC-1} |
| from      |        |        | 46.75% | 52.45% | 44.8%   |          |
| Baselin   |        |        |        |        |         | #  {#se  |
| e^(5)(6)^ |        |        | (3.1%, | (      | #       | ction-17 |
|           |        |        | 100%)  | 17.9%, | (+63.5% |  .TOC-1} |
| Mean SD   |        |        |        | 100%)  | , -50%) |          |
|           |        |        |        |        |  {#sect | #  {#se  |
| Median    |        |        |        |        | ion-15  | ction-18 |
|           |        |        |        |        | .TOC-1} |  .TOC-1} |
| Range     |        |        |        |        |         |          |
| (min,     |        |        |        |        |         | # +      |
| max)      |        |        |        |        |         | 26.4% 26 |
|           |        |        |        |        |         | .7% {#se |
|           |        |        |        |        |         | ction-19 |
|           |        |        |        |        |         |  .TOC-1} |
|           |        |        |        |        |         |          |
|           |        |        |        |        |         | # 42     |
|           |        |        |        |        |         | .4% {#se |
|           |        |        |        |        |         | ction-20 |
|           |        |        |        |        |         |  .TOC-1} |
|           |        |        |        |        |         |          |
|           |        |        |        |        |         | (-15.3%, |
|           |        |        |        |        |         | 90.2%)   |
+-----------+--------+--------+--------+--------+---------+----------+
| \# \>50%  | 57 /   | 40/42  | 1 / 60 | 1 / 42 | 18 / 42 | 10 / 27  |
| Stenosis  | 60     | (95%)  | (1.6%) | (2.6%) | (42.9%) | (37%)    |
|           | (95%)  |        |        |        |         |          |
+-----------+--------+--------+--------+--------+---------+----------+

\(1\) All data is from core lab when available. For seven patients
without core lab data, the physician measurements were used.

\(2\) Twenty-one (21) of 53 lesions measured by the core lab exceeded
5mm length pre-procedure. In all instances the investigator had measured
the lesion as [\<]{.underline}5mm pre- procedure, qualifying the
patients for study enrollment. Sixteen (16) of these lesions were
intracranial.

\(3\) Acute gain is defined as the difference in Minimum Lumen Diameter
(MLD) between the pre- and post-procedure. A positive number indicates
that the lumen is larger after the procedure.

\(4\) The core lab measured three lesions as \<50% stenosis
pre-procedure. Investigators measured these lesions as 50%, 53%, and
63%, respectively, qualifying the patients for study enrollment. Two of
these were intracranial lesions.

\(5\) Change is pre-treatment value minus post-treatment value,
therefore a positive number denotes a decrease in percentage stenosis.

\(6\) A negative number for MLD or % stenosis indicates an increase in
lumen diameter or a reduction in % stenosis.

\(7\) Four of 6 patients with lesions of the extracranial vertebral
ostium had asymptomatic total occlusion at follow-up angiography.

**XI. Risk/Probable Benefit Analysis**

Recurrent stroke attributable to intracranial atherosclerosis refractory
to medical therapy is associated with a poor prognosis. This is the
patient group characterized in the HUD designation. The poor prognosis
is related to additional strokes and clinical events due to
atherosclerosis in other arterial locations. Mechanisms for these
additional strokes include reduced blood flow secondary to decrease in
arterial diameter and arterial to arterial embolism based on plaque
morphology. Stents have been shown to increase arterial diameter in a
variety of arterial locations and to reduce arterial-to-arterial
embolism by altering plaque morphology.

Mechanical and animal model performance evaluations of the stent (sizes
8 and 16 mm), the balloon catheter and the stent delivery catheter were
conducted. The mechanical evaluations determined that the NEUROLINK®
System had sufficient device physical attributes for the intended use of
the product. The preclinical animal model evaluations showed that the
System was comparable to other percutaneous catheter-based
interventional products in handling and placement characteristics. The
acute and chronic time point assessments regarding histological and
angiographically-determined endpoints indicated that the stent was
biocompatible and that it maintained a patent lumen. Although the
clinical study only evaluated the 8 mm stent, the 16 mm stent was
evaluated in preclinical and animal testing. The results of the testing
with the 16 mm stent were comparable to the results obtained with the 8
mm stent. Based on these results, it was concluded that the 16 mm stent
would be expected to perform similarly to the 8 mm stent in clinical
use.

