**MEMORANDUM**

Clinical Review of MTI, Onyx® Liquid Embolization System

**DATE:** July 8, 2003

**SUMMARY:** This original PMA is for the Onyx® Liquid Embolization
System.

[Indications for Use]{.underline}

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

[Device Description]{.underline}

Onyx® Liquid Embolization System is intended for use by the
interventional neuroradiologist when therapeutic or palliative
embolization of a BAVM is indicated to minimize blood loss or to reduce
the BAVM size prior to surgery or radiosurgery.

The liquid Onyx is a 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 microcatheter 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 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/DMSO ratio, are appropriate for embolization of
AVMs 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. Onyx-34 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. Onyx-18 will travel more
distally and penetrate deeper into the nidus due to its lower viscosity;
therefore, it is recommended when feeding pedicle injections will be
conducted close to the nidus and the flow rate is lees than 50 ml/min.
Final solidification occurs within 5 min for both product formulations.
Coil placement prior to Onyx injection should be considered for feeding
pedicles with AV fistulae having flow rates in excess of 200 ml/min and
vessel diameters of 3 mm or greater.

The liquid Onyx is delivered through a DMSO primed micro catheter
selectively placed within a feeding pedicle of an AVM at a slow rate of
approximately 0.16 ml/min. Precipitation 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.

The MTI UltraFlow™ micro catheters are intravascular flow directed micro
catheters intended for delivery of specified agents for diagnosing or
treating vascular diseases of the distal and peripheral anatomy. The
catheters are DMSO compatible single lumen end-hole catheters. The MTI
Rebar™ micro catheters are designed for use in the neuro vasculature and
for delivery of DMSO and Onyx after selective placement in the target
lesion. The Rebar catheter is a single-lumen catheter designed to be
introduced over a steerable guidewire.

Adjunctive device compatibility testing 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.

[Alternative Procedures]{.underline}

Endovascular embolization of BAVMs involves the use of catheters to
deliver various occlusive agents, such as permanent balloons, sclerosing
drugs, thrombosing coils, PVA particles, and rapidly acting glues, such
as n-Butyl cyanoacrylate.

[Background]{.underline}

Onyx was initially used in clinical feasibility studies at UCLA, Mexico
City, and various European countries. To date an estimated 1575 patients
with AVMs have been treated with Onyx throughout Europe, Australia,
Canada, and select Eastern and South American countries. *Please provide
any available safety data on the estimated 1575 patients with AVMs have
been treated with Onyx throughout Europe, Australia, Canada, and select
Eastern and South American countries.*

Cerebral AVMs occur 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 capillary beds are missing in AVMs. AVMs
develop as an abnormal tangle of vessels where the arteries are directly
connected to the veins. Without the capillary bed, blood is allowed to
flow from arteries to veins at high pressure. This high pressure through
the veins causes them to dilate and may continue to hemorrhage.

AVMs are thought to develop during the early stages of life and
generally do not become symptomatic for the patients until between 20
and 50 years of age. 3 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. 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 AVMs is between 1 and 3 per 100,000.

There are currently several treatments for 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 proven track record,
and 3) it can be used to treat small and large AVMs; the disadvantages
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
demonstrated that for lesions of all sizes, a "favorable" outcome can be
expected from microsurgical resection in 81% to 95% of patients; the
mortality rate varies from 1 to 4%.

Radiosurgery involves an intense targeted radiation that induces
endothelial damage, subendothelial deposition of collagen, and
proliferation of vascular smooth muscle in vessels, leading to eventual
obliteration of the malformation. The advantages of radiosurgery are
that it does not require a craniotomy and it allows for treatment of
some small deep lesions that can not be treated by microsurgery; the
disadvantages 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. Total obliteration rates of AVMs have been reported to be
greater than 80% with the gamma knife, particle beam, and linear
accelerator techniques for lesions with a diameter under 1-3 cm.

Endovascular embolization involves the use of catheters to deliver a
variety of occlusive agents such as permanent balloons, sclerosing
agents, thrombosing coils, and rapidly acting glues. The advantages of
embolization 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 to
determine the reaction of the area prior to the permanent treatment; the
disadvantages are: 1) they often require multiple treatments and 2) they
are not effective in completely obliterating the malformation. Gobin has
reported that embolization has little chance of completely occluding an
AVM unless the lesion is small or has less than 3 feeding vessels.
Embolization is useful when combined with microsurgery or radiosurgery.
The most widely used embolization technique for AVMs is the injection of
acrylic-based glues. Morbidity and mortality rates associated with
embolization procedures were reported by Gobin as 13% and 2%
respectively. Vinuela 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. The most widely
used embolic agents for AVMs are the liquid acrylic-based glues. The
difficulties with the glues are the lack of control in delivery and the
adhesion to all surfaces, including the catheter.

DMSO is an organic solvent used in a variety of medical applications,
including the treatment of intracranial hypertension, and as a bladder
irrigant. DMSO is excreted unchanged in the urine or oxidized to
dimethyl sulfone. Chaloupka reported on the potential angiotoxicity of
DMSO and observed significant technical difficulties, vasospasm and
angionecrosis is a swine endovascular emobolization model. Subsequent
studies using Onyx and DMSO in a similar swine model, showed no
significant vasotoxicity or vasospasm when these materials were injected
in accordance with the method described in the labeling.

[Clinical Study]{.underline}

[Objective]{.underline}

Demonstrate that Onyx was no worse than n-BCA in terms of efficacy
within a 20% specified clinical tolerance.

[Design]{.underline}

The study was designed as a non-inferiority trial with the objective of
demonstrating that Onyx is no worse than the Cordis TRUFILL n-BCA.
Informed consent was obtained from 113 patients. 108 patients were
randomized (57 n-BCA and 51 Onyx). Two of the patients randomized were
late screen failures identified at the time of the initial embolization
procedure prior to attempted treatment. During the diagnostic angiogram
for one of the patients, 18-003, the physician discovered that the AVM
was in a territory of the brain that was not suitable for embolization;
the other patient, 21-009, underwent an angiogram for the procedure and
the physician noted that the lesion had a very rapid filling rate of a
very large venous matrix and did not continue with any embolization
treatment. Patient 21-009 was subsequently treated with PVA particles
and liquid coils over 3 staged embolizations; there were two adverse
events, back pain and groin hematoma, both of which resolved prior to
hospital discharge. Thus, 106 patients were enrolled in the study and
randomized ( 55 n-BCA and 51 Onyx). 6 patients originally enrolled as
AVM cases were subsequently reviewed by the core lab and determined to
have dural ateriovenous fistulae, 1 n-BCA and 5 Onyx, (2-008, 5-005,
8-010, 8-014, 38-001, and 8-008). The core lab has categorized these
patients as protocol violations and has recommended they be removed from
the analysis since they have a different pathology. A total of 100 true
BAVM patients had treatment attempted and were included in the ITT
analysis, 54 n-BCA and 46 Onyx. Patients underwent embolization 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 at
3 and 12 months. 86 patients had a total resection, 45 n-BCA and 41
Onyx. 9 have either had a partial resection, radiosurgery, or no
surgery, 6 n-BCA and 3 Onyx; these patients will be followed for safety
at 3 and 12 months post-procedure. *You state that* *9 patients have
either had a partial resection, radiosurgery, or no surgery, 6 n-BCA and
3 Onyx; these patients will be followed for safety at 3 and 12 months
post-procedure. Please state the patient ID and the procedure they had
and why total surgical resection was not possible. According to
information in the PMA, it appears that 6 n-BCA and 3 Onyx patients had
partial resections.* 3 patients are ongoing, 1 n-BCA and 2 Onyx. One of
the ongoing patients, 3-003, received a single embolization with Onyx;
the second embolization was a failure for Onyx delivery and the patient
was crossed over to n-BCA; another embolization procedure is not yet
scheduled. One of the other two patients, 38-004 had their latest
embolization on Feb. 28, 2003 and is anticipated to go to surgery on
March 13, 2003; the third patient will have the embolization on March 5,
2003. 2 n-BCA patients were lost to follow-up. One of the patients,
20-002 received 2 embolization treatments and was lost to follow-up; the
other patient, 10-003 received one embolization treatment and withdrew
from the study. A total of 98 patient, 52 n-BCA and 46 Onyx, were
available for post-embolization treatment.

+-----------------------+-----------------------+-----------------------+
|                       | N-BCA                 | Onyx                  |
+-----------------------+-----------------------+-----------------------+
| \# Pts enrolled       | 55                    | 51                    |
+-----------------------+-----------------------+-----------------------+
| Protocol violation    | 1                     | 5                     |
|                       |                       |                       |
| Dural fistulae        |                       |                       |
| patients              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Complete surgical     | 45                    | 41                    |
| resection             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Partial resection     | 6                     | 3                     |
+-----------------------+-----------------------+-----------------------+
| Pts ongoing           | 1                     | 2                     |
+-----------------------+-----------------------+-----------------------+
| Pts lost to follow-up | 2                     | 0                     |
+-----------------------+-----------------------+-----------------------+

  ----------- ------------------- ----------- ----------- ----------- -----------
  Site \#     Site Name           N-BCA       Onyx        Total       \%

  8           Watson              7           7           14          13.0%

  6           Pryor               7           6           13          12.0%

  2           Barnwell            6           6           12          11.1%

  21          Purdy               5           4           9           8.3%

  29          DeNardo             5           4           9           8.3%

  38          Mericle             5           4           9           8.3%

  5           Rasmussen           4           4           8           7.4%

  10          Mawad               4           2           6           5.6%

  3           Berenstein          3           3           6           5.6%

  1           Duckwiler           2           2           4           3.7%

  18          Rosenwasser         2           2           4           3.7%

  34          Sanders             2           2           4           3.7%

  20          Rodriguez-Mercado   1           2           3           2.8%

  32          Malisch             1           2           3           2.8%

  30          Marks               2           0           2           1.9%

  19          Dion                1           0           1           0.9%

  28          McDougall           0           1           1           0.9%

  40          Fessler             0           0           0           0.0%

  33          Solander            0           0           0           0.0%

  17          Chaloupka           0           0           0           0.0%

  Total                           57          51          108         100%
  ----------- ------------------- ----------- ----------- ----------- -----------

3 sites did not enroll any patients due to late timing of IRB approval.

*Please provide the name of the sites involved in the study and explain
why they are not numbered 1 through 20.*

Patient enrollement, excluding patients with dural fistulae

  ----------- ------------------- ----------- ----------- ----------- -----------
  Site \#     Site Name           N-BCA       Onyx        Total       \%

  6           Pryor               7           6           13          12.7%

  2           Barnwell            6           5           11          10.8%

  8           Watson              7           4           11          10.8%

  29          DeNardo             5           4           9           8.8%

  21          Purdy               5           4           9           8.8%

  38          Mericle             5           3           8           7.8%

  5           Rasmussen           3           4           7           6.9%

  10          Mawad               4           2           6           5.9%

  3           Berenstein          3           3           6           5.9%

  1           Duckwiler           2           2           4           3.9%

  18          Rosenwasser         2           2           4           3.9%

  34          Sanders             2           2           4           3.9%

  20          Rodriguez-Mercado   1           2           3           2.9%

  32          Malisch             1           2           3           2.9%

  30          Marks               2           0           2           2.0%

  19          Dion                1           0           1           1.0%

  28          McDougall           0           1           1           1.0%

  40          Fessler             0           0           0           0.0%

  33          Solander            0           0           0           0.0%

  17          Chaloupka           0           0           0           0.0%

  Total                           56          46          102         100%
  ----------- ------------------- ----------- ----------- ----------- -----------

Patient Demographics by Group n=102

+-----------------------+-----------------------+-----------------------+
| Demographics          | N-BC                  | Onyx                  |
|                       |                       |                       |
|                       | n=56                  | N=46                  |
+-----------------------+-----------------------+-----------------------+
| Age (yrs)             | 35.1 [+]{.underline}  | 40.3 [+]{.underline}  |
|                       | 14.3 (56)             | 16.3 (46)             |
| Mean +/- SD (n)       |                       |                       |
|                       | 36.0 (10.0-66.0)      | 42.5 (7.0-72.0)       |
| Median (range)        |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Gender                | 48.2% (27/56)         | 43.5% (20/46)         |
|                       |                       |                       |
| Male                  | 51.7% (26/56)         | 56.5% (26/46)         |
|                       |                       |                       |
| Female                |                       |                       |
+-----------------------+-----------------------+-----------------------+
| BMI                   | 24.4 [+]{.underline}  | 28.1 [+]{.underline}  |
|                       | 4.6 (53)              | 6.3 (39) p\<0.05      |
| Mean +/- SD (n)       |                       |                       |
|                       | 23.6 (15.1-37.2)      | 27.4 (16.7-45.0)      |
| Median (range)        |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Systolic Blood        | 123 [+]{.underline}   | 126 [+]{.underline}   |
| Pressure (mmHg)       | 14 (56)               | 16 (46)               |
|                       |                       |                       |
| Mean +/- SD (n)       | 120 (80-171)          | 123 (98-167)          |
|                       |                       |                       |
| Median (range)        |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Diastolic Blood       | 70 [+]{.underline} 10 | 71 [+]{.underline} 12 |
| Pressure (mmHg)       | (56)                  | (46)                  |
|                       |                       |                       |
| Mean +/- SD (n)       | 70 (50-90)            | 70 (48-98)            |
|                       |                       |                       |
| Median (range)        |                       |                       |
+-----------------------+-----------------------+-----------------------+

No statistical differences were noted except for BMI which was slightly
lower in the n-BCA group; fewer of the Onyx patients had data on height
and weight, 39 of 46, which may explain the difference.

In general, the medical history showed no marked differences were noted
between the Onyx and n-BCA groups except for a higher number of patients
with aneurysms in the n-BCA group.

+-----------------------+-----------------------+-----------------------+
| Medical History       | N-BCA                 | Onyx                  |
|                       |                       |                       |
| n=102                 | n=56                  | n=46                  |
+-----------------------+-----------------------+-----------------------+
| CAD                   | 1.8% (1/56)           | 6.5% (3/46)           |
+-----------------------+-----------------------+-----------------------+
| HTN                   | 19.6% (11/56)         | 17.4% (8/46)          |
+-----------------------+-----------------------+-----------------------+
| Diabetes              | 5.4% (3/56)           | 4.3% (2/46)           |
+-----------------------+-----------------------+-----------------------+
| **Neuro History**     |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Seizure               | 19.6% (11/56)         | 10.9% (5/46)          |
+-----------------------+-----------------------+-----------------------+
| Stroke                | 0.0% (0/56)           | 2.2% (1/46)           |
+-----------------------+-----------------------+-----------------------+
| Aneursym              | \*8.9% (5/56)         | 0.0% (0/46)           |
+-----------------------+-----------------------+-----------------------+
| Other AVM             | 3.6% (2/56)           | 0.0% (0/46)           |
+-----------------------+-----------------------+-----------------------+
| Intracranial          | 11% (6/56)            | 6.5% (3/46)           |
| Hemorrhage (\>1 yr)   |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Neuro               |                       |                       |
| Interventions**       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Surgery (Clipping)    | 5.4% (3/56)           | 0.0% (0/46)           |
+-----------------------+-----------------------+-----------------------+

\*p\<0.05

Presenting symptoms were hierarchically evaluated based on the worst
presenting symptom, i.e. acute bleed, remote bleed, neurologic deficit,
neurologic symptoms, or no clinical symptoms. Neurological deficit
includes seizures, hemiparesis, visual disturbances, and difficulty
speaking. Neurologic symptom includes headache/migraine,
nausea/vomiting, and nystagmus.

+-----------------------+-----------------------+-----------------------+
| Hierarchical          | N-BCA                 | Onyx                  |
| Presenting Symptoms   |                       |                       |
|                       | n=56                  | n=46                  |
| n=102                 |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Acute Bleed (\<30     | 14.3% (8/56)          | 15.2% (7/46)          |
| days)                 |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Remote Bleed (\>30    | 17.9% (10/56)         | 19.6% (9/46)          |
| days\<1 year)         |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Neurologic Deficit    | 51.8% (29/56)         | 39.1% (18/46)         |
+-----------------------+-----------------------+-----------------------+
| Neurologic Symptoms   | 14.3% (8/56)          | 19.6% (9/46)          |
+-----------------------+-----------------------+-----------------------+
| None                  | 1.8% (1/56)           | 6.5% (3/46)           |
+-----------------------+-----------------------+-----------------------+

Approximately 34% of the total patients presented with some type of
intracranial hemorrhage, i.e. either acute or remote. The majority of
the patients had some type of neurologic deficit.

Patient 1-004 had more than one AVM treated and therefore the table
represents 103 AVMs in 102 randomized patients. One patient who was a
late screen had missing information on AVM characteristics so this
patient is missing from the table. The pre-embolization AVM size was
determined by the core laboratory.

