Panel Pack

(Redacted for Distribution)

**Panel Meeting**

**August 5, 2003**

**PMA 030004 - Onyx^®^ Liquid Embolic System for Treatment of Brain
Arteriovenous Malformations**

**Sponsor: Micro Therapeutics, Inc**.

**2 Goodyear**

**Irvine, CA 92618**

# GENERAL INFORMATION

## Device Generic Name

Artificial Embolization Device (21 CFR 882.5950)

Medical Specialty: Neurology, Product Code MFE, Class III

## Device Trade Name

Onyx® Liquid Embolic System (Onyx® LES):

a)  Onyx® 18 (6% EVOH, Model 105-7100-060)

b)  Onyx® 34 (8% EVOH, Model 105-7100-080)

## Intended Use

The Onyx® LES is an artificial embolization device intended for use in
the treatment of brain arteriovenous malformations, when embolization is
indicated to minimize blood loss or to reduce the BAVM size prior to
surgery or radiosurgery.

## Sponsor / Manufacturer Name and Address

Micro Therapeutics, Inc.\
2 Goodyear\
Irvine, CA 92618\
Establishment Registration No. 2029214

## Contact Information

  ----------------------------------- -----------------------------------
  Tom Daughters                       Amy Walters

  Director, Regulatory Affairs        Vice President, Regulatory Affairs

  Phone: (949) 837-3700 ext. 237      Phone: (949) 837-3700 ext. 247

  Fax: (949) 837-2044                 Fax: (949) 837-2044

  <tom.daughters@1mti.com>            <amy.walters@1mti.com>

                                      
  ----------------------------------- -----------------------------------

# TABLE OF CONTENTS

[**1.** **GENERAL INFORMATION 2**](#__RefHeading___Toc45007991)

[1.1. Device Generic Name 2](#device-generic-name)

[1.2. Device Trade Name 2](#device-trade-name)

[1.3. Intended Use 2](#intended-use)

[1.4. Sponsor / Manufacturer Name and Address
2](#sponsor-manufacturer-name-and-address)

[1.5. Contact Information 2](#contact-information)

[2. TABLE OF CONTENTS 3](#table-of-contents)

[3. LIST OF FIGURES 5](#list-of-figures)

[4. LIST OF TABLES 6](#list-of-tables)

[5. BACKGROUND 7](#background)

[5.1. Overview of Disease State 7](#overview-of-disease-state)

[6. SUMMARY OF SAFETY AND EFFECTIVENESS DATA
11](#summary-of-safety-and-effectiveness-data)

[6.1. Device Generic Name 11](#device-generic-name-1)

[6.2. Device Trade Name 11](#device-trade-name-1)

[6.3. Applicants Name and Address 11](#applicants-name-and-address)

[6.4. Pre-Market Approval Application
11](#pre-market-approval-application)

[6.5. Date of Panel Recommendation 11](#date-of-panel-recommendation)

[6.6. Date of GMP Inspection 11](#date-of-gmp-inspection)

[6.7. Date of Notice of Application Approval
11](#date-of-notice-of-application-approval)

[6.8. Indications for Use 12](#indications-for-use)

[6.9. Device Description 12](#device-description)

[6.10. Principle of Operation 12](#principle-of-operation)

[6.11. Materials of Composition 13](#materials-of-composition)

[6.12. Onyx LES Kit Components 13](#onyx-les-kit-components)

[6.13. Ancillary Devices 13](#ancillary-devices)

[6.14. Cautions, Contraindications, Warnings, and Precautions
14](#cautions-contraindications-warnings-and-precautions)

[6.15. Potential Adverse Effects of the Device on Health
17](#potential-adverse-effects-of-the-device-on-health)

[6.16. Alternative Practices And Procedures
18](#alternative-practices-and-procedures)

[6.17. Marketing History 18](#marketing-history)

[6.18. Summary of Pre-Clinical Studies
18](#summary-of-pre-clinical-studies)

[6.19. Summary Of Clinical Studies 24](#summary-of-clinical-studies)

[6.20. Conclusions 29](#conclusions)

[6.21. Panel Recommendations 29](#panel-recommendations)

[6.22. CDRH Decision 29](#cdrh-decision)

[6.23. Approval Specifications 29](#approval-specifications)

[7. DEVICE DESCRIPTION 30](#device-description-1)

[7.1. Trade Name 30](#trade-name)

[7.2. Onyx Description 30](#onyx-description)

[7.3. Principle of Operation 31](#principle-of-operation-1)

[7.4. Onyx Formulation Specification
32](#onyx-formulation-specification)

[7.5. Onyx Viscosity Validation 32](#onyx-viscosity-validation)

[7.6. Onyx Precipitate Morphology 32](#onyx-precipitate-morphology)

[7.7. Materials of Composition 33](#materials-of-composition-1)

[7.8. Component Material Source 34](#component-material-source)

[7.9. Onyx LES Kit Components 35](#onyx-les-kit-components-1)

[7.10. Ancillary Devices 35](#ancillary-devices-1)

[8. PRE-CLINICAL STUDIES 38](#pre-clinical-studies)

[8.1. Pre-Clinical Summary 38](#pre-clinical-summary)

[9. CLINICAL STUDY RESULTS 39](#clinical-study-results)

[9.1. Overview of Clinical Trial 39](#overview-of-clinical-trial)

[10. OTHER RELEVANT STUDIES AND PUBLICATIONS
40](#other-relevant-studies-and-publications)

[10.16. Other Published Onyx Reports 40](#other-published-onyx-reports)

[10.17. Bibliography 49](#bibliography)

[11. LABELING -- INSTRUCTIONS FOR USE
50](#labeling-instructions-for-use)

[12. PHYSICIAN TRAINING PROGRAM 54](#physician-training-program)

# LIST OF FIGURES

[Clinical Protocol Summary 26](#__RefHeading___Toc45008046)

# LIST OF TABLES

**Error! No table of figures entries found.**

# BACKGROUND

## Overview of Disease State

Cerebral arteriovenous malformations (AVMs) are observed when there is
an abnormal development between the arteries and veins. Normally, blood
flows from the arteries to the veins via a capillary bed, but AVMs are
missing this capillary bed. AVMs develop as an abnormal tangle of
vessels (nidus) where the arteries are directly connected to the veins.
Without the existence of the capillary bed, whose role is to dampen the
high pressure as blood flows from the arteries to the veins, blood is
allowed to flow across at high pressure. This high pressure through the
veins causes them to dilate and may continue to hemorrhage.

AVMs have been theorized to develop during the early stages of life and
don't typically become symptomatic for the patients until between 20 and
50 years of age[^1]. Three out of every 10,000 persons are thought to
have an AVM. About 50% of malformations present with intracranial
hemorrhage, and 25% with partial seizures and epilepsy[^2]. The
remaining 25% present in the form of migraine headaches, focal or
general neurological deficits, and cranial nerve dysfunctions. The
annual incidence of intracranial hemorrhage due to arteriovenous
malformations is between 1 and 3 per 100,000^1^.

There are currently several approaches to treating AVMs including
microsurgery, radiosurgery, and endovascular embolization in combination
with micro- or radiosurgery. Microsurgery uses bipolar cauterization and
surgical clips to remove the arterial feeders and retain the transit
artery. The advantages of microsurgery are: 1) The procedure can remove
the total AVM abnormality during the procedure; 2) it has a long proven
track record; and 3) it can be used to treat small and large AVMs. The
disadvantages of microsurgery are: 1) it is invasive, requiring a
craniotomy; 2) the patient is placed under general anesthesia for the
surgical procedure; and 3) certain deep intracranial AVMs cannot be
treated. Results discussed by Deruty et al.^3^ demonstrated that for
lesions of all sizes, a "favorable" outcome can be expected from
microsurgical resection in 81% to 95% of the patients. The mortality
rate from surgical procedures varies from 1% to 14%[^3].

Radiosurgery, unlike microsurgery, involves an intense targeted
radiation that induces endothelial damage, subendothelial deposition of
collagen, and proliferation of vascular smooth muscle in the vessels,
leading to eventual obliteration of the malformation [^4]^,^[^5]. The
advantages of radiosurgery are that it does not require a craniotomy and
it allows for treatment of some small deep lesions that cannot be
treated by microsurgery. The disadvantages of radiosurgery are: 1)
typically lesions larger than 2.5 cm are not treated effectively; 2)
there is an increased possibility of hemorrhage post procedure; and 3)
there exists a risk of injuring adjacent brain tissue[^6]. Total
obliteration rates of AVMs have been reported to be greater than 80%
with the gamma knife[^7], particle beam, and linear accelerator
techniques for lesions with a diameter under 1--3 cm[^8]^,^[^9]. The
complication rates for radiosurgery cannot accurately be compared to
microsurgery and/or embolization procedures due to delayed events (e.g.,
radiation-induced necrosis, and vascular changes) associated with this
treatment.

Endovascular embolization involves the use of catheters to deliver a
variety of occlusive agents such as permanent balloons, sclerosing
drugs, thrombosing coils and rapidly acting glues. The advantages to
performing an embolization procedure are: 1) no craniotomy is required;
2) can treat deep AVMs by treating small areas at a time and allowing
the surrounding brain tissue to recover; and 3) the area to be treated
can be tested prior to determine the reaction of the area before
permanent treatment occurs. The disadvantages of embolization procedures
are: 1) they often require multiple treatments; and 2) they are not
effective in completely obliterating the malformation. Indeed, Gobin et
al[^10] reported that embolization has little chance of completely
occluding an AVM unless the lesion is small or has less than three
feeding vessels. However, embolization has been shown to be useful when
combined with microsurgery or radiosurgery. Currently, the most widely
used embolization technique for AVMs is the injection of acrylic-based
glues. Morbidity and mortality rates associated with embolization
procedures was reported by Gobin et al^10^ as 13% and 2%, respectively.

As discussed above, surgical procedures have advantages and
disadvantages in the treatment of AVMs. Recent studies have shown,
however, that treating the AVM initially with one or more embolization
procedures followed by surgery may provide the best outcome for the
patient. When using this approach, the endovascular embolization
procedure(s) can reduce the size and vascularity of the AVM prior to
microsurgery or radiosurgery and take care of residual malformations
following microsurgery or radiosurgery[^11]. Vinuela et al[^12],
reported a cumulative rate of persistent deficits of 9% and a mortality
rate of 4% for patients who underwent staged embolization procedures
followed by surgical resection. Deruty et al[^13], reported in his paper
that the contribution of endovascular embolization to the management of
cerebral AVMs is generally considered very positive and that it offers
great advantages, making surgical resection safer and easier and
radiosurgery feasible for large malformations.

The most widely used embolic agents for AVMs are the liquid,
acrylic-based glues. Recently, one such glue was approved by FDA
(TRUFILL, PMA #P990040, September 25, 2000) for the embolization of
cerebral arteriovenous malformations when presurgical devascularization
is desired. The challenges faced by clinicians using the acrylic-based
glues are the lack of control in delivery of the product and the extreme
adhesion to all surfaces, including the catheter.

To provide the physician with an effective liquid embolic agent that may
address some of the issues inherent with acrylic-based glues, Micro
Therapeutics Inc., has developed the Onyx^®^ Liquid Embolic System
(LES™). Onyx LES is intended for use in treating patients with brain
AVMs that are intended to undergo subsequent surgical resection. The
system is to be used to reduce the vascular supply to the AVM in order
to reduce the potential for bleeding during the subsequent surgical
resection.

Onyx is a non-adhesive liquid embolic agent comprised of an EVOH
(ethylene vinyl alcohol) copolymer dissolved in DMSO (dimethyl
sulfoxide), and suspended micronized tantalum powder to provide contrast
for visualization under fluoroscopy. The Onyx Liquid Embolic System
consists of a 1.5 ml vial of Onyx, a 1.5 ml vial of DMSO, and three 1 ml
Onyx delivery syringes. A DMSO compatible delivery micro catheter that
is indicated for use in the neurovasculature (e.g. Rebar™ or UltraFlow™
HPC catheters) is used to access the embolization site.

Onyx is delivered through a micro catheter into the feeding vessels of
the AVM under fluoroscopic control. The DMSO solvent dissipates into the
blood and interstitial fluids, causing the EVOH copolymer and suspended
tantalum to precipitate *in situ* into a spongy, coherent embolus. Onyx
immediately forms a skin as the polymeric embolus solidifies from the
outside to the inside. Since Onyx is non-adhesive, the micro catheter
can be left in place while slow, controlled injections are performed.
Post embolization angiography can be conducted with the delivery micro
catheter in place, enabling the physician to make additional injections
of the embolic agent through the same micro catheter, if necessary.

*Onyx Nomenclature*

Three designations have been used for Onyx: one is a historical name,
one is a reference to the polymer concentration, and one is currently
the product name, which correlates to solution viscosity. Prior to
selecting the name Onyx, the historical product name was Embolyx.

[(
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
Data Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
)]{.mark}

Additionally, MTI has licensed the Onyx LES technology to Genyx Medical,
Inc. under the trade name "Uryx" for treatment of female urinary
incontinence, and Enteric Medical, Inc. under the trade name "Enteryx"
for treatment of gastro-esophageal reflux disease. MTI, Genyx and
Enteric have participated in joint biocompatibility and safety studies
for the Onyx material. Hence some studies described herein may reference
one or more of the trade names Onyx, Uryx or Enteryx.

  ----------------------- ----------------------- -----------------------
  **Current Product       **Synonymous Name #1**  **Synonymous Name #2**
  Name**                                          

  Onyx-18                 Embolyx-6% or Onyx-6%   Embolyx E-6%

  Onyx-34                 Embolyx- 8% or Onyx-8%  Embolyx E-8%

  Uryx                    Embolyx - 8% or Onyx-8% NA

  Enteryx                 Embolyx - 8% or Onyx-8% NA
  ----------------------- ----------------------- -----------------------

It is important to note that a direct relationship exists between the
EVOH concentration and the viscosity. For example, a 6% Onyx solution
has an approximate viscosity of 18 cSt and an 8% Onyx solution has an
approximate viscosity of 34 cSt. Both solutions -- Onyx-18 and -34 --
were used for the treatment of AVM in the clinical trial (e.g. \~85%
cases were Onyx-18 & \~15% cases were Onyx-34). Given that the majority
of test reports refer to the % polymer, this designation will be used
throughout this pre-clinical section.

