+------------+-------------------+----------------+--------------------+
| ####       |                   | # PMA REV      |                    |
|  DEPARTMEN |                   | IEW MEMORANDUM |                    |
| T OF HEALT |                   |                |                    |
| H AND HUMA |                   |                |                    |
| N SERVICES |                   |                |                    |
+------------+-------------------+----------------+--------------------+
| #### Divi  |                   |                | **Food and Drug    |
| sion of Ge |                   |                | Administration**   |
| neral and  |                   |                |                    |
| Restorativ |                   |                | **Office of Device |
| e Devices  |                   |                | Evaluation**       |
|            |                   |                |                    |
| **         |                   |                | **9200 Corporate   |
| Orthopedic |                   |                | Boulevard**        |
| Devices    |                   |                |                    |
| Branch,    |                   |                | **Rockville, MD    |
| HFZ-410**  |                   |                | 20850**            |
+------------+-------------------+----------------+--------------------+
| **Date:**  | **July 13, 2004** |                |                    |
+------------+-------------------+----------------+--------------------+
| **To:**    | **File**          |                |                    |
+------------+-------------------+----------------+--------------------+
| **From:**  | ##                |                |                    |
|            | # Medical Officer |                |                    |
+------------+-------------------+----------------+--------------------+
| **         | **X-Stop          |                |                    |
| Subject:** | Interspinous      |                |                    |
|            | Process           |                |                    |
|            | Distraction       |                |                    |
|            | System**          |                |                    |
+------------+-------------------+----------------+--------------------+
| **         | **St. Francis     |                |                    |
| Sponsor:** | Medical           |                |                    |
|            | Technologies,     |                |                    |
|            | Inc.**            |                |                    |
+------------+-------------------+----------------+--------------------+
| **CLINICAL |                   |                |                    |
| SUMMARY    |                   |                |                    |
| P040001**  |                   |                |                    |
+------------+-------------------+----------------+--------------------+

**[Clinical Background/Rationale for the device:]{.underline}**

[Lumbar Stenosis]{.underline}

Lumbar stenosis is a condition of the spine with multiple etiologies
that creates a clinical syndrome characterized by back, buttock or leg
pain with characteristic provocative or palliative features caused by
narrowing of the spinal canal or neural foramina producing nerve
compression, and ischemia. Central stenosis involves compression of the
spinal cord and thecal sac, while lateral stenosis involves compression
of the nerve root medially or laterally by facet hypertrophy. Tumor and
infectious masses can also be the cause of stenosis of the spine.
Symptoms usually occur after late middle age affecting men more often
than women. Etiologies of stenosis can be congenital or acquired, (the
most common type), often due to degenerative enlarged facet joints, or
degenerative spondylolisthesis. Soft tissue (ligamentum flavum or disc)
can contribute to thecal sac compression (up to 40%). Often degeneration
is not limited to one level but encompasses more than one level in the
spine. It is not uncommon at all to have lumbar stenosis that primarily
affects only one or two levels. In some cases there may be an amount of
degeneration at multiple (or all) levels, but often the canal stenosis
is severe in only one two adjoining levels and good symptomatic relief
can be achieved by decompressing only the levels where there is
significant canal stenosis and nerve root compression. If multiple
levels are involved, one cannot easily differentiate which are causing
symptoms, and thus all levels where the stenosis is causing root
compression are usually decompressed.

Symptoms include insidious onset of leg and back pain and paresthesias
with ambulation

and extension of the spine, relieved by lying supine or with flexion of
the spine. Patients complain of pain numbness or giving way, with
radicular pain being uncommon. Neurogenic claudication occurs in less
than half of patients with stenosis. Ordinarily abnormal neurologic
signs or positive tension signs are seen in less than ½ of the patients
unless induced by provocative testing or ambulation until claudication
symptoms occur. The natural history of degenerative stenosis is not well
characterized. Some authors conclude that severe progression is unlikely
while others state that clinical improvement occurs in approximately 1/3
to ½ of the patients with stenosis associated with or without
degenerative spondylolisthesis.

Treatment for stenosis involves initial rest, abdominal exercises,
pelvic tilt and flexion exercises, NSAIDS and weight reduction. Epidural
Steroids may be helpful for short term relief but have not shown long
term efficacy in sparse controlled studies. Surgical decompression with
and without fusion is indicated when patients with positive imaging
studies experience unacceptable impaired quality of life due to
symptoms. There are multiple variations of procedures that decompress
and then, if necessary, restabilize the spine following decompression.

Frequently, patients with lumbar spinal stenosis have multiple
co-existing medical conditions that may make them unsuitable risky
candidates for lengthy surgical procedures and general anesthesia. This
device proposes to fill in the continuum between conservative care and
invasive surgical procedures to decompress the spinal cord or nerve
roots, with a minimally invasive procedure which can be done as an
outpatient under local anesthesia.

**[The Device]{.underline}**

The device that is the subject of this PMA is the X-Stop™, an
interspinous process distraction device. The device is implanted between
the spinous processes in order to block lumbar extension, following
distraction of the interspinous space by the patient's position on the
operating room table and dilation of the soft tissue by the surgeon. The
device is manufactured from Ti6Al-4V ELI titanium alloy and consists of
two components: a spacer and two wings. The spacer is comprised of a
tissue expander, a fixed wing and oval spacer. The wing consists of an
adjustable wing and locking screw. The device is implanted with the
patient in the right lateral decubitus, spine flexed position, under
local anesthesia with IV sedation, through a small 1-2 inch midline
incision posteriorly over the spinous processes. After the spacer is
implanted under the supraspinous ligament and through the interspinous
ligament, the wing assembly is attached. The width is adjusted and the
set screw tightened with a torque limiting screwdriver.

There have been 4 versions of the design of the device. The first was a
one piece device with an H shape and one elongated arm and implanted in
1 patient. The second was a multi-piece square spacer design implanted
in the remaining 9 pilot study patients and the third a multi-piece
design with an oval spacer. The fourth version welded the components of
the multi-piece design so they would not disassemble. The first two
versions were implanted in the pilot study patients only. The third and
fourth versions were implanted in the patients in the pivotal studies

**[Intended Use]{.underline}**

The sponsor states: "The X-Stop™, an interspinous process implant
system, is intended to be used in patients with symptomatic lumbar
stenosis at one or two levels who have failed at least six months of
conservative treatment."

**[Clinical Study Overview]{.underline}**

Studies to support safety and effectiveness were completed in two
phases: a pilot phase and two pivotal phases.

The review that follows summarizes the clinical safety and effectiveness
data from the three clinical studies which are submitted to support the
device use in humans. This review focuses on the final pivotal
superiority study which evaluates the final version of the device and
encompasses the data provided that is intended to support the safety and
effectiveness of the device the sponsor intends to market. This study
was a prospective, randomized, controlled, multicenter clinical
investigation of the fourth version of X-stop™ device involving 191
patients at 9 investigational sites implanted via a minimal posterior
approach or enrolled in the control group. The control group was a group
of patients who had continued non-operative therapy which included the
use of bed rest, controlled physical activity, physiotherapy,
anti-inflammatory drugs, lumbar corset and a varied number of epidural
steroids. Patients were 50 years or older, had a radiographic and
clinical diagnosis of one or two level lumbar spinal stenosis with leg,
buttock, groin pain with/without back pain that can be relieved by
flexion , and completed 6 months of conservative therapy. Details of the
protocol and analysis follow under the discussion of the clinical
studies. Patients were considered failures if their symptoms required
treatment by laminectomy and decompression. In addition to the primary
analysis of pain and function, analysis of the successful X-stop and
control patients was compared to a non-randomized group of study
failures who went on to have laminectomies.

[Summary of Results]{.underline}

Outcomes for patients receiving the investigational device are compared
to outcomes for patients receiving a non operative, conservative care
control.

For the primary effectiveness endpoint: overall success, the 24-month
overall success rate for the X-Stop group was 45.7% (42/92) and for the
Control group 4.9% (4/81). Of note the results for the site where the
device was invented had a higher effectiveness success outcome (85%) as
compared to the other investigational sites ([\<]{.underline}50% ) The
effectiveness outcome was compared to the results for laminectomy in the
literature and the patients in this study who underwent laminectomy. For
the secondary effectiveness endpoint: back and leg pain, at 24 months,
*mean* back and leg pain scores were significantly less frequent and
less severe in the X-stop group as compared to the control group while
sitting, standing or walking. When looking at actual *mean* improvement,
the X-stop group had significantly greater improvement than the control
group in frequency and severity of back pain while standing and walking,
while there was [no]{.underline} significant difference in improvement
scores for back pain while sitting.

The safety of the profile of the device is not remarkable. Device
related events are minor and few in number, including secondary
surgeries (laminectomy or removal with or without fusion), spinous
process fractures, migration, death and local wound events. However the
incidence of what the sponsor calls "systemic" events particularly the
musculoskeletal and accidental events are much higher in those patients
receiving the X-STOP implant. It is not clear if these events are
related to prior co-morbid conditions, lumbar stenosis symptoms
unrecognized preoperatively or progressive symptoms as a result of
biomechanical changes in the spine due to implantation of the
distraction device.

**[Panel Issues]{.underline}**

There are several issues that the panel will be asked to focus on in
their discussion which are the subject of the panel questions. These are
summarized below and detailed in the review that follows, and will be
the basis of FDA's questions to the panel.

[Long Term effectiveness information]{.underline}

In the case of this device, a decision as to the safety and
effectiveness of this device is based solely on 24 month data and
information on the patient outcomes after 24 months is not available.
This information becomes important when looking at pain relief and
return to function. Even though the goal of the study was accomplished
showing a significant, statistical difference between the
investigational and control groups, more patients report improvement at
12 months than at 24 months. Contrary to what has been observed in
spinal fusion studies, in this study, a percentage of patients whose
symptoms improved at 6 and 12 months show a trend of regression of pain
and function symptoms toward baseline levels. Because follow-up on
patients stopped immediately after the last patient reached the 24 month
evaluation point, it is not clear how long the effect of treatment is
maintained.

[Defining the population]{.underline}

The outcomes of this study were worse than expected based on the
sponsors literature review and pre-study calculations. The sponsor
projected very low success rates based on the literature; 60% for the
investigational group and 37.5% for the placebo/control . The overall
success for the intent to treat population is 47.5% and 4.9% for the
investigational and control groups respectively, much lower than that
expected from literature review. Based on the low effectiveness in both
groups, including a slightly worse rate of outcome for those patients
with longer symptom duration in both the X-stop and control groups, did
the enrollment criteria and patient demographics discern the comparable
patients, and did the study define the population in the continuum of
lumbar spinal stenosis patients who would most benefit from the device
or did this population of stenosis patients all require some type of
surgical /reconstructive/decompressive intervention at the time of entry
into the study.