The sponsor has completed a clinical study in 61 patients with
symptomatic extracranial vertebral and intracranial atherosclerosis.
Data obtained for stent use in this more broadly defined patient group
is applicable to the evaluation of safety and probable benefit of the
HUD patient group.

Clinical and angiographic follow-up was completed at 6 months for 48
patients. Pre-dilation of the target lesion and/or post-stent deployment
dilation was performed as clinically indicated. For comparison,
information from two retrospective studies of the same type of patient
population treated under traditional medical therapy was used. In the
Warfarin-Aspirin Intracranial Disease Study ^(1)^, the rate of fatal and
non-fatal stroke was 14.6% and total stroke/death rate was 22.5%
(follow-up of 15-19 months). In the Stanford Study^(2)^ the rate of
fatal and non-fatal stroke was 24.1% and all stroke and death was 27.5%
(mean follow-up of 14.6 months). Therefore in these studies, the
incidence of stroke ranges from 14.6% to 24.1% and the death rate ranges
from 6.8% to 11.7%. The composite rates range from 22.5% to 27.5%. The
data is representative of events occurring over a 14.6 to 19.3 month
time line. The composite death and stroke rate observed in the SSYLVIA
study was 13.2%. Therefore, there was an apparent reduction in the death
and stroke rate of patients treated with the NEUROLINK® System. An
increase in arterial diameter was also demonstrated by angiography in
the SSYLVIA study. The binary angiographic restenosis rate (\>50%) needs
to be interpreted in the context of the clinical event rate.
Dissociation between clinical outcome and angiographic findings in the
treatment of coronary artery disease has been recognized for a number of
years.

Adverse events are noted in Table 3. No unanticipated adverse events
were noted. A total of 8 strokes occurred. Four strokes were considered
device- or procedure-related and occurred at the time of stent
placement. The other 4 occurred after 30 days of follow-up. The type and
frequency of other adverse events are consistent with those generally
reported for percutaneous catheter-based interventions in the
neurovasculature and other arterial locations.

Data for patient outcome at 30 days and 6 months was combined for both
symptomatic extracranial vertebral and intracranial lesions in the
evaluation for the intended stent use. Although the NEUROLINK System is
indicated for only intracranial lesions, data from the treatment of
patients with extracranial lesions supports the conclusion that the
frequency of adverse events experienced with this device is low.

Therefore, it is reasonable to conclude that the probable benefit to
health from using the NEUROLINK System for intracranial stenting for
recurrent stroke attributable to intracranial atherosclerosis refractory
to medical therapy outweighs the risk of illness or injury, taking into
account the probable risks and benefits of currently available devices
or alternative forms of treatment, when used as indicated in accordance
with the directions for use.

XII. **Panel Recommendation**

Review of this application was performed by FDA and by a member of the
Neurological Devices Advisory Panel. The NEUROLINK® Stent (8 mm and
16mm) are very similar in design and device materials to the approved
ACS MULTILINK^TM^ Coronary Stent and the ACS MULTILINK DUET^TM^ Coronary
Stent and it was determined that the clinical issues raised by the HDE
did not require full Panel review.

**XIII. CDRH Decision**

CDRH determined that, based on the data submitted in the HDE, the
NEUROLINK® System will not expose patients to an unreasonable or
significant risk of illness or injury, and the probable benefit to
health from using the device for the treatment of patients with
recurrent intracranial stroke attributable to atherosclerotic disease
refractory to medical therapy in intracranial vessels ranging from 2.5
to 4.5 mm in diameter with ≥ 50% stenosis and that are accessible to the
stent system outweighs the risks of illness or injury, and issued an
approval order on August 9, 2002.

**XIV. Approval Specifications**

**[indications for use:]{.smallcaps}** See Labeling (Attachment 1)

**[information for the patient:]{.smallcaps}** See Patient Brochure
(Attachment 2)

**[hazards to health from use of this device:]{.smallcaps}** See
Indications, Contraindications, Warnings and Precautions, and Adverse
Events in the labeling.

XV. **REFERENCES**

1\. Chimowitz, M.I., Kokkinos, J. and Fayad, P.B. "The Warfarin-Aspirin
Symptomatic Intracranial Disease Study". Neurology 45: 1488-93, 1995.

2\. Thijs, V.N. and Albers, G.W. "Symptomatic intracranial
atherosclerosis: outcome of patients who fail antithrombotic therapy,"
Neurology 55(4):490-7, 2000.