+-----------------------+-----------------------+-----------------------+
| Pretreatment          | N-BCA                 | Onyx                  |
| Assessment            |                       |                       |
|                       | n=57 AVMs in 56       | n=46 AVMs in 46       |
| n=103 AVMs in 102 pts | patients              | patients              |
+-----------------------+-----------------------+-----------------------+
| **AVM Location**      |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Right                 | 55.4% (31/56)         | 63.0% (29/46)         |
+-----------------------+-----------------------+-----------------------+
| Left                  | 41.1% (23/56)         | 34.8% (16/46)         |
+-----------------------+-----------------------+-----------------------+
| Midline               | 3.6% (2/56)           | 2.2% (1/46)           |
+-----------------------+-----------------------+-----------------------+
| **AVM in eloquent     | 48.2% (27/56)         | 45.7% (21/46)         |
| area of brain**       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Venous Drainage**   |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Deep                  | 8.9% (5/56)           | 15.2% (7/46)          |
+-----------------------+-----------------------+-----------------------+
| Superficial           | 62.5% (35/56)         | 63.0% (29/46)         |
+-----------------------+-----------------------+-----------------------+
| Both                  | 28.6% (16/56)         | 21.7% (10/46)         |
+-----------------------+-----------------------+-----------------------+
| **Spetzler-Martin     |                       |                       |
| Grade**               |                       |                       |
+-----------------------+-----------------------+-----------------------+
| I                     | 25.0% (14/56)         | 10.9% (5/46)          |
+-----------------------+-----------------------+-----------------------+
| II                    | 25.0% (14/56)         | 43.5% (20/46)         |
+-----------------------+-----------------------+-----------------------+
| III                   | 30.4% (17/56)         | 26.1% (12/46)         |
+-----------------------+-----------------------+-----------------------+
| IV                    | 19.6% (11/56)         | 19.6% (9/46)          |
+-----------------------+-----------------------+-----------------------+
| **AVM Size (Core Lab, |                       |                       |
| mm^3^)**              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Mean[+]{.underline}SD | 16                    | 26                    |
|                       | .0[+]{.underline}20.0 | .3[+]{.underline}45.2 |
+-----------------------+-----------------------+-----------------------+
| Median                | 8.1                   | 13.6                  |
+-----------------------+-----------------------+-----------------------+
| Range                 | 0.08-94.9             | 0.17-290.5            |
+-----------------------+-----------------------+-----------------------+

AVM size was slightly higher in the Onyx group but this difference was
not statistically significant, p=0.17. Both groups had the majority of
the patients treated with AVMs having a Spetzler-Martin grade of either
II or III.

*On page 3147, you state that one patient who was a late screen had
missing information on AVM characteristics so this patient is missing
from the AVM Characteristics table. However, data is provided on 102
patients, 56 treated with n-BCA and 46 treated with Onyx. Please clarify
this apparent discrepancy.*

Baseline neurological status was evaluated using the Glasgow Coma Score,
Barthel Index, and NIH stroke scale. Patients with a GCS of 8 or less
are considered to be in a coma. All 3 scales indicated that the majority
of patients treated in the study did not have severe neurological
deficits at baseline. The Onyx group had a slightly higher percentage of
patients with worse scores at baseline on these neurologic scales, i.e.
almost 40% of the Onyx patients and only about 25% of the n-BCA patients
had an NIH stroke scale\>0 on entry into the study; the difference was
not statistically significant.

+-----------------------+-----------------------+-----------------------+
| Pretreatment          | N-BCA                 | Onyx                  |
| Assessment            |                       |                       |
|                       | n=56                  | n=46                  |
+-----------------------+-----------------------+-----------------------+
| **Glasgow Coma        |                       |                       |
| Score**               |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 0-6                   | 3.6% (2/55)           | 2.2% (1/46)           |
+-----------------------+-----------------------+-----------------------+
| 7-14                  | 3.6% (2/55)           | 8.7% (4/46)           |
+-----------------------+-----------------------+-----------------------+
| \>14                  | 92.7% (51/54)         | 89.1% (41/46)         |
+-----------------------+-----------------------+-----------------------+
| **Barthel Index       |                       |                       |
| (Total Score)**       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 0-25                  | 3.7% (2/54)           | 8.7% (4/46)           |
+-----------------------+-----------------------+-----------------------+
| 26-75                 | 1.9% (1/54)           | 4.3% (2/46)           |
+-----------------------+-----------------------+-----------------------+
| 76-100                | 94.4% (51/54)         | 87.0% (40/46)         |
+-----------------------+-----------------------+-----------------------+
| **NIH Stroke Scale    |                       |                       |
| (Total Score)**       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 0                     | 75.5% (40/53)         | 60.9% (28/46)         |
+-----------------------+-----------------------+-----------------------+
| 1-4                   | 18.9% (10/53)         | 30.4% (14/46)         |
+-----------------------+-----------------------+-----------------------+
| 5-10                  | 5.7% (3/53)           | 2.2% (1/46)           |
+-----------------------+-----------------------+-----------------------+
| \>10                  | 0.0% (0/53)           | 6.5% (3/46)           |
+-----------------------+-----------------------+-----------------------+

A poolability analysis was done to ensure that data across all sites
could be combined for analysis.

  ----------------------- ----------------------- -----------------------
  Characteristic          Fisher's Exact          F

  Gender                  P=0.86                  

  Assignment Group        P=0.99                  

  AVM Location            P=0.55                  

  Eloquent Part of Brain  P=0.40                  

  Spetzler-Martin Grade   P=0.02                  
  (1/2 vs 3/4)                                    

  Presence of Bleed       P=0.11                  

  Age                                             1.26 p=0.24

  BMI                                             0.93 p=0.54

  SBP                                             0.71 p=0.78

  DBP                                             1.50 p=0.12

  AVM Size                                        1.92 p=0.03
  ----------------------- ----------------------- -----------------------

The only significant differences were for Spetzler-Martin Grade and AVM
size. The sponsor argues that since the Spetzler-Martin Grade was not
found predictive of the primary safety and efficacy endpoints in the
trial, it should not preclude pooling the results by site. The AVM size
at site 34 had a considerably larger median AVM than the other sites;
this variability is consistent with BAVMs and thus is representative of
the general population.

Since 2 of the randomized patients were considered late screen failures,
these tables and all subsequent tables are based on the number of
patients enrolled which is 100.

+-----------------------+-----------+-----------+-----------+-----------+
| \# Embolization       | n-BCA     |           | Onyx      |           |
| Procedures            |           |           |           |           |
|                       | n-54      |           | n=46      |           |
+-----------------------+-----------+-----------+-----------+-----------+
|                       | \# Pts    | \% Pts    | \# Pts    | \% Pts    |
+-----------------------+-----------+-----------+-----------+-----------+
| 1                     | 34        | 63.0%     | 26        | 56.5%     |
+-----------------------+-----------+-----------+-----------+-----------+
| 2                     | 9         | 16.7%     | 11        | 23.9%     |
+-----------------------+-----------+-----------+-----------+-----------+
| 3                     | 7         | 13.0%     | 6         | 13.0%     |
+-----------------------+-----------+-----------+-----------+-----------+
| 4                     | 2         | 3.7%      | 1         | 2.2%      |
+-----------------------+-----------+-----------+-----------+-----------+
| 5                     | 2         | 3.7%      | 1         | 2.2%      |
+-----------------------+-----------+-----------+-----------+-----------+
| 6                     | 0         | 0.0%      | 0         | 0.0%      |
+-----------------------+-----------+-----------+-----------+-----------+
| 7                     | 0         | 0.0%      | 1         | 2.2%      |
+-----------------------+-----------+-----------+-----------+-----------+
| Total \# Pts          | 54        | 100%      | 46        | 100%      |
+-----------------------+-----------+-----------+-----------+-----------+
| Total Procedures      | 91        |           | 82        |           |
+-----------------------+-----------+-----------+-----------+-----------+
| Avg \# Procedures/Pt  | 1.7       |           | 1.8       |           |
|                       |           |           |           |           |
| (min, max)            | (1,5)     |           | (1,7)     |           |
+-----------------------+-----------+-----------+-----------+-----------+

A total of 173 embolizations were performed in 100 patients, i.e. 82 in
46 patients treated with Onyx and 91 in 54 patients treated with n-BCA.
The majority of patients were able to be treated with one embolization
procedure.

+-----------------------+-----------------------+-----------------------+
|                       | n-BCA                 | Onyx                  |
|                       |                       |                       |
|                       | n-54                  | n=46                  |
+-----------------------+-----------------------+-----------------------+
| \# Procedures         | 83                    | 72                    |
+-----------------------+-----------------------+-----------------------+
| \# Injections         | 203                   | 183                   |
+-----------------------+-----------------------+-----------------------+
| Avg \#                | 2.5                   | 2.5                   |
| Injections/Procedure  |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Onyx Usage          |                       |                       |
| Details**             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Microcatheter Use   |                       |                       |
| (202 catheters)**     |                       |                       |
+-----------------------+-----------------------+-----------------------+
| FlowRider             |                       | 22                    |
+-----------------------+-----------------------+-----------------------+
| Ultraflow             |                       | 151                   |
+-----------------------+-----------------------+-----------------------+
| Rebar                 |                       | 17                    |
+-----------------------+-----------------------+-----------------------+
| MTI Unknown           |                       | 12                    |
+-----------------------+-----------------------+-----------------------+
| **Initial Catheter    |                       |                       |
| Position**            |                       |                       |
|                       |                       |                       |
| **n=183 Injections**  |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Wedged                |                       | 36                    |
+-----------------------+-----------------------+-----------------------+
| Unwedged              |                       | 144                   |
+-----------------------+-----------------------+-----------------------+
| Missing               |                       | 3                     |
+-----------------------+-----------------------+-----------------------+
| **Onyx Formulation    |                       |                       |
| Used**                |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Onyx-18 Alone         |                       | 55/72 (76%)           |
+-----------------------+-----------------------+-----------------------+
| Onyx-34 Alone         |                       | 9/72 (13%)            |
+-----------------------+-----------------------+-----------------------+
| Onyx-18 and 34        |                       | 8/72 (11%)            |
+-----------------------+-----------------------+-----------------------+
| No Agent Delivered    |                       | 10 Procedures         |
+-----------------------+-----------------------+-----------------------+
| **Mean Vol            |                       | 0.50 ml               |
| Injection**           |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Mean Duration       |                       | 5.44 min              |
| Injection**           |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **DMSO Usage**        |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Mean vol DMSO         |                       | 0.27 ml               |
| Injected              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Mean DMSO Injection   |                       | 90.9 sec              |
| Time                  |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **N-BCA Usage         |                       |                       |
| Details**             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Oil:n-BCA Ratio**   |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Within Guidelines     | 71%                   |                       |
| (3:1-1:2)             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Higher Concentration  | 23%                   |                       |
| Oil                   |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Higher Concentration  | 6%                    |                       |
| n-BCA                 |                       |                       |
+-----------------------+-----------------------+-----------------------+
| No Agent Delivered    | 8 Procedures          |                       |
+-----------------------+-----------------------+-----------------------+
| **Mean Vol n-BCA      | 0.38 ml               |                       |
| Delivered**           |                       |                       |
+-----------------------+-----------------------+-----------------------+

Of the 82 procedures in the Onyx group, 72 had Onyx injected; of the 91
procedures in the n-BCA group, 83 had n-BCA injected. Patients did not
receive injection of the embolic agent for various technical reasons
such as failed access or physician decision to utilize an alternative
treatment. There were about 2.5 injections of the embolic agent per
procedure.

The clinical protocol allowed for adjunctive procedures to be performed.

+-----------------------+-----------------------+-----------------------+
|                       | n-BCA                 | Onyx                  |
|                       |                       |                       |
|                       | n-54                  | n=46                  |
+-----------------------+-----------------------+-----------------------+
| **\# Procedures in    | 23/91 (25.3%)         | \*8/82 (9.8%)         |
| which Coils were used |                       |                       |
| as adjunct**          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Reason for Coil     |                       |                       |
| Usage**               |                       |                       |
+-----------------------+-----------------------+-----------------------+
| High Flow Fistula     | 20                    | 4                     |
+-----------------------+-----------------------+-----------------------+
| Other                 | 3                     | 4                     |
+-----------------------+-----------------------+-----------------------+
| **Type of Coils       |                       |                       |
| Used^+^**             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| GDC                   | 2                     | 4                     |
+-----------------------+-----------------------+-----------------------+
| Straight Fiber Coil   | 1                     | 2                     |
+-----------------------+-----------------------+-----------------------+
| 3D                    | 0                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Liquid Coils          | 20                    | 4                     |
+-----------------------+-----------------------+-----------------------+

\*p=0.008

^+^Multiple types of coils were used for a single patient

In most cases, the reason given for use of adjunctive coils was the
presence of a high flow fistula. In 3 n-BCA cases and 4 Onyx cases, the
adjunctive devices were used for other reasons. In 1 n-BCA case and 1
Onyx case, coils were used to treat an aneurysm. In the remaining cases,
coils were categorized by the investigator to be necessary for some
other safety reason, as allowed by the clinical protocol.

Events are considered technical or procedural if they are not associated
with clinical sequelae. All technical and procedural events reported by
the site underwent review by a medical monitor to ensure that these
events did not result in clinical sequelae. When technical or procedural
events that were not documented on the CRFs were identified by the
medical monitor, these events were adjudicated and entered into the
adjudication database as either technical or procedural.

+------------------------------+-------------------+------------------+
| Technical Events             | N-BCA             | Onyx             |
|                              |                   |                  |
|                              | n=54              | n=46             |
+------------------------------+-------------------+------------------+
| **System-Related Agent**     |                   |                  |
+------------------------------+-------------------+------------------+
| Delayed polymerization       | 1                 | 0                |
+------------------------------+-------------------+------------------+
| Fragmentation of Onyx        | 0                 | 1                |
+------------------------------+-------------------+------------------+
| Delivery Catheter Removal    | 0                 | 2                |
| Difficulty                   |                   |                  |
+------------------------------+-------------------+------------------+
| Poor                         | 0                 | 5                |
| Penetration/Visualization    |                   |                  |
+------------------------------+-------------------+------------------+
| Premature Polymerization     | 1                 | 0                |
+------------------------------+-------------------+------------------+
| Prolonged Polymerization     | 3                 | 0                |
| Time                         |                   |                  |
+------------------------------+-------------------+------------------+
| Small Amount of Onyx in Vein | 0                 | 1                |
+------------------------------+-------------------+------------------+
| **System-Related Catheter**  |                   |                  |
+------------------------------+-------------------+------------------+
| Catheter Shaft Rupture       | 0                 | \*1              |
+------------------------------+-------------------+------------------+
| Delivery Catheter Removal    | 0                 | 5                |
| Difficulty                   |                   |                  |
+------------------------------+-------------------+------------------+
| Failed Access                | 3                 | 3                |
+------------------------------+-------------------+------------------+
| **Treatment Related**        |                   |                  |
+------------------------------+-------------------+------------------+
| Failed Access                | 1                 | 0                |
+------------------------------+-------------------+------------------+
| **Disease Related**          |                   |                  |
+------------------------------+-------------------+------------------+
| Failed Access                | 1                 | 0                |
+------------------------------+-------------------+------------------+
| **Other**                    |                   |                  |
+------------------------------+-------------------+------------------+
| High Flow Fistula            | 1                 | 0                |
+------------------------------+-------------------+------------------+
| Total Technical Failures     | 11                | 18               |
+------------------------------+-------------------+------------------+
| **Procedural Events**        |                   |                  |
+------------------------------+-------------------+------------------+
| Embolization of unintended   | 2                 | 0                |
| vessel                       |                   |                  |
+------------------------------+-------------------+------------------+
| Laboratory/Imaging           | 6                 | 2                |
| Abnormalities                |                   |                  |
+------------------------------+-------------------+------------------+
| Vasospasm                    | 4                 | 1                |
+------------------------------+-------------------+------------------+
| Total Procedural Events      | 12                | 3                |
+------------------------------+-------------------+------------------+
| **Technical and Procedural   |                   |                  |
| Events**                     |                   |                  |
+------------------------------+-------------------+------------------+
| Total Technical and          | 23                | 21               |
| Procedural Events            |                   |                  |
+------------------------------+-------------------+------------------+
| Total \# Pts with            | 31.5%             | 30.4%            |
| Technical/Procedural Events  |                   |                  |
+------------------------------+-------------------+------------------+
| #Events/#Pts                 | 17/54             | 14/46            |
+------------------------------+-------------------+------------------+

\*Device malfunction

There were 7 reported incidences of delivery catheter removal difficulty
recorded on the CRFs. In 2 cases, the catheter removal difficulty was
felt to be related to the agent having precipitated around the tip of
the catheter. In the other 5 cases, it was attributed to the catheter
itself; this may be related to different performance characteristics of
the catheters required for Onyx administration as opposed to those used
for standard embolization techniques. There were no clinical events
related to these reported difficulties.

In one patient, 06-010, breakup of the embolic material occurred during
injection into an undetected high flow component of the AVM. There were
8 reports of laboratory or imaging abnormalities; 4 (3 n-BCA and 1 Onyx)
had silent infarctions in the distribution of the AVM on post
embolization CT or MRI and 2 (1 n-BCA and 1 Onyx) had small areas of
hemorrhage following embolization.

In all cases of vasospasm, the spasm resolved spontaneously and did not
impede completion of the procedure.

Two n-BCA patients had embolization of an unintended vessel. In one
patient, 08-006, embolic material was found on a routine chest x-ray.
Work-up demonstrated a small, sub-segmental occlusion consistent with
embolic material having transited the AVM to the venous system and
having become lodged in a small pulmonary artery. In the second patient,
08-012, the site reported a prolonged polymerization time and subsequent
small amount of embolic material in the draining vein.