[Choosing Levels of treatment]{.underline}

The use of this device at one or two levels may be different with regard
to patient populations, postoperative outcomes and what the long term
impact of the device implantation on spinal mechanics is. The majority
of patients in both groups had multiple co-existing variables noted on
radiographs. These include a thickened ligamentum flavum, narrowed
lateral recess, hypertrophied facets, central canal narrowing by 50% and
spondylolisthesis. In both groups there was more than one level
involved. The sponsor's subgroup analysis noted that the patients with
2-level implantation had a slightly better outcome in all aspects of the
effectiveness evaluations, with more single level patients undergoing
laminectomy than those with two levels implanted. Adverse event
occurrence in 2-level treated patients was also less frequent than those
with single level treatment. Cadaveric biomechanical studies showed that
the dimensions of spinal foramen and the spinal canal were larger in
X-stop implanted levels than without the X-stop. However, these results
were observed only at the implanted level, but not at adjacent spinal
levels (Module 2, Attachments 4-30, Binder). Given these demographics,
outcome results and the results of the cadaveric biomechanical studies,
is it appropriate to treat just one level in cases where the ligamentum
flavum is thickened, degenerative changes are noted at multiple levels
and the spinal canal is decreased by 50% at more than one level?

[Effect on Spinal Biomechanics]{.underline}

Is there concern about the effect on adjacent levels, since the
preclinical testing did not examine the effect of the device on the
biomechanics of the spine other than at the implanted level. Has the
preclinical testing fully addressed the biomechanical effect on the
adjacent spinal levels and other areas of the spine in the case where
more than one X-stop is implanted?

[Concomitant Treatments: Epidural injections and
laminectomy]{.underline}

The protocol did not define what criteria were to be used in either
group to proceed to laminectomy or whether,in the control group, to
administer additional epidural injections. Since it was up to surgeons
to decide when the subsequent epidural injections were to take place and
decisions were not applied in a standard fashion across all the sites or
groups, just as there is a bias by defining laminectomy as a failure of
treatment, there is a potential bias in deciding what subsequent
treatment the patients should get for the study. In addition, some
patients in the investigational (X-stop) group got the control (epidural
injection for pain) rather than proceeding to laminectomy. What effect
does this have on the effectiveness outcomes of this study?

[Radiographic evidence of Effectiveness]{.underline}

Radiographic measurements of each level treated were made on plain AP
and lateral views to determine spinous process distance, anterior and
posterior disc height angulation, foraminal height and percentage of
spondylolisthesis. There were no significant differences between the
X-Stop and control groups in any of the *mean* radiographic measurements
made at either the 12 or 24 months follow-up visits. Measuring the
maintenance of distraction was measured by the distance between the
spinous process. Of 113 levels treated, a decrease greater than 4 mm was
measured in 5 levels at 24 months as compared to 6 weeks; 50 levels
remained radiographically the same as baseline, and the remainder (63
levels) showed some change (loss of distraction) of 1 mm or more; with
59% of the remaining levels (37 levels) showing [\>]{.underline} 2 mm of
apparent loss of height from baseline at 6 weeks. In the absence of
flexion extension radiographic evaluations, in light of the claim that
this device limits a specific amount of extension of the spine what is
the best way to interpret the radiographic measurements as they relate
to device effectiveness?

[Clinical measurement of effectiveness]{.underline}

When evaluating the outcomes of treatment in the lumbar stenosis
population, is there evidence that 0.5 points decrease on each of the
Zurich Claudication Questionnaire domains (symptom severity domain and
physical function) is clinically significant or predicts short/long term
effectiveness of the device?

[Biomechanical effect and safety profile]{.underline}

When looking at adverse events deemed "not related to the implant" in
the pivotal trial, those who had the X-stop implanted had a higher
incidence of lower back disorders, lower extremity disorders, hip
disorder, upper back disorder, neurological and neuropathological
disorders. Although a possible explanation is that once the stenosis
associated pain was relieved, other comorbid conditions responsible for
pain were unmasked and came to the forefront, the changes in the spinal
dynamics and biomechanical function that occur with the limitation of
extension may also be responsible for referred pain that is noted in the
X-stop group. This investigational study does not evaluate whether these
or an additional explanation is the cause.

[Pain and Function Outcome results for X-stop and control failures who
received laminectomies]{.underline}

In the additional analysis, the sponsor provides a comparison between
the successful X-Stop patients and the patients who were failures in
both the X-Stop and Control groups and went on to have laminectomies.
Symptom severity, physical function and satisfaction data was collected
from the failures who had laminectomies up to a mean of 1.2 years.
Comparison of a randomized and a non-randomized group, and a comparison
of successes to failures is not a valid comparison. In addition, the
patients who failed initial treatment may have been in worse physical
condition may have been more likely to require a laminectomy. It is
difficult to discern the clinically meaningful implication of such a
comparison.

[Differences in outcomes between sites]{.underline}

When evaluating the outcomes at different sites there is a significant
difference in outcome between the patients treated at Site 01 ( 85%
success) and all the other centers (less than 50% success). This
suggests some learning curve for the implantation technique or improved
ability to properly select patients who would benefit from the device. .

[Overall Final Effectiveness Risk/Benefit Analysis]{.underline}

In relation to the risk of surgical intervention and non
resolution/short term deterioration of symptoms, has this study provided
evidence that this device a viable alternative to either a conservative
treatment approach, or a more invasive intervention, thereby delaying a
potentially successful intervention?

# 

# SUMMARY OF THE CLINICAL STUDIES 

# Pilot study (Appendix A)

The pilot study consisted of 10 patients with lumbar stenosis who
received the first generation of the device between May 1997 and April
1998. Patients were evaluated preoperatively at 6 months and 12 months
using the Zurich Claudication Questionnaire. Of these, 2 patients (20%)
were failures (One had device related complication and in one, symptoms
recurred). Both of these patients had the X-stop device removed and
laminectomy performed. The remaining 8 patients (80%) showed some level
of improvement in their symptom severity score. The sponsor reports that
radiographs at 12 months showed no sign of device breakage, slippage,
subsidence or angulation of the vertebrae.

Patients in this study ranged in age from 64-89 with an average of 72.4
years. There were 7 women and 3 men. Eight patients had one level
diagnosis at L4-5 and 2 patients had 2 level disease. The estimated
blood loss ranged from 10-60cc with an average of 24cc. No information
is provided detailing other complications associated with the study.

**[Pivotal Study- Part I- Unwelded Implant (Appendix B)]{.underline}**

The clinical study using the third version of the device was initiated
in February 2000, but had to be stopped three months later on May 9,
2000 because a radiograph at 6 weeks showed disassembly of the device.
Twenty-two patients in 6 sites had this version of the device implanted
before it was modified by laser welding to prevent disassembly of the
implant.

These patients and the concurrent 20 control patients are reported
separately from the second pivotal trial using the newer design. Of
these 42 patients, there were 3 patient deaths in the implant group, 2
of whom died after the 3 year post operative point.

**[Pivotal Study Part I]{.underline}** Accountability at 24 months

+------------------------------------+---------------+-----------------+
|                                    | **24 months** |                 |
+------------------------------------+---------------+-----------------+
| #####                              | **Inv**       | **Con**         |
+------------------------------------+---------------+-----------------+
| ##### Theoretical                  | **22**        | **20**          |
+------------------------------------+---------------+-----------------+
| ##### Deaths, ^1^                  | **1**         | **0**           |
+------------------------------------+---------------+-----------------+
| **Failures^2^,**                   | **4**         | **5**           |
+------------------------------------+---------------+-----------------+
| **Expected**                       | **17**        | **15**          |
+------------------------------------+---------------+-----------------+
| **Evaluated**                      | **17**        | **14**          |
+------------------------------------+---------------+-----------------+
| **% Follow-up**                    | **100%**      | **93.3%**       |
+------------------------------------+---------------+-----------------+
| ##### Lost                         | **0**         | **1**           |
+------------------------------------+---------------+-----------------+

^1^There were a total of 3 deaths for the investigational group. 2
occurred after the 2 year study period.

^2^ The sponsor has counted one patient twice in the control group for 2
modes of failure.

[Demographics]{.underline}:

The patients in the implant group were on average older, taller and
heavier, but not to statistical significance. Mean operative time was
about 50 minutes with 24 cc blood loss on average.

[Efficacy]{.underline}

Based on the success criterion of 0.5% improvement on the ZCQ, the
overall success for the patients receiving the implant was 47% and for
the control was 5.3%. It is not clear whether a number of patients
received epidural steroid or pain injections, or any other concommitant
care in the control group. There is a large difference between the
surgical group and the control group in regard to successful efficacy
results. It appears the sponsor may have pooled in the effectiveness
data report those patients who had a second surgical treatment together
with those that had disassembly.. Based on the accounting 21 patients
should have been evaluated at 24 months. Of these, 6 had failure of the
implant and cannot be considered successful. There was one death.
Therefore Table 4 ZCQ scores at 24 months is not accurate. The overall
success may be closer to 30% (4/14 patients with overall success.)

[Radiographic evaluation]{.underline}

One patient in the implant group had a decrease in the distraction
postoperatively at one year. It is not clear whether this was due to
implant failure or bony failure/subsidence. Radiologists were asked to
report the presence of metallosis. This is ordinarily an intraoperative
diagnosis and can rarely be seen on radiograph. By the sponsors
explanation the term "metallosis" was adopted because the X STOP is
comprised of only titanium alloy. Metallosis in the protocol refers to
the secondary osteolysis as a result of metal particles being released
by the implant, as adopted from the hip arthroplasty literature, where
it well-described that polyethylene and/or metal alloy particles can
cause osteolysis of the femur and acetabulum. Osteolysis was not
identified radiographically in any patient during the study and, based
on the mechanical fatigue testing performed on the X STOP, is unlikely
to occur for any short duration of implantation.

[Adverse events]{.underline}

-   Control group

    -   One patient had a dural tear/spinal fluid leak during an
        epidural injection

-   Implant group

    -   No intraoperative complications were reported

    -   6 patients had implant disassembly, 5 of these occurred in the
        postoperative period, 1 occurred at 36 months (the sponsor does
        not detailed how soon after surgery the disassembly occurred.
        This device failed in 6 patients in a 3 year period for a
        revision rate of 6/22 = 27% The sponsor provides outcomes after
        secondary surgery for these patients which is not supportive of
        the effectiveness of the device.

    -   The sponsor has not clearly delineated which patients were
        failures. In the accounting table they note 4 failures however,
        6 devices disassembled .

    -   Based on the accounting on page 1, Appendix B, 21 patients
        should have been evaluated at 24 months. Of these, 6 had failure
        of the implant and cannot be considered
        successful(#0112,0207,0502,0601,and 0701).

    -   The sponsor has determined 3 patients #0406, 0601, and 0701 in
        whom the implant disassembled, to be effectiveness successes.
        This does not make sense as the device failed.

    -   Device related adverse events reported include disassembly(6),
        removal(4) replacement of device (2), laminectomy(2), stenosis
        pain (2)

    -   When looking at adverse events deemed *not related* to the
        implant, those who had the X-stop implanted had a higher
        incidence of lower back disorders, lower extremity disorders,
        hip disorder upper, back disorder, neurological and
        neuropathological disorders. These adverse events associated
        with the musculoskeletal system may be related to the
        effectiveness of the device and may be potentially due to the
        change in spinal biomechanics that may occur with the device.