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA

## Device Generic Name

Artificial Embolization Device (21 CFR 882.5950)

Medical Specialty: Neurology, Product Code HCG, Class III

## Device Trade Name

Onyx® Liquid Embolic System (Onyx® LES):

c)  Onyx® 18 (6% EVOH, Model 105-7100-060)

d)  Onyx® 34 (8% EVOH, Model 105-7100-080)

## Applicants Name and Address

Micro Therapeutics, Inc.\
2 Goodyear\
Irvine, CA 92618\
Establishment Registration No. 2029214

## Pre-Market Approval Application

TBD

## Date of Panel Recommendation

TBD

## Date of GMP Inspection

May 27, 2003

## Date of Notice of Application Approval

TBD

## Indications for Use

The Onyx® LES is an artificial embolization device intended for use in
the treatment of brain arteriovenous malformations, when embolization is
indicated to minimize blood loss or to reduce the BAVM size prior to
surgery or radiosurgery.

## Device Description

Onyx is the trade name for a liquid embolization device manufactured by
Micro Therapeutics, Inc. The device is intended for use by the
Interventional Neuro-Radiologist when therapeutic or palliative
embolization of a brain arteriovenous malformation (BAVM) is indicated
to minimize blood loss or to reduce the BAVM size prior to surgery or
radiosurgery.

The liquid Onyx is a simple mixture of ethylene vinyl alcohol co-polymer
(EVOH) dissolved in dimethyl sulfoxide (DMSO). Micronized tantalum
powder is suspended in the liquid polymer/DMSO mixture to provide
fluoroscopic visualization. The Onyx material is delivered in a liquid
phase through a micro catheter to the target lesion under fluoroscopic
control. Upon contact with blood (or body fluids) the solvent (DMSO)
rapidly diffuses away causing in-situ precipitation of a soft radiopaque
polymeric embolus.

Onyx is available to the physician in a range of liquid viscosities
intended to have delivery and precipitation characteristics optimized
for the type of lesion being treated. Lower viscosity Onyx formulations,
achieved by reducing the polymer/DSMO ratio, are appropriate for
embolization of arteriovenous malformations where depth of penetration
in small diameter vessels is required for effective embolization. These
Onyx formulations, designated as Onyx-18 and Onyx-34, have a nominal
liquid viscosity of 18 and 34 centistokes respectively.

## Principle of Operation

Onyx is a pre-mixed, radiopaque injectable embolic agent that is not a
glue and has no adhesive properties. It solidifies through the process
of precipitation. Precipitation is initiated when Onyx comes into
contact with an aqueous solution (e.g., blood, body fluids normal
saline, water) and the solvent DMSO rapidly diffuses out of the polymer
mass.

The liquid Onyx is delivered through a DMSO primed micro catheter
selectively placed within a feeding pedicle of an AVM. Precipitation or
solidification of the material begins immediately upon injection,
beginning as a "skin" on the outside of the mass. Total precipitation
occurs within minutes. The distance that Onyx travels before solidifying
within the vasculature depends on a number of factors, including the
flow rate in the vessel and the rate of injection. In AVM applications,
embolization is intended to reduce the risk of rupture and subsequent
stroke.

## Materials of Composition

### Ethylene Vinyl Alcohol Copolymer (EVOH)

Ethylene Vinyl Alcohol Copolymer (EVOH) is the primary component of the
Onyx material. The EVOH polymer is synthesized by polymerizing a mixture
of ethylene gas (MW 28.05, BP -103.7^o^ C) and vinyl acetate (MW 86.1,
BP 72.2^o^ C). The resulting ethyl vinyl acetate is treated in a basic
pH environment with sodium hydroxide and methanol to hydrolyze the
acetate from the polymeric chain resulting in ethyl vinyl alcohol
(EVOH). The EVOH polymer is washed with methanol to remove the acetate
and other low molecular weight oligomers.

### Dimethyl Sulfoxide (DMSO)

Dimethyl Sulfoxide (DMSO) is used in the Onyx system as a solvent for
the EVOH co-polymer. DMSO is a widely used commercial solvent derived
from trees as a byproduct from the production of paper. In the body,
DMSO rapidly oxidizes to dimethyl sulfone (methlysulfonylmethane-MSM)
and dimethyl sulfide. Both DMSO and MSM are quite soluble in both oil
and water based liquids. However, dimethyl sulfide is hydrophobic and
tends to be insoluble in water and soluble in oil-based liquids. The
elimination of DMSO and MSM happens not only by excretion in the urine
and feces but also by elimination through the lungs and skin in the form
of dimethyl sulfide.

### Tantalum

*Tantalum:* The tantalum component of Onyx is a high radiodensity
material that provides fluoroscopic visualization of Onyx when using
conventional fluoroscopic equipment. The micronized tantalum has
particle size ranging from 0.7 to 22 µm. with approximately 10% of
particles greater than 11 µm, 22% between 6 to 11 µm, and 68% less than
5.5 µm. The 33% w/v of tantalum powder in formulation yields excellent
visualization of Onyx during embolization procedures. As Onyx
precipitates in-situ, the tantalum particles are trapped and
encapsulated within the EVOH polymer.

## Onyx LES Kit Components

Onyx is provided in a kit containing one vial of Onyx (1.5 ml), one vial
of DMSO (1.5 ml) for priming the micro catheter used during the
embolization procedure, and three DMSO compatible syringes (1 ml).
Components are provided sterile and non-pyrogenic, for single use only.

## Ancillary Devices

The Onyx material requires use of compatible delivery devices to assure
patient safety and effective performance of the embolic material. The
Onyx Instructions for Use provides detailed instructions for preparation
and use of recommended syringes and delivery catheters. Each of the
recommended devices has been extensively tested for compatibility with
the Onyx material, DMSO solvent, and embolization procedures.

### MTI UltraFlow Micro Catheter 

The MTI Flow Directed micro catheters are intravascular flow directed
micro catheters intended for delivery of physician specified agents for
diagnosing or treating vascular diseases of the distal neuro and
peripheral anatomy. The catheters are DMSO compatible single lumen
end-hole catheters.

### MTI Rebar Micro Catheter

The Rebar catheters are designed for use in the neuro vasculature and
for delivery of DMSO and the Onyx liquid embolic material after
selective placement in the target lesion. The Rebar catheter is a
single-lumen catheter designed to be introduced over a steerable
guidewire.

### Syringe, 1 ml (DMSO / Onyx Syringes)

Within each Onyx AVM System kit, MTI provides a set of three sterile 1
ml syringes. The syringes are manufactured by MTI using materials
compatible with DMSO and Onyx. One syringe is intended for the injection
of DMSO, and the remaining two syringes are intended for injection of
Onyx. The two syringe types are identical except for the colorant in the
plunger and the printing on the outside syringe barrel.

## Cautions, Contraindications, Warnings, and Precautions

### Cautions

-   Performing embolization to occlude blood vessels is a high risk
    procedure. This device should be used only by physicians with
    neurointerventional training and a thorough knowledge of the
    pathology to be treated, angiographic techniques, and
    super-selective embolization.

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-   Failure to wait a few seconds to retrieve the micro catheter after
    Onyx injection may result in fragmentation of Onyx into non-target
    vessels.

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-   Difficult catheter removal or catheter entrapment may be caused by
    any of the following:

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-   Angioarchitecture: very distal AVM fed by afferent, lengthened, and
    tortuous pedicles

-   Vasospasm

-   Reflux

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-   Should catheter removal become difficult, the following will assist
    in catheter retrieval:

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-   Carefully pull the catheter to assess any resistance to removal.

-   If resistance is felt, remove any \"slack\" in the catheter.

-   Gently apply traction to the catheter (approximately 3-4 cm of
    stretch to the catheter).

-   Hold this traction for a few seconds and release. Assess traction on
    vasculature to minimize risk of hemorrhage.

-   This process can be repeated intermittently until catheter is
    retrieved.

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-   For entrapped catheters:

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-   Under some difficult clinical situations, rather than risk rupturing
    the malformation and consequent hemorrhagic complications by
    applying too much traction on an entrapped catheter, it may be safer
    to leave the micro catheter in the vascular system.

-   This is accomplished by stretching the catheter and cutting the
    shaft near the entry point of vascular access allowing the catheter
    to remain in the artery.

-   If the catheter breaks during removal, distal migration or coiling
    of the catheter may occur. Same day surgical resection should be
    considered to minimize the risk of thrombosis.

### Contraindications

-   Not for use with premature infants (\<1,500 g) or individuals with
    significant liver function impairment.

### Warnings

-   Inspect product packaging prior to use. Do not use if sterile
    barrier is open or damaged.

-   Verify that adequate sedation is used throughout the embolization
    procedure. Insufficient sedation may result in patient discomfort or
    movement. Patient movement during embolic agent injection may result
    in embolization of an unintended vessel.

> **NOTE:** Adjunctive coil use should be considered if angiography
> shows that venous drainage of the AVM appears almost simultaneously
> with arterial opacification. Based on results from *in* *vitro* and
> *in vivo* testing, coil placement prior to Onyx injection should be
> considered for feeding pedicles with AV fistulae having flow rates
> exceeding 200 ml/min and vessel diameters of 3 mm or greater.

-   Failure to continuously mix Onyx for the required time may result in
    inadequate suspension of the tantalum, resulting in inadequate
    fluoroscopic visualization during delivery.

-   Use only MTI micro catheters. Other micro catheters may not be
    compatible with DMSO and their use can result in thromboembolic
    events due to catheter degradation.

-   Use only the MTI 1 ml syringe to inject DMSO and Onyx. Other
    syringes may not be compatible with DMSO.

-   Premature solidification of Onyx may occur if micro catheter luer
    contacts saline, blood or contrast of any amount.