Two events which occurred in the Onyx patients were considered device
malfunctions, both catheter rupture, and the catheters were returned to
MTI for analysis. In the first patient, 38-006, there was slight
difficulty with delivery catheter removal following angiographic
assessment at the close of the procedure; a Micro Therapeutics UltraFlow
HPC flow directed micro catheter was used and gentle traction applied on
a second attempt at catheter removal resulted in catheter release, there
were no clinical sequelae. The catheter was returned for engineering
analysis because the catheter shaft was noted to have ruptured during
selective angiography utilizing a 1 cc syringe and normal pressure; the
analysis concluded that the catheter was built to specification and
experienced a high pressure burst resulting from tube constriction
(kink/prolapse) during use. In the second patient, 20-003, the site
reported that a catheter shaft rupture of a Micro Therapeutics FlowRider
Plus micro catheter, resulted in leakage of Onyx into the anterior and
middle cerebral arteries with worsening seizures and neurologic changes;
the event was categorized as a severe worsening neurologic status that
was system related; the neurologic sequelae resolved by discharge. This
event was similar to an event in Europe that prompted an advisory
notice, August 2001, to all sites that recommended a modified technique
for Onyx delivery, including recommendations to stop injection if
resistance is felt or Onyx is not visualized exiting the catheter tip.
The FlowRider Plus catheter is no longer a marketed product and has been
replaced by an optimized UltraFlow catheter. The engineering report
notes catheter rupture approximately 10 cm from the tip which is
consistent with a very slow infusion rate imposed on a distal occlusion;
there is a possibility that a slug of Onyx precipitated and became
lodged in the catheter resulting in high pressurization and catheter
burst just proximal.

A total of 89 patients had an attempt at surgical resection; 86 had a
total resection, 45 n-BCA and 41 Onyx. Three patients had a partial
resection and are being followed for safety at 3 and 12 months
post-procedure. In general, patients required one surgical procedure to
obtain total resection; a total of 98 surgical procedures were required
to treat 89 patients; 7 patients, 5 n-BCA and 2 Onyx, required multiple
staged procedures. The maximum number of surgical treatments attempted
was 4 in one n-BCA patient, 29-003, resulting in complete surgical
resection of the AVM. One n-BCA patient, 29-001, required a staged
course of embolization and surgery based on physician assessment of the
pathology; the patient had surgery after the first series of
embolization procedures; another series of embolization procedures with
a second surgical resection was then performed. The patient had
successful embolization of the AVM and total resection after the second
surgery.

*On page 3153, in the Technical and Procedural Events table, 5 Onyx
patients had poor penetration/visualization. Please specify which
patients had poor penetration and which ones had poor visualization and
discuss these events in detail.*

[Assessments]{.underline}

Baseline neurological examination and grading scales, including NIHSS,
Barthel Index, and GCS, CT, MRI, and/or angiograms

After embolization, the patients were evaluated with the same scales
except the Glasgow Outcome Scale Post Procedure was used.

[Endpoint]{.underline}

Primary: 50% or greater angiographic reduction in AVM size by core
laboratory was required for success.

Secondary:

Surgical blood loss

Surgical resection time

+-----------+--------+------------+-------------+---------+---------+
| NIH Score | Status | Change     |             | Change  |         |
| Change    |        | Post-Em    |             | Post-   |         |
| from      |        | bolization |             | Surgery |         |
| Baseline  |        |            |             |         |         |
+-----------+--------+------------+-------------+---------+---------+
|           |        | N-BCA      | Onyx        | N-BCA   | Onyx    |
|           |        |            |             |         |         |
|           |        | n=49       | n=43        | n=38    | n=39    |
+-----------+--------+------------+-------------+---------+---------+
| \>0       | De     | 10.2%      | 11.6%       | 36.8%   | 28.2%   |
|           | clined | (5/49)     | (5/43)      | (14/38) | (11/39) |
+-----------+--------+------------+-------------+---------+---------+
| 0         | Unc    | 71.4%      | 72.1%       | 52.6%   | 59.0%   |
|           | hanged | (35/49)    | (31/43)     | (20/38) | (23/39) |
+-----------+--------+------------+-------------+---------+---------+
| 1-5       | Im     | 18.3%      | 14.0%       | 10.5%   | 10.3%   |
|           | proved | (9/49)     | (6/43)      | (4/38)  | (4/39)  |
+-----------+--------+------------+-------------+---------+---------+
| \>5       | Im     | 0% (0/49)  | 2.3% (1/43) | 0%      | 2.6%    |
|           | proved |            |             | (0/38)  | (1/39)  |
+-----------+--------+------------+-------------+---------+---------+

+-----------+--------+------------+-------------+---------+---------+
| Barthel   | Status | Change     |             | Change  |         |
| Score     |        | Post-Em    |             | Post-   |         |
| Change    |        | bolization |             | Surgery |         |
| from      |        |            |             |         |         |
| Baseline  |        |            |             |         |         |
+-----------+--------+------------+-------------+---------+---------+
|           |        | N-BCA      | Onyx        | N-BCA   | Onyx    |
|           |        |            |             |         |         |
|           |        | n=50       | n=43        | n=40    | n=38    |
+-----------+--------+------------+-------------+---------+---------+
| 1-10      | Im     | 2% (1/50)  | 0% (0/43)   | 5.0%    | 0%      |
|           | proved |            |             | (2/40)  | (0/38)  |
+-----------+--------+------------+-------------+---------+---------+
| 0         | Unc    | 68.0%      | 72.1%       | 50.0%   | 52.6%   |
|           | hanged | (34/50)    | (31/43)     | (20/40) | (20/38) |
+-----------+--------+------------+-------------+---------+---------+
| 5-10      | De     | 12.0%      | 4.7% (2/43) | 5.0%    | 7.9%    |
|           | clined | (6/50)     |             | (2/40)  | (3/38)  |
+-----------+--------+------------+-------------+---------+---------+
| 15-50     | De     | 12.0%      | 16.3%       | 12.5%   | 15.8%   |
|           | clined | (6/50)     | (7/43)      | (5/40)  | (6/38)  |
+-----------+--------+------------+-------------+---------+---------+
| 51-100    | De     | 6.0%       | 7.0% (3/43) | 27.5%   | 23.7%   |
|           | clined | (3/50)     |             | (11/40) | (9/38)  |
+-----------+--------+------------+-------------+---------+---------+

Some patients did show a decline in their neurologic assessment but the
percentage of patients was similar in both groups. This is likely due to
a temporal correlation between the time of the intervention,
embolization or surgery, and the time the neurologic assessments were
made. For example, in many cases a Barthel Index was either unassessable
or declined because the patient was prescribed strict bed rest post
procedure and therefore the indices associated with ambulation were
scored as a decline by default or the evaluation was not performed.

The Glasgow Outcome Scale is stratified based on the patients presenting
Glasgow Coma Scale at baseline. Patients were categorized with either no
deficit as baseline, Glasgow Coma Scale=15, or patients presenting with
some level of deficit, Glasgow Coma Scale\<15. Six of the patients with
a Glasgow Outcome Scale reported post-embolization and/or post-surgery
had a presenting Glasgow Coma Scale that categorized them as having some
neurologic deficit, 3 n-BCA and 3 Onyx. All other patients had a normal
Glasgow Coma Scale at baseline.

+-----------+-----------+-----------+-----------+-----------+-----------+
| P         |           |           |           |           |           |
| resenting |           |           |           |           |           |
| with      |           |           |           |           |           |
| normal    |           |           |           |           |           |
| Glasgow   |           |           |           |           |           |
| Coma      |           |           |           |           |           |
| Scale     |           |           |           |           |           |
| (=15)     |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| GOS       | Post-Emb  |           |           | Pos       |           |
|           | olization |           |           | t-Surgery |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | N-BCA     | Onyx      |           | N-BCA     | Onyx      |
|           |           |           |           |           |           |
|           | n=46      | n=40      |           | n=36      | n=34      |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 0         | 80.4%     | 67.5%     |           | 66.7%     | 47.1%     |
|           | (37/46)   | (27/40)   |           | (24/36)   | (16/34)   |
+-----------+-----------+-----------+-----------+-----------+-----------+
| I         | 17.4%     | 22.5%     |           | 11.1%     | 23.5%     |
|           | (8/46)    | (9/40)    |           | (4/36)    | (8/34)    |
+-----------+-----------+-----------+-----------+-----------+-----------+
| II        | 0% (0/46) | 7.5%      |           | 5.5%      | 17.6%     |
|           |           | (3/40)    |           | (2/36)    | (6/34)    |
+-----------+-----------+-----------+-----------+-----------+-----------+
| III       | 2.2%      | 2.5%      |           | 11.1%     | 11.8%     |
|           | (1/46)    | (1/40)    |           | (4/36)    | (4/34)    |
+-----------+-----------+-----------+-----------+-----------+-----------+
| IV        | 0% (0/46) | 0% (0/40) |           | 2.8%      | 0% (0/34) |
|           |           |           |           | (24/36)   |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| V         | 0% (0/46) | 0% (0/40) |           | 0% (0/36) | 0% (0/34) |
+-----------+-----------+-----------+-----------+-----------+-----------+
| P         |           |           |           |           |           |
| resenting |           |           |           |           |           |
| with      |           |           |           |           |           |
| Glasgow   |           |           |           |           |           |
| Coma      |           |           |           |           |           |
| Scale     |           |           |           |           |           |
| with Some |           |           |           |           |           |
| Deficits  |           |           |           |           |           |
| (\<15)    |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| GOS       | Post-Emb  |           |           | Pos       |           |
|           | olization |           |           | t-Surgery |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
|           | N-BCA     | Onyx      |           | N-BCA     | Onyx      |
|           |           |           |           |           |           |
|           | n=3       | n=3       |           | n=3       | n=3       |
+-----------+-----------+-----------+-----------+-----------+-----------+
| 0         | 0% (0/3)  | 0% (0/3)  |           | 0% (0/3)  | 0% (0/3)  |
+-----------+-----------+-----------+-----------+-----------+-----------+
| I         | 33.3%     | 33.3%     |           | 33.3      | 33.3%     |
|           | (1/3)     | (1/3)     |           | (1/3)     | (1/3)     |
+-----------+-----------+-----------+-----------+-----------+-----------+
| II        | 0% (0/3)  | 0% (0/3)  |           | 0% (0/3)  | 0% (0/3)  |
+-----------+-----------+-----------+-----------+-----------+-----------+
| III       | 66.7%     | 66.7%     |           | 66.7%     | 66.7%     |
|           | (2/3)     | (2/3)     |           | (2/3)     | (2/3)     |
+-----------+-----------+-----------+-----------+-----------+-----------+
| IV        | 0% (0/3)  | 0% (0/3)  |           | 0% (0/3)  | 0% (0/3)  |
+-----------+-----------+-----------+-----------+-----------+-----------+
| V         | 0% (0/3)  | 0% (0/3)  |           | 0% (0/3)  | 0% (0/3)  |
+-----------+-----------+-----------+-----------+-----------+-----------+

One patient, 29-004, treated with Onyx, declined from baseline; all
other patients remained the same.

The Glasgow Outcome Scale did not show any difference between the two
groups either post-final embolization or post-surgery.

*Please discuss the patients in the Glasgow Outcome Scale table on page
3158, since a higher percentage of Onyx treated patients had a score of
I or II post-embolization and post-surgery.*

[Primary Efficacy Endpoint Analysis]{.underline}

An independent angiographic core lab read all angiograms at baseline and
after the completion of all embolization procedures. The reader was
masked to the treatment allocation and calculated the volume of the AVM
obliteration based on a standardized method. The films were digitized
using an automated system and stored on electronic media. The
independent reviewer identified the margins of the AVM and digitized
these points. The automated software algorithm was used to calculate the
volume of the AVM and this information was stored on electronic media
for each patient's AVM. In some cases, the automated system was not
viable for technical reasons such as poor film quality or inconsistent
views between baseline and post-embolization. In these cases, the core
lab evaluated the volume of obliteration of the AVM using visual
estimation against the dichotomous endpoint of \>50% AVM exclusion.

Angiograms will include one AP and one lateral view, early, middle, and
late phases for each of the three circulations, posterior, right
anterior and left anterior. Adjunctive coil use was
permitted/recommended for complete blockage of a large artery after
embolization more distally with the liquid embolic agent; to block off
arterial feeder which could not be safely embolized with the liquid
embolic agent; to protect a normal arterial branch off a main artery
from distal embolization with the liquid embolic agent; for flow
arrest/reduction if angiography shows a high flow situation defined as
the simultaneous appearance on angiography of venous drainage with
arterial opacification,; to prevent trans-nidus passage of the liquid
embolic agent into the venous side; or for other safety reasons
determined by the investigator.

Percentage of Patients with [\>]{.underline}50% Exclusion of AVM

+----------------+----------+-------------+-------------+-------------+
| Inte           | N-BCA    | Onyx        | Difference  | Relative    |
| ntion-to-Treat |          |             |             | Risk        |
|                |          |             | \[95%       |             |
|                |          |             | C.I.\]      |             |
+----------------+----------+-------------+-------------+-------------+
| Primary        | 84.3%    | 97.6%       | 13.3%       | 1.16        |
| Efficacy by    |          |             |             |             |
| Core Lab       | (43/51)  | (41/42)     | \[2.3%,     | \[1.01,     |
|                |          |             | 24.3%\]     | 1.32\]      |
+----------------+----------+-------------+-------------+-------------+
| Conservative   | 84.6%    | 93.2%       | 8.6%        | 1.10        |
| Estimate with  |          |             |             |             |
| Ongoing Pts    | (44/52)  | (41/44)     | \[-3.8%,    | \[0.96,     |
|                |          |             | 20.9%\]     | 1.27\]      |
+----------------+----------+-------------+-------------+-------------+
| Per-Protocol   |          |             |             |             |
+----------------+----------+-------------+-------------+-------------+
| Primary        | 85.7%    | 95.4%       | 9.6%        | 1.16        |
| Efficacy by    |          |             |             |             |
| Core Lab       | (42/49)  | (41/43)     | \[-2.0%,    | \[0.97,     |
|                |          |             | 21.3%\]     | 1.27\]      |
+----------------+----------+-------------+-------------+-------------+
| Conservative   | 86.0%    | 93.2%       | 7.2%        | 1.08        |
| Estimate with  |          |             |             |             |
| Ongoing Pts    | (43/50)  | (41/44)     | \[-5.0%,    | \[0.94,     |
|                |          |             | 19.4%\]     | 1.24\]      |
+----------------+----------+-------------+-------------+-------------+

Diff=Onyx-n-BCA

RR=Onyx/n-BCA

Intention-to Treat Population

Two patients in the n-BCA group had films that were not analyzable based
on the core lab assessment; the films were not in compliance with the
protocol in that inconsistent views, required for assessment pre- and
post-embolization were not submitted to the sponsor. These patients were
removed from the analysis and categorized as protocol violations. One
patient in the n-BCA group is still receiving embolization treatments
and therefore has been removed from the analysis until embolization
treatment is completed. A total of 51 patients were therefore available
for the efficacy analysis in the n-BCA group.

Two patients in the Onyx group had films that were not analyzable on the
core lab assessment; the films provided to the core lab did not contain
the required consistent views from pre- to post-embolization. These
patients were considered protocol deviations and have been removed from
the efficacy cohort. In addition, two of the Onyx patients are still
receiving embolization treatments and therefore cannot be assessed for
efficacy yet. Therefore, a total of 42 patients are included in the
efficacy analysis for the Onyx group.

+----------------+-------+--------------------+------------------------+
|                | Total | N-BCA=n            | Onyx=n                 |
|                | Pts=n |                    |                        |
+----------------+-------+--------------------+------------------------+
| Randomized     | 108   | 57                 | 51                     |
+----------------+-------+--------------------+------------------------+
| Late Screen    | 2     | 2                  |                        |
| Failures       |       |                    |                        |
|                |       | (18-003, 21-009)   |                        |
+----------------+-------+--------------------+------------------------+
| Enrolled Pts   | 106   | 55                 | 51                     |
+----------------+-------+--------------------+------------------------+
| Protocol       | 6     | 1                  | 5                      |
| violations     |       |                    |                        |
|                |       | (5-005)            | (2-008, 8-001, 8-010,  |
| (Dural         |       |                    | 8-014, 38-001)         |
| Fistulas)      |       |                    |                        |
+----------------+-------+--------------------+------------------------+
| Films not      | 4     | 2                  | 2                      |
| Analyzable     |       |                    |                        |
|                |       | (21-008, 8-004)    | (32-003, 2-001)        |
+----------------+-------+--------------------+------------------------+
| Pts Ongoing    | 3     | 1                  | 2                      |
|                |       |                    |                        |
|                |       | (38-004)           | (38-006, 3-003)        |
+----------------+-------+--------------------+------------------------+
| Total          | 94    | 51                 | 42                     |
| Accessible     |       |                    |                        |
|                |       | Success n=43       | Success n=41           |
|                |       |                    |                        |
|                |       | \*Failure n=8      | \*Failure n=1          |
|                |       |                    |                        |
|                |       | Success Rate=84%   | Success Rate=98%       |
|                |       | (43/51)            | (41/42)                |
+----------------+-------+--------------------+------------------------+

\*n-BCA Failures:

By core lab: 6-013, 19-001, 34-001, 2-012, 8-012, 8-007

Procedure failures: 8-006, 8-009

\*Onyx Failures

By core lab: 6-007

Conservative Analysis

The conservative analysis takes into account the patients currently
ongoing in the trial. Patients were assigned as a failure if they were
randomized to Onyx and a success if randomized to n-BCA.

ITT Efficacy including Dural Fistula Patients

The n-BCA success rate remained at 84% and the Onyx success rate was
reduced to 95%.