<table>
<colgroup>
<col style="width: 34%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="13"><strong>SECONDARY SURGICAL INTERVENTIONS</strong></td>
</tr>
<tr class="even">
<td><strong>Type of Adverse Event/Complication</strong></td>
<td colspan="2"><strong>Surgery/ Discharge</strong></td>
<td colspan="2"><p><strong>6</strong></p>
<p><strong>Weeks</strong></p></td>
<td colspan="2"><p><strong>6</strong></p>
<p><strong>Months</strong></p></td>
<td colspan="2"><p><strong>12</strong></p>
<p><strong>Months</strong></p></td>
<td colspan="2"><p><strong>24</strong></p>
<p><strong>Months</strong></p></td>
<td colspan="2"><strong>Total # Events</strong></td>
</tr>
<tr class="odd">
<td><p><strong>Treatment Group</strong></p>
<p>(U = Un-welded; C = Control)</p></td>
<td><strong>U</strong></td>
<td><strong>C</strong></td>
<td><strong>U</strong></td>
<td><strong>C</strong></td>
<td><strong>U</strong></td>
<td><strong>C</strong></td>
<td><strong>U</strong></td>
<td><strong>C</strong></td>
<td><strong>U</strong></td>
<td><strong>C</strong></td>
<td><strong>U</strong></td>
<td><strong>C</strong></td>
</tr>
<tr class="even">
<td><strong># of Patients at Each Follow-up Interval</strong></td>
<td><strong>22</strong></td>
<td><strong>20</strong></td>
<td><strong>22</strong></td>
<td><strong>20</strong></td>
<td><strong>22</strong></td>
<td><strong>20</strong></td>
<td><strong>22</strong></td>
<td><strong>19</strong></td>
<td><strong>22</strong></td>
<td><strong>19</strong></td>
<td><strong>22</strong></td>
<td><strong>20</strong></td>
</tr>
<tr class="odd">
<td>Laminectomy*</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td>1</td>
<td></td>
<td>1</td>
<td>1</td>
<td>2</td>
<td>2</td>
<td>5</td>
</tr>
<tr class="even">
<td>Device removed without replacement</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td></td>
<td>4</td>
<td></td>
</tr>
<tr class="odd">
<td>Device removed and replaced</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td></td>
</tr>
<tr class="even">
<td><strong>TOTAL</strong></td>
<td><strong>0</strong></td>
<td><strong>0</strong></td>
<td><strong>1</strong></td>
<td><strong>1</strong></td>
<td><strong>3</strong></td>
<td><strong>1</strong></td>
<td><strong>2</strong></td>
<td><strong>1</strong></td>
<td><strong>2</strong></td>
<td><strong>2</strong></td>
<td><strong>8</strong></td>
<td><strong>5</strong></td>
</tr>
</tbody>
</table>

> \*Both X STOP patients had device(s) removed at time of laminectomy;
> one control patient (#0402) had two laminectomy surgeries

**[Pivotal Trial 2- Welded Implant]{.underline}**

**[INVESTIGATIONAL PLAN FOR THE PIVOTAL STUDIES]{.underline}**

The sponsor provided the data from the prospective, randomized,
controlled, multicenter clinical investigations of the fourth version of
X-stop™ device, (the welded implant,) implanted via a minimal posterior
approach. The control group was a group of patients who had continued
non-operative therapy which included the use of bed rest, controlled
physical activity, physiotherapy, anti-inflammatory drugs, lumbar corset
and epidural steroids.

**[Inclusion/Exclusion Criteria]{.underline}**

+-----------------------------------+-----------------------------------+
| ### Inclusion                     | **Exclusion**                     |
+-----------------------------------+-----------------------------------+
| ≥50 years old.                    | Multiple surgeries of the lumbar  |
|                                   | spine.                            |
+-----------------------------------+-----------------------------------+
| Lumbar spinal stenosis.           | Previous back surgery at the      |
|                                   | affected level.                   |
+-----------------------------------+-----------------------------------+
| Completed 6 months of             | Axial back pain only with no leg, |
| conservative therapy (e.g., P.T., | buttock, or groin pain.           |
| bracing, traction, systemic or    |                                   |
| injected medications).            |                                   |
+-----------------------------------+-----------------------------------+
| Leg, buttock, groin pain          | Fixed motor deficit.              |
| with/without back pain that can   |                                   |
| be relieved by flexion (e.g.,     |                                   |
| sitting in a chair).              |                                   |
+-----------------------------------+-----------------------------------+
| Qualifies for surgery at a single | Spondylolisthesis \>Grade I       |
| or double level L~1~ through L~5~ |                                   |
| (L~6~).                           |                                   |
+-----------------------------------+-----------------------------------+
| Has a score of 2.5 on the         | Cauda equina syndrome or          |
| Physical Function Scale in the    | neurogenic bowel/bladder          |
| Zurich Claudication               | dysfunction.                      |
| Questionnaire.                    |                                   |
+-----------------------------------+-----------------------------------+
| Signed Informed Consent           | Severe arterial insufficiency of  |
|                                   | the legs., peripheral vascular    |
|                                   | disease                           |
+-----------------------------------+-----------------------------------+
| Physically/mentally willing and   | Significant scoliosis. (Cobb \>   |
| able to comply.                   | 25^o^)                            |
+-----------------------------------+-----------------------------------+
| Lives nearby or willing to comply | Pregnancy, planning to become     |
| with postoperative evaluations    | pregnant                          |
+-----------------------------------+-----------------------------------+
| Sits for 50 minutes without pain  | Sustained pathologic fractures of |
|                                   | the vertebra or multiple          |
|                                   | fractures of the vertebra or hip. |
+-----------------------------------+-----------------------------------+
| Able to walk 50 feet or more      | Physically or mentally            |
|                                   | compromised.                      |
+-----------------------------------+-----------------------------------+
| Had narrowing of the lumbar       | Systemic disease that would       |
| spinal canal, nerve root          | affect the subject's welfare or   |
| canal/intervertebral foramen at 1 | overall outcome of the study.     |
| or 2 levels using CT scans/MRI    | Angina, RA, DM or other systemic  |
| where the area of spinal canal is | disease                           |
| \< 50% compared to segments above |                                   |
| and below                         |                                   |
+-----------------------------------+-----------------------------------+
|                                   | Immune suppression or receiving   |
|                                   | steroids in excess of usual       |
|                                   | doses.                            |
+-----------------------------------+-----------------------------------+
|                                   | Active systemic disease, such as  |
|                                   | AIDS, HIV, or active infection.   |
+-----------------------------------+-----------------------------------+
|                                   | Obesity (BMI \>40kg/m^2^).        |
+-----------------------------------+-----------------------------------+
|                                   | H/O narcotic abuse.               |
+-----------------------------------+-----------------------------------+
|                                   | involved in another               |
|                                   | investigational spinal study      |
+-----------------------------------+-----------------------------------+
|                                   | Allergy to any component of the   |
|                                   | device. Ti                        |
+-----------------------------------+-----------------------------------+
|                                   | Not able to sit for 50 minutes    |
+-----------------------------------+-----------------------------------+
|                                   | Not able to walk more than 50     |
|                                   | feet                              |
+-----------------------------------+-----------------------------------+
|                                   | Unremitting pain in any spinal    |
|                                   | position                          |
+-----------------------------------+-----------------------------------+
|                                   | Severe symptomatic lumbar         |
|                                   | stenosis at \> 2 levels           |
+-----------------------------------+-----------------------------------+
|                                   | Significant peripheral neuropathy |
|                                   | by NCVT (peroneal and sural       |
|                                   | nerves)                           |
+-----------------------------------+-----------------------------------+
|                                   | Acute denervation 2^o^ to         |
|                                   | radiculopathy as shown by EMG     |
+-----------------------------------+-----------------------------------+
|                                   | Osteoporosis of the spine or      |
|                                   | hip(DEXA and NOF def) \<2.5 SD    |
|                                   | below mean                        |
+-----------------------------------+-----------------------------------+
|                                   | Paget's dz at involved segment or |
|                                   | mets                              |
+-----------------------------------+-----------------------------------+
|                                   | Immunologically suppressed,       |
|                                   | received steroids \>1 mo in past  |
|                                   | 12 mos.                           |
+-----------------------------------+-----------------------------------+

Of note: patients with malignancies were not excluded. Three of the 8
patients who died in this study had diagnosis of malignancy. Patients
who use alcohol and or tobacco were not excluded.

**[Evaluations]{.underline}**

The protocol specifies that subjects will be evaluated preoperatively,
and postoperatively at 6 weeks, 6 months, and 12 months.

Baseline demographic and medical information will be documented at the
preoperative evaluation, including:

HPI: (date of onset, duration, treatments, medications, litigation
status, working status),

Past Medical History (prior surgeries), Physical Exam

Neurological assessment: sensory, motor, DTR, SLR, rSLR, ROM)

Radiographic evaluation (will include either MRI, CT, or myelogram).

Zurich Claudication Questionnaire

SF-36 Quality of Life Questionnaire

The radiographic review was completed by an independent radiologist.

CT or MRI were obtained and plain radiographs to document baseline:

-   Involved level

-   Status of the ligamentum flavum, lateral recess, foramina, facets

-   Comparison of spinal canals

-   Percentage of spondylolisthesis

-   Curvature of the spine

-   Angulation of the vertebrae

-   Anterior and posterior disc height

-   Distance between spinous processes

-   Foraminal height

The following measurements were taken on the AP and lateral radiographs
(Volume 1, Appendix L)

-   Percent Slip (Spondylolisthesis)

-   Curvature (Coronal Cobb Angle) of the Spine \[test for exclusion
    criterion\]

-   Anterior Angulation (Sagittal Cobb Angle) of the Spine \[vertebrae
    above and below implanted level(s)\]

-   Anterior Angulation (Sagittal Cobb Angle) of the Spine \[L1 to L5\]

-   Curvature (Coronal Cobb Angle) of the Spine \[for Case Report Form
    R\]

-   Anterior and Posterior Disc Height Measurements \[at the implanted
    levels\]

-   Distance Between the Spinous Processes

-   Distraction of the Intervertebral Foramina

## [Study Endpoints]{.underline} 

The [primary efficacy]{.underline} endpoints are:

Patient success rates

1\. Physical function measured by ZCQ at 24 months

2\. Symptom Severity measures by ZCQ at 24 months

3\. Patient satisfaction as measured by ZCQ at 24 months

4\. Maintenance of the distraction as measured by radiographs

The [Secondary Efficacy Endpoints]{.underline} are:

1\. SF-36 General Health Index

2\. Use of analgesic agents (narcotic, non-narcotic, and frequency)

3\. Time to laminectomy

4\. Leg and Back Pain: severity(none, mild, moderate, severe, 0-3) and
frequency(none, minimal, moderate, severe) measured

[Primary Safety Endpoints]{.underline}

1.  No additional surgery

2.  No dislodgement of the device

3.  Absence of device related complications

[Secondary Safety Variables include]{.underline}:

Complications (implant fracture, collapse, failure, migration, spinous
process fracture, pain at implant site, pain other, death, infection,
neurologic deficit, bleeding, dural tear, dural leak, epigastric
bleeding and all others)

**[Success/Failure Criteria]{.underline}**

The primary clinical and radiographic endpoints in the pivotal study are
the endpoints used in the definition of individual patient success.

1\. Improvement in Physical Function measured as a decrease of 0.5
points on the

ZCQ at 24 months,

2\. Improvement in Symptom Severity measured as a decrease of 0.5 points
on the

ZCQ at 24 months

3.  A report of satisfied or very satisfied on the Satisfaction domain
    of the ZCQ and

the device in proper position at 24 months , a score of \< 2.5

4\. Did not require additional surgery for lumbar stenosis

5\. Distraction must be maintained at 24 months (X-Stop group only)

6\. Implant must be positioned properly at 24 months (X-Stop group only)

7\. Absence of device related complications (X-Stop group only)

A patient in the implant group must satisfy all the above to be a
success; in the control group a patient must satisfy the first 4 to be
considered a success.