-   Inject Onyx immediately after mixing. If Onyx injection is delayed,
    tantalum settling can occur within the syringe resulting in poor
    visualization of Onyx during injection.

```{=html}
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```
-   Do not exceed 0.3 ml/min injection rate. Animal studies have shown
    that rapid injection of DMSO into the vasculature may lead to
    vasospasm and/or angionecrosis.

-   Only use thumb pressure to inject Onyx. Using palm of hand to
    advance plunger may result in catheter rupture due to
    overpressurization in the event of catheter occlusion.

-   Adequate fluoroscopic visualization must be maintained during Onyx
    delivery or non-target vessel embolization may result. If
    visualization is lost at any time during the embolization procedure,
    HALT Onyx delivery until adequate visualization is re-established.

-   Do not allow more than 1 cm of Onyx to reflux back over catheter
    tip. Excessive Onyx reflux may result in difficult catheter removal.

-   After using a micro catheter with Onyx, do not attempt to clear or
    inject any material through it. Such attempts may lead to embolus or
    embolization of an unintended area.

-   STOP injection if Onyx is not visualized exiting catheter tip. If
    the catheter becomes occluded, over-pressurization can occur. During
    Onyx injection, continuously verify that Onyx is exiting the
    catheter tip. Testing has shown that over-pressurization and rupture
    can occur if 0.05 ml of Onyx is injected and is not visualized
    exiting the catheter tip.

-   STOP injection if increased resistance to Onyx injection is
    observed. If increased resistance occurs, determine the cause (e.g.,
    Onyx occlusion in catheter lumen) and replace the catheter. Do not
    attempt to clear or overcome resistance by applying increased
    injection pressure, as use of excessive pressure may result in
    catheter rupture and embolization of unintended areas.

-   DO NOT interrupt Onyx injection for longer than two minutes prior to
    re-injection. Solidification of Onyx may occur at the catheter tip
    resulting in catheter occlusion, and use of excessive pressure to
    clear the catheter may result in catheter rupture.

## Potential Adverse Effects of the Device on Health

Safety was examined for all patients enrolled in the clinical trial.
This section presents a summary of all patients in the Intention to
Treat (ITT) cohort, which includes all patients in which treatment of
the assigned device was attempted. Safety was assessed based on the
nature and severity of adverse events.

The safety profile for the two groups was also comparable. Although more
patients in the Onyx group experienced a serious adverse event, the
number of serious adverse events experienced was equal in the two
groups, and there was not a statistically significant difference between
the two groups for patient based serious AE rates. In addition, many of
the events occurred during or post surgery as opposed to during or post
embolization with the Onyx Liquid Embolic System. None of the events was
considered unanticipated and the rate of the device related adverse
events was very similar in both groups.

The table below provides a summary of the hierarchical events with only
one event (worst event) listed per patient. A total of 15 patients in
the n-BCA group and 19 patients in the Onyx group experienced at least
one serious adverse event. The worst event for each patient whether it
was the primary or a cascaded event from another less severe event is
presented in the table. There were no unanticipated adverse device
effects. In the case of the patients that had an event and subsequently
expired, the event that is listed in the table is death.

Two patients died during the course of the clinical trial. Both deaths
occurred in the Onyx group and both occurred following surgical
resection.

There were no unanticipated adverse device events reported in this
trial.

  ------------------------------- ------------------- ---------- -------------------
  **EVENT NAME**                  **Group**                      

                                  **n-BCA\            **Onyx\    
                                  (n=54 pts)**        (n=46      
                                                      pts)**     

  *Death*                         0 (0%)              2 (4.4%)   

  *Intracranial Hemorrhage*       8 (15%)             6 (13%)    

  *Stroke*                        0 (0%)              1 (2%)     

  *Worsening Neuro Status*        5 (9.3%)            7 (15%)    

  *Hydrocephalus*                 0 (0%)              2 (4.4%)   

  *Seizures*                      0 (0%)              1 (2%)     

  *Headache +/- nausea and        2 (3.7%)            0 (0%)     
  vomiting*                                                      

  ***TOTAL***                     ***15***            ***19***   

                                                                 
  ------------------------------- ------------------- ---------- -------------------

Additional adverse events, which may be associated with embolization
procedures (including those not observed during the clinical study\*)
include:

+-----------------------------------+-----------------------------------+
| -   Access site bleeding          | -   Laboratory/imaging            |
|                                   |     abnormalities                 |
| -   Headache                      |                                   |
|                                   | -   Infection                     |
| -   Nausea and vomiting           |                                   |
|                                   | -   Fever                         |
| -   Medication reaction           |                                   |
|                                   | -   Tongue swelling               |
| -   Patient discomfort            |                                   |
|                                   | -   Psychotic episode             |
| -   Cardiac arrhythmia            |                                   |
|                                   | -   Thrombocytopenia              |
| -   Allergic reaction             |                                   |
|                                   | -   AVM rupture\*                 |
| -   Passage of embolic material   |                                   |
|     into normal vessels adjacent  | -   Pulmonary embolism\*          |
|     to the lesion                 |                                   |
+-----------------------------------+-----------------------------------+
|                                   |                                   |
+-----------------------------------+-----------------------------------+

## Alternative Practices And Procedures

Endovascular embolization of cerebral arteriovenous malformations (AVMs)
as described in the literature, involves the use of catheters to deliver
a variety of occlusive agents such as permanent balloons, sclerosing
drugs, thrombosing coils, polyvinyl alcohol (PVA) particles, and rapidly
acting glues, such as n-Butyl cyanoacrylate. Currently, the most widely
used embolization technique for AVMs is the injection of acrylic-based
glues.

## Marketing History

The Onyx LES system was first placed on the market in August 1999, in
Europe with the CE mark for use in the treatment of arteriovenous
malformations. Onyx continues to be marketed throughout most European
countries, Canada, Turkey, Australia, and some Latin American countries.
Onyx has not been withdrawn from the market in any country for any
reason.

## Summary of Pre-Clinical Studies

This section presents summaries of important preclinical studies in
support of safety and effectiveness of the Onyx LES system. The
following pre-clinical studies were conducted to ensure that the Onyx
LES is safe and effective for its intended use and environment:
Mechanical/Chemical Tests, Biocompatibility Studies, Animal Studies, and
Pre-trial Clinical Experience.

### Mechanical/Chemical Tests

These tests cover the basic characterization of Onyx as a solution and
as an implanted precipitate, as well as compatibility with
syringes/catheters and other embolic devices, such as coils.

+-------------+--------------------------------------------------------+
| **Study**   | **Results and Conclusions**                            |
+=============+========================================================+
| Tantalum    | This test was performed to determine the minimum       |
| Suspension  | required shake time to mix and assure homogenous       |
|             | tantalum dispersion in Onyx. Data from this study      |
|             | demonstrates that using the IFU‑ recommended shake     |
|             | time results in consistent and homogeneous tantalum    |
|             | dispersion within the vial, supported by an            |
|             | appropriate safety factor.                             |
+-------------+--------------------------------------------------------+
| Onyx        | To determine Onyx solidification time, MTI             |
| Sol         | precipitated Onyx in saline to create spherical Onyx   |
| idification | masses (approximately 3 mm in diameter). At controlled |
| Time        | time intervals, MTI compressed the Onyx spheres to     |
|             | determine when liquid could no longer be expelled from |
|             | the mass. The results demonstrated that Onyx spheres   |
|             | were completely solidified (no liquid expelled from    |
|             | the Onyx mass) within 3 minutes.                       |
+-------------+--------------------------------------------------------+
| Material    | To determine Onyx expansion characteristics during or  |
| Expansion   | after precipitation, MTI precipitated several aliquots |
|             | of Onyx in saline and evaluated the resulting Onyx     |
|             | masses over time for various mechanical properties,    |
|             | including appearance and size. Results demonstrated    |
|             | that the Onyx masses remained coherent for the 7-day   |
|             | test period, with no measurable size differences.      |
+-------------+--------------------------------------------------------+
| Particulate | To determine whether Onyx generates particles in its   |
| Generation  | final precipitated form, MTI precipitated Onyx in      |
|             | bottles containing 60 mL of saline to create spherical |
|             | Onyx masses (approximately 3 to 4 mm in diameter). The |
|             | bottles were capped and repeatedly inverted in order   |
|             | to create fluid shear forces. The Onyx spheres were    |
|             | removed and the effluent tested using a                |
|             | spectrophotometer. The test results demonstrated that  |
|             | Onyx particulate generation was less than the maximum  |
|             | allowable per USP XXV \<788\> .                        |
+-------------+--------------------------------------------------------+
| Material    | To characterize the adhesive properties of Onyx, MTI   |
| Adhesion    | (1) measured the force required to extract various     |
|             | catheters from a precipitated Onyx mass and (2)        |
|             | compared catheter Onyx extraction force to n-butyl     |
|             | cyanoacrylate (n-BCA) embolic agents or "glues." MTI   |
|             | allowed a catheter to remain entrapped in an Onyx mass |
|             | for 60 minutes. After 60 minutes, when pulled at       |
|             | approximately 1-2 cm, the catheters released from the  |
|             | Onyx mass with relatively low force as compared to the |
|             | minimum tensile strength requirements of the           |
|             | catheters. No evidence of Onyx adhesion or             |
|             | fragmentation was observed. MTI then allowed a         |
|             | catheter to become entrapped in glue for 2 minutes     |
|             | (due to the adhesive nature of glues, the previous     |
|             | 60-minute wait time associated with Onyx was reduced   |
|             | to 2 minutes). The study demonstrated that glues       |
|             | require significantly higher extraction force (after   |
|             | significantly less time) than Onyx.                    |
+-------------+--------------------------------------------------------+
| Effects of  | To determine if Onyx precipitates are affected by a    |
| Radiation   | radiation dosage of 30 Gray, MTI divided 70 grams of   |
| and         | Onyx into small aliquots of precipitate. The test      |
| Stability   | samples were exposed to 30 Gray of radiation at the    |
| Onyx        | UCLA Medical Center; aged at 55°C for 210 days (2 year |
| P           | equivalent) and tested for biocompatibility, chemical  |
| recipitates | stability, and physical integrity. The test samples    |
|             | exhibited no significant differences from the control  |
|             | samples. The test results demonstrated that Onyx was   |
|             | unaffected by radiation levels encountered during      |
|             | radiosurgery.                                          |
+-------------+--------------------------------------------------------+
| Infusion    | To verify that infusion pressures generated during     |
| Pressures   | delivery of Onyx were within safe burst specification  |
|             | limits of the IFU recommended catheters, MTI infused   |
|             | Onyx at various infusion rates at 37°C into the        |
|             | UltraFlow and the Rebar micro catheters. The maximum   |
|             | recommended infusion rate for Onyx is 0.3 ml/min. Onyx |
|             | at an infusion rate of 0.5 ml/min was considered a     |
|             | worst-case test. The study demonstrated that infusion  |
|             | rates of 0.1 to 0.5 ml/min generated infusion          |
|             | pressures significantly below the minimum burst        |
|             | specification of the IFU-recommended catheters.        |
+-------------+--------------------------------------------------------+
| Device      | To determine if DMSO (the active solvent in Onyx)      |
| (Catheter   | degrades the supplied/recommended delivery devices     |
| and         | (the UltraFlow and the Rebar micro catheters and the 1 |
| Syringe)    | mL syringes), MTI assessed chemical and functional     |
| Chemical    | performance of the delivery devices after exposure to  |
| Co          | DMSO. MTI infused DMSO through each delivery device,   |
| mpatibility | then tested the DMSO-exposed catheters for static      |
| Testing     | burst and tensile strength and the syringes for peak   |
|             | force and visualization of gradations. The test        |
|             | results demonstrated that delivery device strength     |
|             | values (burst, tensile and peak force) and the         |
|             | visibility of the gradations did not degrade after     |
|             | extended DMSO exposure and were significantly similar  |
|             | to non-DMSO exposed samples. MTI also tested the       |
|             | effluent (from the DMSO infusion) through High         |
|             | Performance Liquid Chromatography (HPLC) and compared  |
|             | the result to a pure DMSO control sample. The results  |
|             | showed no additional peaks other than DMSO,            |
|             | demonstrating that DMSO (and therefore Onyx) is        |
|             | chemically compatible with both recommended delivery   |
|             | catheters and the syringes.                            |
+-------------+--------------------------------------------------------+
| Adjunctive  | To verify chemical and functional compatibility of     |
| Device      | Onyx and DMSO with other embolic devices, MTI          |
| Co          | identified and tested the following two types of       |
| mpatibility | embolic agents: (1) hydraulically delivered 0.010"     |
| (Coils and  | embolic metal coils; and (2) n-BCA based embolic       |
| Glues)      | agents or "glues".                                     |
|             |                                                        |
|             | The results demonstrated that Onyx successfully        |
|             | solidified and occluded simulated vessels up to 5 mm   |
|             | with deployed coils and that DMSO did not leach any    |
|             | materials from the tested coils. Also, there was no    |
|             | chemical interaction shown with Onyx and histoacryl    |
|             | glue.                                                  |
+-------------+--------------------------------------------------------+
| St          | Dry Heat sterilization of Onyx and DMSO is performed   |
| erilization | and validated using a half cycle approach with BI      |
| Validation  | indicators (consistent with EN550) to achieve an SAL   |
|             | of 10^‑6^.                                             |
|             |                                                        |
|             | Ethylene Oxide Sterilization of the packaged Syringes  |
|             | is performed and validated according to ANSI/AAMI/ISO  |
|             | 11135-1994, Medical Devices Validation and Routine     |
|             | Control of Ethylene Oxide Sterilization.               |
+-------------+--------------------------------------------------------+
| Package     | The Onyx system was subjected to a Federal Express     |
| Integrity   | vibration and drop testing for packages 0 -- 75 lbs    |
|             | according to ISTA 1A / D4169 following 4 days at       |
|             | --20ºC, 29 days at 55ºC and humidity less than 20% and |
|             | 27 days at 55ºC and 70-80% relative humidity. The test |
|             | results demonstrated appropriate package integrity.    |
+-------------+--------------------------------------------------------+
| Sterile     | To demonstrate appropriate sterile barrier, aged vials |
| Product --  | (three years accelerated aging) were subjected to      |
| DMSO and    | pressure leak testing and were tested for sterility.   |
| Onyx        | No leaks were observed, and all tested samples were    |
| sterile     | sterile. Based on test results, the sterile barrier    |
| barrier     | vial package system for DMSO and Onyx is an effective  |
|             | sterile barrier.                                       |
+-------------+--------------------------------------------------------+
| Onyx Real   | MTI evaluated the effects of aging on the performance  |
| Time and    | of Onyx by conducting accelerated and real time aging  |
| Accelerated | testing to support a 3-year product shelf life. The    |
| Aging       | tests consisted of Leakage, Product Sterility,         |
|             | Cytotoxicity, Molecular Weight Distribution,           |
|             | Viscosity, Density, Precipitation and Extractables on  |
|             | Precipitation. Based on the testing results, Onyx      |
|             | System met the necessary criteria for a 3-year shelf   |
|             | life.                                                  |
+-------------+--------------------------------------------------------+
| DMSO Real   | MTI evaluated the effects of aging on the performance  |
| Time and    | of DMSO by conducting accelerated and real time aging  |
| Accelerated | testing to support a 3-year product shelf life. The    |
| Aging       | testing consisted of analysis for impurities,          |
|             | including dimethyl sulfone. There were no trends in    |
|             | the levels or types of impurities. Based on the        |
|             | testing results, DMSO met the necessary criteria for a |
|             | 3-year shelf life.                                     |
+-------------+--------------------------------------------------------+
|             |                                                        |
+-------------+--------------------------------------------------------+

###  Biocompatibility Studies

Biocompatibility studies were performed per ISO 10993-1, Biological
evaluation of medical devices for permanent implants, blood contact.
Additional biocompatibility testing was performed per FDA's *Guidance on
Biocompatibility Requirements for Long Term Neurological Implants.*

Summary Table: ISO 10993-1 Biocompatibility Test Results

+-------------+---------------------------------+---------------------+
| **Test      | **Title**                       | **Results**         |
| De          |                                 |                     |
| scription** |                                 |                     |
+=============+=================================+=====================+
| *Cy         | MEM Elution Test Evaluation     | No evidence of      |
| totoxicity* |                                 | cytotoxicity at     |
|             |                                 | dilution of 1:4 or  |
|             |                                 | greater             |
+-------------+---------------------------------+---------------------+
| *Cy         | MEM Elution Test Evaluation of  | No evidence of      |
| totoxicity* | DMSO                            | cytotoxicity at     |
|             |                                 | dilution of 1:4 or  |
|             |                                 | greater             |
+-------------+---------------------------------+---------------------+
| *Sen        | Guinea Pig Maximization         | Grade I, Weak       |
| sitization* | (Magnussen/Kligman Method)      | response;           |
|             |                                 | equivalent to       |
|             | (Saline & cottonseed oil        | negative control    |
|             | extracts)                       |                     |
+-------------+---------------------------------+---------------------+
| *Int        | USP Intracutaneous Reactivity   | Met USP             |
| racutaneous | (Saline & cottonseed oil        | requirements        |
| Reactivity* | extracts)                       |                     |
+-------------+---------------------------------+---------------------+
| *Acute      | USP Systemic Toxicity           | Met USP             |
| Systemic    |                                 | requirements        |
| Toxicity*   | (Saline & cottonseed oil        |                     |
|             | extracts)                       |                     |
+-------------+---------------------------------+---------------------+
| *Subacute   | Fourteen Day Subacute           | Non-Toxic           |
| Toxicity*   | Intravenous Dosing Study        |                     |
|             | (Saline extract)                |                     |