Predictors of Core Lab Success (n=100)

+-----------------+-----------------+-----------------+-----------------+
| Characteristic  | Core Lab ITT    | Core Lab ITT    | p-value         |
|                 | Failure         | Success         |                 |
|                 |                 |                 |                 |
|                 | n=9             | n=84            |                 |
+-----------------+-----------------+-----------------+-----------------+
| Gender (%male)  | 44%             | 46%             | P=1.00          |
+-----------------+-----------------+-----------------+-----------------+
| AVM Location    | 89%             | 98%             | P=0.27          |
| (%right/left)   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Eloquent Part   | 22%             | 50%             | P=0.16          |
| of Brain        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Spetzler-Martin | 22%             | 49%             | P=0.17          |
| Grade           |                 |                 |                 |
|                 |                 |                 |                 |
| (% 3 or 4)      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Venous Drainage | 22%             | 39%             | P=0.48          |
|                 |                 |                 |                 |
| (% deep)        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Presence of     | 44%             | 31%             | P=0.46          |
| Bleed           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Glasgow Coma    | 11%             | 10%             | P=1.00          |
| Scale           |                 |                 |                 |
|                 |                 |                 |                 |
| (\<15)          |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Age             | 39[+            | 37[+            | P=0.71          |
|                 | ]{.underline}13 | ]{.underline}15 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd, |                 |                 |                 |
| years)          |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| BMI             | 34[             | 25[             | P=0.29          |
|                 | +]{.underline}4 | +]{.underline}6 |                 |
+-----------------+-----------------+-----------------+-----------------+
| SBP             | 130[+           | 123[+           | P=0.36          |
|                 | ]{.underline}22 | ]{.underline}14 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd, |                 |                 |                 |
| mmHg)           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| DBP             | 75[             | 70[+            | P=0.27          |
|                 | +]{.underline}6 | ]{.underline}12 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd, |                 |                 |                 |
| mmHg)           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| AVM Size        | 8.7             | 11.6            | P=0.95          |
|                 |                 |                 |                 |
| (median, mm^3^) |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| \# Embolization | 1.7[+]          | 1.7[+]          | P=1.00          |
| Procedures      | {.underline}0.9 | {.underline}1.1 |                 |
|                 |                 |                 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd) |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Randomization   | 11%             | 49%             | P=0.04          |
| Group           |                 |                 |                 |
|                 |                 |                 |                 |
| (% Onyx)        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

The only predictor of success by ITT is randomization group.
Randomization to Onyx was associated with a higher success rate by ITT
than n-BCA. Using a Fisher's Exact Test demonstrated a significantly
better success rate for the Onyx group vs the n-BCA group (p=0.0377).

*Please provide p-value for randomization group (% n-BCA).*

*On page 3163, in the Predictors of Core Labe Success (n=100) table,
there are data for Core Lab ITT Failure (n=9) and Core Lab ITT Success
(n-84) which is a total of 93 patients. Please explain this apparent
inconsistency and recalculate the table based on the appropriate sample
size.*

Core Lab Measurements Quantitative Assessments

+----------------------------+-----------------+-----------------------+
|                            | N-BCA           | Onyx                  |
|                            |                 |                       |
|                            | n=54            | n=46                  |
+----------------------------+-----------------+-----------------------+
|                            | With            |                       |
|                            | Quantitative    |                       |
|                            | Assessment      |                       |
+----------------------------+-----------------+-----------------------+
| \% AVM Reduction           | n=37            | n=23                  |
| post-embolization (mm^3^)  |                 |                       |
+----------------------------+-----------------+-----------------------+
| Mean[+]{.underline}SD      | 80[+            | 84[+]{.underline}13   |
|                            | ]{.underline}19 |                       |
+----------------------------+-----------------+-----------------------+
| Median                     | 85              | 83                    |
+----------------------------+-----------------+-----------------------+
| Range                      | 17-100          | 59-100                |
+----------------------------+-----------------+-----------------------+
| Frequency Distribution of  | \% Pts With     |                       |
| % Reduction                | Quantitative    |                       |
|                            | Assessment      |                       |
+----------------------------+-----------------+-----------------------+
| 0                          | 0%              | 0%                    |
+----------------------------+-----------------+-----------------------+
| 10-24                      | 2.7%            | 0%                    |
+----------------------------+-----------------+-----------------------+
| 25-49                      | 5.4%            | 0%                    |
+----------------------------+-----------------+-----------------------+
| 50-74                      | 24.3%           | 21.7%                 |
+----------------------------+-----------------+-----------------------+
| 75-99                      | 54.0%           | 60.9%                 |
+----------------------------+-----------------+-----------------------+
| 100                        | 13.5%           | 17.4%                 |
+----------------------------+-----------------+-----------------------+

The AVM size was larger in the Onyx group, although this difference did
not reach statistical significance.

In the Cordis n-BCA randomized trial, mean percent reduction in AVM size
was 79.4% for the n-BCA-treated group and 86.9% for the PVA control
group.

Per-Protocol Analysis

A per-protocol analysis is defined as all patients in the intent to
treat population that had at least one treatment with their assigned
device; this group excludes any patient that is a primary technical
failure since they did not receive any assigned embolic agent.

Primary Technical Failures: Four patients were technical failures during
the first embolization procedure, 3 patients in the n-BCA group and 1 in
the Onyx group. One patient in the n-BCA group, 19-001, could not be
treated due to a high flow AVM that was not amenable to embolization
with glue; the patient received PVA particles. The other two patients,
8-009 and 34-001, assigned to n-BCA did not receive any embolic agent
because the physician could not access the AVM with the delivery
catheter. The patient that was assigned to Onyx, 32-003, had a treatment
attempt with Onyx but the physician was unsuccessful in reaching the
target vessel with the delivery catheter; the patient was subsequently
treated with n-BCA as standard of care. Thus 96 patients received the
assigned embolic agent on their first attempt at treatment, 51 in the
n-BCA group and 45 in the Onyx group and are included in a per-protocol
analysis for efficacy. All the technical failure patients have been
included in the intention-to-treat analysis and in the safety analysis.

One patient that was a primary technical failure with n-BCA, 34-001,
went directly to surgery after the first embolization procedure and had
a partial resection; this patient subsequently received another
embolization treatment with n-BCA after this surgery. The patient is
included in the ITT analysis and evaluated under the second series of
embolization procedures, but was removed from the per-protocol analysis
since they did not meet the criteria for inclusion. The patient films
were reviewed by the core laboratory and the patient was classified as a
treatment failure in the ITT analysis.

Two patients in the n-BCA group and 2 patients in the Onyx group were
removed from the analysis because they had films that were unassessable
or are still ongoing in the trial This results in a total of 49 patients
in the n-BCA group and 43 patients in the Onyx group for the
per-protocol analysis.

The per-protocol analysis defines a failure as either unsuccessful AVM
angiographic exclusion as assessed by core laboratory or the inability
to treat with the assigned agent for all staged embolization procedures.
3 patients in the n-BCA group were failures because they did not receive
all embolizations with the assigned device. One Onyx patient, still
receiving embolizations, is considered a failure in this per-protocol
analysis since the investigator terminated treatment with Onyx and
reverted to n-BCA during the second embolization procedure. The
remaining failures, 4 n-BCA and 1 Onyx, were the result of incomplete
exclusion of the AVM as assessed by the core lab.

Per-Protocol Analysis

+-------------------+--------------+-----------------+-----------------+
|                   | Total        | N-BCA           | Onyx            |
+-------------------+--------------+-----------------+-----------------+
| Randomized n      | 108          | 57              | 51              |
+-------------------+--------------+-----------------+-----------------+
| Late Screen       | 2            | 2               |                 |
| Failures          |              |                 |                 |
|                   |              | (18-003,        |                 |
|                   |              | 21-009)         |                 |
+-------------------+--------------+-----------------+-----------------+
| Enrolled Pts      | 106          | 55              | 51              |
+-------------------+--------------+-----------------+-----------------+
| Protocol          | 6            | 1               | 5               |
| violations        |              |                 |                 |
|                   |              | (5-005)         | (2-008, 8-001,  |
| (Dural Fistulas)  |              |                 | 8-010, 8-014,   |
|                   |              |                 | 38-001)         |
+-------------------+--------------+-----------------+-----------------+
| ITT Analysis      | 100          | 54              | 46              |
|                   |              |                 |                 |
| (Ever Attempted   |              |                 |                 |
| Treatment)        |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+
| Technical         | 4            | 3               | 1               |
| Failures          |              |                 |                 |
|                   |              | (8-009, 19-001, | (32-003)        |
| (During 1^st^     |              | 34-001)         |                 |
| attempt)          |              |                 |                 |
|                   |              |                 |                 |
| No embolization   |              |                 |                 |
| with Intended     |              |                 |                 |
| Device            |              |                 |                 |
+-------------------+--------------+-----------------+-----------------+
|                   |              | 51              | 45              |
+-------------------+--------------+-----------------+-----------------+
| Films not         | 2            | 1               | 1               |
| Analyzable        |              |                 |                 |
|                   |              | (8-004)         | (2-001)         |
+-------------------+--------------+-----------------+-----------------+
| Pts Ongoing       | 2            | 1               | 1               |
|                   |              |                 |                 |
|                   |              | (38-004)        | (38-006)        |
+-------------------+--------------+-----------------+-----------------+
| Total Accessible  | 92           | 49              | 43              |
|                   |              |                 |                 |
|                   |              | Success n=42    | Success n=41    |
|                   |              |                 |                 |
|                   |              | \*Failure n=7   | \*Failure n=2   |
|                   |              |                 |                 |
|                   |              | Success         | Success         |
|                   |              | Rate=86%        | Rate=95%        |
|                   |              | (42/49)         | (41/43)         |
+-------------------+--------------+-----------------+-----------------+

\*n-BCA Failures:

By core lab: 6-013, 2-012, 8-012, 8-007

Procedure failures (Abandon treatment): 8-006, 21-007,21-008

\*Onyx Failures

By core lab: 6-007

Procedure failure: 3-003

*Please discuss the patients who are designated "late screen failures."*

Blood loss during the surgical procedure was estimated based on the
volume of blood lost in the suction canister and any other amount of
blood loss from other sources that could be estimated from the site. In
cases where a patient had more than one surgical procedure, an average
value for each patient was calculated to provide an estimate of blood
loss on a per patient basis.

  ----------------------- ------------------------ -------------------------
                          N-BCA                    Onyx

  Intention-to-Treat      n=44                     n=43

  Blood Loss Index\*                               

  Mean[+SD]{.underline}   892[+]{.underline}1067   1127[+]{.underline}1401

  Median                  475                      550

  Range                   100-5000                 50-6550

  \*p=0.55                                         
  ----------------------- ------------------------ -------------------------

No statistical differences were seen for estimated blood loss based on
Spetzler-Martin Grade.

Data on surgical resection time for at least one surgical procedure was
available for 42 patients in the Onyx group; 46 patients had surgical
resection in the n-BCA group and surgical resection time was available
for 42 of these patients. For those patients that had more than one
surgical procedure, the average of all their surgical resection times
was used for this per-patient analysis.

  ----------------------- ----------------------- -----------------------
                          N-BCA                   Onyx

  Intention-to-Treat      n=42                    n=42

  Surgical Resection Time                         
  (min)                                           

  Mean[+SD]{.underline}   411[+]{.underline}201   399[+]{.underline}179

  Median                  344                     366

  Range                   150-1019                82-940

  p=0.99                                          
  ----------------------- ----------------------- -----------------------

No statistically significant differences between the two groups were
seen on surgery time by Spetzler-Martin Grade.

[Safety]{.underline}

Adverse events were collected through hospital discharge for those
patients that had a total surgical resection. For those patients, with
either a partial resection or no surgery attempted, patient adverse
events were summarized through 3 and 12 month follow-up.

The clinical trial had a DSMB that evaluated clinical events that were
reported to MTI as serious or device related. In addition, all adverse
events were reviewed by an independent medical monitor. This person is a
physician independent of the clinical trial who reviewed all CRFs and
source documents for all patients with reported AEs; this was performed
by an independent consulting group, Boston Biomedical Associates. Once
the adjudication of a patient's adverse events was completed by the
medical monitor, a final review and approval was performed by the DSMB
chairman. All serious or device-related adverse events, as adjudicated
by the medical monitor or as reported by the sites, were reviewed. The
DSMB chairman had the authority to override the adjudicator's assessment
of the event if he deemed it necessary and appropriate.

+----------------+-------------+-------------+-----------+-----------+
| Event          | n-BCA       | Onyx        | Diff %    | Relative  |
|                |             |             |           | Risk      |
|                | n=54        | N=46        | \[CI\]    |           |
+----------------+-------------+-------------+-----------+-----------+
| Death          | 0 (0%)      | 2 (4.4%)    | 4.4%      | n/a       |
|                |             |             | \[-1.5,   |           |
|                |             |             | 10\]      |           |
+----------------+-------------+-------------+-----------+-----------+
| Intracranial   | 8 (15%)     | 6 (13%)     | -1.8%     | 0.88      |
| Hemorrhage     |             |             | \[-15,    | \[0.33,   |
|                |             |             | 12\]      | 2.4\]     |
+----------------+-------------+-------------+-----------+-----------+
| Stroke         | 0 (0%)      | 1 (2%)      | 2%        | n/a       |
|                |             |             | \[-2.6\]  |           |
+----------------+-------------+-------------+-----------+-----------+
| Worsening      | 5 (9.3%)    | 7 (15%)     | 6% \[-7,  | 1.64      |
| Neuro Status   |             |             | 19\]      | \[0.56,   |
|                |             |             |           | 4.8\]     |
+----------------+-------------+-------------+-----------+-----------+
| Hydrocephalus  | 0 (0%)      | 2 (4.4%)    | 4.4%      | n/a       |
|                |             |             | \[-2,     |           |
|                |             |             | 10\]      |           |
+----------------+-------------+-------------+-----------+-----------+
| Seizures       | 0           | 1 (2%)      | 2%        | n/a       |
|                |             |             | \[-2,6\]  |           |
+----------------+-------------+-------------+-----------+-----------+
| Headache +/-   | 2 (3.7%)    | 0 (0%)      | -3.7%     | 0.0       |
| nausea and     |             |             | \[-9,     |           |
| vomiting       |             |             | 1.3\]     |           |
+----------------+-------------+-------------+-----------+-----------+
| Total patients | 15 (27.8%)  | 19 (41.3%)  | P=0.20    |           |
+----------------+-------------+-------------+-----------+-----------+

Diff=Onyx-n-BCA RR=Onyx/n-BCA

In this table, only one event (worst event) is listed per patient. 15
patients in the n-BCA group and 19 patients in the Onyx group
experienced at least one serious adverse event. There were no
unanticipated adverse device effects.

The safety profile for the two groups is 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.

Both deaths occurred following surgical resection. Patient 06-012, was a
52 year old woman with a right neck bruit which was found on a routine
PE. Work-up revealed a frontal lobe AVM, Spetzler-Martin Grade II. She
was asymptomatic and neurologically intact. On 10/9/02, she underwent
embolization with multiple injections of Onyx which resulted in a 72%
reduction of the AVM; except for headache and mild access femoral
discomfort, the procedure was uncomplicated; she had no new neurological
findings. On 10/11/02, the patient underwent elective surgical resection
of the AVM; during the surgical procedure, the patient had extensive
bleeding, EBL 5-6 L with transient hypotension. The bleeding source was
difficult to control but ultimately adequate hemostasis was obtained and
the surgery was completed; she had an initially uncomplicated post-op
course, including a post-op angiogram that documented total resection of
the AVM. She was extubated, awake and responsive. That evening she
experienced a severe headache, became less responsive, and required
re-intubation; this was performed emergently on 10/11/02. At the time of
this operation, a hematoma in the previous resection bed was evacuated
and bleeding sites were coagulated. After lining the resection cavity
with Surgicel, no further bleeding was seen and the procedure was
completed. Following this reoperation, she was maintained in a
barbituate coma. During her post-op course she had increasing
intracranial pressure that required ventriculostomy placement on
10/17/02 for management. By CT, she also had persistent hematomas and
ultimately significant infarction felt to be related to herniation
through her craniotomy site. She was pressor dependent to maintain the
barbituate coma and developed renal failure requiring CVVH. She
demonstrated no improvement in neurologic function throughtout this
period. Ultimately after discussion with the family, care was withdrawn
and she expired on 10/19/02. Please clarify whether the radiopaque
material that was found in the vein of Galen in patient 06-012, was
Onyx. Please provide copies of angiograms for panel review.