Note: The authors of the ZCQ estimated after validity analysis that
0.3-0.5 point change was significant. Although this value may be
statistically significant, it is not clear that 0.5 points on the Zurich
Claudication Questionnaire is clinically meaningful or comparable to
other assessment scales such as the Oswestry Disability Index.

**[Study success criterion]{.underline}**

The X-Stop™ group has a higher success rate than the control group with
the difference statistically significant (p\<0.05 two-sided).

**[Statistical predictions]{.underline}** *For complete statistical
analysis see statisticians report.*

> Based on the literature, the sponsor predicted a success rate of the
> control as 37.5% and for the investigational group 60%. A detailed
> comparison of outcomes of the control patients compared to outcomes
> reported in the literature is included in Appendix I in the PMA (Vol
> 1, pp 168-170).

# CLINICAL DATA FOR THE WELDED X-STOP™ 

# PIVOTAL TRIAL

# Study Description

The study was conducted at 9 investigational sites by 11 surgeons in a
total of 229 enrolled and randomized patients. These Investigators and
co-investigators and devices used are listed in Volume 1,Appendix D,
p.155. There were 2 surgeons who implanted the majority of the devices,
and 5 of the investigators implanted the device in 10 or more patients.
Each was a trained neurosurgeon or orthopaedic surgeon. The study was
initiated on June 6, 2000 and the last patient was treated on July 23,
2001. The date of database closure was December 19, 2003 Therefore all
patients have reached their 24 month follow-up postoperative
anniversary. The sponsor states that due to the rapid rate of subject
enrollment, there was no significant overlap between the due date of the
last enrolled patient's 24 month follow-up visit and the due date of the
first patients' annual follow-up visits per the requirement stated
above. Therefore, the Sponsor did not require annual follow-up visits
beyond the 24 month time point.

Patients were selected based on the presence of clinical signs and
symptoms of intermittent neurogenic Claudication, confirmed by
radiographic evidence of lumbar spinal stenosis. (see
inclusion/exclusion criteria above)

The protocol did not define what criteria were to be used in either
group to proceed to laminectomy or whether in the control group to
administer additional epidural injections. Since it was up to surgeons
to decide when the subsequent epidural injections were to take place,
there is a potential bias in deciding what subsequent treatment the
patients should get for the study. In addition, some patients in the
investigational (X-stop) group got the control (epidural injection for
pain) rather than proceeding to laminectomy.

These decisions were left to the investigator and were apparently not
applied in a standard fashion across all the sites or groups. In
amendment 3, the sponsor provided an explanation of what principles,
though not specifically written in the protocol were applied to
determine the appropriate course of treatment following the initial
injection:

-   If the initial injection resulted in relief of symptoms for a
    satisfactory period of time and the patient was willing to undergo a
    repeat injection, then a repeat injection was performed upon return
    or worsening of symptoms beyond a level tolerable to the patient.
    Relief of symptoms for a month was generally considered a
    satisfactory response to warrant another injection if the patient
    agreed.

-   A partial response to the epidural steroid injection with residual
    symptoms could warrant a repeat injection if the patient remained
    symptomatic at least 2 to 3 weeks after the first injection.

-   Patients were generally limited to a series of 3 injections, 1 to 3
    months apart, or 4 injections in a 12 month period.

-   If inadequate or no relief of symptoms was obtained following the
    initial injection, repeat injections were not given.

-   If conservative treatment and epidural steroid injections resulted
    in unsatisfactory relief of symptoms and the investigator felt no
    other options were available to the patient, laminectomy surgery was
    offered to the patient.

The study protocol did not specify these criteria, but allowed for
investigators to follow these standard medical practices. Although the
sponsor does point out the lack of consensus in the literature, for a
clinical trial, all the patients should be treated equally according to
a pre-described protocol, to avoid any confounding factors that would
confuse the study outcomes. The decision to leave the frequency and
timing of repeat injections to the discretion of the investigator, It
appears that the patients were not all treated the same within a group
or between groups when deciding who had symptoms requiring surgical
decompression**.** For example, the X-stop patient with progressing pain
(1022) who required serial nerve root injections, was not operated on,
however the patient 0706 was, but not until 66 days following injection
despite progressive neurologic deficit pain and loss of sexual function
less than 2 weeks after epidural injection. In addition, in the X-stop
group, eight patients had pain injections after the implantation of the
device, while patients in the control treatment group had varying
numbers of epidural injections; 32 patients had only one injection while
some had more than 4 injections There is still not good evidence that
success in those patients in the X stop group receiving an injection
after the implantation of the device could be discerned between
temporary relief from the injection or from decompression by the device.

# Patient Populations

A total of 229 patients were enrolled and randomized into the study. Of
these, 38 (16.6%; 14 investigational, 24 control) patients withdrew or
were excluded prior to receiving treatment leaving 100 patients
receiving the X-stop ™ and 91 Control patients to complete the
randomization portion of the study.\[these patients are defined in Table
4 and section 6.2 , page 26.\] Fifteen additional patients were
considered "discontinued" leaving a total of 176 patients in the
"evaluable" population according to the sponsor.

Of the original 191 treated patients, 146 patients (76%) completed
follow-up at 24 months without secondary surgical intervention. Thirty
patients had a subsequent laminectomy because of continuing symptoms
prior to the 24 month evaluation; 6 in the X-stop group and 24 in the
control group. The following table summarizes patient follow-up.

# Patient Accounting (Vol. 1 Tables 5 & 6 , page 28, Vol 7, Table 1)

<table style="width:100%;">
<colgroup>
<col style="width: 14%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2"><strong>Preop</strong></td>
<td colspan="2"><strong>Intraop</strong></td>
<td colspan="2"><strong>6 Weeks</strong></td>
<td colspan="2"><strong>6 months</strong></td>
<td colspan="2"><strong>12 months</strong></td>
<td colspan="2"><strong>24 months</strong></td>
</tr>
<tr class="even">
<td><h5 id="section-2"></h5></td>
<td><strong>Inv</strong></td>
<td><strong>Con</strong></td>
<td><strong>Inv</strong></td>
<td><strong>Con</strong></td>
<td><strong>Inv</strong></td>
<td><strong>Con</strong></td>
<td><strong>Inv</strong></td>
<td><strong>Con</strong></td>
<td><strong>Inv</strong></td>
<td><strong>Con</strong></td>
<td><strong>Inv</strong></td>
<td><strong>Con</strong></td>
</tr>
<tr class="odd">
<td><h5 id="theoretical-1">Theoretical</h5></td>
<td>114</td>
<td>115</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
</tr>
<tr class="even">
<td><h5 id="deaths-cumulative">Deaths, (cumulative)</h5></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>1 (2)</td>
<td>1 (1)</td>
<td>(2)</td>
<td>1(2)</td>
<td>2 (4)</td>
<td>2 (4)</td>
</tr>
<tr class="odd">
<td><strong>Failures<sup>2</sup>, (cumulative)</strong></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>2</td>
<td>3</td>
<td>13</td>
<td>5</td>
<td>17</td>
<td>(7)</td>
<td>25</td>
</tr>
<tr class="even">
<td><strong>Expected<sup>3</sup></strong></td>
<td></td>
<td></td>
<td>99</td>
<td>91</td>
<td>98</td>
<td>89</td>
<td>95</td>
<td>77</td>
<td>93</td>
<td>72</td>
<td>89</td>
<td>63</td>
</tr>
<tr class="odd">
<td><strong>Evaluated*</strong></td>
<td></td>
<td></td>
<td>99</td>
<td>91</td>
<td>94</td>
<td>70</td>
<td>88</td>
<td>64</td>
<td>88</td>
<td>69</td>
<td>88</td>
<td>58</td>
</tr>
<tr class="even">
<td><h5 id="lost-1">Lost</h5></td>
<td>14*</td>
<td>24*</td>
<td>0</td>
<td>0</td>
<td>4</td>
<td>19</td>
<td>7</td>
<td>13</td>
<td>5</td>
<td>3</td>
<td>1</td>
<td>5</td>
</tr>
<tr class="odd">
<td><h5 id="actual-follow-up">Actual % Follow-up*</h5></td>
<td>88%</td>
<td>79%</td>
<td></td>
<td></td>
<td>96%</td>
<td><strong>78.7%</strong></td>
<td>92.6%</td>
<td><strong>83%</strong></td>
<td>95%</td>
<td>96%</td>
<td>98.8%</td>
<td>92%</td>
</tr>
</tbody>
</table>

1.  Theoretical = Patients enrolled in the study

2.  For example, device removals, replacement, laminectomy

3.  Expected = Theoretical -- (Deaths + Failures)

\* This number includes those patients who were evaluated outside the
prescribed follow-up windows

\*\* These patients were enrolled but not treated

At 24 months, the goal of 85% follow-up was obtained for the patients
who were treated*.* However the patients available for determining
efficacy of the treatment was less, particularly in the control group
(approximately 60%). In addition, this table accounts for all patients
not those that had data available for efficacy determination.

**[Patients enrolled but not treated]{.underline}**

Thirty-eight patients (14 investigational, 24 control) enrolled and
randomized in this trial did not receive treatment. Of these, only 2
were excluded due to the study inclusion criteria. The majority of the
remainder "voluntarily withdrew from the study (8 and 19 patients
respectively). This reduces the number of patients in the study by 15%in
the investigational group and 26% in the control group.

**[Discontinued patients]{.underline}**

Of the 191 patients treated after enrollment, 15 patients were
discontinued leaving 176 according to the sponsor as being considered
"evaluable" in the sponsor's analysis at 24 months for effectiveness.
The discontinued patients included patients who died, patients in whom
the X-stop was removed, a patient in whom an epidural injection was
aborted and 6 patients (one X-stop treated) who withdrew from the study.
Three of the control patients had exacerbations of medical problems that
preceded their withdrawal. One got better and one could not tolerate
treatment. Two additional patients in the X-stop group withdrew from the
study but completed the SF-36 and ZCQ at 24 months.

The sponsors provide the patient status (success or failure) at the time
of withdrawal in Amendment 3.

**[Protocol Deviations]{.underline}**

Protocol deviations occurred both at enrollment, and after treatment was
initiated.

There were 7 patients who were protocol deviations at enrollment, 4 in
the control, and 3 in the X-stop group. Three X-stop and one control
patients did not meet the inclusion criteria.

One X-stop and two control patient did not meet the intended use with
stenosis at a level outside the intended use(L5-S1). Five of these were
treatment failures, One X-stop patient was a treatment success, and one
patient was lost to follow-up at 6 weeks. On table 8.8, the sponsor
states that there were 3/5 patients in the X-stop group who were
successes while none of the epidural patients were a success. This is
inconsistent with what is noted in the executive summary in Volume 1. In
addition, Table 1.4 (Vol 7 p. 1640) lists 7 X-stop and 6 Control
patients in this category. In table 1.4, success is inconsistently
defined, however 3 of the X stop protocol deviation patients were
reported as failures, 1 success and 3 of the control protocol deviations
were considered failures, (1 additional died) at 24 months. Again this
does not correspond to the statement in the executive summary.