+-------------+---------------------------------+---------------------+
| *Im         | USP Seven Day Muscle Implant    | USP requirements    |
| plantation* |                                 | not met due to      |
|             |                                 | acute tissue        |
|             |                                 | response. Greater   |
|             |                                 | irritant than       |
|             |                                 | control             |
+-------------+---------------------------------+---------------------+
| *Im         | One Year Intramuscular Implant  | Stabilized as       |
| plantation* | With and Without Tantalum in    | minimal to mild     |
|             | Rabbits                         | inflammatory        |
|             |                                 | response            |
+-------------+---------------------------------+---------------------+
| *Ge         | Bacterial Reverse Mutation      | Extracts were       |
| notoxicity* | Assay Conducted with Test       | negative,\          |
|             | Article Extracts                | passed test.        |
|             |                                 |                     |
|             | (Saline and DMSO extracts)      |                     |
+-------------+---------------------------------+---------------------+
| *Ge         | In Vitro Mammalian Cell Gene    | Extracts were       |
| notoxicity* | Mutation Test Conducted with    | negative,\          |
|             | Test Article Extracts           | passed test.        |
|             |                                 |                     |
|             | (Saline and DMSO extracts)      |                     |
+-------------+---------------------------------+---------------------+
| *Ge         | Micronucleus Cytogenic Assay in | Extracts were       |
| notoxicity* | Mice Conducted with Test        | negative,\          |
|             | Article Extracts                | passed test.        |
|             |                                 |                     |
|             | (Saline and corn oil extracts)  |                     |
+-------------+---------------------------------+---------------------+
| *Carci      | Carcinogenicity Using the       | Not carcinogenic    |
| nogenicity* | *ras*H2 Transgenic Mouse Model  |                     |
+-------------+---------------------------------+---------------------+
|             |                                 |                     |
+-------------+---------------------------------+---------------------+

### Animal Studies

Study of DMSO Angiotoxicity in a Swine Model:

MTI evaluated acute and chronic effects of dimethyl sulfoxide (DMSO)
injection into the vascular system by injecting varied DMSO volumes and
injection rates into swine rete. MTI used angiography to detect
vasospasm or occlusion of the exposed vessels and performed gross and
microscopic histological analysis to detect possible angiotoxicity. MTI
performed hemodynamic monitoring and clinical evaluation on all test
swine. The study indicated that no clinical abnormalities were observed
for animals tested with any combination of DMSO volume or injection rate
and "slow" DMSO infusion rates (0.33 mL/min) resulted in no evidence for
long-term damage to the retia.

Acute and Chronic Histopathological Changes in a Swine AVM Model:

MTI used Onyx 6% to embolize an animal (swine rete) model to establish
the effectiveness of Onyx as an occlusive agent, the tolerance of
tissues and inflammatory reactions and the likely embolization of
non-target areas. MTI used angiography to confirm placement of the
delivery catheter, advancement of the Onyx material during delivery and
subsequent occlusion of the rete. To establish acute and chronic
effects, animals were sacrificed acutely and chronically (3, 6, and 12
months following the embolization). The study indicated that acute and
chronic specimens showed total or near total occlusion of the target
rete with no evidence of endothelial denudation or arterial wall
angionecrosis. No arterial wall angionecrosis or extravasation of
embolic material was observed in any specimen. There was no evidence of
embolization of non-target areas. Points of focal disruption of the
elastica were observed without extravasation of Onyx into the
perivascular space, however at 12 months specimens exhibited a
substantial decrease in chronic inflammation.

Pathology Comparison to GDCs:

To demonstrate equivalent chronic tissue response to a currently
approved embolic device, MTI compared histological and pathological
results of Guglielmi Detachable Coils (GDCs) to Onyx at 3 and 6-month
chronic periods. The study showed that the Onyx had acceptable tissue
response comparable to GDC with inflammation diminishing to mild focal
collections of lymphocytes and giant cells in 12-month chronic
specimens. Healthy neointimal tissue remodeling with variably mature
endothelial cell growth was observed in continuity with the parent
artery lumen in all Onyx. The study results indicate that histological
and pathological response to Onyx is acceptable and at least equivalent
to the response to GDCs.

Biocompatibility for Long Term Neurological Implants:

To characterize the chronic effect of Onyx in direct contact with
neurological tissue in the subarachnoid space, MTI injected (cisterna
magna) 60 rabbits (15 per group) with either Onyx-6%, Onyx-25%, saline
control, or autologous blood control. Within each group, 5 animals each
were survived for 2, 4, or 90 days prior to DSA angiography, sacrifice,
gross pathology, and histopathology. There was no evidence of direct
toxicity of Onyx when injected into the subarachnoid space of a rabbit
model.

One-Year Intramuscular Implant Evaluation:

To determine the effects of EVOH with and without tantalum when
implanted intramuscularly, thirty rabbits each received six
intramuscular injections of either EVOH or EVOH‑T and two intramuscular
implants of the control article, USP Reference Standard High‑Density
Polyethylene. The study results demonstrated that there is no difference
between the effects (either local or systemic) of EVOH materials when
implanted intramuscularly for a period of one year. While chronic
minimal to mild inflammation occurred at almost all sites implanted with
both EVOH material types, there was no evidence of tissue changes beyond
the margins of the implant site, and there was no evidence of implant
material migration to other sites.

### Pre-trial Clinical Experience

Histopathology Study of AVMs Embolized with Onyx:

Seven patients with AVMs were treated using Onyx as an embolic agent.
There were no reported ischemic or hemorrhagic complications resulting
from untoward migration or abrupt occlusion of an AVM nidus. In order to
assess the histopathologic changes seen in the vasculature exposed to
Onyx, BAVMs embolized with Onyx were surgically excised from 7 patients.
The histopathology results compared favorably to changes described with
endovascular embolization with other commonly used embolic materials,
such as cyanoacrylates, polyvinyl alcohol particles, ethanol and
combination materials. The use of Onyx for embolization of BAVMs does
not appear to be definitively associated with any morphologic changes
expected to produce adverse clinical sequelae.

MRI/CT Evaluation of AVMs treated with Onyx or n-BCA:

A retrospective, masked review was conducted on Onyx and
n-butylcyanoacrylate (n‑BCA) patients to determine if any direct
neurotoxicity was detected in the brain post‑AVM embolization using
current imaging methods. A central reader reviewed pre- and
post-embolization MRI or CT scans, from 73 patients. Fifty-four AVM
patients were treated with Onyx and 19 AVM patients were treated with
n-BCA. All MRI and CT studies were evaluated for the presence or absence
of gliosis, encephalomalacia, edema, leptomeningeal or parenchymal
enhancement and hemorrhage. The study indicated that there is no imaging
evidence that these embolic devices are associated with cerebral imaging
abnormalities.

### Pre-clinical Studies Conclusion

In conclusion, the pre-clinical data presented in this submission
demonstrate that:

-   Onyx and its associated devices performed within engineering
    specifications.

-   Onyx is biocompatible, non-carcinogenic, and non-toxic to
    neurological tissue. The data showed that Onyx implantation was
    coincident with a local inflammatory response that resolved over
    time.

-   Onyx, tested in relevant animal models, safely and effectively
    embolized blood vessels. Local inflammatory responses, similar to
    those observed with GDCs, resolved over time. Angiotoxicity was not
    observed when Onyx was injected slowly into the blood vessels.

Onyx pre-clinical human experience agreed with the above results and
illustrated the promise of the technology for AVM treatment.

## Summary Of Clinical Studies

The purpose of the study entitled "U.S. Multicenter, Randomized,
Controlled Study \[IDE G000296\] Comparing the Performance of
Onyx^®^(EVOH) and TRUFILL^®^ (n-BCA) in the Presurgical Embolization of
Brain Arteriovenous Malformations (BAVMs)" was to evaluate the safety
and effectiveness of Onyx LES compared to TRUFILL for the presurgical
treatment of brain AVMs.

The clinical investigation was approved by FDA to enroll up to 106
patients (53 per treatment arm) at up to 20 clinical sites throughout
the U.S. All patients who met the inclusion and exclusion criteria at
the investigational sites were randomized to either the Onyx or TRUFILL
treatment arms. Patients underwent embolization procedure(s) to reduce
the size of the AVM prior to surgical resection. Neurological
assessments (i.e., NIH scale, Barthel Index, and Glasgow Index) were
performed prior to and post embolization and/or surgical resection, when
surgery was performed. Patients without total resection were followed
for 1 year. Both safety and efficacy analysis were performed to compare
the results of the investigational treatment arm (i.e., Onyx) to the
approved, control treatment arm (i.e., TRUFILL, n-BCA). These results
and analysis are reported in the following sections of this submission.
This multicenter trail was conducted at 20 investigational sites, with a
total of 108 patients randomized and 106 patients enrolled.

### Study Purpose

The purpose of this study was to obtain prospective clinical data on the
performance of Onyx and TRUFILL in the presurgical embolization of AVMs.
Device safety was assessed by comparing overall and device-related
morbidity and mortality. The primary efficacy endpoint was the
angiographic reduction in AVM size (volume) achieved. A level of 50% or
greater reduction in size was established as a criterion for success.
The objective was to demonstrate that Onyx is no worse than TRUFILL in
terms of efficacy within a specified clinical tolerance (20%).

### Design

This study was designed as a prospective, randomized, multi-center
clinical comparison of the MTI Onyx Liquid Embolic System to the Cordis
TRUFILL n-Butyl cyanoacrylate (n-BCA) liquid adhesive for the
presurgical treatment of brain arteriovenous malformations. Patients
were randomized on a 1:1 basis for embolization with either Onyx or
TRUFILL to result in 53 patients per group.

### Methods

Patients were evaluated for potential enrollment based on the inclusion
and exclusion criteria of the protocol. Upon enrollment, a baseline
clinical neurological examination was performed and grading scales
including Barthel Index, Glasgow Coma Scale (GCS) and NIH Stroke Scale
(NIHSS) were recorded. In addition, baseline CT, MRI, and/or angiograms
were performed for complete characterization of the AVM prior to
randomization. Patients were randomized when the AVM and clinical
characteristics aligned with the inclusion and exclusion criteria
outlined in the clinical protocol. Once randomized, patients entered a
regime of embolization as deemed appropriate by the investigator. After
each embolization procedure, patients were neurologically evaluated
using the same scales as pre procedure except for the Glasgow Scale
which was measured utilizing the Glasgow Coma Scale pre procedure and
the Glasgow Outcome Scale Post Procedure. Upon completion of the
embolization phase, patients were referred for surgery or other
nonsurgical course of treatment including radiosurgery or no further
treatment. Patients that were completely resected received a final
neurological examination with grading scale assessments as a final
evaluation of the protocol. Those patients with AVMs that were not
completely resected underwent follow-up evaluations at 3 and 12 months.
The follow-up assessments included a complete neurological examination
with grading scales including Barthel Index, Glasgow Outcome Score (GOS)
and NIH Stroke Scale (NIHSS) and evaluation of safety. A clinical
protocol summary flowchart is shown below.

[]{#__RefHeading___Toc45008046 .anchor}Clinical Protocol Summary

![](media/image1.wmf)

### Efficacy Endpoints

The primary efficacy measure was technical success as measured by
angiographic reduction in AVM size (volume) of 50% or greater as
assessed by core laboratory. Angiographic size reduction is defined as
the change from the original AVM size prior to any embolization
procedure, to the AVM size after the last embolization procedure.

The results for the primary efficacy endpoint demonstrate that the two
products are comparable with regard to AVM exclusion efficacy, and thus,
the primary study hypothesis (i.e., Onyx is no worse than n-BCA in terms
of AVM obliteration defined as ≥ 50% occlusion as assessed by core
angiographic laboratory) was achieved using both an Intention to Treat
and Per Protocol analysis approach. In fact, the intention to treat
analysis demonstrated superiority of the Onyx performance over n-BCA
(p = 0.0377).

### Primary Endpoint Summary

+-------------+-----------+-----------+--------------+--------------+
| **Core Lab  | **n-BCA\  | **Onyx\   | *            | **Relative   |
| A           | (n= 54)** | (n= 46)** | *Difference\ | Risk\        |
| ngiographic |           |           | \[95% CI\]** | \[95% CI\]** |
| Success**   |           |           |              |              |
+-------------+-----------+-----------+--------------+--------------+
| *Inte       | 84.3%     | 97.6%     | 13.3%        | 1.16         |
| nt-to-Treat | (43/51)   | (41/42)   | \[2.3%,      | \            |
| Analysis*   |           |           | 24.3%,\]     | [1.01,1.32\] |
+-------------+-----------+-----------+--------------+--------------+
| *Per        | 85.7%     | 95.4%     | 9.6%         | 1.11 \[0.97, |
| Protocol    | (42/49)   | (41/43)   | \[-2.0%,     | 1.27\]       |
| Analysis*   |           |           | 21.3%\]      |              |
+-------------+-----------+-----------+--------------+--------------+
| Diff = Onyx |           |           |              |              |
| -- n-BCA;   |           |           |              |              |
| SE =        |           |           |              |              |
| s           |           |           |              |              |
| qrt(p~1~q~1 |           |           |              |              |
| ~/n~1~+p~2~ |           |           |              |              |
| q~2~/n~2~); |           |           |              |              |
| CI =        |           |           |              |              |
| Di          |           |           |              |              |
| ff±1.96\*SE |           |           |              |              |
|             |           |           |              |              |
| RR =        |           |           |              |              |
| Onyx/n-BCA; |           |           |              |              |
| SE =        |           |           |              |              |
| sqrt{(1-    |           |           |              |              |
| p~1~)/      |           |           |              |              |
| n~11~+(1-   |           |           |              |              |
| p~2~)/      |           |           |              |              |
| n~21~}; CI  |           |           |              |              |
| =           |           |           |              |              |
| RR\*exp     |           |           |              |              |
| (±1.96\*SE) |           |           |              |              |
+-------------+-----------+-----------+--------------+--------------+
|             |           |           |              |              |
+-------------+-----------+-----------+--------------+--------------+

The study had two secondary efficacy endpoints, surgical blood loss and
surgical resection time. There was considerable variability in these
endpoints primarily due to the complexity of this disease state and the
associated surgery for resection. No statistically significant
differences were observed for either of these two secondary endpoints.

### Secondary Efficacy Endpoint Summary

  -------------------------------------- ---------------- ----------------
  **Secondary Endpoints**                **n-BCA\         **Onyx\
                                         (n= 54)**        (n= 46)**

  ***Blood loss index (p Value =                          
  0.55)***                                                

  mean±sd (n)                            892 ± 1067 (44)  1127 ± 1401 (43)

  Median                                 475              550

  range (min, max)                       100-5000         50-6550

  ***Surgical resection time (p Value =                   
  0.99)***                                                

  mean±sd (n)                            411 ± 201 (42)   399 ± 179 (42)

  Median                                 344              366

  range (min, max)                       150, 1019        82, 940

                                                          
  -------------------------------------- ---------------- ----------------

### Safety Endpoints

Safety was assessed by the nature and severity of adverse events. An
adverse event is defined by the clinical protocol as a clinical
deviation away from a patient's baseline health.

The safety profile for the two groups was also comparable. Although more
patients in the Onyx group experienced a serious adverse event, the
number of serious adverse events experienced was equal in the two
groups, and there was not a statistically significant difference between
the two groups for patient based serious AE rates. In addition, many of
the events occurred during or post surgery as opposed to during or post
embolization with the Onyx Liquid Embolic System. None of the events was
considered unanticipated and the rate of the device related adverse
events was very similar in both groups.

### Safety Endpoint Summary

  ------------------------------ -------------- -------------- ------------
  **Safety (Pt based) % of       **n-BCA\       **Onyx\        **p
  patients\                      (n= 54)**      (n= 46)**      Value\***
  (pts. with SAE/total sample)**                               

  *Serious Adverse Event*        27.8% (15/54)  41.3% (19/46)  0.20

  *System-related SAE*           3.7% (2/54)    8.7% (4/46)    0.41

  *Treatment-related SAE*        5.6% (3/54)    10.9% (5/46)   0.46

  *Surgery related SAE*          20.4% (11/54)  21.7% (10/46)  1.00

  *Disease related SAE*          1.9% (1/54)    4.3% (2/46)    0.60

  \* Fisher's Exact Test                                       
  ------------------------------ -------------- -------------- ------------

### Technical and Procedural Events

Technical Events were reported for each device and included any
malfunction of the embolic device or accessory devices (including the
delivery catheter) during the embolization procedure. Procedural Events
included any unintended or undesirable result, observation or
abnormality noted by the physician during the embolization procedure
(such as vasospasm or a minor vessel dissection). These events were
specifically related to technical aspects of the product or procedural
aspects of the treatment and were *NOT* associated with any adverse
events. If there was an adverse event that was associated with the
investigational product, it was summarized as an adverse event and
categorized as system related.

In addition to safety and efficacy, technical and procedural events were
analyzed. The results of these analyses demonstrated that the frequency
of these types of events between the two treatment groups was
comparable, as shown in the table below.

### Technical/Procedural Events Summary

  ------------------------------------------ -------------- --------------
                                             **n-BCA\       **Onyx\
                                             (n= 54)**      (n= 46)**

  *Technical Events (# of events)*           11             18

  *Procedural Events (# of events)*          12             3

  *Total Technical/Procedural Events (# of   23             21
  events)*                                                  

  *Percent of Patients with                  31.5% (17/54)  30.4% (14/46)
  Technical/Procedural Events\*\                            
  (# of events/# of patients)* \*p=0.91                     

                                                            
  ------------------------------------------ -------------- --------------

Thus, Onyx demonstrated equivalent performance to n-BCA in terms of
technical and procedural performance.

### Clinical Study Conclusions

In conclusion, the clinical study has met its study hypothesis,
demonstrating non‑inferiority of Onyx in comparison to n-BCA in the
ability to occlude an AVM prior to surgical resection. In fact, the
Intention to Treat analysis demonstrates superior performance of Onyx
over n-BCA. Secondary efficacy endpoint analysis shows no difference in
surgical blood loss and surgical resection time between the two groups.
Although not a study endpoint, adjunctive use of coils was found to be
lower in the Onyx group. The safety profile has been shown to be similar
between the two groups. There were no unanticipated adverse device
effects, and there were no technical or performance issues that would
preclude generalized use of the Onyx system. The summary of this
clinical study supports the marketing approval for the Onyx Liquid
Embolic System.

## Conclusions

This study provides reasonable assurance of the safety and effectiveness
of the Onyx® Liquid Embolic System (Onyx® LES) for the treatment of
brain arteriovenous malformations, when embolization is indicated to
minimize blood loss or to reduce the BAVM size prior to surgery or
radiosurgery.

## Panel Recommendations

TBD

## CDRH Decision

TBD

## Approval Specifications

TBD

# DEVICE DESCRIPTION

## Trade Name

Onyx^®^ Liquid Embolization System (LES)

a)  Onyx 18, Model 105-7100-060