The other patient, 08-005, was a 50 year old man who had a subarachnoid
hemorrhage in October 1989, apparently related to an aneurysm that
underwent surgical clipping. He had a stroke in May 2001, presenting
with hemiparesis and at this time his AVM was diagnosed. The AVM was a
large, high flow, predominantly dural based, Spetzler-Martin Grade III.
He had a history of seizures and headaches. On enrollement into the
study, he had a moderately severe hemianopia, an NIH Stroke score of 1
and a Barthel of 100. He was randomized to Onyx and had the initial
embolization on 11/20/01. There were no technical difficulties but
follow-up examination demonstrated slight worsening of the NIH Stroke
scale to 3, due to progression of his hemianopia to complete as well as
mild right lower extremity weakness; this latter finding had resolved by
the next evaluation. He subsequently underwent 6 additional staged
embolization procedures. During this course, he was intermittently
reported to have a facial palsy; he also experienced access site
(femoral) complications (bleeding) from at least 4 of these procedures.
Onyx-18 was used for all procedures, except for the next to last
procedure; on 4/28/02, Onyx was not administered because the physician
felt it was necessary to embolize one of the feeders with Embospheres, a
nonassigned embolic agent; at the last embolization, performed
immediately pre-operatively, Onyx-18 was delivered to one of the feeders
and Embospheres was administered to another of the feeding arteries. At
the completion of the series of embolizations, the AVM had a 97%
reduction. On 6/21/02, approximately 9 days after his last embolization,
he underwent elective surgery. Post-op angiography documented complete
resection of the AVM but there was marked attenuation of the left middle
cerebral artery and its branches. A follow-up CT demonstrated a large
MCA distribution infarction and the patient had a dense right
hemiparesis. He remained intubated and receiving supportive care until
6/27/02 when the family requested he be extubated. The patient expired
on 6/28/02. *The complication report fpr patient 08-005, states that
"Large blood vessels remote from the AVM were found to be occluded on a
post-surgical angiogram." Please describe what material caused the
occlusion and provide copies of angiograms for panel review.*

In the Cordis study comparing n-BCA to PVA, 4 patient deaths occurred,
4%, and a total hemorrhagic complication rate of 13 to 29% was reported.

[Patient Terminations]{.underline}

Patient 03-003 had the second embolization procedure done through both
left and right femoral artery access; patient was randomized to Onyx. At
the second embolization, the patient was crossed over to n-BCA. *Please
clarify whether n-BCA and Onyx were used during the second embolization
attempt on patient 03-003. Please discuss the finding on a small right
superior cerebellar ischemic lesion found on the MRI, following
embolization and state which agent had been used for this embolization.*
*Please state why the patient was terminated and whether the patient had
radiosurgery following the embolization.*

Patient 08-006 was randomized to n-BCA. The patient had a "procedural
event," a pulmonary embolism. Onyx was used for the second embolization,
but the delivery catheter could not reach the target and therefore the
patient could not be treated. After the second embolization, the patient
had radiosurgery.

Patient 08-009 was randomized to n-BCA; no embolization was done because
microcatheter access was lost and was unable to recannulate. Therefore,
the patient was a failure to treat and terminated.

Patient 10-003 was randomized to n-BCA. After the first embolization,
the patient's insurance refused to pay for additional treatment of the
AVM; therefore, the second embolization and surgical resection were not
done and the patient was terminated from the study.

Patient 19-001 was randomized to n-BCA. The AVM involved the middle
temporal lobe and the blood supply was from the branches of the middle
cerebral artery. It was not possible to embolize the AVM because of high
flow. *You state that the AVM in patient 19-001 involved the middle
temporal lobe and the blood supply was from the branches of the middle
cerebral artery. Therefore, it was not possible to embolize the AVM with
n-BCA because of high flow. Please discuss whether this patient had any
other embolization treatment, surgery, or radiosurgery.*

Patient 20-002 was randomized to n-BCA. For the second embolization,
Berenstein liquid coils were used with n-BCA. This patient was lost to
follow-up.

Patient 21-007 was randomized to n-BCA. The patient was terminated
because the neurointerventionalist decided the feeding vessels were
better treated with PVA as the primary embolic agent. *You state that
patient 21-007, who was randomized to n-BCA, was terminated because the
neurointerventionalist decided the feeding vessels were better treated
with PVA as the primary embolic agent. Please discuss whether this
patient had any other embolization treatment, surgery, or radiosurgery.*

Patient 21-008 was randomized to n-BCA. It is stated that the coils were
used because the "anatomy defined during microcatheterization favored
particulate embolization." One day postembolization, the patient
suffered a small Subarachnoid and intraventricular hemorrhage; no
neurologic changes were noted by the MD. *You state that coils were used
because the "anatomy defined during microcatheterization favored
particulate embolization" in patient 21-008 who was randomized to n-BCA.
One day postembolization, the patient suffered a small Subarachnoid and
intraventricular hemorrhage; no neurologic changes were noted by the MD.
Please discuss whether this patient had any other embolization
treatment, surgery, or radiosurgery.*

Patient 32-003 was randomized to Onyx, however, the n-BCA embolization
CRF was completed. Berenstein liquid coils were used during the
embolization procedure. The CRF stated that there was an inability to
adequately position the ultraflow resulting in use of Spinnauer-elite
and crossover to n-BCA. *You state that patient 32-003 was randomized to
Onyx, however, the n-BCA embolization CRF was completed. Berenstein
liquid coils were used during the embolization procedure. The CRF stated
that there was an inability to adequately position the ultraflow
resulting in use of Spinnauer-elite and crossover to n-BCA. Please
discuss whether this patient had any other embolization treatment,
surgery, or radiosurgery.*

Patient 34-001 was randomized to n-BCA but none was used because the
physician could not advance the catheter distally. Post-surgery, the
patient had severe left sided hemiparesis, meningitis, GI bleed,
hydrocephalus which required a ventriculostomy, an intraventricular
hemorrhage involving both lateral ventricles, third and fourth
ventricles, acute respiratory failure, and a large hematoma in the right
frontal lobe, temporal lobe, and right basal ganglia. *You state that
patient 34-001 was randomized to n-BCA but none was used because the
physician could not advance the catheter distally. Post-surgery, the
patient had severe left sided hemiparesis, meningitis, GI bleed,
hydrocephalus which required a ventriculostomy, an intraventricular
hemorrhage involving both lateral ventricles, third and fourth
ventricles, acute respiratory failure, and a large hematoma in the right
frontal lobe, temporal lobe, and right basal ganglia. Please discuss
whether this patient's medical condition returned to normal and whether
he had any other embolization treatment, surgery, or radiosurgery.*

*You provided CRFs for the following terminated patients, 10-003,
20-002, 21-007 and 34-001. However, these patients are not listed in the
ITT Analysis Flowchart on page 3161 as terminations or lost to
follow-up. Please explain this discrepancy and revise the table if
necessary. Furthermore, CRFs were not provided for patients 8-004 and
2-001 whose films were not analyzable and patients 2-012, 6-007, 6-013,
8-007, and 8-012 who were treatment failures.*

[Device Malfunctions]{.underline}

The Flow Rider Plus catheter ruptured 10 cm from the top of the catheter
on patient 20-003; there was Onyx leakage with "untoward embolization"
and no clinical sequelae. *Please discuss the "untoward embolization"
that occurred when the Flow Rider Plus catheter ruptured on patient
20-003.*

This table includes a summary of all serious adverse events that
occurred in patients and therefore, patients may be cited more than
once. However, if a patient had a series of cascading events that were
linked together, the primary leading serious adverse event is listed in
the table. A total of 48 events were observed in 34 patients; the
majority of the events were categorized as either an intracranial
hemorrhage or a worsening of neurologic status.

+-----------------------+-----------------------+-----------------------+
| Event                 | N-BCA                 | Onyx                  |
|                       |                       |                       |
|                       | n=54                  | n=46                  |
+-----------------------+-----------------------+-----------------------+
| Intracranial          | 9                     | 7                     |
| Hemorrhage            |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Stroke                | 0                     | 2                     |
+-----------------------+-----------------------+-----------------------+
| Worsening Neuro       | 4                     | 7                     |
| Status                |                       |                       |
|                       | 3                     | 5                     |
| Persistent            |                       |                       |
|                       | 1                     | 2                     |
| Transient             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Multi-Organ System    | 1                     | 0                     |
| Complications         |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Severe Bleeding/Low   | 1                     | 0                     |
| Hct requiring         |                       |                       |
| transfusion           |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Hydrocephalus         | 0                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Respiratory Failure   | 1                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Infection             | 2                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Seizures              | 0                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Fever                 | 1                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Catabolic State       | 1                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Vessel Dissection     | 0                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Limb Ischemia         | 1                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Headache +/- Nausea   | 3                     | 1                     |
| and Vomiting          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Medication Reaction   | 0                     | 2                     |
+-----------------------+-----------------------+-----------------------+
| Total \# SAEs         | 24                    | 24                    |
+-----------------------+-----------------------+-----------------------+
| \# Pts with SAE       | 15                    | 19                    |
+-----------------------+-----------------------+-----------------------+

Intracranial hemorrhage is a known risk of surgery for AVM resection.

*Please provide the patient ID for each of the serious adverse events
listed in the Serious Adverse Event -- Non-Hierarchical on page 3177.*

+-----------------------+-----------------------+-----------------------+
|                       | \# SAEs               |                       |
+-----------------------+-----------------------+-----------------------+
| Spetzler-Martin Grade | N-BCA                 | Onyx                  |
|                       |                       |                       |
| #Events (#Pts with    |                       |                       |
| Event)                |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 1                     | 4 (3)                 | 2 (1)                 |
+-----------------------+-----------------------+-----------------------+
| 2                     | 4 (3)                 | 8 (7)                 |
+-----------------------+-----------------------+-----------------------+
| 3                     | 4 (4)                 | 10 (7)                |
+-----------------------+-----------------------+-----------------------+
| 4                     | 12 (5)                | 4 (4)                 |
+-----------------------+-----------------------+-----------------------+
| Total                 | 24 (15)               | 24 (19)               |
+-----------------------+-----------------------+-----------------------+

A Spetzler-Martin Grade of 3 or 4 was associated with a higher number of
events in both the n-BCA and Onyx groups than the patients presenting
with a Spetzler-Martin Grade of 1 or 2.

*Please provide the patient ID for each of the serious adverse events
listed in the Serious Adverse Events by Spetzler-Martin Grade on page
3179 and state the serious adverse event associated with each patient.*

Intracranial Hemorrhage and Persistent Worsening Neuro Status by
Spetzler-Martin Grade

+-----------------------+-----------------------+-----------------------+
|                       | \# SAEs               |                       |
+-----------------------+-----------------------+-----------------------+
| Spetzler-Martin Grade | N-BCA                 | Onyx                  |
|                       |                       |                       |
| #Events (#Pts with    |                       |                       |
| Event)                |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 1                     | 2 (2)                 | 1 (1)                 |
+-----------------------+-----------------------+-----------------------+
| 2                     | 3 (3)                 | 5 (5)                 |
+-----------------------+-----------------------+-----------------------+
| 3                     | 2 (2)                 | 4 (3)                 |
+-----------------------+-----------------------+-----------------------+
| 4                     | 6 (5)                 | 2 (2)                 |
+-----------------------+-----------------------+-----------------------+
| Total                 | 13 (12)               | 12 (11)               |
+-----------------------+-----------------------+-----------------------+

Intracranial Hemorrhage by Spetzler-Martin Grade

+-----------------------+-----------------------+-----------------------+
|                       | \# SAEs               |                       |
+-----------------------+-----------------------+-----------------------+
| Spetzler-Martin Grade | N-BCA                 | Onyx                  |
|                       |                       |                       |
| #Events (#Pts with    |                       |                       |
| Event)                |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 1                     | 2 (2)                 | 0                     |
+-----------------------+-----------------------+-----------------------+
| 2                     | 2 (2)                 | 2 (2)                 |
+-----------------------+-----------------------+-----------------------+
| 3                     | 0                     | 4 (4)                 |
+-----------------------+-----------------------+-----------------------+
| 4                     | 5 (4)                 | 1 (1)                 |
+-----------------------+-----------------------+-----------------------+
| Total                 | 9 (8)                 | 7 (7)                 |
+-----------------------+-----------------------+-----------------------+

*Please provide the patient ID for each of the serious adverse events
listed in the Serious Adverse Events by Spetzler-Martin Grade on page
3179 and state the serious adverse event associated with each patient.
In addition, provide the patient ID for each of the patients referred to
in the Intracranial Hemorrhage and Persistent Worsening Neuro Status by
Spetzler-Martin Grade and Intracranial Hemorrhage by Spetzler-Martin
Grade on page 3180.*

Event relationship attribution is separated into the following
categories:

1.  System related which includes any event caused by the micro catheter
    and/or embolic agent

2.  Treatment related including any event associated with the
    embolization procedure including the guidewire or other ancillary
    devices

3.  Surgery related

4.  Disease related.

+-----------------------------+------------+----------------+---------+
| Event                       | n-BCA      | Onyx           | p-value |
|                             |            |                |         |
|                             | n=54       | n=46           |         |
+-----------------------------+------------+----------------+---------+
| System                      |            |                |         |
+-----------------------------+------------+----------------+---------+
| Stroke                      | 0          | 1              |         |
+-----------------------------+------------+----------------+---------+
| Vessel Dissection           | 0          | 1              |         |
+-----------------------------+------------+----------------+---------+
| Worsening Neurological      | 1          | 2              |         |
| Status                      |            |                |         |
+-----------------------------+------------+----------------+---------+
| Intracranial Hemorrhage     | 1          | 0              |         |
+-----------------------------+------------+----------------+---------+
| Total #Events               | 2          | 4              |         |
+-----------------------------+------------+----------------+---------+
| Total #Pts with Events      | 2/54       | 4/46 (8.7%)    | 0.41    |
|                             | (3.7%)     |                |         |
+-----------------------------+------------+----------------+---------+
| Treatment                   |            |                |         |
+-----------------------------+------------+----------------+---------+
| Headache +/- Nausea and     | 0          | 1              |         |
| Vomiting                    |            |                |         |
+-----------------------------+------------+----------------+---------+
| Intracranial Hemorrhage     | 2          | 2              |         |
+-----------------------------+------------+----------------+---------+
| Limb Ischemia               | 1          | 0              |         |
+-----------------------------+------------+----------------+---------+
| Medication Reaction         | 0          | 2              |         |
+-----------------------------+------------+----------------+---------+
| Worsening Neurologic Status | 1          | 2              |         |
+-----------------------------+------------+----------------+---------+
| Total #Events               | 4          | 7              |         |
+-----------------------------+------------+----------------+---------+
| Total #Pts with Events      | 3/54       | 5/46 (10.9%)   | 0.46    |
|                             | (5.6%)     |                |         |
+-----------------------------+------------+----------------+---------+
| Surgery                     |            |                |         |
+-----------------------------+------------+----------------+---------+
| Infection                   | 2          | 1              |         |
+-----------------------------+------------+----------------+---------+
| Catabolic State             | 1          | 0              |         |
+-----------------------------+------------+----------------+---------+
| Headache +/- Nausea and     | 2          | 0              |         |
| Vomiting                    |            |                |         |
+-----------------------------+------------+----------------+---------+
| Intracranial Hemorrhage     | 6          | 5              |         |
+-----------------------------+------------+----------------+---------+
| Multi-Organ System          | 1          | 0              |         |
| Complications               |            |                |         |
+-----------------------------+------------+----------------+---------+
| Respiratory Failure         | 1          | 0              |         |
+-----------------------------+------------+----------------+---------+
| Severe Bleeding/Low HCT     | 1          | 0              |         |
| ReqTransfusion              |            |                |         |
+-----------------------------+------------+----------------+---------+
| Stroke                      | 0          | 1              |         |
+-----------------------------+------------+----------------+---------+
| Worsening Neurological      | 2          | 3              |         |
| Status                      |            |                |         |
+-----------------------------+------------+----------------+---------+
| Fever                       | 1          | 0              |         |
+-----------------------------+------------+----------------+---------+
| Total #Events               | 17         | 10             |         |
+-----------------------------+------------+----------------+---------+
| Total #Pts with Events      | 11/54      | 10/46 (21.7%)  | 1.00    |
|                             | (20.4%)    |                |         |
+-----------------------------+------------+----------------+---------+
| Disease                     |            |                |         |
+-----------------------------+------------+----------------+---------+
| Seizures                    | 0          | 1              |         |
+-----------------------------+------------+----------------+---------+
| Headache +/- Nausea and     | 1          | 0              |         |
| Vomiting                    |            |                |         |
+-----------------------------+------------+----------------+---------+
| Hydrocephalus               | 0          | 1              |         |
+-----------------------------+------------+----------------+---------+
| Respiratory Failure         | 0          | 1              |         |
+-----------------------------+------------+----------------+---------+
| Total #Events               | 1          | 3              |         |
+-----------------------------+------------+----------------+---------+
| Total #Pts with Events      | 1/54       | 2/46 (4.4%)    | 0.60    |
|                             | (1.9%)     |                |         |
+-----------------------------+------------+----------------+---------+
| Overall Total #Events       | 24         | 24             |         |
+-----------------------------+------------+----------------+---------+

There were 2 system related adverse events in the n-BCA group and 4 in
the Onyx group; each of these events was associated with a specific
patient. One event in each treatment group was considered to be
associated with the embolic agent itself and the other events were
considered to be associated with the micro catheter. One of the events
in the n-BCA group, 05-001 was associated with either the micro catheter
or the guidewire. All other events with known association to the
guidewire are summarized in the treatment-related category. Patient
05-001 was noted to have an intracranial hemorrhage; this was documented
on CT following the patient's third embolization procedure and required
emergency surgery; it was felt that this perforation was related to
either guidewire or delivery catheter manipulation. One patient in the
n-BCA group, 38-002 and two patients in the Onyx group, 32-002, 20-003
experienced events categorized as worsening neurologic status. The
patient in the n-BCA group experienced a severe deficit of right sided
weakness that was associated with the embolic agent being administered
to an unintended vessel. One of the patients that had a worsening
neurologic status in the Onyx group, 32-002, has vasospasm that caused
the neurologic deficit; the vasospasm was associated with difficulty
removing the Onyx delivery catheter but the neurologic deficit was
transient and resolved completely prior to patient discharge. The second
patient, 20-003, that had a worsening neurologic status was considered
to be associated with difficulties the physician had with the Onyx
delivery catheter, the FlowRider Plus; the catheter malfunctioned and
ruptured during Onyx administration; the micro catheter was withdrawn
from the market and replaced with the UltraFlow catheter; the worsening
neurological status that was associated with this malfunction was
transient and completely resolved over the subsequent several days. One
patient in the Onyx group, 06-007 had a vessel dissection in the
vertebral artery that was considered to be associated with either the
micro catheter or the guidewire; the dissection occurred during the
first embolization but was not identified until the patient presented
for the scheduled second embolization treatment; no embolization was
performed at that time. The patient was initially followed clinically
with the addition of antiplatelet agents. During a subsequent procedure,
the vessel dissection was treated with percutaneous balloon angioplasty
and stent placement. Approximately 1 month later the treated vessel was
widely patent and embolization was performed with no complications or
sequelae; another embolization was performed with no sequelae. The
stroke that occurred in the Onyx patient, 06-004, was associated with
the embolic material being deliverd to a non-target vessel.