Eight patients were treated with one or more epidural or nerve root
blocks injections post operatively. Six of these patients were
considered failures at 24 months. All of these patients cannot be
compared to those who followed the protocol. Since they required
additional treatment they should be considered failures. Again these
patients should not be included in the final comparative analysis.

# Data Accounting

The effectiveness data available for review for the X-STOP and Control
treatment groups were 92 and 81 patients. The following tables list the
data accountability for the primary and secondary effectiveness
endpoints for the two groups.

**Data Accounting Primary endpoints**

<table>
<colgroup>
<col style="width: 20%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2"><strong>Preop</strong></td>
<td colspan="2"><strong>6 Weeks</strong></td>
<td colspan="2"><strong>6 months</strong></td>
<td colspan="2"><strong>12 months</strong></td>
<td colspan="2"><strong>24 months</strong></td>
</tr>
<tr class="even">
<td><h5 id="enrolled">Enrolled</h5></td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
</tr>
<tr class="odd">
<td>ZQC symptom severity</td>
<td>100</td>
<td>91</td>
<td>94</td>
<td>70</td>
<td>88</td>
<td>64</td>
<td>88</td>
<td>69</td>
<td>86</td>
<td>56</td>
</tr>
<tr class="even">
<td>ZCQ physical function</td>
<td>100</td>
<td>91</td>
<td>94</td>
<td>69</td>
<td>88</td>
<td>63</td>
<td>87</td>
<td>68</td>
<td>86</td>
<td>56</td>
</tr>
<tr class="odd">
<td>ZCQ satisfaction</td>
<td><strong>-</strong></td>
<td><strong>-</strong></td>
<td>94</td>
<td>71</td>
<td>91</td>
<td>77</td>
<td>93</td>
<td>85</td>
<td>93</td>
<td>78</td>
</tr>
<tr class="even">
<td>No additional surgery</td>
<td>-</td>
<td>-</td>
<td></td>
<td>-</td>
<td></td>
<td>-</td>
<td></td>
<td>-</td>
<td></td>
<td>-</td>
</tr>
<tr class="odd">
<td>Maintenance of distraction</td>
<td></td>
<td>-</td>
<td>95-98</td>
<td>-</td>
<td>82-88</td>
<td>-</td>
<td>88-89</td>
<td></td>
<td>84/100</td>
<td>-</td>
</tr>
<tr class="even">
<td>No dislodgement of device</td>
<td></td>
<td>-</td>
<td>95-98</td>
<td>-</td>
<td>85-88</td>
<td>-</td>
<td>88-89</td>
<td>-</td>
<td>84/100</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Absence of device related AE</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
<td>100</td>
<td>91</td>
</tr>
<tr class="even">
<td>Overall Success</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>-</td>
<td>92</td>
<td>81</td>
</tr>
</tbody>
</table>

The sponsor states that there were 93 patients with 2 year data in the
X-Stop group and 81 patients with 2 year data in the control group.

Data Accounting Secondary Endpoints

+-----------------+-------+-------+-------+-------+-------+-------+
|                 | **Pr  |       | **6   |       | **24  |       |
|                 | eop** |       | We    |       | mon   |       |
|                 |       |       | eks** |       | ths** |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| ####            | X     | Co    | X     | Co    | X     | Co    |
| #  {#section-3} | -stop | ntrol | -stop | ntrol | -stop | ntrol |
+-----------------+-------+-------+-------+-------+-------+-------+
| ##### Enrolle   | **    | *     | **    | *     | **    | *     |
| d {#enrolled-1} | 100** | *91** | 100** | *91** | 100** | *91** |
+-----------------+-------+-------+-------+-------+-------+-------+
| **Back Pain**   | 100   | 90    | 98    | 72    | 84    | 54    |
+-----------------+-------+-------+-------+-------+-------+-------+
| **Leg pain**    | 100   | 90    | 98    | 72    | 84    | 54    |
+-----------------+-------+-------+-------+-------+-------+-------+
| **SF-36 PCS**   | 100   | 90    | 91    | 68    | 82    | 53    |
+-----------------+-------+-------+-------+-------+-------+-------+
| **SF-36 MCS**   | 100   | 90    | 91    | 68    | 82    | 53    |
+-----------------+-------+-------+-------+-------+-------+-------+
| *               | 100   | 90    | 84    | 0     | 82    | 49    |
| *Radiographic** |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| **ROM**         | 100   | 90    | 98    | 72    | 83    | 54    |
+-----------------+-------+-------+-------+-------+-------+-------+
| **Leg pain      | 100   | 90    | 98    | 72    | 84    | 54    |
| present**       |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| **Clinical      | 100   | 90    | 98    | 72    | 83/84 | 54    |
| evaluations**   |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+
| *               | 100   | 90    | 98    | 72    | 83    | 54    |
| *Medications/** |       |       |       |       |       |       |
|                 |       |       |       |       |       |       |
| **work          |       |       |       |       |       |       |
| status/**       |       |       |       |       |       |       |
|                 |       |       |       |       |       |       |
| **post op       |       |       |       |       |       |       |
| therapy**       |       |       |       |       |       |       |
+-----------------+-------+-------+-------+-------+-------+-------+

#  {#section-4}

#  {#section-5}

# Demographics

The two treatment groups were very similar demographically, and there
were no statistically significant (p\< 0.05) differences for any of the
demographic covariates.

+------------------------+----------------------+----------------------+
| **Description of the   |                      |                      |
| Study Populations**    |                      |                      |
+------------------------+----------------------+----------------------+
|                        | **X-STOP**           | **CONTROL**          |
+------------------------+----------------------+----------------------+
| Number of patients     | **100**              | **91**               |
+------------------------+----------------------+----------------------+
| Men / Women            | 57/43                | 46/45                |
+------------------------+----------------------+----------------------+
| Age, year (mean)       | 50-94 (70)           | 50-88 (69.1)         |
+------------------------+----------------------+----------------------+
| Height (in)            | 56-74 (67.3)         | 56-75 (66.3)         |
+------------------------+----------------------+----------------------+
| Weight (lbs)           | 105-265 ( 177.1)     | 98-293 (180.2)       |
+------------------------+----------------------+----------------------+
| Duration of symptoms   | 20                   | 15                   |
| 6-12 mo                |                      |                      |
|                        | 18                   | 16                   |
| 1-2 years              |                      |                      |
|                        | 57                   | 55                   |
| \> 2 years             |                      |                      |
+------------------------+----------------------+----------------------+

Keep in mind that patients in this study had already failed conservative
treatment including epidural injections and had symptoms for more than 2
years prior to entering the study and in the control group, patients
were offered further treatment that had already proven to be
ineffective. There were no statistically significant differences in
co-morbid characteristics between groups (p\<0.05).

+------------------------+----------------------+----------------------+
| ###### Comorbidity     |                      |                      |
+------------------------+----------------------+----------------------+
| #####  {#section-6}    | **X-STOP**           | **Control**          |
+------------------------+----------------------+----------------------+
| Patients               | 100                  | 91                   |
+------------------------+----------------------+----------------------+
| Worker's Compensation: | 4                    | 2                    |
| Yes                    |                      |                      |
+------------------------+----------------------+----------------------+
| ##### Preo             | 33                   | 27                   |
| p Work Status: Working |                      |                      |
+------------------------+----------------------+----------------------+
| ##### Preop Wo         | 67                   | 64                   |
| rk Status: Not Working |                      |                      |
|                        | 7                    | 11                   |
| ##### \                |                      |                      |
| # due to back symptoms |                      |                      |
+------------------------+----------------------+----------------------+

The majority of patients in both groups (about 60%) were retired and not
working. Smoking and alcohol use was not evaluated in the covariate
analysis.

# Preoperative Patient Characteristics

The sponsor states that there were no statistically significant (p\<
0.05) differences between the treatment groups related to the
preoperative medical conditions. The two groups were closely matched in
most preoperative evaluations and by medical history showing that
randomization was effective based on the demographic variables analyzed.

The majority of patients in both groups had multiple coexisting
variables noted on radiographs. These include a thickened ligamentum
flavum, narrowed lateral recess, hypertrophied facets, central canal
narrowing (Over 90% in both groups) and all patients had spinal canal
smaller by 50%, and spondylolisthesis. In both groups, there was more
than one level involved (30% in the X-stop and 10% in the control). This
brings up the question whether it is a appropriate to treat just one
level in cases where the ligamentum flavum is thickened and the spinal
canal is decreased by 50% with more than one level involved.

Approximately 3% of the population had prior surgery, but about ¾ of the
population had used medications for pain. **The X-Stop group had a
higher percentage of epidural injection treatments as compared to the
control group which reached statistical significance**. Details of prior
treatments in both groups of patients are found in Vol. 1, page 36,
Table 14.

As per the inclusion criteria, all except one patient had leg pain; over
50% had bilateral leg pain. Few of the patients had a bowel or bladder
symptoms or motor deficit, but most had reduced reflexes and a sensory
deficit (Volume 1, Table 17, p.37) There was no statistical difference
in co-morbidities between the two treatment groups. Cardiovascular,
musculoskeletal, endocrine and respiratory disorders were the most
frequent categories of co-morbidities.

Baseline Evaluations

+------------------------+----------------------+----------------------+
| **Baseline             |                      |                      |
| Evaluations**          |                      |                      |
+------------------------+----------------------+----------------------+
| #####  {#section-7}    | **X-STOP**           | **Control**          |
+------------------------+----------------------+----------------------+
| ##### Patients         | 100                  | 91                   |
+------------------------+----------------------+----------------------+
| ####                   | 3.14                 | 3.10                 |
| # ZCQ Symptom Severity |                      |                      |
+------------------------+----------------------+----------------------+
| ZCQ Physical Function  | 2.48                 | 2.48                 |
+------------------------+----------------------+----------------------+
| SF-36 PCS              | 27.8                 | 28.9                 |
+------------------------+----------------------+----------------------+
| SF-36 MCS              | 51.5                 | 50.6                 |
+------------------------+----------------------+----------------------+
| Back Pain Score (mean  | 0.5/0.49             | 0.69/67              |
| ) frequency/severity   |                      |                      |
|                        | 1.79/1.74            | 1.99/1.93            |
| > Sitting              |                      |                      |
| >                      | 1.85/1.78            | 2.11/2.14            |
| > Standing             |                      |                      |
| >                      |                      |                      |
| > Walking              |                      |                      |
+------------------------+----------------------+----------------------+
| Leg Pain Score (mean)  | 0.39/0.38            | 0.36/0.37            |
|                        |                      |                      |
| frequency/severity     | 2.34/2.27            | 2.24/2.24            |
|                        |                      |                      |
| > Sitting              | 2.58/2.53            | 2.57/2.59            |
| >                      |                      |                      |
| > Standing             |                      |                      |
|                        |                      |                      |
| Walking                |                      |                      |
+------------------------+----------------------+----------------------+
| ROM                    | 78.9                 | 77.4                 |
|                        |                      |                      |
| > Flexion              | 11.9                 | 14.7                 |
| >                      |                      |                      |
| > Extension            | 19.9                 | 21.6                 |
| >                      |                      |                      |
| > Lateral              | 22.1                 | 23.0                 |
| >                      |                      |                      |
| > Rotation             |                      |                      |
+------------------------+----------------------+----------------------+

There was no statistically significant differences in baseline scores
between the two groups, except for back and leg pain. In every case, the
X-stop group had less *mean* back pain when sitting, standing and
walking in both frequency and severity than the control group. However,
in every case, the X-stop group had less mean leg pain when sitting,
standing and walking in both frequency and severity than the control
group. The severity of back pain while walking was significantly
different between the two groups.