```{=html}
<!-- -->
```
e)  Onyx 34, Model 105-7100-080

## Onyx Description

Onyx is the trade name for a liquid embolization device manufactured by
Micro Therapeutics, Inc. The device is intended for use by the
Interventional Neuro-Radiologist when therapeutic or palliative
embolization of a brain arteriovenous malformation (BAVM) is indicated
to minimize blood loss or to reduce the BAVM size prior to surgery or
radiosurgery.

![](media/image2.jpeg){width="2.9791666666666665in" height="2.125in"}The
liquid Onyx is a simple mixture of ethylene vinyl alcohol co-polymer
(EVOH) dissolved in dimethyl sulfoxide (DMSO). Micronized tantalum
powder is suspended in the liquid polymer/DMSO mixture to provide
fluoroscopic visualization. The Onyx material is delivered in a liquid
phase through a micro catheter to the target lesion under fluoroscopic
control. Upon contact with blood (or body fluids) the solvent (DMSO)
rapidly diffuses away causing in-situ precipitation of a soft radiopaque
polymeric embolus.

Onyx is available to the physician in a range of liquid viscosities
intended to have delivery and precipitation characteristics optimized
for the type of lesion being treated. Lower viscosity Onyx formulations,
achieved by reducing the polymer/DSMO ratio, are appropriate for
embolization of arteriovenous malformations where depth of penetration
in small diameter vessels is desirable for effective embolization. These
Onyx formulations, designated as Onyx-18 and Onyx-34, have a nominal
liquid viscosity of 18 and 34 centistokes respectively.

#### ![](media/image3.jpeg){width="1.3743055555555554in" height="1.9236111111111112in"} ![](media/image4.wmf) ![](media/image5.jpeg){width="1.31875in" height="1.9340277777777777in"}

The appropriate viscosity for a given procedure is determined by
physician preference, the BAVM morphology, and the extent of distal
penetration desired. The higher viscosity Onyx 34 (nominal viscosity of
33 cSt at 40 °C) is recommended when feeding pedicle injections will be
conducted close to the nidus, at flow rates up to 200 ml/min, and in 3
mm or smaller diameter vessels. The lower viscosity Onyx 18 (nominal
viscosity of 18 cSt at 40°C) is recommended when feeding pedicle
injections will be conducted close to the nidus, and the flow rate is
less than 50 ml/min. Onyx-18 will travel more distally and penetrate
deeper into the nidus due to its lower viscosity compared to Onyx-34.
Final solidification occurs within five minutes for both product
formulations.

## Principle of Operation

Onyx is a pre-mixed, radiopaque injectable embolic agent that is not a
glue and has no adhesive properties. It solidifies through the process
of precipitation. Precipitation is initiated when Onyx comes into
contact with an aqueous solution (e.g., blood, body fluids normal
saline, water) and the solvent DMSO rapidly diffuses out of the polymer
mass.

The liquid Onyx is delivered through a DMSO primed micro catheter
selectively placed within a feeding pedicle of an AVM. The DMSO priming
volume assures separation of Onyx from blood, saline or contrast media
within the catheter lumen that may cause early precipitation and
catheter occlusion. The Onyx material is injected into the AVM at a slow
rate of approximately 0.16 ml/min. Precipitation or solidification of
the material begins immediately upon injection, beginning as a "skin" on
the outside of the mass. Total precipitation occurs within minutes. The
distance that Onyx travels before solidifying within the vasculature
depends on a number of factors, including the flow rate in the vessel
and the rate of injection. In AVM applications, embolization is intended
to reduce the risk of rupture and subsequent stroke.

![](media/image6.jpeg){width="2.5145833333333334in" height="1.8875in"}
![](media/image7.jpeg){width="2.5145833333333334in"
height="1.8895833333333334in"}

## Onyx Formulation Specification

The following table specifies the formulation and the components of
Onyx-18 (6%) and Onyx-34 (8%).

[( \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
Data Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
)]{.mark}

## Onyx Viscosity Validation

The Onyx formulations have been characterized by their kinematic
viscosity and are measured in Centistokes (cSt). For example, Onyx-18
(6% EVOH) has an approximate viscosity of 18 cSt and Onyx-34 (8% EVOH)
has an approximate viscosity of 34 cSt at 40°C. Validation activities
were performed on various attributes of the Onyx formulations including
kinematic viscosity. Post sterilization viscosity measurements were
taken using calibrated glass Zeitfuchs (capillary) cross-arm
viscometers. Test results met all acceptance criteria and yielded
average viscosities within the specifications.

[]{.mark}

[( \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
Data Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
)]{.mark}

## Onyx Precipitate Morphology

The internal and external morphology of a solidified Onyx mass is shown
in the pictures below. Onyx formulations, ranging from 6% - 50%, were
precipitated in saline forming spheres of approximately 3 mm in
diameter. The Onyx spheres were solidified, sectioned, and examined
under high magnification. Results showed that as the % EVOH increased,
the outside surface of the spheres became smoother in appearance.
Internal morphology revealed a soft spongy mass containing several small
voids. Voids decreased as % EVOH increased (e.g. higher viscosity Onyx
formulations).

[( \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
Data Redacted \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-- )]{.mark}

## Materials of Composition

### Ethylene Vinyl Alcohol Copolymer (EVOH)

Ethylene Vinyl Alcohol Copolymer (EVOH) is the primary component of the
Onyx material. The EVOH polymer is synthesized by polymerizing a mixture
of ethylene gas (MW 28.05, BP -103.7^o^ C) and vinyl acetate (MW 86.1,
BP 72.2^o^ C). The resulting ethyl vinyl acetate is treated in a basic
pH environment with sodium hydroxide and methanol to hydrolyze the
acetate from the polymeric chain resulting in ethyl vinyl alcohol
(EVOH). The EVOH polymer is washed with methanol to remove the acetate
and other low molecular weight oligomers.

[(\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--Data
Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--)]{.mark}

The homopolymers of EVOH, polyethylene and polyvinyl alcohol (PVA), from
which the copolymer EVOH is derived, have a long history as implant
materials. Polyethylene is used in numerous implant applications,
including surgical spinal cable, auricular reconstruction, prostheses
for spinal disk replacement, and in joint implants for the acetabular,
patellar, and tibial surfaces. In addition to these well-established
uses, polyethylene is a USP reference standard often employed as a
negative polymer control during biocompatibility testing. Similarly, PVA
has been used clinically in topical ophthalmic solutions, plasma
expanders, and, in the application most closely related to Onyx, as a
permanent particle embolization material. The ethylene vinyl alcohol
copolymer is used as a hemodialysis and plasmapheresis membrane.

### Dimethyl Sulfoxide (DMSO)

Dimethyl Sulfoxide (DMSO is used in the Onyx system as a solvent for the
EVOH co-polymer. DMSO is a widely used commercial solvent derived from
trees as a byproduct from the production of paper. In the body, DMSO
rapidly oxidizes to dimethyl sulfone (methlysulfonylmethane-MSM) and
dimethyl sulfide. Both DMSO and MSM are quite soluble in both oil and
water based liquids. However, dimethyl sulfide is hydrophobic and tends
to be insoluble in water and soluble in oil-based liquids. The
elimination of DMSO and MSM happens not only by excretion in the urine
and feces but also by elimination through the lungs and skin in the form
of dimethyl sulfide.

DMSO is a widely used treatment for interstitial cystitis (IC). Its
liquid form, *Rimso-50*, was approved by the FDA for use in treating IC
in 1978 (NDA 017788). In this application a 50% solution of DMSO is
instilled intravesically via catheter into the bladder for10-20 minutes.
The solution has both anti-inflammatory and analgesic properties. It is
believed to inhibit free-radical production, thus reducing pain and
inflammation. It also aids in the absorption of other bladder-instilled
medication.

[(\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--Data
Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--)]{.mark}

### Tantalum

*Tantalum:* The tantalum component of Onyx is a high radiodensity
material that provides fluoroscopic visualization of Onyx when using
conventional fluoroscopic equipment.[^14]

[(\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--Data
Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--)]{.mark}

In addition to high radiodensity properties, tantalum was chosen as the
contrast agent because it is insoluble, inert, and has a history of
successful use in medicine.[^15] Tantalum powder has been used
successfully over many years by several investigators as a radiocontrast
agent in embolic compositions such as PVA particles, cyanoacrylate glues
and silicones.[^16]^,^ [^17]^,^ [^18]^,^ [^19] Tantalum is an inert
metal with a history of use in implants requiring incorporation of a
contrast agent, such as arterial stents, hip prostheses, and
embolization materials. In addition to its use in embolization
materials, tantalum powder has been used as a contrast agent injected
into the cervical spinal cord for visualization during percutaneous
cordotomy. Additionally, tantalum powder has found uses in neurosurgery,
to mark the plane of section in lobotomy or leucotomy, to provide
visualization or definition of a site for tumor removal, and for
detection of recurrent subdural hematoma after surgery.

## Component Material Source

[( \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
Data Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
)]{.mark}

## Onyx LES Kit Components

![](media/image8.png){width="2.4277777777777776in" height="2.5in"}Onyx
is provided in a kit containing one vial of Onyx (1.5 ml), one vial of
DMSO (1.5 ml) for priming the micro catheter used during the
embolization procedure, and three DMSO compatible syringes (1 ml).
Components are provided sterile and non-pyrogenic, for single use only.

Onyx and DMSO are packaged in 2mL glass injection vials each with an
elastomeric stopper crimped in place with an aluminum cap. The cap does
not contact the Onyx or DMSO solution at any time.

The glass vial is low extractable highly resistant borosilicate glass
that meets ASTM Type I, Class A and USP Type I standards. This is a
glass type defined in the USP as suitable for pharmacopeial preparations
and is typically used for heat sterilized, parentrally administered
solutions. The vial stopper is an elastomeric chlorobutyl-isoprene blend
with a Teflon™ (tetrafluroethylene) liner for all surfaces in contact
with Onyx or DMSO.

## Ancillary Devices

The Onyx material requires use of compatible delivery devices to assure
patient safety and effective performance of the embolic material. The
Onyx Instructions for Use provides detailed instructions for preparation
and use of recommended syringes and delivery catheters. Each of the
recommended devices has been extensively tested for compatibility with
the Onyx material, DMSO solvent, and embolization procedures. Relevant
compatibility data is provided in the Pre-clinical Studies section of
this submission.

The ancillary devices referenced below have been approved for CE marking
in accordance with the requirements of ISO 9001 Quality System, EN
46001, Medical Device Particular Requirements for the Application of EN
ISO 9001; and FDA cleared for commercial distribution in the U.S. as
noted.

### MTI UltraFlow Micro Catheter 

The MTI Flow Directed micro catheters are intravascular flow directed
micro catheters intended for delivery of physician specified agents for
diagnosing or treating vascular diseases of the distal neuro and
peripheral anatomy. The catheters are generally inserted via a femoral
artery puncture site and advance to the desired vascular anatomy.

The catheters are DMSO compatible single lumen end-hole catheters. The
catheters have a semi-rigid proximal shaft that tapers into a highly
flexible distal end section to facilitate catheter advancement in the
distal peripheral and neuro vasculature. The proximal end of the
catheter incorporates a standard luer adapter hub to facilitate
attachment of accessories. The distal end of the catheter has a
radiopaque marker band for fluoroscopic visualization.

Initially introduced in 1998 as the FlowRider Flow Directed Catheter
(Model 105-5060), the catheter has undergone performance improvements
and is currently marketed as the UltraFlow HPC Flow Directed Micro
Catheter, Models 105-5065 and 105-5066. (Note: Previous catheter names
\"EnRoute\" and "Modified FlowRider" were abandoned due to trademark
conflicts.) Re.: 510(k) - K980104, K010004, K024118

### MTI Rebar Micro Catheter

The Rebar catheters are designed for use in the neuro vasculature and
for delivery of DMSO and the Onyx liquid embolic material after
selective placement in the target aneurysm. The Rebar catheter is a
single-lumen catheter designed to be introduced over a steerable
guidewire. The catheter has a semi-rigid proximal shaft which
transitions into the flexible distal shaft to facilitate catheter
advancement in the neuro vasculature. The catheters have dual radiopaque
markers at the distal end to facilitate fluoroscopic visualization. The
catheters have a hydrophilic outer surface coating. Re.: 510(k) -
K993672, K001966

### Syringe, 1 ml (DMSO / Onyx Syringes)

Within each Onyx AVM System kit, MTI provides a set of three sterile 1
ml syringes. The syringes are manufactured by MTI using materials
compatible with DMSO and Onyx. One syringe is intended for the injection
of DMSO, and the remaining two syringes are intended for injection of
Onyx. The two syringe types are identical except for the colorant in the
plunger and the printing on the outside syringe barrel. The color
differences between the two syringes facilitate the delivery of their
intended injectants. The three syringes are packaged within a sterile
Tyvek peel pouch and chipboard carton. Re.: 510(k) - K991225

![](media/image9.jpeg){width="3.285416666666667in" height="4.0625in"}

# PRE-CLINICAL STUDIES

## Pre-Clinical Summary

The Mechanical/Chemical Tests present in vitro data collected on Onyx as
a precipitate and as a liquid injected through accessory devices. These
tests cover the basic characterization of Onyx as a solution and as an
implanted precipitate through to its compatibility with
syringes/catheters and other embolic devices (e.g. Guglielmi Detachable