Events related to the embolic procedure itself or adjunctive devices
during the procedure have been categorized as treatment related. There
were 4 events in the n-BCA group and 7 in the Onyx group; these events
occurred in 3 of the 54 total n-BCA patients and 5 of the 46 Onyx
patients. In the n-BCA group, one ICH was determined to be associated
with a guidewire perforation; also one worsening neurologic status was
caused by contrast extravasation that occurred after a guidewire
perforation. None of the treatment related AEs in the Onyx group were
associated with any ancillary devices.

The majority of SAEs were related to the surgical resection of the AVM.
17 of the 24 total events in the n-BCA, 71%, group were surgery related;
these 17 events occurred in 11 patients resulting in a surgery related
SAE rate of 20% in the n-BCA group. 10 of the 24 events in the Onyx
group were surgery related; the 10 events in 10 patients resulted in a
surgery related SAE rate of 22% in the Onyx group.

One SAE in the n-BCA group and 3 in the Onyx group were considered to be
caused by the clinical disease state. One patient experienced
respiratory failure but this patient was enrolled in the trial in a
comatose state and the respiratory failure was considered to be more
associated with the poor clinical state than any of the procedures that
the patient had for treatment of the AVM.

*Please provide the patient ID and a description of each of the serious
adverse events listed in the Serious Adverse Events by Relationship on
page 3181.*

Predictors of Serious Adverse Events

+-----------------+-----------------+-----------------+-----------------+
| Characteristic  | No SAE          | SAE             | p-value         |
|                 |                 |                 |                 |
|                 | n=66            | n=384           |                 |
+-----------------+-----------------+-----------------+-----------------+
| Gender (%male)  | 52%             | 38%             | P=0.30          |
+-----------------+-----------------+-----------------+-----------------+
| AVM Location    | 95%             | 100%            | P=0.55          |
| (%right/left)   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Eloquent Part   | 44%             | 56%             | P=0.30          |
| of Brain        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Spetzler-Martin |                 |                 | P=0.20          |
| Grade           |                 |                 |                 |
|                 |                 |                 |                 |
| (% 3 or 4)      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Venous Drainage | 40%             | 35%             | P=0.83          |
|                 |                 |                 |                 |
| (% deep)        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Presence of     | 29%             | 41%             | P=0.26          |
| Bleed           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Glasgow Coma    | 6%              | 15%             | P=0.26          |
| Scale           |                 |                 |                 |
|                 |                 |                 |                 |
| (%\<15)         |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Corelab-ITT     | 93%             | 85%             | P=0.27          |
| Success         |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| C               | 93%             | 90%             | P=0.70          |
| orelab-Protocol |                 |                 |                 |
| Success         |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Age             | 37[+            | 39[+            | P=0.54          |
|                 | ]{.underline}17 | ]{.underline}16 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd, |                 |                 |                 |
| years)          |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| BMI             | 26[             | 26[             | P=0.93          |
|                 | +]{.underline}6 | +]{.underline}5 |                 |
+-----------------+-----------------+-----------------+-----------------+
| SBP             | 126[+           | 121[+           | P=0.16          |
|                 | ]{.underline}13 | ]{.underline}19 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd, |                 |                 |                 |
| mmHg)           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| DBP             | 71[+            | 70[+            | P=0.56          |
|                 | ]{.underline}11 | ]{.underline}11 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd, |                 |                 |                 |
| mmHg)           |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| AVM Size        | 8.1             | 15.5            | P=0.04          |
|                 |                 |                 |                 |
| (median, mm^3^) |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| \# Embolization | 1.6[+]          | 2.1[+]          | P=0.02          |
| Procedures      | {.underline}1.0 | {.underline}1.3 |                 |
|                 |                 |                 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd) |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| #Surgeries      | 1.0[+]          | 1.3[+]          | P=0.06          |
|                 | {.underline}0.1 | {.underline}0.7 |                 |
| (mean[+]        |                 |                 |                 |
| {.underline}sd) |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Length of       | 328             | 505             | P=0.0004        |
| Surgery         |                 |                 |                 |
|                 |                 |                 |                 |
| (median, min)   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Blood Loss      | 497             | 994             | P=0.003         |
|                 |                 |                 |                 |
| (median, ccs)   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Randomization   | 41%             | 56%             | P=0.20          |
| Group           |                 |                 |                 |
|                 |                 |                 |                 |
| (% Onyx)        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

Predictors of SAEs included AVM size, number of embolization procedures,
length of surgery, and blood loss. The significant parameters from the
univariate anslysis were entered into a multivariate regression model to
determine the predictors of SAEs. By multivariate analysis, surgical
blood loss was the only predictor of SAE, p=0.03.

Non-serious AEs include anything categorized as minor or moderate as
defined in the protocol. This summary table represents a compilation of
all events that occurred in the patients and thus patients may be cited
more than once. However, if a patient had a series of cascading events
that were linked together, only the primary leading AE is listed.

Non-Serious AEs

+-----------------------------+----------------+-----------------------+
| Event by Relationship       | N-BCA          | Onyx                  |
|                             |                |                       |
|                             | n=54           | n=46                  |
+-----------------------------+----------------+-----------------------+
| System Related              |                |                       |
+-----------------------------+----------------+-----------------------+
| Total                       | 0              | 0                     |
+-----------------------------+----------------+-----------------------+
| Treatment Related           |                |                       |
+-----------------------------+----------------+-----------------------+
| Access Site Bleeding        | 0              | 5                     |
+-----------------------------+----------------+-----------------------+
| Headache +/- Nausea and     | 20             | 21                    |
| Vomiting                    |                |                       |
+-----------------------------+----------------+-----------------------+
| Medication Reaction         | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 4              | 7                     |
+-----------------------------+----------------+-----------------------+
| Worsening Neurologic Status | 13             | 9                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 38             | 43                    |
+-----------------------------+----------------+-----------------------+
| Surgery Related             |                |                       |
+-----------------------------+----------------+-----------------------+
| Cardiac Arrhythmia          | 0              | 1                     |
+-----------------------------+----------------+-----------------------+
| Medication Reaction         | 1              | 0                     |
+-----------------------------+----------------+-----------------------+
| Laboratory/Imaging          | 1              | 1                     |
| Abnormalities               |                |                       |
+-----------------------------+----------------+-----------------------+
| Intracranial Hemorrhage     | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Infection                   | 1              | 2                     |
+-----------------------------+----------------+-----------------------+
| Seizures                    | 1              | 0                     |
+-----------------------------+----------------+-----------------------+
| Fever                       | 1              | 3                     |
+-----------------------------+----------------+-----------------------+
| Severe Bleeding/Low HCT Req | 1              | 0                     |
| Transfusion                 |                |                       |
+-----------------------------+----------------+-----------------------+
| Headache +/- Nausea and     | 7              | 9                     |
| Vomiting                    |                |                       |
+-----------------------------+----------------+-----------------------+
| Tongue Swelling             | 0              | 1                     |
+-----------------------------+----------------+-----------------------+
| Worsening Neurologic Status | 8              | 6                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 5              | 7                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 27             | 31                    |
+-----------------------------+----------------+-----------------------+
| Disease Related             |                |                       |
+-----------------------------+----------------+-----------------------+
| Psychotic Episode           | 0              | 1                     |
+-----------------------------+----------------+-----------------------+
| Worsening Neurologic Status | 2              | 2                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 1              | 0                     |
+-----------------------------+----------------+-----------------------+
| Laboratory/Imaging          | 1              | 0                     |
| Abnormalities               |                |                       |
+-----------------------------+----------------+-----------------------+
| Infection                   | 2              | 2                     |
+-----------------------------+----------------+-----------------------+
| Hydrocephalus               | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Headache +/- Nausea and     | 2              | 1                     |
| Vomiting                    |                |                       |
+-----------------------------+----------------+-----------------------+
| Thrombocytopenia            | 1              | 0                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 10             | 7                     |
+-----------------------------+----------------+-----------------------+
| Other Related               |                |                       |
+-----------------------------+----------------+-----------------------+
| Medication Reaction         | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 2              | 2                     |
+-----------------------------+----------------+-----------------------+
| Unknown Related             |                |                       |
+-----------------------------+----------------+-----------------------+
| Worsening Neurologic Status | 2              | 0                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 0              | 2                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 2              | 2                     |
+-----------------------------+----------------+-----------------------+
| Total #Non-Serious AEs      | 79             | 85                    |
+-----------------------------+----------------+-----------------------+
| Total \# Pts with           | 50             | 41                    |
| Non-Serious AEs             |                |                       |
+-----------------------------+----------------+-----------------------+

Similar to the SAEs, intracranial hemorrhage and worsening neurologic
status comprised the majority of events. One patient in the n-BCA group
had a worsening of neurological status that was caused by contrast
extravasation; the event occurred following a guidewire perforation.

Although the patient based rate of SAEs is higher for the Onyx group,
the total number of SAEs is equal in both groups and no differences were
found to be statistically significantly different.

*Please provide the patient ID and a description of each of the non
Serious adverse events listed in the Non Serious Adverse Events on page
3187.*

Adverse events not observed during the study include AVM rupture and
pulmonary embolism.

+-----------------+-----------------+-----------------+-----------------+
| Pts with        | N-BCA           | Onyx            | p-value         |
| serious AE      |                 |                 |                 |
|                 | N=54            | N=46            |                 |
+-----------------+-----------------+-----------------+-----------------+
| Serious AE      | 27.8% (15)      | 41.3% (19)      | 0.20            |
+-----------------+-----------------+-----------------+-----------------+
| System-related  | 3.7% (2)        | 8.7% (4)        | 0.41            |
| SAE             |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Tr              | 5.6% (3)        | 10.9% (5)       | 0.46            |
| eatment-related |                 |                 |                 |
| SAE             |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Surgery-related | 20.4% (11)      | 21.7% (10)      | 1.00            |
| SAE             |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Disease-related | 1.9% (1)        | 4.3% (2)        | 0.60            |
| SAE             |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

[Labelling]{.underline}

[Cautions]{.underline}

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

-   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 thrombus.

[Contraindications]{.underline}

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

[Warnings]{.underline}

-   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 degredation.

-   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.

-   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 than 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.

Pathological Assessment of Human AVMs

Studies were conducted to assess the effects of brain and neurovascular
tissue exposure to Onyx and n-BCA materials. For one retrospective
masked study, CT, MRI, and flat film skull X-rays obtained from patients
in a sponsor-investigator IDE, with AVMs treated with Onyx were reviewed
and compared to a cohort of patients with n-BCA treated AVMs. A total of
54 patients were studied in the Onyx group and 19 in the n-BCA group,
for a total of 73 patients. The analysis spanned a post-embolization
period of up to 50 months. An independent blinded central reader
reviewed both pre- and post-embolization CT and MRI films to determine
whether any direct neurotoxicity due to Onyx or n-BCA could be detected.
Films were evaluated for the presence or absence of gliosis,
encephalomalacia, edema, leptomeningeal , or parenchymal enhancement and
hemorrhage. These parameters were predefined based on specific imaging
characteristics. Analysis of the films revealed no immediate or delayed
imaging abnormalities that could be attributed to the presence of the
embolic material.

In a second study, histopathological evaluations of 7 human brain AVMs
were performed following embolization with Onyx and surgical resection.
BAVM sizes ranged from 2.30 to 93.65 cm^3^ , mean size 35 cm^3^. Prior
to surgery, one patient received a single embolization treatment, 2
patients received 2 treatments, 1 patient received 3 treatments, and 3
received 4 treatments. All AVMs had pre-surgical embolization periods of
at least 3 months, with 4 of 7 embolized more than 6 months, and 3 of 7
at approximately 12 months up to 19 months. \>90% of the Onyx material
was within blood vessels of 500µm or greater. The remaining 10% of
material was seen in vessels 100-500 µm. There was no reported evidence
of fragmentation or distal migration of material; there were no reported
ischemic or hemorrhagic complications resulting from untoward migration
or abrupt occlusion of an AVM nidus.

+-------+-------+-----------+-------+------+--------+--------+-----+
| Pt    | #Em   | Path Eval | DMSO  | Onyx | I      | Final  | \%  |
|       | bolic | Onyx      | Vol   | Vol  | nitial | AVM    | S   |
|       | Proc  | Implanted | (ml)  | (ml) | AVM    | Size   | ize |
|       |       | Period    |       |      | Size   | (      |     |
|       |       |           |       |      | (      | cm^3^) | Red |
|       |       |           |       |      | cm^3^) |        |     |
+-------+-------+-----------+-------+------+--------+--------+-----+
| KACN  | 4     | 1 wk,     | 1.12  | 2.65 | 93.7   | 13.6   | 85  |
|       |       | 6,7,19 mo |       |      |        |        |     |
+-------+-------+-----------+-------+------+--------+--------+-----+
| LRR   | 3     | 4,8 mo    | 1.02  | 1.40 | 2.3    | 0.6    | 77  |
+-------+-------+-----------+-------+------+--------+--------+-----+
| AZB   | 3     | 6,11,12   | 2.05  | 1.35 | 21.8   | 2.0    | 91  |
|       |       | mo        |       |      |        |        |     |
+-------+-------+-----------+-------+------+--------+--------+-----+
| SGC   | 4     | 1         | 1.64  | 0.71 | 67.6   | 25.0   | 63  |
|       |       | wk        |       |      |        |        |     |
|       |       | ,10,12,13 |       |      |        |        |     |
|       |       | mo        |       |      |        |        |     |
+-------+-------+-----------+-------+------+--------+--------+-----+
| LMC   | 2     | 1,2,3 mo  | 1.20  | 0.69 | 25.7   | 0.4    | 98  |
+-------+-------+-----------+-------+------+--------+--------+-----+
| PW    | 4     | 1,2,3 mo  | 1.90  | 4.08 | 14.4   | 2.6    | 82  |
+-------+-------+-----------+-------+------+--------+--------+-----+
| LMRM  | 1     | 11 mo     | 0.60  | 0.60 | 20.2   | 3.2    | 84  |
+-------+-------+-----------+-------+------+--------+--------+-----+

The histopathology reports show no indication of vascular necrosis,
rupture, or extravasation of the Onyx material. Numerous vessels were
noted with disruption of the internal elastic lamina, but there did not
appear to be any serious adverse effect on the vessel wall. The finding
of intramural accumulations of neutrophils at multiple sites in the
vessels or SGC was the most adverse morphologic change observed. The
finding was inconsistent with other specimens in the study and
attributed to an unrelated infection or presence of a strongly
birefringent foreign material other than Onyx found in the vessels.

Summary of Dural Fistulae Patients

  ----------------------- ----------- --------------------- ----------- ------------------------ -------------------------
  Pt                      Tx          Age                   Gender      SBP                      DBP

  02-008                  Onyx        64                    Female      135                      46

  05-005                  N-BCA       34                    Male        100                      76

  08-008                  Onyx        53                    Male        144                      92

  08-010                  Onyx        57                    Male        106                      66

  08-014                  Onyx        66                    Male        170                      95

  38-001                  Onyx        66                    Male        100                      58

  Mean[+]{.underline}SD               58[+]{.underline}14               126[+]{.underline}28.6   72.2[+]{.underline}19.3
  ----------------------- ----------- --------------------- ----------- ------------------------ -------------------------

3 patients were enrolled with a presenting acute intracranial
hemorrhage, 2 patients with neurological deficit, and 1 with
neurological symptoms. 3 patients were unassessable by the core lab; 2
were failures and 1, 08-014, was a success. 4 patients underwent
surgical resection; there are no plans for surgery for the other 2
patients. Pneumonia developed in patient 08-008 that was secondary to
his inability to protect his airway due to the development of worsening
neurologic status; the patient was hospitalized, treated with
antibiotics and steps were taken to prevent aspiration.

Adverse Events

  -------------- -------------- -------------- -------------- --------------
                 Relationship                                 

  AE             Disease        Treatment      Surgery        Total

  Headache                      1                             1
  +/-Nausea and                                               
  Vomiting                                                    

  Infection                     1                             1

  Medication                    1                             1
  Reaction                                                    

  Pt. Discomfort                               1              1

  Seizures       2                                            2

  Worsening      1              2              2              3
  Neurologic                                                  
  Status                                                      
  -------------- -------------- -------------- -------------- --------------

6 of the 9 events resolved by the end of the follow-up interval. One
event was ongoing and the remainder had recovered but with some residual
deficit.