In both groups, almost all patients had leg and back pain relieved in
flexion.

**[RESULTS]{.underline}**

# Treatments

A number of patients received conscious IV sedation in addition to local
anesthesia and/or general anesthesia.

+------------------------------------+---------------------------------+
| #####  {#section-8}                | **X-Stop**                      |
+------------------------------------+---------------------------------+
| [Anesthesia]{.underline}           | 1                               |
|                                    |                                 |
| General anesthesia only            |                                 |
+------------------------------------+---------------------------------+
| Local anesthesia only              | 30                              |
+------------------------------------+---------------------------------+
| Conscious IV sedation only         | 46                              |
+------------------------------------+---------------------------------+
| Local anesthesia + conscious IV    | 21                              |
| sedation                           |                                 |
+------------------------------------+---------------------------------+
| Local anesthesia + general         | 1                               |
| anesthesia                         |                                 |
+------------------------------------+---------------------------------+
| Local anesthesia + general         | 1                               |
| anesthesia + conscious IV sedation |                                 |
+------------------------------------+---------------------------------+
| **TOTAL**                          | **100**                         |
+------------------------------------+---------------------------------+
| ##### Mean Operative Time (min)    | 53.6                            |
+------------------------------------+---------------------------------+
| Mean EBL (ml)                      | 46.4                            |
+------------------------------------+---------------------------------+
| LOS (\<1days)                      | 96                              |
|                                    |                                 |
| > 1 day                            | 3                               |
| >                                  |                                 |
| > 3 days                           | 1                               |
+------------------------------------+---------------------------------+
| Levels treated                     | 64                              |
|                                    |                                 |
| > 1 level                          | 36                              |
| >                                  |                                 |
| > 2 levels                         |                                 |
+------------------------------------+---------------------------------+
| Treatment Levels:                  | 3                               |
|                                    |                                 |
| > L~2-3~                           | 43                              |
| >                                  |                                 |
| > L~3-4~                           | 89                              |
| >                                  |                                 |
| > L~4-5~                           | 1                               |
| >                                  |                                 |
| > L~5-~S~1~                        |                                 |
+------------------------------------+---------------------------------+

The majority of patients (80) were given narcotics at discharge,7
patients were discharged with NSAIDs (1), antibiotics (16) or no
medications (6). The single level operative time (51 min) and blood loss
(40cc) were less than those of the two level (58 minutes, 58 cc) All X
STOP patients enrolled in the Pivotal Trial received pretreatment
intravenous (IV) antibiotics prior to implantation.

**[Control Patient Treatments]{.underline}**

> **Number of Epidural Injections Given to Patients in Control Group**

+--------------------+--------+------+--------+---------+--------------+
| **\# of Injections | **     |      | *      | **\#    | **Mean \# of |
| per Patient**      | Number |      | *Total | Surg    | Days to      |
|                    | of     |      | \# of  | eries** | Surgery      |
|                    | Pati   |      | Inject |         | (Range)**    |
|                    | ents** |      | ions** | *       |              |
|                    |        |      |        | *Perfor |              |
|                    |        |      |        | med\*** |              |
+--------------------+--------+------+--------+---------+--------------+
|                    | **(    | *    |        |         |              |
|                    | n/N)** | *%** |        |         |              |
+--------------------+--------+------+--------+---------+--------------+
| Initial Treatment  | 91/91  | 10   | 91     | 10      | 189 (56-541) |
|                    |        | 0.0% |        |         |              |
| (1 injection only) |        |      |        |         |              |
+--------------------+--------+------+--------+---------+--------------+
| *Following Initial |        |      |        |         |              |
| Treatment*         |        |      |        |         |              |
+--------------------+--------+------+--------+---------+--------------+
| 1                  | 22/91  | 2    | 22     | 9       | 264 (103 --  |
|                    |        | 4.2% |        |         | 507)         |
+--------------------+--------+------+--------+---------+--------------+
| 2                  | 21/91  | 2    | 42     | 3       | 386 (123 --  |
|                    |        | 3.1% |        |         | 465)         |
+--------------------+--------+------+--------+---------+--------------+
| 3                  | 8/91   | 8.8% | 24     | 0       | N/A          |
+--------------------+--------+------+--------+---------+--------------+
| 4 or more          | 8/91   | 8.8% | 37     | 2       | 631 (586 --  |
|                    |        |      |        |         | 676)         |
+--------------------+--------+------+--------+---------+--------------+
| **Total**          |        |      | *      | **24**  |              |
|                    |        |      | *216** |         |              |
+--------------------+--------+------+--------+---------+--------------+

\* Number of patients who ultimately underwent laminectomy surgery.

> Twenty-two patients in the control group received 1 additional
> injection following the initial treatment, 9 of whom went on to a
> laminectomy. The mean time to surgery in this group was 264 days. With
> increasing numbers of injections per patient, the average time to
> surgery increased, to 631 days for patients who received 4 or more
> injections.
>
> Those patients who responded positively to initial injections received
> additional injections when symptoms warranted treatment, thereby
> extending the course of their conservative therapy. Patients who did
> not obtain adequate symptom relief from injections received fewer
> total injections and proceeded to laminectomy surgery more rapidly.
>
> Of the 91 patients, 59 patients had [\>]{.underline}2 injections;
> however 32 patients had only one injection. Second injections were
> left to the discretion of the investigator. The protocol does not
> stipulate what criteria qualified patients for additional injections.
> This practice may have introduced some potential bias in the decision
> for progressing to laminectomy treatment.

# Effectiveness Evaluation Overview

+-------------+------+------+------+------+------+------+------+------+
| #####  {    | #    |      | **6  |      | **12 |      | **24 |      |
| #section-9} | #### |      | mont |      | mont |      | mont |      |
|             |  6 w |      | hs** |      | hs** |      | hs** |      |
|             | eeks |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| ###  {#     | ##   | **C  | ##   | **C  | ##   | **C  | ##   | **C  |
| section-10} | # X- | ontr | # X- | ontr | # X- | ontr | # X- | ontr |
|             | STOP | ol** | STOP | ol** | STOP | ol** | STOP | ol** |
+-------------+------+------+------+------+------+------+------+------+
| #           | ###  | ###  | 95   | 77   | 93   | 72   | ###  | **   |
| ## Number p | 99 { | 91 { |      |      |      |      | 83 { | 54** |
| atients per | #sec | #sec |      |      |      |      | #sec |      |
|  accounting | tion | tion |      |      |      |      | tion |      |
|             | -11} | -12} |      |      |      |      | -13} |      |
+-------------+------+------+------+------+------+------+------+------+
| **Zurich    |      |      |      |      |      |      |      |      |
| C           |      |      |      |      |      |      |      |      |
| laudication |      |      |      |      |      |      |      |      |
| Questi      |      |      |      |      |      |      |      |      |
| onnaire\*** |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **Symptom   | 8    | 3    | 7    | 3    | 7    | 3    | 7    | 2    |
| Severity**  | 4/95 | 7/72 | 5/91 | 8/77 | 6/93 | 8/86 | 3/93 | 6/81 |
+-------------+------+------+------+------+------+------+------+------+
| *           | 8    | 3    | 7    | 3    | 7    | 3    | 6    | 3    |
| *Physical** | 0/95 | 2/71 | 4/91 | 1/76 | 6/92 | 6/85 | 8/93 | 0/81 |
+-------------+------+------+------+------+------+------+------+------+
| **Patient   | 8    | 3    | 7    | 3    | 7    | 3    | 6    | 2    |
| Sat         | 4/94 | 7/71 | 0/91 | 2/77 | 2/93 | 4/85 | 8/93 | 8/78 |
| isfaction** |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **Overall   | 5    | 8/71 | 5    | 7/76 | 5    | 1    | 4    | 4/81 |
| ZCQ         | 0/94 |      | 2/91 |      | 7/92 | 0/86 | 5/93 |      |
| success**   |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| *           |      |      |      |      |      |      | 8    | n/a  |
| *Maintained |      |      |      |      |      |      | 0/84 |      |
| Di          |      |      |      |      |      |      |      |      |
| straction** |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **Overall   | 5    | 8/71 | 5    | 7/76 | 5    | 1    | 4    | 4/81 |
| Success     | 0/94 |      | 2/91 |      | 7/92 | 0/86 | 2/92 |      |
| w/di        |      |      |      |      |      |      |      |      |
| straction** |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
|             |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **Leg pain  | 5    | 6    | 5    | 5    | 3    | 5    | 3    | 4    |
| present**   | 1/98 | 9/72 | 0/88 | 5/63 | 7/89 | 9/65 | 0/84 | 6/54 |
+-------------+------+------+------+------+------+------+------+------+
| **Painful   | 1    | 2    | 5/87 | 2    | 7/89 | 2    | 8/83 | 1    |
| rotation**  | 1/98 | 3/71 |      | 3/62 |      | 0/65 |      | 3/54 |
+-------------+------+------+------+------+------+------+------+------+
| **Reflexes  | 6    | 4    | 5    | 4    | 6    | 3    | 5    | 3    |
| abnormal**  | 1/98 | 5/72 | 5/88 | 1/63 | 0/89 | 8/65 | 6/83 | 6/54 |
+-------------+------+------+------+------+------+------+------+------+
| **SLR       | 6/98 | 1    | 4/88 | 1    | 2/89 | 2    | 5/83 | 1    |
| pain**      |      | 6/72 |      | 4/63 |      | 1/65 |      | 8/54 |
+-------------+------+------+------+------+------+------+------+------+
| **Sensory   | 1    | 1    | 1    | 1    | 1    | 1    | 1    | 1    |
| Deficit**   | 5/98 | 6/72 | 8/88 | 3/63 | 2/89 | 2/65 | 6/84 | 2/54 |
+-------------+------+------+------+------+------+------+------+------+
| **Muscle    | 1/98 | 3/72 | 2/88 | 0    | 3/89 | 2/65 | 3/84 | 3/54 |
| Strength    |      |      |      |      |      |      |      |      |
| impaired**  |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **Babinski  | 1    | 8/72 | 7/88 | 8/63 | 7/89 | 7/65 | 7/84 | 7/54 |
| reflex      | 0/98 |      |      |      |      |      |      |      |
| present**   |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **SF-36**   |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **SF-36     | 39.5 | 31.1 | 40.1 | 31.9 | 41.1 | 32.6 | 38.6 | 31.2 |
| PCS**       |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **SF-36     | 55.6 | 51.1 | 54.7 | 50.4 | 54.8 | 49.9 | 54.3 | 32.5 |
| MCS**       |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| **Range of  |      |      |      |      |      |      |      |      |
| Motion      |      |      |      |      |      |      |      |      |
| (mean)**    |      |      |      |      |      |      |      |      |
+-------------+------+------+------+------+------+------+------+------+
| Flexion     | 78.9 | 77.4 | 82.6 | 78.4 | 82.3 | 76.3 | 82   | 78.3 |
+-------------+------+------+------+------+------+------+------+------+
| Extension   | 11.9 | 14.7 | 18   | 16.4 | 18   | 15.9 | 17.2 | 18.1 |
+-------------+------+------+------+------+------+------+------+------+
| Lateral     | 19.9 | 21.6 | 23.2 | 22.8 | 22   | 21   | 22.7 | 21.6 |
+-------------+------+------+------+------+------+------+------+------+
| Rotation    | 22.1 | 23.0 | 27.8 | 28.4 | 26.3 | 25.6 | 27.2 | 25.5 |
+-------------+------+------+------+------+------+------+------+------+

\* The denominator includes all patients seen at each follow-up + those
patients defined as treatment failures including those who had partial
data that indicated failure in any assessments. Missing data

included those with partial data that was not considered a failure, and
these patients do not appear in the numerator or denominator of these
results. (Thus, the denominators do not match with the accountability
tables.)