Coils). The combined conclusion from these tests demonstrates that the
mechanical/chemical behavior of Onyx and its accessory devices, from
sterile, packaged product to final implant, is well characterized within
engineering specifications.

The Biocompatibility Studies present the ISO-10993-1 tests, a
neurological implant test, and DMSO safety/toxicology data. The
ISO-10993-1 tests used Onyx-8% that contains the greatest amount of
polymer in the final implant configuration, which is worst-case.
Departures from this strategy were made for two specific tests. The
carcinogenicity test in transgenic mice was performed with Onyx-6% at
two different dosing volumes to give a high and low range. The
neurological implant study in the rabbit cerebellomedullary cistern was
performed with Onyx-6% and with Onyx-25% to ensure adequate safety
margin. Additional information is presented on the stability and
toxicology of DMSO. In total, these reports show that Onyx injections in
the cerebrovasculature are safe.

The Animal Studies extend the characterization and safety data by
illustrating the safe and efficacious use of Onyx in several animal
models. Two peer-reviewed, published swine neurovacular studies show
that (1) Onyx is safe and effective for vascular embolization and that
(2) the injection of the DMSO/EVOH/Ta solution can be accomplished
without angiotoxicity. Although not an AVM study, an aneurysm study was
performed in surgically created swine aneurysms with GDC controls that
demonstrated comparable tissue responses between Onyx and GDC. These
relevant animal models demonstrated that Onyx safely and effectively
embolized blood vessels, without angiotoxicity or systemic
complications.

The pre-trial Human Experience demonstrates consistent results when
compared to the above safety and efficacy data. Seven AVM patients
treated with Onyx showed histopathological results that were comparable
to other embolic agents such as cyanoacrylate, poly vinyl alcohol,
ethanol, and combination materials. Finally, MRI/CT scans from AVM
patients treated with Onyx and n-BCA were reviewed and did not show any
cerebral imaging abnormalities. The preliminary patient data agree with
the above in vitro/in vivo data and suggest the promise of the Onyx AVM
treatment.

[( \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
Data Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
)]{.mark}

# CLINICAL STUDY RESULTS

## Overview of Clinical Trial

The PMA summary data presented were collected under IDE G000296. A
summary of the clinical protocol is provided in Exhibit 4. A review of
the regulatory history for this IDE is provided in Exhibit 5. Copies of
the two clinical protocols with the Case Report Forms (Version C and D)
are located in Exhibits 6 and 7, respectively. An IDE supplement was
approved for an additional 20 patients (Protocol Rev. E, Exhibit 8). It
should be noted that this version of the protocol is currently enrolling
patients and at the time of this writing a total of 10 patients have
been enrolled. The results for this cohort of patients are not included
as part of this summary and will be provided as an update report to the
PMA within three months of the PMA filing date. Device accountability
for the investigational system has been compiled and is presented in
Exhibit 9.

[( \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
Data Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
)]{.mark}

# OTHER RELEVANT STUDIES AND PUBLICATIONS

The following section contains information available from Micro
Therapeutics, Inc. regarding the use of Onyx. This section is separated
into three parts; 1) clinical studies conducted using Onyx in brain
AVMs; 2) analysis of post-embolization imaging when either Onyx or n-BCA
was used as the embolic agent, and; 3) other published literature on the
clinical and non-clinical use of Onyx in various anatomic locations.

[( \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
Data Redacted
\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
)]{.mark}

## Other Published Onyx Reports

The following section presents abstracts and summaries from published
animal studies and/or human clinical experience using the Onyx Liquid
Embolic System (LES). The discussions generally conclude that
polymer/DMSO based liquid embolics are safe and efficacious for
treatment of a variety of neurovascular lesions when used in a slow and
controlled delivery procedure. Publication of studies, case reports and
clinical experience include the following:

-   Non-adhesive liquid embolic agent for cerebral arteriovenous
    malformations: preliminary histopathological studies in swine rete
    mirabile.

-   A reexamination of the angiotoxicity of superselective injection of
    DMSO in the swine rete embolization model.

-   Treatment of Type 11 Endoleaks with Onyx

-   Embolization of Arteriovenous Malformations with Onyx:
    Clinicopathological Experience in 23 Patients

-   Embolization of Spinal Cord Arteriovenous Malformations with an
    Ethylene Vinyl Copolymer Dissolved in Dimethyl Sulfoxide (Onyx
    Liquid Embolic System).

-   Endovascular Treatment of Experimental Aneurysms by Use of a
    Combination of Liquid Embolic Agents and Protective Devices.

-   Head and Neck Hypervascular Lesions: Embolization with Ethylene
    Vinyl Alcohol Copolymer -- Laboratory Evaluation in Swine and
    Clinical Evaluation in Humans.

-   Treatment of Pelvic Arteriovenous Malformations with Ethylene Vinyl
    Alcohol copolymer (Onyx)

-   A New Liquid Embolic Material for Liver Tumors

-   Surgical handling characteristics of an ethylene vinyl alcohol
    copolymer compared with N-butyl cyanoacrylate used for embolization
    of vessels in an arteriovenous malformation resection model in swine

Abstracts of these studies follows.

### Non-adhesive liquid embolic agent for cerebral arteriovenous malformations: preliminary histopathological studies in swine rete mirabile 

OBJECTIVE*:* To assess acute and chronic histopathological changes
observed in a swine arteriovenous malformation model after endovascular
delivery of Embolyx E (Micro Therapeutics Inc., San Clemente, CA) and
its organic solvent dimethyl sulfoxide (DMSO). To develop standard
endovascular delivery techniques of Embolyx through microcatheters into
swine rete mirabile (RMB).

METHODS*:* Forty RMBs in 22 swine were used to analyze acute and chronic
angiographic and histological changes after superselective delivery of
Embolyx E and/or its organic solvent (DMSO). Four RMBs (two for DMSO and
two for Embolyx E study) were used as control specimens. Angiographic
and histological evaluations were obtained 18 days, 1 month, 3 months,
and 6 months after the procedure. Particular attention was paid to the
presence of focal or diffuse angionecrosis, arterial revascularization,
and perivascular inflammatory response.

RESULTS: Staged and/or continuous delivery of Embolyx E were performed
through the DMSO-compatible microcatheters without untoward catheter
\"gluing.\" All subacute/chronic specimens embolized with Embolyx E
showed no evidence of angiographic recanalization. Twelve RMBs were used
in acute studies, and all specimens showed no evidence of angionecrosis
or aggressive inflammatory reaction. Subacute and chronic (total, n =
14) histological examinations of the RMBs showed mild inflammatory
response manifested by monocellular infiltration and scattered foreign
body giant cell reaction. In the 9 of 14 subacute and chronic specimens,
focal disruption of elastica was observed along with embolic materials.
Fourteen RMBs in eight swine were used to determine the safety range for
DMSO injection. Two RMBs were used as control specimens. Rapid
intra-arterial delivery (0.5 ml/5-15 s, n = 6) of DMSO caused
angiographic vasospasm and histological endothelial necrosis. Slow
injection (0.5 ml/30-120 s, n = 8) of DMSO showed minimum or no
angiographic vasospasm, minimal adventitial inflammatory response, and
no clinical complications.

CONCLUSION: Embolyx E, an occlusive and non-adhesive embolic agent, is
capable of producing permanent occlusion of swine RMB with the
development of mild intra- and perivascular inflammatory changes and no
clinical complications. The slow endovascular delivery of DMSO produces
no untoward angiographic, pathological, or clinical changes. A fast
injection of DMSO causes endothelial necrosis and severe inflammatory
response in the arterial wall. This embolic material seems to have
appropriate biochemical, anatomic, and histopathological characteristics
to be used in the treatment of cerebral arteriovenous malformations or
vascular cranial base tumors.

*Murayama Y, Viñuela F, Ulhoa A, Akiba Y, Duckwiler GR, Gobin YP,
Vinters HV, Greff RJ. Non-adhesive liquid embolic agent for cerebral
arteriovenous malformations: preliminary histopathological studies in
swine rete mirabile. Neurosurgery 43(5):1164-75, 1998*

### A reexamination of the angiotoxicity of superselective injection of DMSO in the swine rete embolization model 

BACKGROUND AND PURPOSE: There are a variety of embolization applications
for non-adhesive, liquid agents. We reevaluated the potential
microvascular angiotoxicity of superselective infusions of dimethyl
sulfoxide (DMSO) using very long infusion rates in a previously
described animal model.

METHODS: Twenty-six swine underwent percutaneous femoral puncture for
superselective catheterization of the artery of the rete while being
continuously monitored for ECG and intraarterial pressure. Two volumes
(0.5 or 0.8 mL) and three durations (30, 60, and 90 seconds) of
superselective infusion of DMSO were used to evaluate the effect of a
single-dose rate within an ipsilateral rete. Contralateral control
infusions of normal saline were also administered. Acute hemodynamic and
angiographic outcomes were assessed. After recovery, follow-up
angiography and sacrifice were performed at either 10 or 28 days. Brains
and retia were harvested for gross and microscopic histopathologic
evaluation.

RESULTS: No significant hemodynamic alterations occurred acutely.
Twenty-three of the 24 infused retia showed variable acute vasospasm
that typically was mild to moderate in severity and transient (10 to 20
minutes). Follow-up angiography at sacrifice always showed normal retial
arterial anatomy. No adverse clinical sequelae were noted. Gross
inspection of brains showed no evidence of infarction or subarachnoid
hemorrhage. Microscopic histopathologic examination of retia showed
mostly nonspecific changes in both exposed and control samples. Possible
causal histotoxicity was seen in four retia (three of four exposed to
higher dose rates), in which involvement was limited to one to three
retial arteries.

CONCLUSION: Lower total dose and dose rates of superselective infusion
of DMSO into the retial microarterial network resulted in substantially
less angiotoxicity than that found in a previous study, as defined by
clinical, angiographic, gross, and histopathologic criteria.

Chaloupka JC, Huddle DC, Alderman J, Fink S, Hammond R, Vinters HV: A
reexamination of the angiotoxicity of superselective injection of DMSO
in the swine rete embolization model. AJNR Am J Neuroradiol 20:401-410,
1999

### Treatment of Type 11 Endoleaks with Onyx 

OBJECTIVE*:* Endoleaks are defined as persistent perfusion of an
abdominal aortic aneurysm (AAA) after endovascular stent-graft
deployment. The authors describe their experience treating six endoleaks
with the liquid embolic agent Onyx (ethylene-vinyl-alcohol copolymer).

BACKGROUND*:* Type 11 endoleaks have been treated surgically, both with
graft explantation and, more recently, with retroperitoneal ligation of
collateral feeding vessels. These invasive methods require hospital
admission and carry with them the accompanying morbidity of surgery.
Several reports of treatment of type 11 endoleaks with use of vascular
coils have been published, typically describing the selective
catheterization and occlusion of a single feeding vessel. In three of
the five type 11 endoleaks in our series, two or more vessels were
involved. Occlusion of a single feeding vessel with a coil in these
cases may have allowed continued perfusion of the endoleak, and, as a
result, continued pressurization of the aneurysm sac. Recanalization of
blood flow within the interstices of coils and coil compaction also
potentially limit the effectiveness and durability of coil repair of
type 11 endoleaks.

METHODS*:* Translumbar access of the endoleaks was attempted in four
patients (Fig 1). Patients were positioned prone and intravenous
sedation was administered. Prophylactic antibiotics were not given. A
suitable direction of endoleak puncture was selected by reviewing CT
images. A 3-F DMSO-compatible microcatheter (Rebar-14 or Rebar-27; Micro
Therapeutics) was passed coaxially into the endoleak sac. Onyx was
slowly injected while the delivery catheter was gradually withdrawn,
forming a cast of the endoleak sac. Translumbar sheaths were removed at
the termination of the embolization procedure and the patients were
positioned in a supine position to apply pressure from their own weight
to the puncture site.

RESULTS*:* Complete endoleak occlusion was achieved in five of six
cases. Follow-up imaging has demonstrated decreased aneurysm diameter in
all patients 7-29 weeks (mean = 19.2 weeks) after treatment. In our
experience, embolization of type 11 endoleaks with use of the liquid
embolic agent Onyx was feasible and, in early follow-up, successful.
Procedure times were short, the majority of patients were treated on an
outpatient basis, and no persistent complications were encountered.

CONCLUSION*:* The principal advantage of the use of a liquid embolic
agent in the treatment of type 11 endoleaks relates to the ability of a
liquid to fill the endoleak sac completely, including all inflow and
outflow vessels, without selective catheterization of each patent
vessel. The solid cast formed by a liquid embolic agent should result in
a noncompressible structure through which recanalization does not occur,
providing more durable repair than that provided by coils.

Martin M, Dolmatch B, Fry P, Machan L. Treatment of Type 11 Endoleaks
with Onyx. J Vascular and Interventional Radiology Vol. 12 No. 5 May
2001

### Embolization of Arteriovenous Malformations with Onyx: Clinicopathological Experience in 23 Patients 

OBJECTIVE*:* To report our experience in treatment of arteriovenous
malformations (AVMs) using a new liquid embolic agent, Onyx (Micro
Therapeutics, Inc., Irvine, CA).

METHODS: Between January 1998 and May 1999, 23 patients (8 men and 15
women) were treated. The patients\' average age was 40 years, with
seizure being the most common presenting symptom (39%). The average
Spetzler-Martin grade on presentation was 3. The average AVM volume