*Please provide the patient ID and a description of each of the adverse
events listed in the Dural Fistulae Adverse Events table on page 3705.*

Patients who did not have a complete surgical resection

9 patients did not undergo complete surgical resection of the AVM and
therefore are being followed at 3 and 12 months. 3 patients had partial
resection of their AVM and 6 had no attempt at resection. 5 of the 9
patients were determined to be successes by the core lab, 3 were
failures, and 1 was not assessable. 4 of the patients are scheduled to
undergo some type of radiosurgery.

  -------- ------- ---------- --------- --------- ----- ----- ------ ----- ----- --------- ----- -----
  Pt       Tx      Date Last  Result    Barthel               NIH                Glasgow         

                   Embo or Sx           Last Tx   3 mos 12    Last   3 mos 12    Last Tx   3 mos 12
                                                        mos   Tx           mos                   mos

  10-005   N-BCA   7/8/02     Success   90        100   N/A   0      0     N/A   0         0     N/A

  29-002   Onyx    10/15/01   Success   25        85    100   0      0     0     1         1     0

  29-006   Onyx    11/5/02    Success   35        100   N/A   0      0     N/A   0         2     N/A

  08-004   N-BCA   1/29/02    Missing   100             100   0            0     0               0

  08-006   N-BCA   1/8/02     Failure   100                   0                  15              

  08-012   N-BCA   7/23/02    Failure   100             N/A   0            N/A   15              N/A

  20-003   Onyx    7/8/02     Success   45              N/A   7            N/A   15              N/A

  34-001   N-BCA   12/3/02    Success   \*              N/A   \*           N/A   \*              N/A

  38-008   N-BCA   12/3/02    Success   100       N/A   N/A   0      N/A   N/A   15        N/A   N/A
  -------- ------- ---------- --------- --------- ----- ----- ------ ----- ----- --------- ----- -----

\*Primary technical failure, no post treatment information provided

N/A= Not due

No serious AEs occurred following their last treatment, surgery or
embolization. 29-006 had a reduction in functional status as
demonstrated by the increase in Glasgow score due to multiple systemic
complaints. 08-006 had generalized pain that was reported at the time of
hospital visit for scheduled radiosurgery.

Summary of Protocol Deviations

+----------------------------------------------------------+-----------+
| Deviation                                                | #Oc       |
|                                                          | currences |
+----------------------------------------------------------+-----------+
| Dural Fistula Pts                                        | 6         |
+----------------------------------------------------------+-----------+
| Neuro Assessment not Performed or Performed Outside      | 85        |
| Specified Window                                         |           |
+----------------------------------------------------------+-----------+
| Core Lab Issues                                          | 32        |
|                                                          |           |
| -Different Views Pre and Post Proc                       |           |
|                                                          |           |
| -No Dimes on Films                                       |           |
|                                                          |           |
| -Missing Films                                           |           |
|                                                          |           |
| -Pre Images Contain Embolic Material                     |           |
+----------------------------------------------------------+-----------+
| Use of Outdated MRI/CTcrf                                | 29        |
+----------------------------------------------------------+-----------+
| Sequential Embolization Performed Beyond the Protocol    | 26        |
| Recommendation of 4 Weeks                                |           |
+----------------------------------------------------------+-----------+
| CRF Not Filled Out or Items on CRF Missing               | 11        |
+----------------------------------------------------------+-----------+
| Patient did not Go to Surgery                            | 7         |
+----------------------------------------------------------+-----------+
| Not Blinded                                              | 6         |
+----------------------------------------------------------+-----------+
| Rate of Onyx Release Exceeded Recommended Guidelines     | 5         |
+----------------------------------------------------------+-----------+
| EBL Not Assessable/Not Documented Properly               | 4         |
+----------------------------------------------------------+-----------+
| Use of Embospheres with Onyx                             | 2         |
+----------------------------------------------------------+-----------+
| Opened Randomization Envelope Prior to Full Patient      | 2         |
| Assessment                                               |           |
+----------------------------------------------------------+-----------+
| CT Not Done                                              | 2         |
+----------------------------------------------------------+-----------+
| Crossover to n-BCA                                       | 2         |
+----------------------------------------------------------+-----------+
| LTFU                                                     | 2         |
+----------------------------------------------------------+-----------+
| Other                                                    | 4         |
+----------------------------------------------------------+-----------+

The 85 neurologic assessments represent approximately 12% of the
expected neurologic exams to be performed. Neurologic outcome was
available in almost all cases post final embolization and post surgery.
Although the core lab was listed as having 32 protocol deviations, these
angiographic assessment deviations only resulted in a few cases were the
efficacy endpoint was not able to be assessed, a total of 4 films were
missing or unassessible.

*In the Protocol Deviation Summary on page 3722, please specify the
number of protocol deviations associated with each of the 32 core lab
issues. In addition, please discuss the four "other" protocol
deviation.*

Patient Demographics by Group (All Patients, n=108)

+-----------------------+-----------------------+-----------------------+
| Demographics          | N-BC                  | Onyx                  |
|                       |                       |                       |
|                       | n=57                  | N=51                  |
+-----------------------+-----------------------+-----------------------+
| Age (yrs)             | 35.1 [+]{.underline}  | 42.5 [+]{.underline}  |
|                       | 14.2 (57)             | 17.0 (51)             |
| Mean +/- SD (n)       |                       |                       |
|                       | 35.0 (10.0-66.0)      | 44.0 (7.0-73.0)       |
| Median (range)        |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Gender                | 49.1% (28/57)         | 45.1% (23/51)         |
|                       |                       |                       |
| Male                  | 50.9% (29/57)         | 54.9% (28/51)         |
|                       |                       |                       |
| Female                |                       |                       |
+-----------------------+-----------------------+-----------------------+
| BMI                   | 24.4 [+]{.underline}  | 28.1 [+]{.underline}  |
|                       | 4.5 (54)              | 6.3 (41)              |
| Mean +/- SD (n)       |                       |                       |
|                       | 23.7 (15.1-37.2)      | 27.4 (16.7-45.0)      |
| Median (range)        |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Systolic Blood        | 123 [+]{.underline}   | 127 [+]{.underline}   |
| Pressure (mmHg)       | 14 (57)               | 17 (51)               |
|                       |                       |                       |
| Mean +/- SD (n)       | 120 (80-171)          | 127 (98-170)          |
|                       |                       |                       |
| Median (range)        |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Diastolic Blood       | 71 [+]{.underline} 10 | 71 [+]{.underline} 13 |
| Pressure (mmHg)       | (57)                  | (51)                  |
|                       |                       |                       |
| Mean +/- SD (n)       | 70 (50-90)            | 70 (46-98)            |
|                       |                       |                       |
| Median (range)        |                       |                       |
+-----------------------+-----------------------+-----------------------+

Medical History by Treatment Group (All Patients, n=108)

+-----------------------+-----------------------+-----------------------+
| Medical History       | N-BCA                 | Onyx                  |
|                       |                       |                       |
| n=108                 | n=57                  | n=51                  |
+-----------------------+-----------------------+-----------------------+
| CAD                   | 1.8% (1/57)           | 5.9% (3/51)           |
+-----------------------+-----------------------+-----------------------+
| HTN                   | 19.3% (11/57)         | 21.6% (11/51)         |
+-----------------------+-----------------------+-----------------------+
| Diabetes              | 5.3% (3/57)           | 9.8% (5/51)           |
+-----------------------+-----------------------+-----------------------+
| **Neuro History**     |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Seizure               | 21.1% (12/57)         | 9.8% (5/51)           |
+-----------------------+-----------------------+-----------------------+
| Stroke                | 0.0% (0/57)           | 2.0% (1/51)           |
+-----------------------+-----------------------+-----------------------+
| Aneursym              | 8.8% (5/57)           | 0.0% (0/51)           |
+-----------------------+-----------------------+-----------------------+
| Other AVM             | 3.5% (2/57)           | 2.0% (1/51)           |
+-----------------------+-----------------------+-----------------------+
| **Neuro               |                       |                       |
| Interventions**       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Surgery (Clipping)    | 5.3% (3/57)           | 0.0% (0/51)           |
+-----------------------+-----------------------+-----------------------+

*Please provide the number and percentage of patients in each group who
had an intracranial hemorrhage \> 1year.*

Hierarchical Presenting Symptoms by Treatment Group (All Patients,
n=108)

+-----------------------+-----------------------+-----------------------+
| Hierarchical          | N-BCA                 | Onyx                  |
| Presenting Symptoms   |                       |                       |
|                       | n=57                  | n=51                  |
| n=108                 |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Acute Bleed (\<30     | 14.0% (8/57)          | 19.6% (10/51)         |
| days)                 |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Remote Bleed (\>30    | 17.5% (10/57)         | 17.6% (9/51)          |
| days\<1 year)         |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Neurologic Deficit    | 52.6% (30/57)         | 37.3% (19/51)         |
+-----------------------+-----------------------+-----------------------+
| Neurologic Symptoms   | 14.0% (8/57)          | 19.6% (10/51)         |
+-----------------------+-----------------------+-----------------------+
| None                  | 1.8% (1/57)           | 5.9% (3/51)           |
+-----------------------+-----------------------+-----------------------+

Baseline Neurologic Assessments by Treatment Group (All Patients, n=108

+-----------------------+-----------------------+-----------------------+
| Pretreatment          | N-BCA                 | Onyx                  |
| Assessment            |                       |                       |
|                       | n=57                  | n=51                  |
+-----------------------+-----------------------+-----------------------+
| **Glasgow Coma        |                       |                       |
| Score**               |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 0-6                   | 3.6% (2/56)           | 3.9% (2/51)           |
+-----------------------+-----------------------+-----------------------+
| 7-14                  | 3.6% (2/56)           | 7.8% (4/51)           |
+-----------------------+-----------------------+-----------------------+
| \>14                  | 92.9% (52/56)         | 88.2% (45/51)         |
+-----------------------+-----------------------+-----------------------+
| **Barthel Index       |                       |                       |
| (Total Score)**       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 0-25                  | 3.6% (2/55)           | 9.8% (5/51)           |
+-----------------------+-----------------------+-----------------------+
| 26-75                 | 1.8% (1/55)           | 5.9% (3/51)           |
+-----------------------+-----------------------+-----------------------+
| 76-100                | 94.5% (52/55)         | 84.3% (43/51)         |
+-----------------------+-----------------------+-----------------------+
| **NIH Stroke Scale    |                       |                       |
| (Total Score)**       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 0                     | 75.5% (41/54)         | 56.9% (29/51)         |
+-----------------------+-----------------------+-----------------------+
| 1-4                   | 18.5% (10/54)         | 29.4% (15/51)         |
+-----------------------+-----------------------+-----------------------+
| 5-10                  | 5.6% (3/53)           | 5.9% (3/51)           |
+-----------------------+-----------------------+-----------------------+
| \>10                  | 0.0% (0/54)           | 7.8% (4/51)           |
+-----------------------+-----------------------+-----------------------+

Pretreatment Assessment (All Patients, n=108)

+-----------------------+-----------------------+-----------------------+
| Pretreatment          | N-BCA                 | Onyx                  |
| Assessment            |                       |                       |
|                       | n=57 AVMs             | n=54 AVMs             |
| n=111 AVMs in 108 pts |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **AVM Location**      |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Right                 | 56.1% (32/57)         | 55.6% (30/54)         |
+-----------------------+-----------------------+-----------------------+
| Left                  | 40.4% (23/57)         | 35.2% (19/54)         |
+-----------------------+-----------------------+-----------------------+
| Midline               | 3.5% (2/57)           | 9.3% (5/54)           |
+-----------------------+-----------------------+-----------------------+
| **AVM in eloquent     | 47.4% (27/57)         | 48.1% (26/54)         |
| area of brain**       |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Venous Drainage**   |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Deep                  | 8.8% (5/57)           | 18.5% (10/53)         |
+-----------------------+-----------------------+-----------------------+
| Superficial           | 61.4% (35/57)         | 61.1% (33/53)         |
+-----------------------+-----------------------+-----------------------+
| Both                  | 29.8% (17/57)         | 18.5% (10/53)         |
+-----------------------+-----------------------+-----------------------+
| **AVM Size (Core Lab, |                       |                       |
| mm^3^)**              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Mean[+]{.underline}SD | 16                    | 26                    |
|                       | .0[+]{.underline}20.0 | .3[+]{.underline}44.0 |
+-----------------------+-----------------------+-----------------------+
| Median                | 7.9                   | 13.4                  |
+-----------------------+-----------------------+-----------------------+
| Range                 | 0.1-94.9              | 0.2-290.5             |
+-----------------------+-----------------------+-----------------------+

*In the Pretreatment Assessment table of all patients, please provide
the Spetzler-Martin Grade for both groups.*

ITT Analysis (All Patients, n=108)

+----------------+-------+--------------------+------------------------+
|                | Total | N-BCA=n            | Onyx=n                 |
|                | Pts=n |                    |                        |
+----------------+-------+--------------------+------------------------+
| Randomized     | 108   | 57                 | 51                     |
+----------------+-------+--------------------+------------------------+
| Late Screen    | 2     | 2                  |                        |
| Failures       |       |                    |                        |
|                |       | (18-003, 21-009)   |                        |
+----------------+-------+--------------------+------------------------+
| Enrolled Pts   | 106   | 55                 | 51                     |
+----------------+-------+--------------------+------------------------+
| Protocol       | 6     | 1                  | 5                      |
| violations     |       |                    |                        |
|                |       | (5-005)            | (2-008, 8-001, 8-010,  |
| (Dural         |       |                    | 8-014, 38-001)         |
| Fistulas)      |       |                    |                        |
+----------------+-------+--------------------+------------------------+
| ITT Analysis   | 100   | 54                 | 46                     |
| n=100          |       |                    |                        |
|                |       |                    |                        |
| Ever Attempted |       |                    |                        |
| Tx             |       |                    |                        |
+----------------+-------+--------------------+------------------------+
|                |       | 55                 | 50                     |
+----------------+-------+--------------------+------------------------+
| Films not      | 7     | 3                  | 4                      |
| Analyzable     |       |                    |                        |
|                |       | (21-008, 8-004,    | (32-003, 2-001, 8-008, |
|                |       | 5-005))            | 8-010)                 |
+----------------+-------+--------------------+------------------------+
| Pts Ongoing    | 3     | 1                  | 2                      |
|                |       |                    |                        |
|                |       | (38-004)           | (38-006, 3-003)        |
+----------------+-------+--------------------+------------------------+
| Total          | 96    | 51                 | 45                     |
| Accessible     |       |                    |                        |
|                |       | Success n=43       | Success n=42           |
|                |       |                    |                        |
|                |       | Failure n=8        | Failure n=3            |
|                |       |                    |                        |
|                |       | Success Rate=84%   | Success Rate=93%       |
|                |       | (43/51)            | (42/45)                |
|                |       |                    |                        |
|                |       | (Failures by CL:   | (Failures by CL:       |
|                |       | 6-003, 19-001,     | 6-007,2-008,38-001)    |
|                |       | 34-001, 2-012,     |                        |
|                |       | 8-012, 8-007)      |                        |
|                |       |                    |                        |
|                |       | (Procedure         |                        |
|                |       | Failure: 8-006,    |                        |
|                |       | 8-009)             |                        |
+----------------+-------+--------------------+------------------------+

*Please explain in the ITT Analysis of all patients on page 3710, how
you jump from 100 patients that ever attempted treatment (n-BCA=54,
Onyx=51) to n-BCA, n=55 and Onyx, n=50 and how in the n-BCA group, there
are 51 patients that are totally accessible if 3 had films that were not
analyzable and 1 is ongoing and in the Onyx group there are 45 patients
if 4 had films that were not analyzable and 2 patients were ongoing.
Please explain the difference between patients who were failures by core
lab and those who were procedure failures.*

Per-Protocol Analysis (All Patients, n=108)

+----------------+-------+--------------------+------------------------+
|                | Total | N-BCA=n            | Onyx=n                 |
|                | Pts=n |                    |                        |
+----------------+-------+--------------------+------------------------+
| Randomized     | 108   | 57                 | 51                     |
+----------------+-------+--------------------+------------------------+
| Late Screen    | 2     | 2                  |                        |
| Failures       |       |                    |                        |
|                |       | (18-003, 21-009)   |                        |
+----------------+-------+--------------------+------------------------+
| Enrolled Pts   | 106   | 55                 | 51                     |
+----------------+-------+--------------------+------------------------+
| Protocol       | 6     | 1                  | 5                      |
| violations     |       |                    |                        |
|                |       | (5-005)            | (2-008, 8-001, 8-010,  |
| (Dural         |       |                    | 8-014, 38-001)         |
| Fistulas)      |       |                    |                        |
+----------------+-------+--------------------+------------------------+
| ITT Analysis   | 100   | 54                 | 46                     |
| n=100          |       |                    |                        |
|                |       |                    |                        |
| Ever Attempted |       |                    |                        |
| Tx             |       |                    |                        |
+----------------+-------+--------------------+------------------------+
| Technical      | 4     | 3                  | 1                      |
| Failures       |       |                    |                        |
| (during 1^st^  |       | (8-009, 19-001,    | (32-003)               |
| attempt): no   |       | 34-001)            |                        |
| embolization   |       |                    |                        |
| with intended  |       |                    |                        |
| device         |       |                    |                        |
+----------------+-------+--------------------+------------------------+
|                |       | 52                 | 50                     |
+----------------+-------+--------------------+------------------------+
| Films not      | 5     | 2                  | 3                      |
| Analyzable     |       |                    |                        |
|                |       | (8-004, 5-005))    | (2-001, 8-008, 8-010)  |
+----------------+-------+--------------------+------------------------+
| Pts Ongoing    | 3     | 1                  | 1                      |
|                |       |                    |                        |
|                |       | (38-004)           | (38-006)               |
+----------------+-------+--------------------+------------------------+
| Total          | 96    | 49                 | 46                     |
| Accessible     |       |                    |                        |
|                |       | Success n=42       | Success n=42           |
|                |       |                    |                        |
|                |       | Failure n=7        | Failure n=2            |
|                |       |                    |                        |
|                |       | Success Rate=86%   | Success Rate=95%       |
|                |       | (42/49)            | (42/46)                |
|                |       |                    |                        |
|                |       | (Failures by CL:   | (Failures by CL:       |
|                |       | 6-003, 2-012,      | 6-007,2-008,38-001)    |
|                |       | 8-012, 8-007)      |                        |
|                |       |                    | (Procedure Failure:    |
|                |       | (Procedure Failure | 3-003)                 |
|                |       | abandon treatment: |                        |
|                |       | 8-006, 21-007,     |                        |
|                |       | 21-008)            |                        |
+----------------+-------+--------------------+------------------------+