[**Primary Effectiveness Endpoint**]{.underline}

**[Zurich Claudication Questionnaire: Symptom Severity and Physical
Function]{.underline}**

The sponsor states that a greater percentage of patients experienced a
clinically significant improvement in symptom severity and physical
function. By the sponsor's calculations, there are 56 and 53 successful
patients in the X-Stop group and only 15 and 12 successful patients
respectively in the control group for this endpoint. At 24 months, the
mean absolute values for symptom severity are similar for the X-stop
group (2.14) and the control group (2.84) ,but somewhat different for
physical function (1.7 and 2.25 respectively). Patient satisfaction was
reduced over time in both groups but more so in the control group (1.70
and 2.53 respectively). A larger percentage of patients were successful
in both groups at early time points (until 12 months) and by 24 months
the number of patients who were successful had decreased by about 15% in
the symptom severity score and about 10% in the function score for the
X-stop, although the control group did not change much from the 6 week
time point in function. This is not explained by the number of patients
who had laminectomies or device removals. In addition, it is not clear
why in the control group the "N" increases. All of these factors affect
the rates as reported.

In the Physical Function domain, the absolute success rate change in the
X STOP group was lower at all time points except for the 24-month time
point where the absolute success rates were 10.4% and 4.9% in the X STOP
and control groups, respectively. The relative change in the X STOP
group was lower than in the control group at each time point including
the 24-month time point

**The Absolute and Relative Change Success Rates for the X STOP and
Control Groups -- Physical F**unction

  -------------- ------------ ----------- --------- --------- ------------- ----------- --------- ---------
  **Interval**   **X-stop**                                   **Control**                         

                 **N**        **%         **ABS     **REL     **N**         **%         **ABS     **REL
                              Success**   Δ^\*^**   Δ^\*^**                 Success**   Δ^\*^**   Δ^\*^**

  6 wk           95           67.4%       \-        \-        71            19.7%       \-        \-

  6 mo           91           62.6%       4.7%      7.0%      76            11.8%       7.9%      39.9%

  12 mo          92           67.4%       0.0%      0.0%      85            18.8%       0.9%      4.5%

  24 mo          93           57.0%       10.4%     15.4%     81            14.8%       4.9%      24.9%
  -------------- ------------ ----------- --------- --------- ------------- ----------- --------- ---------

The terms ABS Δ and REL Δ represent the absolute and relative success
rate change scores from the 6‑week time point respectively

**[Zurich Claudication Questionnaire: Patient
Satisfaction]{.underline}**

The patients who were satisfied with the result decreased in both groups
over time but the number of patients who were satisfied with the result
decreased by a factor of 2 in the X-stop group by 24 months even though
the numbers of satisfied patients were greater in the X-stop group
overall. These results suggest that in about 15% of patients the
treatment by X-stop offered only temporary relief, and /or the
population who should receive this device was not adequately defined.

Overall success based on the ZCQ is significantly greater in the X-stop
group. It appears that the X-stop is effective to about a year and then
begins to decline in efficacy toward baseline.

The *mean* improvement for the X-stop group was greater than the *mean*
improvement in the control group in the symptom severity and physical
function scores. The mean improvement was 0.99 and 0.76 for the X-stop
and 0.17 and 0.08 for the control group respectively. The number of
patients in the X-stop evaluated were also higher than the number of
patients evaluated in the control group. By the sponsors calculation the
improvement in symptom severity was almost 25% and in physical function
was 19%. In the control group there was a 4.3% improvement in symptom
severity and 2% in physical function.

**[Clinical Evaluations]{.underline}**

There was a significant difference in the patients with leg pain between
the remaining X-stop and control patients who did not go on to have
laminectomy, with the 30/84 patients in the X-stop and 46/54 control
patients at 24 months having leg pain still present. Although this is
statistically significant, based on the treatment variability for the
control group, the clinical significance of this is not clear.

At 24 months and compared to preoperative values, there was a
significant difference between the X-stop and control groups with
respect to the SLR and femoral stretch test.(Patients in both groups
showed improvement from preoperative status: Pre operative SLR 21/100
compared to 4/84 patients in the X-Stop group had a positive SLR, while
in the control group 20/90 at enrollment and 10/ 54 had a positive SLR.

There were no significant differences in the mean range of motion,
reflexes, or pulses evaluations at 24 months postoperatively between the
X-stop and control groups.

**[Missing data]{.underline}**

At 24 months, 1 X-Stop patient and 5 control patients did not have
follow-up data and are unaccounted for according to the sponsor.

**[Primary Effectiveness Endpoint: Distraction]{.underline}**

Radiographs including plain AP and lateral radiographs were performed at
each follow-up visit. Dynamic (Flexion/Extension) radiographs were not
performed. An independent radiologist made measurements to determine
disc height, increase in angulation or curvature, change in
spondylolisthesis, and maintenance of distraction on the plain
radiographs. Measuring the maintenance of distraction was measured by
the distance between the spinous process. Failure to maintain
distraction was defined as a measurable loss of 4mm distraction at 24
months. Patients with implants at two levels were required to have
maintenance of distraction at both levels to be considered a treatment
success. There were 2 patients who were failures by this definition. One
patient refused to have follow-up radiographs at 24 months and was not
included in the 24 month data calculations. The sponsor states that
95.6% of the patients maintained distraction (less than 4 mm of loss of
height).

Of 113 levels treated, a decrease greater than 4 mm was measured in 5
levels at 24 months as compared to 6 weeks; 50 levels remained
radiographically the same as baseline, and the remainder (63 levels)
showed some change (loss of distraction) of 1 mm or more; with 59% of
the remaining levels (37 levels) showing [\>]{.underline} 2 mm of
apparent loss of height from baseline at 6 weeks. (volume 1, Table 51,
page 91)

On table 8. Volume 7, page 1505, 80/84 patients were noted to have
successful maintenance of distraction in the X-stop group. This leaves
by the accounting 16 patients without distraction results. (There were 4
deaths and 7 failures by 24 months. 100-11=89. This leaves 5 patients
unaccounted for in this parameter.

There were no significant differences between the X-Stop and control
groups in the *mean* values of any radiographic measurements made at
either the 12 or 24 months follow-up visits.

**[Primary Effectiveness Endpoint: Overall Success]{.underline}**

The 24-month overall success rate for the X-Stop group was 45.7% (42/92)
and for the Control group 4.9% (4/81). This was compared to the results
for laminectomy in the literature and the patients in this study who
underwent laminectomy.

**[Secondary Effectiveness Results]{.underline}**

**[Secondary Effectiveness Endpoint: Back and Leg pain]{.underline}**

At 24 months mean back and leg pain scores were significantly less
frequent and less severe in the X-stop group as compared to the control
group while sitting, standing or walking. When looking at actual mean
improvement the X-stop group had significantly greater improvement than
the control group in frequency and severity of back pain while standing
and walking, while there was no significant difference in improvement
scores for back pain while sitting. The X-stop group had a significantly
greater improvement than the control group in the frequency and severity
of leg pain while sitting, standing or walking at 24 months. It appears
that treatment with the X stop has the most effect on leg pain when
standing and walking as compared to the relief of back pain ( i.e. for
claudication)

> **Improvement in Leg and Back Pain at the 24 Month Follow-up Compared
> to Baseline**

  -------------------- ----------- --------- ------- ------------- ------- ---------------
  **Variable**                     **X               **Control**           **p-value\***
                                   STOP**                                  

                                   **n/N**   **%**   **n/N**       **%**   

  Back pain when       Frequency   20/89     22.5%   9/63          14.3%   0.295
  sitting                                                                  

                       Severity    20/89     22.5%   11/63         17.5%   0.542

  Back pain when       Frequency   45/89     50.6%   17/63         27.0%   0.004\*
  standing                                                                 

                       Severity    46/89     51.7%   21/63         33.3%   0.031\*

  Back pain when       Frequency   49/89     55.1%   18/63         28.6%   0.002\*
  walking                                                                  

                       Severity    50/89     56.2%   21/63         33.3%   0.008\*

  Leg pain when        Frequency   18/89     20.2%   7/63          11.1%   0.183
  sitting                                                                  

                       Severity    18/89     20.2%   8/63          12.7%   0.277

  Leg pain when        Frequency   71/89     79.8%   17/63         27.0%   \<0.001\*
  standing                                                                 

                       Severity    73/89     82.0%   24/63         38.1%   \<0.001\*

  Leg pain when        Frequency   72/89     80.9%   23/63         36.5%   \<0.001\*
  walking                                                                  

                       Severity    74/89     83.1%   27/63         42.9%   \<0.001\*
  -------------------- ----------- --------- ------- ------------- ------- ---------------

> \* indicating a level of significance \< 0.05; p-values determined
> using the Fisher exact test

**[Secondary Effectiveness Endpoint: Analgesic Use]{.underline}**

There was apparently some difficulty in collecting this data according
to the sponsor, so its reliability may not be valid. Analgesic use, both
narcotic and non-narcotic, was decreased in both treatment groups.
Although the use of narcotics was significantly less in th X-stop group
at the 6 week and 12 month visit, there was no significant statistical
difference between the two groups at 6 or 24 months. This is consistent
with the pain scores noted.

**[Secondary Effectiveness Endpoint: Radiographic
Endpoints]{.underline}**

Measurements of each level treated were made to determine spinous
process distance, anterior and posterior disc height angulation,
foraminal height and percentage of spondylolisthesis. There were no
significant differences between the X-STOP and control groups in the
mean values of any radiographic measurements made at either the 12 or 24
months follow-up visits. (table 52: Mean radiographic Measurements
Volume 1, page 91)

One fracture and heterotopic bone formation was noted in another patient
by radiographic review. The implant was noted to be malpositioned in 2
patients, with one implant noted to be dislodged after a fall from a
chair.

**[Secondary Effectiveness Endpoint: SF-36.]{.underline}**

In each of the physical domains the X-stop group had a significantly
higher values, However, there was improvement in both the physical and
mental component summary in both treatment groups over the course of the
study. There are no statistical differences in the mental summary scores
between the groups. When comparing improvement over baseline at 24
months, the X-stop patients improved significantly over baseline in all
domains except general health. In the control group there was no
statistically significant improvement in any domain. (Vol.1, Table 38,
page 55)

**[Sample Radiographs]{.underline}** (Amendment 4)

Of note, the sponsor provided sample radiographs both in hard copy and
scanned on a CD ROM, which is included in the panel packs. Review of
each radiograph is not relevant as they are only samples of a series of
radiographs in patients considered overall successes and overall
failures. What is pertinent is the observation that the radiographs are
of a quality that may make it difficult to perform the measurements
required in the trial. Many of the samples are coned down views which
may make evaluation of spinal angulation (Cobb angle) and alignment
difficult. Others show severe degenerative disease, or osteopenia which
may impede evaluations of disc height and measurement of foramen height
to determine distraction of the intervertebral foramina.