before embolization was 14.5 CM3.

RESULTS: We observed an average 63% reduction in AVM volume after 129
arterial feeders were embolized. There were four adverse events. Two
patients experienced ischemia because of inadvertent occlusion of an
arterial feeder. One of these patients made a full recovery, but the
other patient had a permanent deficit. Two other patients experienced
transient neurological deficits that resolved within 1 week of
embolization. Permanent morbidity was thus 4% (1 of 23 patients). There
were no deaths. Twelve patients underwent subsequent radiosurgery, and
11 patients had surgery that resulted in complete resection of their
AVMs. Histopathological examinations showed mild acute inflammation in
specimens resected 1 day after embolization. Chronic inflammatory
changes were observed in specimens resected more than 4 days after
embolization. In two patients, angionecrosis of the embolized vessels
was noted. No evidence of parenchymal hemorrhage was observed in these
patients, and vessel wall integrity was maintained as well.

CONCLUSION: Onyx is a new non-adhesive liquid embolic agent that has
been used to treat 23 patients at our institution with good results. Its
non-adhesive nature and ease of use make it a promising agent in the
future treatment of AVMs.

Jahan R, Y, Gobin P, Duckwiler G, Vinters H, Vinuela F. Embolization of
Arteriovenous Malformations with Onyx: Clinicopathological Experience in
23 Patients. Neurosurgery Vol. 48 No. 5 May 2001

### Embolization of Spinal Cord Arteriovenous Malformations with an Ethylene Vinyl Copolymer Dissolved in Dimethyl Sulfoxide (Onyx Liquid Embolic System). 

OBJECTIVE: The authors describe the first use of a new liquid embolic
agent (Onyx) to treat spinal cord arteriovenous malformations (AVMs).

METHODS AND MATERIALS: Following superselective angiography to delineate
the angioarchitecture of the malformation in Patient #1, 0.2 ml of 6%
Onyx liquid embolic material was injected through a flow directed
microcatheter. The malformation was on the anterior aspect of the spinal
cord at the C-5 level. Similarly, for Patient #2, following MRI and
angiography a complex malformation was identified at T-11. 0.2 ml of 6%
Onyx was injected in the malformation using a flow directed
microcatheter. 0.6 ml6% Onyx was also injected proximal to a fistula
associated with the malformation. A second procedure was performed 4
weeks later on patient #2 to occlude completely a residual nidal
component of the malformation.

RESULTS: The malformation in patient #1 was successfully obliterated
following delivery of the Onyx solution. There was no adherence of the
Onyx to the catheter. The patient experienced marked motor weakness
immediately following the procedure that largely resolved over 48 hours
with a mild residual proximal arm weakness and left leg weakness. The
cause of the neurological deterioration is unknown. The malformations in
patient #2 were successfully treated and showed no blood flow through
the fistulous component and diffuse, slow blood flow through the nidal
component. There were no neurological complications in patient #2.

CONCLUSION: Because its properties make it more predictable to use than
currently available liquid agents, the authors believe that this
material has great potential in the endovascular management of both
spinal cord and brain AVMs.

*Molyneux A, Chir B, Coley S: Embolization of Spinal Cord Arteriovenous
Malformations with an Ethylene Vinyl Copolymer Dissolved in Dimethyl
Sulfoxide (Onyx Liquid Embolic System). J Neurosurg (Spine 2)
93:304-308, 2000*

### Endovascular Treatment of Experimental Aneurysms by Use of a Combination of Liquid Embolic Agents and Protective Devices.

BACKGROUND AND OBJECTIVE*:* The use of liquid embolic agents for
embolization of cerebral aneurysms has been reported in the
neurosurgical literature. The most important limitation of this
technique is the relatively poor control of migration of the liquid
ernbolic agent into the parent artery. We performed an experimental
aneurysm study using a liquid embolic agent and different protective
devices to evaluate the safety and technical feasibility of this
endovascular technique.

METHODS: Forty lateral aneurysms were surgically constructed on 20
common carotid arteries of swine. Onyx alone was used to obliterate
eight aneurysms. Onyx was also used in combination with microcoils (n =
11), microstents (n = 6), balloons inflated proximally to the neck of
the aneurysm (n = 6), and across the neck of the aneurysm (n = 7). One
control aneurysm was embolized with Guglielmi detachable coils (GDCs)
alone.

RESULTS: The use of a microballoon across entire neck of the aneurysm, a
microstent deployed across the neck of the aneurysm, or the deposit of
GDCs into the aneurysm allowed faster and more complete filling of the
aneurysm with Onyx. However, these protection devices did not totally
preclude intractable migration of Onyx into the parent artery (migration
rate, 9-33%.

CONCLUSION: Although complete occlusion of experimental aneurysms with
Onyx is feasible using protective devices, migration of the liquid
embolic agent into the parent artery or intracranially remains a
difficult challenge. Further experimental studies need to be performed
to master this technique and to select those aneurysms that can be
safely treated in clinical practice.

Murayama Y, Vinuela F, Takeshima S, Vinuela F Jr., Akiba Y; Endovascular
Treatment of Experimental Aneurysms by Use of a Combination of Liquid
Embolic Agents and Protective Devices. AJNR Am J Neuroradiol 21:1726
1735. October 2000

### Head and Neck Hypervascular Lesions: Embolization with Ethylene Vinyl Alcohol Copolymer -- Laboratory Evaluation in Swine and Clinical Evaluation in Humans. 

OBJECTIVE*:* (a) To assess in swine long-term (12-month) histopathologic
changes, particularly, those related to recanalization and angiotoxicity
after endovascular delivery of ethylene vinyl alcohol copolymer (EVAC),
and (b) to evaluate initial clinical experience in 18 patients with head
and neck tumors and arteriovenous malformations.

MATERIALS AND METHODS: Embolization with EVAC was performed in one rete
each in five swine. After 12 months, an angiogram was obtained, and the
contralateral rete was also embolized (acute). Swine were sacrificed and
the retia harvested for pathologic examination. In the clinical study,
18 patients with tumors (n = 14), facial arteriovenous malformations (n
= 3), and vertebral arteriovenous fistula (n = 1) underwent therapeutic
embolization. The technical aspects of EVAC embolization, percentage of
occlusion, and clinical complications were evaluated.

RESULTS: Angiographic 12 month follow-up in swine revealed persistent
occlusion of the embolized rete or retia. Histologic examination of the
same rete showed vascular occlusion and moderate intraluminal foreign
body giant cell reaction; the acutely embolized rete showed no
endothelial denudation or angionecrosis. Clinical evaluation in patients
revealed satisfactory penetration of lesion vasculature with EVAC when
the microcatheter was advanced within 2 cm of a lesion or when
percutaneous puncture was performed. There were two transient
complications: one increase in a preexisting fifth nerve palsy and one
increase in preexisting hemiparesis.

CONCLUSION: EVAC is a promising liquid embolic material providing
long-term occlusion of blood vessels.

Gobin YP, Murayama Y, Milanese W, Chow K, Gonzalez NR, Duckwiler GR,
Vinuela F. Head and Neck Hypervascular Lesions: Embolization with
Ethylene Vinyl Alcohol Copolymer -- Laboratory Evaluation in Swine and
Clinical Evaluation in Humans. Radiology, 11-02:309-317

### Treatment of Pelvic Arteriovenous Malformations with Ethylene Vinyl Alcohol copolymer (Onyx)

OBJECTIVE: Case studies of two patients treated with ethylene vinyl
alcohol, a radiopaque, non-adhesive liquid casting agent, are reported.

METHODS AND MATERIALS: Both patients presented with large symptomatic
pelvic AVMs requiring therapy. Coaxial microcatheter techniques were
used to deliver the liquid embolic agent.

RESULTS: Two successful embolizations of large pelvic arteriovenous
malformations (AVMs) were done to achieve complete clinical success in
one case and partial success in the other. Clinical success has been
maintained in both patients at 2-year follow-up.

Castaneda F. Goodwin SC, Swischuk JL, Wong GC, Bonilla SM, Wang MJ,
Treatment of Pelvic Arteriovenous Malformations with Ethylene Vinyl
Alcohol copolymer (Onyx). J Vascular Interventional Radiology 2002 May;
13 (5): 513-6.

### A New Liquid Embolic Material for Liver Tumors

OBJECTIVE: The authors evaluated the feasibility of a new liquid embolic
material, Onyx, for treating liver tumors.

MATERIAL AND METHODS: Onyx is a mixture of 6% (w/v)
ethylene-vinyl-alcohol copolymer dissolved in anhydrous dimethyl
sulfoxide (DMSO) with 28% (w/v) tantalum powder. In addition to 6% Onyx,
we also tried 4%, 2% and 1% solutions, prepared by adjusting the amount
of DMSO. We used 15 white rabbits with liver tumors created by
percutaneous injection of VX2 tumor cells. In 4 groups with 3 rabbits in
each, the liver arteries were embolized with 6%, 4%, 2% and 1% Onyx,
respectively, and in 3 rabbits DMSO alone was injected. The injections
were performed just proximal to the bifurcation of the proper hepatic
artery, followed by celiac arteriography. Post mortem, the livers were
examined by soft-tissue radiography, and liver-tissue section
microscopy.

RESULTS: The maximum number of arterial branching points passed by
embolic material in either the right or left hepatic arteries was 11, 15
and 16, for 6%, 4% and 2% Onyx, respectively, but was non-measurable for
1% Onyx. Minimum diameters of arteries reached by 6%, 4%, 2% and 1% Onyx
in tumorous areas were 40 micron, 35 micron, 20 micron and 10 micron,
respectively, and in non-tumorous areas 35 micron, 5 micron, 5 micron
and 5 micron, respectively.

CONCLUSION: This study suggests that Onyx may be feasible for treatment
of hepatic tumors.

Komemushi A, Tanigawa N, Okuda Y, Kojima H, Fijii H, Shomura Y, Sougawa
M, Sawada S. A New Liquid Embolic Material for Liver Tumors. Acta
Radiology 2002 March; 43 (2): 186-91.

### Surgical handling characteristics of an ethylene vinyl alcohol copolymer compared with N-butyl cyanoacrylate used for embolization of vessels in an arteriovenous malformation resection model in swine 

OBJECTIVE: There have been significant improvements in neurovascular
technology and implants over the past decade. One such material, N-butyl
cyanoacrylate (NBCA), is now commercially available for cerebral
arteriovenous malformation (AVM) embolization in the US. An ethylene
vinyl alcohol copolymer preparation, Onyx, winch is currently being
evaluated, is approved for use outside North America. Although reports
indicate that Onyx may be superior to NBCA from an endovascular
perspective, little information exists about its surgical handling
characteristics. The purpose of this study was to compare the surgical
handling characteristics of Onyx-treated vessels with those of
NBCA-embolized vessels in an AVM resection model.

METHODS: Fourteen pigs (two groups of seven) were anesthetized. A
femoral artery was cannulated, followed by selective catheterization of
the ascending pharyngeal arteries. Nidal rete mirabile (RM)
embolizations were performed using either 6% Onyx or 20% NBCA. After
angiographically confirmed obliteration of flow in the right RM,
microsurgical resection of this structure was performed. Surgical
handling characteristics of the embolized RM were rated on a scale of I
to 5 and blood loss was recorded. Different surgeons performed the
embolizations and resections. The surgeon who performed resections was
blinded to the embolization agent used, and the data analysis was also
performed in a blinded fashion. The surgical handling scores were
superior (p \< 0.05) in the Onyx-treated group. Although there was also
less blood loss in this group, the difference was not significant.

CONCLUSIONS: Onyx, which may offer endovascular advantages, also seems
to provide benefits for the surgeon. Subjectively, the surgeon who
performed the resections believed that Onyx was softer and handled
better than NBCA.

*Akin ED, Perkins E, Ross IB, Surgical handling characteristics of an
ethylene vinyl alcohol copolymer compared with N-butyl cyanoacrylate
used for embolization of vessels in an arteriovenous malformation
resection model in swine. J Neurosurgery, 366-370, 2003.*

###  N-Butyl Cyanoacrylate Embolization of Cerebral Arteriovenous: Results of a Prospective, Randomized, Multi-center Trial. 

BACKGROUND AND PURPOSE: Liquid N-butyl cyanoacrylate (n-BCA) use for the
treatment of arteriovenous malformations (AVM) in the brain has become
part of medial practice. However, no study has led to the Food and Drug
Administration's approval of n-BCA for intravascular use. The purpose of
this study was to verify the effectiveness and safety of an
n-BCA/Tantalum Powder/Ethiodized Oil mixture, compared with conventional
treatment (Trufill polyvinyl alcohol (PVA) for preoperative embolization
of cerebral AVM.

METHODS*:* Between October 15, 1996, and March 24, 1999, 104 patients at
13 centers were prospectively randomized to undergo embolization using
an n-BCA/Tantalum Powder/Ethiodol mixture of Trufill PVA. The
pre-embolization therapy goals were determined in terms of the number of
pedicles to be embolized and the percent of nidus reduction expected.
Embolization results were evaluated by a central laboratory. Subsequent
surgical resection data were recorded. Safety evaluation data included
recording device complications, procedure complications, and
intracranial events/overall neurologic outcomes, which could be either
device-related, procedure-related, or both.

RESULTS*:* The reduction of AVM dimensions (79.4% in the n-BCA group and
86.9% in the PVA group) and the mean number of vessels embolized (2.2 in
the n-BCA group and 2.1 in the PVA group) was similar in the two groups.
Coils were used more commonly with PVA embolization (P \< .0001). No
difference were detected in surgical resection time, number of patients
who required transfusion, volume and number of transfusion units, or
type and volume of fluid replacement. Glasgow Outcome Scale scores were
not significantly different between the two groups before treatment,
after embolization, or after resection. Two of 42 patients who underwent
resection and had been treated with n-BCA experienced post-resection
hematoma, compared with eight of 45 patients who underwent resection and
had been treated PVA (P \< .05).

CONCLUSION*:* This prospective, randomized trial showed that n-BCA is
equivalent to PVA as a preoperative embolic agent for treatment of