*From page 3711, please explain how you calculate that there are 52
patients in the n-BCA group and 50 in the Onyx group when there were 54
in the n-BCA and 46 in the Onyx group in the ITT analysis, that ever
attempted treatment, and 3 in the n-BCA group and 1 in the Onyx group
that were technical failures. Also please explain how you determined
that there were 2 failures in the Total Accessible Onyx group when there
were 3 patient failures assessed by the core lab and 1 procedure
failure.*

Primary Endpoint Summary

+-----------------------+-----------------------+-----------------------+
|                       | N-BCA                 | Onyx                  |
|                       |                       |                       |
|                       | n=54                  | N=46                  |
+-----------------------+-----------------------+-----------------------+
| Core Lab Angiographic |                       |                       |
| Success               |                       |                       |
+-----------------------+-----------------------+-----------------------+
| ITT Analysis          | 84% (43/51)           | 93% (42/45)           |
+-----------------------+-----------------------+-----------------------+
| Per Protocol Analysis | 86% (42/49)           | 91% (42/46)           |
+-----------------------+-----------------------+-----------------------+

*Please explain why you used 54 patients in the n-BCA group and 46 in
the Onyx group for the primary endpoint on page 3712 and 45 in the Onyx
denominator for the ITT analysis.*

Safety Endpoint Summary

+------------------------------+------------------+-------------------+
| Safety (Pt Based) %Patients  | N-BCA            | Onyx              |
| (Pts with SEA/total sample)  |                  |                   |
|                              | N=55             | N=51              |
+------------------------------+------------------+-------------------+
| Serious AE                   | 27.3% (15/55)    | 39.2% (20/51)     |
+------------------------------+------------------+-------------------+
| System-related SAE           | 3.6% (2/55)      | 7.8% (4/51)       |
+------------------------------+------------------+-------------------+
| Treatment-related SAE        | 5.4% (3/55)      | 9.8% (5/51)       |
+------------------------------+------------------+-------------------+
| Surgery-related SAE          | 20.0% (11/55)    | 19.6% (10/51)     |
+------------------------------+------------------+-------------------+
| Disease-related SAE          | 1.8% (1/55)      | 3.9% (2/51)       |
+------------------------------+------------------+-------------------+

Serious AEs Hierarchical

+-------------------------+---------------------+---------------------+
| Event                   | n-BCA               | Onyx                |
|                         |                     |                     |
|                         | n=55                | N=51                |
+-------------------------+---------------------+---------------------+
| Death                   | 0 (0%)              | 2 (3.9%)            |
+-------------------------+---------------------+---------------------+
| Intracranial Hemorrhage | 8 (14.5%)           | 6 (11.8%)           |
+-------------------------+---------------------+---------------------+
| Stroke                  | 0 (0%)              | 1 (2%)              |
+-------------------------+---------------------+---------------------+
| Infection               | 0 (0%)              | 1 (2%)              |
+-------------------------+---------------------+---------------------+
| Worsening Neuro Status  | 5 (9.1%)            | 7 (13.7%)           |
+-------------------------+---------------------+---------------------+
| Hydrocephalus           | 0 (0%)              | 2 (3.9%)            |
+-------------------------+---------------------+---------------------+
| Seizures                | 0 (0%)              | 1 (2%)              |
+-------------------------+---------------------+---------------------+
| Headache +/- nausea and | 2 (3.6%)            | 0 (0%)              |
| vomiting                |                     |                     |
+-------------------------+---------------------+---------------------+
| Total patients          | 15                  | 20                  |
+-------------------------+---------------------+---------------------+

Serious AEs not Hierarchical

+-----------------------+-----------------------+-----------------------+
| Event                 | N-BCA                 | Onyx                  |
|                       |                       |                       |
|                       | n=55                  | n=51                  |
+-----------------------+-----------------------+-----------------------+
| Intracranial          | 9                     | 7                     |
| Hemorrhage            |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Stroke                | 0                     | 2                     |
+-----------------------+-----------------------+-----------------------+
| Worsening Neuro       | 4                     | 7                     |
| Status                |                       |                       |
|                       | 3                     | 5                     |
| Persistent            |                       |                       |
|                       | 1                     | 2                     |
| Transient             |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Multi-Organ System    | 1                     | 0                     |
| Complications         |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Severe Bleeding/Low   | 1                     | 0                     |
| Hct requiring         |                       |                       |
| transfusion           |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Hydrocephalus         | 0                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Respiratory Failure   | 1                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Infection             | 2                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Seizures              | 0                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Fever                 | 1                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Catabolic State       | 1                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Vessel Dissection     | 0                     | 1                     |
+-----------------------+-----------------------+-----------------------+
| Limb Ischemia         | 1                     | 0                     |
+-----------------------+-----------------------+-----------------------+
| Headache +/- Nausea   | 3                     | 1                     |
| and Vomiting          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Medication Reaction   | 0                     | 2                     |
+-----------------------+-----------------------+-----------------------+
| Total \# SAEs         | 24                    | 24                    |
+-----------------------+-----------------------+-----------------------+

*Please state the total number of patients with non-Hierarchical SAEs
for the Serious Adverse Events -- Non-Hierarchical table on page 3714.*

Serious AEs by Relationship

+----------------------------------+--------------+-------------------+
| Event                            | n-BCA        | Onyx              |
|                                  |              |                   |
|                                  | n=55         | n=51              |
+----------------------------------+--------------+-------------------+
| System                           |              |                   |
+----------------------------------+--------------+-------------------+
| Stroke                           | 0            | 1                 |
+----------------------------------+--------------+-------------------+
| Vessel Dissection                | 0            | 1                 |
+----------------------------------+--------------+-------------------+
| Worsening Neurological Status    | 1            | 2                 |
+----------------------------------+--------------+-------------------+
| Intracranial Hemorrhage          | 1            | 0                 |
+----------------------------------+--------------+-------------------+
| Total #Events                    | 2            | 4                 |
+----------------------------------+--------------+-------------------+
| Total #Pts with Events           | 2/55 (3.6%)  | 4/51 (7.8%)       |
+----------------------------------+--------------+-------------------+
| Treatment                        |              |                   |
+----------------------------------+--------------+-------------------+
| Headache +/- Nausea and Vomiting | 0            | 1                 |
+----------------------------------+--------------+-------------------+
| Intracranial Hemorrhage          | 2            | 2                 |
+----------------------------------+--------------+-------------------+
| Limb Ischemia                    | 1            | 0                 |
+----------------------------------+--------------+-------------------+
| Medication Reaction              | 0            | 2                 |
+----------------------------------+--------------+-------------------+
| Worsening Neurologic Status      | 1            | 2                 |
+----------------------------------+--------------+-------------------+
| Total #Events                    | 4            | 7                 |
+----------------------------------+--------------+-------------------+
| Total #Pts with Events           | 3/55 (5.4%)  | 5/51 (9.8%)       |
+----------------------------------+--------------+-------------------+
| Surgery                          |              |                   |
+----------------------------------+--------------+-------------------+
| Infection                        | 2            | 1                 |
+----------------------------------+--------------+-------------------+
| Catabolic State                  | 1            | 0                 |
+----------------------------------+--------------+-------------------+
| Headache +/- Nausea and Vomiting | 2            | 0                 |
+----------------------------------+--------------+-------------------+
| Intracranial Hemorrhage          | 6            | 5                 |
+----------------------------------+--------------+-------------------+
| Multi-Organ System Complications | 1            | 0                 |
+----------------------------------+--------------+-------------------+
| Respiratory Failure              | 1            | 0                 |
+----------------------------------+--------------+-------------------+
| Severe Bleeding/Low HCT          | 1            | 0                 |
| ReqTransfusion                   |              |                   |
+----------------------------------+--------------+-------------------+
| Stroke                           | 0            | 1                 |
+----------------------------------+--------------+-------------------+
| Worsening Neurological Status    | 2            | 3                 |
+----------------------------------+--------------+-------------------+
| Fever                            | 1            | 0                 |
+----------------------------------+--------------+-------------------+
| Total #Events                    | 17           | 10                |
+----------------------------------+--------------+-------------------+
| Total #Pts with Events           | 11/55        | 10/51 (19.6%)     |
|                                  | (20.0%)      |                   |
+----------------------------------+--------------+-------------------+
| Disease                          |              |                   |
+----------------------------------+--------------+-------------------+
| Seizures                         | 0            | 1                 |
+----------------------------------+--------------+-------------------+
| Headache +/- Nausea and Vomiting | 1            | 0                 |
+----------------------------------+--------------+-------------------+
| Hydrocephalus                    | 0            | 1                 |
+----------------------------------+--------------+-------------------+
| Respiratory Failure              | 0            | 1                 |
+----------------------------------+--------------+-------------------+
| Total #Events                    | 1            | 3                 |
+----------------------------------+--------------+-------------------+
| Total #Pts with Events           | 1/55 (1.8%)  | 2/51 (3.9%)       |
+----------------------------------+--------------+-------------------+
| Overall Total #Events            | 24           | 24                |
+----------------------------------+--------------+-------------------+

*Please provide the patient ID and a description of each of the sSerious
adverse events listed in the Serious Adverse Events by Relationship on
page 3715.*

Non Serious AEs

+-----------------------------+----------------+-----------------------+
| Event by Relationship       | N-BCA          | Onyx                  |
|                             |                |                       |
|                             | n=55           | N=51                  |
+-----------------------------+----------------+-----------------------+
| System Related              |                |                       |
+-----------------------------+----------------+-----------------------+
| Total                       | 0              | 0                     |
+-----------------------------+----------------+-----------------------+
| Treatment Related           |                |                       |
+-----------------------------+----------------+-----------------------+
| Access Site Bleeding        | 0              | 5                     |
+-----------------------------+----------------+-----------------------+
| Headache +/- Nausea and     | 21             | 21                    |
| Vomiting                    |                |                       |
+-----------------------------+----------------+-----------------------+
| Infection                   | 0              | 1                     |
+-----------------------------+----------------+-----------------------+
| Medication Reaction         | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 4              | 7                     |
+-----------------------------+----------------+-----------------------+
| Worsening Neurologic Status | 13             | 11                    |
+-----------------------------+----------------+-----------------------+
| Total                       | 39             | 46                    |
+-----------------------------+----------------+-----------------------+
| Surgery Related             |                |                       |
+-----------------------------+----------------+-----------------------+
| Cardiac Arrhythmia          | 0              | 1                     |
+-----------------------------+----------------+-----------------------+
| Medication Reaction         | 1              | 0                     |
+-----------------------------+----------------+-----------------------+
| Laboratory/Imaging          | 1              | 1                     |
| Abnormalities               |                |                       |
+-----------------------------+----------------+-----------------------+
| Intracranial Hemorrhage     | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Infection                   | 1              | 2                     |
+-----------------------------+----------------+-----------------------+
| Seizures                    | 1              | 0                     |
+-----------------------------+----------------+-----------------------+
| Fever                       | 1              | 3                     |
+-----------------------------+----------------+-----------------------+
| Severe Bleeding/Low HCT Req | 1              | 0                     |
| Transfusion                 |                |                       |
+-----------------------------+----------------+-----------------------+
| Headache +/- Nausea and     | 7              | 9                     |
| Vomiting                    |                |                       |
+-----------------------------+----------------+-----------------------+
| Tongue Swelling             | 0              | 1                     |
+-----------------------------+----------------+-----------------------+
| Worsening Neurologic Status | 8              | 6                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 6              | 7                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 28             | 31                    |
+-----------------------------+----------------+-----------------------+
| Disease Related             |                |                       |
+-----------------------------+----------------+-----------------------+
| Psychotic Episode           | 0              | 1                     |
+-----------------------------+----------------+-----------------------+
| Worsening Neurologic Status | 2              | 3                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 1              | 0                     |
+-----------------------------+----------------+-----------------------+
| Laboratory/Imaging          | 1              | 0                     |
| Abnormalities               |                |                       |
+-----------------------------+----------------+-----------------------+
| Infection                   | 2              | 2                     |
+-----------------------------+----------------+-----------------------+
| Hydrocephalus               | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Headache +/- Nausea and     | 2              | 1                     |
| Vomiting                    |                |                       |
+-----------------------------+----------------+-----------------------+
| Thrombocytopenia            | 1              | 0                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 10             | 7                     |
+-----------------------------+----------------+-----------------------+
| Other Related               |                |                       |
+-----------------------------+----------------+-----------------------+
| Medication Reaction         | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 1              | 1                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 2              | 2                     |
+-----------------------------+----------------+-----------------------+
| Unknown Related             |                |                       |
+-----------------------------+----------------+-----------------------+
| Worsening Neurologic Status | 2              | 0                     |
+-----------------------------+----------------+-----------------------+
| Pt Discomfort               | 0              | 2                     |
+-----------------------------+----------------+-----------------------+
| Total                       | 2              | 2                     |
+-----------------------------+----------------+-----------------------+
| Total #Non-Serious AEs      | 81             | 91                    |
+-----------------------------+----------------+-----------------------+
| Total \# Pts with           | 51             | 46                    |
| Non-Serious AEs             |                |                       |
+-----------------------------+----------------+-----------------------+

*Please provide the patient ID and a description of each of the non
serious adverse events listed in the Non Serious Adverse Events on page
3716.*

Technical/Procedural Events Summary

+-----------------------+-----------------------+-----------------------+
|                       | N-BCA                 | Onyx                  |
|                       |                       |                       |
|                       | n=55                  | n=51                  |
+-----------------------+-----------------------+-----------------------+
| Technical Events (#   | 11                    | 18                    |
| of events)            |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Procedural Events (#  | 12                    | 3                     |
| of events)            |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Total                 | 23                    | 21                    |
| Technical/Procedural  |                       |                       |
| Events (# of events)  |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Total Patients with   | 31%                   | 27%                   |
| Technical/Procedural  |                       |                       |
| Events (# of          | (17/55)               | (14/51)               |
| patients/% of         |                       |                       |
| patients)             |                       |                       |
+-----------------------+-----------------------+-----------------------+

[Patient Follow-up Results]{.underline}

During the course of the trial, 9 patients did not undergo complete
surgical resection of the AVM and are thus being followed at 3 and 12
months after the final embolization procedure or surgical attempt; 3
patients had partial resection of their AVM and 6 patients had no
resection attempt. 5 of the 9 patients have been determined by the core
lab to be successful embolization procedures and 3 patients have failed
embolization procedures; the remaining patient's angiogram, 08-004, was
not assessable by the core lab. During the follow-up interval, 4
patients underwent or are scheduled to undergo some type of
radiosurgery.

No follow-up neurologic scale information is available on 5 patients.

  -------- ------- ---------- --------- --------- ----- ----- ------ ----- ----- --------- ----- -----
  Pt ID    Tx      Date last  Outcome   Barthel               NIH                Glasgow         
                   Embo or Sx                                                                    

                                        Last Tx   3 mos 12    Last   3 mos 12    Last Tx   3 mos 12
                                                        mos   Tx           mos                   mos

  10-005   N-BCA   7/8/02     Success   90        100   N/A   0      0     N/A   0         0     N/A

  29-002   Onyx    10/15/01   Success   25        85    100   0      0     0     1         1     0

  29-006   Onyx    11/5/02    Success   35        100   N/A   0      0     N/A   0         2     N/A

  08-004   N-BCA   1/29/02    Missing   100             100   0            0     0               0

  08-006   N-BCA   1/8/02     Failure   100                   0                  15              

  08-012   N-BCA   7/23/02    Failure   100             N/A   0            N/A   15              N/A

  20-003   Onyx    7/8/02     Success   45              N/A   7            N/A   15              N/A

  34-001   N-BCA   7/15/02    Failure   \*              N/A   \*           N/A   \*              N/A

  38-008   N-BCA   12/3/02    Success   100       N/A   N/A   0      N/A   N/A   15        N/A   N/A
  -------- ------- ---------- --------- --------- ----- ----- ------ ----- ----- --------- ----- -----

\*Primary technical failure, no post-treatment information provided

N/A=Not due

Only 2 patients, 08-006 and 29-006 had AEs during the follow-up period;
no serious AEs occurred following their last treatment, surgery or
embolization, episode. One patient, 29-006, had a reduction in their
functional status as demonstrated by the increase in Glasgow score, from
0 to 2, due to multiple systemic complaints. The other patient, 08-006,
had generalized pain that was reported at the time of the hospital visit
for scheduled radiosurgery; the patient underwent radiosurgery without
complication and the symptoms resolved spontaneously.