cerebral AVM as determined by percent of nidus reduction and number of
feeding pedicles embolized.

The n-BCA Trial Investigators. N-Butyl Cyanoacrylate Embolization of
Cerebral Arteriovenous: Results of a Prospective, Randomized,
Multi-center Trial. American Journal of Neuroradiology 23:74a8-755, May
2002

## Bibliography

Akin ED, Perkins E, Ross IB, Surgical handling characteristics of an
ethylene vinyl alcohol copolymer compared with N-butyl cyanoacrylate
used for embolization of vessels in an arteriovenous malformation
resection model in swine. J Neurosurgery, 366-370, 2003

Castaneda F. Goodwin SC, Swischuk JL, Wong GC, Bonilla SM, Wang MJ,
Treatment of Pelvic Arteriovenous Malformations with Ethylene Vinyl
Alcohol copolymer (Onyx). J Vascular Interventional Radiology 2002 May;
13 (5): 513-6.

Chaloupka JC, Huddle DC, Alderman J, Fink S, Hammond R, Vinters HV: A
reexamination of the angiotoxicity of superselective injection of DMSO
in the swine rete embolization model. AJNR Am J Neuroradiol 20:401-410,
1999

Gobin YP, Murayama Y, Milanese W, Chow K, Gonzalez NR, Duckwiler GR,
Vinuela F. Head and Neck Hypervascular Lesions: Embolization with
Ethylene Vinyl Alcohol Copolymer -- Laboratory Evaluation in Swine and
Clinical Evaluation in Humans. Radiology, 11-02:309-317

Jahan R, Y, Gobin P, Duckwiler G, Vinters H, Vinuela F. Embolization of
Arteriovenous Malformations with Onyx: Clinicopathological Experience in
23 Patients. Neurosurgery Vol. 48 No. 5 May 2001

Martin M, Dolmatch B, Fry P, Machan L. Treatment of Type 11 Endoleaks
with Onyx. J Vascular and Interventional Radiology Vol. 12 No. 5 May
2001

Molyneux A, Chir B, Coley S: Embolization of Spinal Cord Arteriovenous
Malformations with an Ethylene Vinyl Copolymer Dissolved in Dimethyl
Sulfoxide (Onyx Liquid Embolic System). J Neurosurg (Spine 2)
93:304-308, 2000

Murayama Y, Vinuela F, Takeshima S, Vinuela F Jr., Akiba Y; Endovascular
Treatment of Experimental Aneurysms by Use of a Combination of Liquid
Embolic Agents and Protective Devices. AJNR Am J Neuroradiol 21:1726
1735. October 2000

Murayama Y, Viñuela F, Ulhoa A, Akiba Y, Duckwiler GR, Gobin YP, Vinters
HV, Greff RJ. Non-adhesive liquid embolic agent for cerebral
arteriovenous malformations: preliminary histopathological studies in
swine rete mirabile. Neurosurgery 43(5):1164-75, 1998

# LABELING -- INSTRUCTIONS FOR USE

  ------------------------ --------------------------------------------------------
  ![](media/image11.wmf)   Onyx^®^ Liquid Embolic System

  ------------------------ --------------------------------------------------------

#  {#section-1 .unnumbered}

**INSTRUCTIONS FOR USE**

US05830178, US05785642, US05755658, US05695480, US05667767,

US05958444 and Other US and Foreign Patents Pending

## CAUTION {#caution .Style2}

-   ~~Investigational device. Limited by Federal (U.S.) law to
    investigational use.~~

-   Performing embolization to occlude blood vessels is a high risk
    procedure. This device should be used only by physicians with
    neurointerventional training and a thorough knowledge of the
    pathology to be treated, angiographic techniques, and
    super-selective embolization.

  ----------------------------------------------------- ------------------------------------------------------
  ![](media/image12.emf)                                It is important to read the instructions for use with
                                                        careful attention to warnings prior to using this
                                                        product.

  ![](media/image13.png){width="0.6083333333333333in"   Onyx and DMSO are sterile (dry heat) and
  height="0.3090277777777778in"}                        non-pyrogenic.

  ![](media/image14.emf)                                Syringes are sterile and non-pyrogenic.

  ![](media/image15.emf)                                This device is intended for SINGLE USE ONLY. DO NOT
                                                        RESTERILIZE AND/OR REUSE.
  ----------------------------------------------------- ------------------------------------------------------

#### DESCRIPTION

Onyx^®^ is a non-adhesive liquid embolic agent comprised of EVOH
(ethylene vinyl alcohol) copolymer dissolved in DMSO (dimethyl
sulfoxide), and suspended micronized tantalum powder to provide contrast
for visualization under fluoroscopy. The Onyx Liquid Embolic System
(LES™) consists of a 1.5 ml vial of Onyx, a 1.5 ml vial of DMSO, and
three 1 ml Onyx delivery syringes. A DMSO compatible delivery micro
catheter that is indicated for use in the neuro vasculature (e.g. Rebar™
or UltraFlow™ HPC catheters) is used to access the embolization site.

#### INDICATIONS FOR USE

Presurgical embolization of brain arteriovenous malformations (AVMs).

#### CONTRAINDICATIONS

Not for use with premature infants (\<1,500 g) or individuals with
significant liver function impairment.

#### POTENTIAL COMPLICATIONS

Potential complications include, but are not limited to:

  ------------------------------------ ----------------------------------
  Stroke                               Hearing problems

  Motor deficits                       Hemorrhage

  Paresis or paralysis                 Seizures

  Numbness                             Dizziness

  Speech deficits                      Brain edema

  Sensory problems                     Death
  ------------------------------------ ----------------------------------

#### PRINCIPLE OF OPERATION

Onyx is delivered through a micro catheter into the AVM under
fluoroscopic control. The DMSO solvent dissipates into the blood and
interstitial fluids, causing the EVOH copolymer and suspended tantalum
to precipitate *in situ* into a spongy, coherent embolus. Onyx
immediately forms a skin as the polymeric embolus solidifies from the
outside to the inside, while traveling more distally in the vessel.
Since Onyx is non-adhesive, the micro catheter can be left in place
while slow, controlled injections are performed. Post embolization
angiography can be conducted with the delivery micro catheter in place,
enabling the physician to make additional injections through the same
micro catheter, if necessary.

#### PRODUCT CONFIGURATIONS

Onyx is available in two product formulations, Onyx-18 (6% EVOH) and
Onyx-34 (8% EVOH).

-   Onyx-18 (nominal viscosity of 18 cSt at 40°C): Recommended when
    feeding pedicle injections will be conducted close to the nidus, and
    the flow rate is less than 50 ml/min.

-   Onyx-34 (nominal viscosity of 33 cSt at 40°C): Recommended when
    feeding pedicle injections will be conducted close to the nidus, at
    flow rates up to 200 ml/min, and in 3 mm or smaller diameter
    vessels.

Onyx-18 will travel more distally and penetrate deeper into the nidus
due to its lower viscosity compared to Onyx-34. Final solidification
occurs within five minutes for both product formulations.

#### STORAGE

Store Onyx and DMSO between -20° and 55°C. Prior to use, maintain
product temperature between 19° and 24°C. If product freezes due to
exposure to colder temperatures, thaw at room temperature before use.

## WARNING {#warning .Style2}

Inspect product packaging prior to use. Do not use if sterile barrier is
open or damaged.

#### DIRECTIONS FOR USE

**WARNING:** Verify that adequate sedation is used throughout the
embolization procedure. Insufficient sedation may result in patient
discomfort or movement. Patient movement during embolic agent injection
may result in embolization of an unintended vessel.

**NOTE:** Adjunctive coil use should be considered if angiography shows
that venous drainage of the AVM appears almost simultaneously with
arterial opacification. Based on results from *in* *vitro* and *in vivo*
testing, coil placement prior to Onyx injection should be considered for
feeding pedicles with AV fistulae having flow rates exceeding 200 ml/min
and vessel diameters of 3 mm or greater.

1.  Shake Onyx at least 20 minutes on an Onyx mixer[^20] at a setting
    of 8. Continue mixing until ready to inject Onyx per step 5.

**WARNING:** Failure to continuously mix Onyx for the required time may
result in inadequate suspension of the tantalum, resulting in inadequate
fluoroscopic visualization during delivery.

2.  Confirm micro catheter placement with injection of contrast agent
    per institutional procedure.

**WARNING:** Use only MTI micro catheters. Other micro catheters may not
be compatible with DMSO and their use can result in thromboembolic
events due to catheter degradation.

3.  Flush contrast from micro catheter with 10 ml of saline. Leave the
    syringe connected.

4.  Filling catheter deadspace: aspirate approximately 0.8 ml of MTI
    DMSO into the yellow MTI 1 ml DMSO syringe. Inject DMSO into
    delivery micro catheter in sufficient volume to fill catheter
    deadspace. Refer to delivery catheter labeling for deadspace volume.

**WARNING:** Use only the MTI 1 ml syringe to inject DMSO and Onyx.
Other syringes may not be compatible with DMSO.

5.  Ensure that Onyx has been mixed per step 1. Fill white MTI 1 ml
    syringe with Onyx through an 18 or 20 gauge needle. As soon as the
    DMSO has been injected into the catheter deadspace, remove the DMSO
    syringe, hold the catheter hub in a vertical position, and overfill
    and wash the luer hub with the balance of the DMSO.

6.  ***Immediately*** connect the Onyx syringe to the hub, making sure
    there is no air in the hub during the connection. For optimal
    fluoroscopic visualization, quickly point the syringe vertically to
    create an interface between the DMSO and the Onyx.

**WARNING**: Premature solidification of Onyx may occur if micro
catheter luer contacts saline, blood or contrast of any amount.

7.  While holding the syringe vertically, begin injecting Onyx to
    displace DMSO. Based on clinical practice, it is recommended that
    Onyx be injected at a slow, steady rate of 0.16 ml/min (0.25 ml/90
    sec). Do not exceed 0.3 ml/min.

**WARNINGS**: Inject Onyx immediately after mixing. If Onyx injection is
delayed, tantalum settling can occur within the syringe resulting in
poor visualization of Onyx during injection.

Do not exceed 0.3 ml/min injection rate. Animal studies have shown that
rapid injection of DMSO into the vasculature may lead to vasospasm
and/or angionecrosis.

Only use thumb pressure to inject Onyx. Using palm of hand to advance
plunger may result in catheter rupture due to overpressurization in the
event of catheter occlusion.

Adequate fluoroscopic visualization must be maintained during Onyx
delivery or non-target vessel embolization may result. If visualization
is lost at any time during the embolization procedure, HALT Onyx
delivery until adequate visualization is re-established.

8.  Continue holding syringe vertically until Onyx passes through the
    catheter hub. Once Onyx passes through the hub, hold syringe in a
    more comfortable position and continue injecting Onyx at the slow,
    steady, recommended rate of 0.16 ml/min. Monitor volume injected to
    correspond to volume of vascular space being filled.

**WARNINGS:** Do not allow more than 1 cm of Onyx to reflux back over
catheter tip. Excessive Onyx reflux may result in difficult catheter
removal.

After using a micro catheter with Onyx, do not attempt to clear or
inject any material through it. Such attempts may lead to embolus or
embolization of an unintended area.

STOP injection if Onyx is not visualized exiting catheter tip. If the
catheter becomes occluded, over-pressurization can occur. During Onyx
injection, continuously verify that Onyx is exiting the catheter tip.
Testing has shown that over-pressurization and rupture can occur if 0.05
ml of Onyx is injected and is not visualized exiting the catheter tip.

STOP injection if increased resistance to Onyx injection is observed. If
increased resistance occurs, determine the cause (e.g., Onyx occlusion
in catheter lumen) and replace the catheter. Do not attempt to clear or
overcome resistance by applying increased injection pressure, as use of
excessive pressure may result in catheter rupture and embolization of
unintended areas.

DO NOT interrupt Onyx injection for longer than two minutes prior to
re-injection. Solidification of Onyx may occur at the catheter tip
resulting in catheter occlusion, and use of excessive pressure to clear
the catheter may result in catheter rupture.

9.  Upon completion of Onyx injection, wait a few seconds, slightly
    aspirate syringe, and then gently pull the catheter to separate it
    from the Onyx cast.

**PRECAUTIONS**

Failure to wait a few seconds to retrieve the micro catheter after Onyx
injection may result in fragmentation of Onyx into non-target vessels.

Difficult catheter removal or catheter entrapment may be caused by any
of the following:

-   Angioarchitecture: very distal AVM fed by afferent, lengthened, and
    tortuous pedicles

-   Vasospasm

-   Reflux

Should catheter removal become difficult, the following will assist in
catheter retrieval:

-   Carefully pull the catheter to assess any resistance to removal.

-   If resistance is felt, remove any \"slack\" in the catheter.

-   Gently apply traction to the catheter (approximately 3-4 cm of
    stretch to the catheter).

-   Hold this traction for a few seconds and release. Assess traction on
    vasculature to minimize risk of hemorrhage.

-   This process can be repeated intermittently until catheter is
    retrieved.

For entrapped catheters:

-   Under some difficult clinical situations, rather than risk rupturing
    the malformation and consequent hemorrhagic complications by
    applying too much traction on an entrapped catheter, it may be safer
    to leave the micro catheter in the vascular system.

-   This is accomplished by stretching the catheter and cutting the
    shaft near the entry point of vascular access allowing the catheter
    to remain in the artery.

-   If the catheter breaks during removal, distal migration or coiling
    of the catheter may occur. Same day surgical resection should be
    considered to minimize the risk of thrombosis.

**Micro Therapeutics, Inc.**

Irvine, CA, U.S.A

\(800\) 684-6733 (U.S.A.)

\(949\) 837-3700 (International)

70178 Rev. 05/02

# PHYSICIAN TRAINING PROGRAM

> [( \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
> Data Redacted
> \-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--
> )]{.mark}

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[^15]: Merck Index, 11^th^ Edition.

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[^19]: Willinsky R, TerBrugge K, Montanera W, Wallace C, Aggarwal S.
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[^20]: Scientific Industries Genie 2, Model No. 120V SI-0240, Vial
    Attachment No. OA- 0570-010