# Other Analyses

## [Pooling Across Investigational Sites]{.underline} (Vol. 1,Table 36, p. 53)

When evaluating success by site, there is a wide divergence of results,
particularly the fact that there is an 85% success rate for the X-stop (
St. Mary's Medical Center) at one site when the majority of other sites
had a less than or equal to 50% success rate. Similarly the success rate
of the control group is greater at two sites (E. Cooper Reg Medical
Center, St. Mary's Medical Center) while it is zero at all the other 6
sites.

While the differences were not statistically significant, the difference
suggests there is a learning curve for the device, differences in
patient expectations, evaluations or other covariates influenced the
outcome. There is a stark difference between a 27% success (GBMC) and an
85% (St. Mary's) success rate in the different sites.

**[Success rates by covariate analysis]{.underline}**

When looking at patients who have had prior epidural injections which
failed, 26/58 patients (44.8%) were successful with X-stop placement,
while 16/34 (47.1) were not. In the control group, there was only 1
patient who had had failed prior epidural injections had success with
subsequent treatment. For those who have no prior epidural injections
only 3/48 (6.3%) were successful. These findings suggest that epidural
injections may not have been appropriate treatment for the patients
enrolled in this study, bringing into question whether the enrollment
criteria defined the population who should get this device***.***

**[Comparing X-stop success with success rates of the failed patients
after laminectomy]{.underline}**

Comparison of the effectiveness results between the X-stop patients and
those patients with laminectomy is provided in Volume 7, table 20.4 and
Amendment 3 Attachment 5 \[Tables 20.1-20.4\]).. Six patients who
received the X STOP did not achieve satisfactory relief of symptoms and
had a decompressive laminectomy performed. Two patients who received an
un-welded implant also went on to a laminectomy. Twenty-six control
patients in the Pivotal Clinical Trial elected to undergo a laminectomy
because of ongoing stenosis symptoms (including 2 patients who underwent
laminectomies after their 24 month follow-up visits), and 5 control
patients treated in the un-welded implant study went on to a
laminectomy. Finally, one X STOP and six control patients enrolled in
the Pivotal Clinical Trial were not treated and elected to have a
laminectomy instead. Thus a total of 46 patients from both the Pivotal
Clinical Trial and un-welded implant study elected to undergo a
laminectomy. Outcomes for 36 of these patients are available.

It is not proper method to compare the success rates of the patients in
the treatment group(also a randomized population) with the rates of
patients who failed treatment in both groups ( also a non-randomized
population) The comparison of a group of successfully treated patients
with a group of failures is not comparing like patients and in the group
that progressed to laminectomy may already have had worse symptomatic
manifestation of spinal stenosis upon entering the study.

**[Financial Interests of the Investigators]{.underline}**

Two of the investigators had a financial interest in the device. The
site at which these investigators operated had higher success rates than
other institutions. See the statistician's discussion of site related
outcomes for a full discussion.

# Subgroup Analysis

Over the course of the study, 64 patients received the X STOP device at
one level and 36 patients received the implant at two levels. A subgroup
analysis for the X STOP patients who had one-level and two-level
implantations is provided below. A significantly greater proportion of
patients with two‑level implantation were successes in the Physical
Function domain compared to patients with one-level implantation.

> **Success Rates for Primary Endpoints at 24 Month Follow-up in the X
> STOP Group**
>
> **-- One Level vs. Two Level Implantation**

+-------------------------------+------+------+------+------+------+
| **Endpoint**                  | **O  |      | **T  |      | **p  |
|                               | ne-L |      | wo-L |      | -val |
|                               | evel |      | evel |      | ue** |
|                               | X    |      | X    |      |      |
|                               | STOP |      | STOP |      |      |
|                               | Im   |      | Im   |      |      |
|                               | plan |      | plan |      |      |
|                               | tati |      | tati |      |      |
|                               | on** |      | on** |      |      |
+-------------------------------+------+------+------+------+------+
|                               | **n  | *    | **n  | *    |      |
|                               | /N** | *%** | /N** | *%** |      |
+-------------------------------+------+------+------+------+------+
| Individual ZCQ Domain         |      |      |      |      |      |
+-------------------------------+------+------+------+------+------+
| -   Symptom Severity          | 3    | 6    | 2    | 6    | 1    |
|                               | 6/58 | 2.1% | 0/31 | 4.5% | .000 |
+-------------------------------+------+------+------+------+------+
| -   Physical Function         | 2    | 5    | 2    | 7    | 0.0  |
|                               | 9/58 | 0.0% | 4/31 | 7.4% | 14\* |
+-------------------------------+------+------+------+------+------+
| -   Patient Satisfaction      | 4    | 7    | 2    | 8    | 0    |
|                               | 1/58 | 0.7% | 7/31 | 7.1% | .116 |
+-------------------------------+------+------+------+------+------+
| Overall ZCQ Success           | 2    | 4    | 1    | 5    | 0    |
|                               | 7/58 | 6.6% | 8/31 | 8.1% | .375 |
+-------------------------------+------+------+------+------+------+
| **Overall Study Success**     | 2    | 4    | 1    | 4    | 0    |
| (all enrolled patients)       | 6/64 | 0.6% | 6/36 | 4.4% | .833 |
+-------------------------------+------+------+------+------+------+

> \* indicating a level of significance \< 0.05; p-values determined
> using the Fisher exact test
>
> Patients who had longer pre enrollment symptom duration had a slightly
> worse outcome than those who had a shorter duration of symptoms though
> not statistically significant for the patients with longer symptom
> duration in both groups
>
> The following table summarizes outcome data for X STOP and control
> patients who had stenosis symptoms for 2 years or less, compared to X
> STOP patients who had stenosis symptoms for more than 2 years prior to
> study entry .
>
> **Success Rates for Primary Endpoints at the 24 Month Follow-up in
> Patients with Symptom Duration ≤ 2 Years vs*.* \> 2 Years -- X STOP
> vs. Control Group**

+-----------------------------+-------+-------+-------+-------+------+
| **Patient Population and    | **X   |       | *     |       | **p  |
| Endpoint**                  | S     |       | *Cont |       | -val |
|                             | TOP** |       | rol** |       | ue** |
+-----------------------------+-------+-------+-------+-------+------+
|                             | **    | **%** | **    | **%** |      |
|                             | n/N** |       | n/N** |       |      |
+-----------------------------+-------+-------+-------+-------+------+
| **Symptom Duration ≤ 2yrs   |       |       |       |       |      |
| duration**                  |       |       |       |       |      |
+-----------------------------+-------+-------+-------+-------+------+
| **Individual ZCQ Domain**   |       |       |       |       |      |
+-----------------------------+-------+-------+-------+-------+------+
| -   Symptom Severity        | 22/37 | 59.5% | 7/23  | 30.4% | 0.0  |
|                             |       |       |       |       | 36\* |
+-----------------------------+-------+-------+-------+-------+------+
| -   Physical Function       | 23/37 | 62.2% | 4/23  | 17.4% | 0.0  |
|                             |       |       |       |       | 01\* |
+-----------------------------+-------+-------+-------+-------+------+
| -   Patient Satisfaction    | 29/37 | 78.4% | 11/23 | 47.8% | 0.0  |
|                             |       |       |       |       | 24\* |
+-----------------------------+-------+-------+-------+-------+------+
| **Overall ZCQ Success**     | 19/37 | 51.4% | 2/23  | 8.7%  | 0.0  |
|                             |       |       |       |       | 01\* |
+-----------------------------+-------+-------+-------+-------+------+
| **Overall Study Success**   | 19/43 | 44.2% | 2/36  | 5.6%  | \<   |
| (all enrolled patients)     |       |       |       |       | 0.0  |
|                             |       |       |       |       | 01\* |
+-----------------------------+-------+-------+-------+-------+------+
| **Symptom Duration \> 2 yrs |       |       |       |       |      |
| duration**                  |       |       |       |       |      |
+-----------------------------+-------+-------+-------+-------+------+
| **Individual ZCQ Domain**   |       |       |       |       |      |
+-----------------------------+-------+-------+-------+-------+------+
| -   Symptom Severity        | 34/52 | 65.4% | 8/40  | 20.0% | \    |
|                             |       |       |       |       | <0.0 |
|                             |       |       |       |       | 01\* |
+-----------------------------+-------+-------+-------+-------+------+
| -   Physical Function       | 30/52 | 57.7% | 8/40  | 20.0% | \    |
|                             |       |       |       |       | <0.0 |
|                             |       |       |       |       | 01\* |
+-----------------------------+-------+-------+-------+-------+------+
| -   Patient Satisfaction    | 39/52 | 75.0% | 17/40 | 42.5% | 0.0  |
|                             |       |       |       |       | 02\* |
+-----------------------------+-------+-------+-------+-------+------+
| **Overall ZCQ Success**     | 26/52 | 50.0% | 2/40  | 5.0%  | \    |
|                             |       |       |       |       | <0.0 |
|                             |       |       |       |       | 01\* |
+-----------------------------+-------+-------+-------+-------+------+
| **Overall Study Success**   | 23/57 | 40.4% | 2/55  | 3.6%  | \<   |
| (all enrolled patients)     |       |       |       |       | 0.0  |
|                             |       |       |       |       | 01\* |
+-----------------------------+-------+-------+-------+-------+------+

> \* indicating a level of significance \< 0.05; p-values determined
> using the Fisher exact test

# Effectiveness Conclusions

The sponsor states that a statistically significant proportion of the
X-Stop patients achieved improvement in symptom severity and physical
function as compared to the control group. This statement though
statistically true requires some discussion.

First one must look at the control group. Comparing an operative group
to a non operative group is subject to bias and expectation differences
for patients which includes a placebo effect. Choosing a control, one in
which the treatment has already failed, will allow easy demonstration of
greater effectiveness by the treated patient group. Laminectomy in the
population with claudication varies in success between 65-85%, but
generally has a good result due to decompression. In this study, symptom
relief was only 60% for pain and function and symptom relief and
satisfaction waned from 6 months to 2 years as was previously noted in
the is review. Approximately 15% of those with initial relief had
return, worsening or increase of symptoms, though better than baseline,
by 24 months.

This population enrolling in this study is a group of patients who, in
majority, had failed 2 or more years of conservative therapy and the
controls got more of the therapy that was ineffective. When one looks at
the results, it is clear that the control therapy was ineffective after
another 2 years. Patients with single level treatment and those with
longer duration of symptoms preoperatively had a worse clinical outcome.

+-----------------------+-----------------------+-----------------------+
| ###                   |                       |                       |
| ### 24-Month Effectiv |                       |                       |
| eness Results (Per sp |                       |                       |
| onsor's calculations) |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Primary Endpoints** | **X-STOP**            | **CONTROL**           |
+-----------------------+-----------------------+-----------------------+
| Symptom Severity      | 60.2 %                | 18.5 %                |
+-----------------------+-----------------------+-----------------------+
| Physical function     | 57 %                  | 14.8 %                |
+-----------------------+-----------------------+-----------------------+
| Satisfaction          | 73.1 %                | 35.9 %                |
+-----------------------+-----------------------+-----------------------+
| Overall Success       | 45.7 %                | 4.9 %                 |
+-----------------------+-----------------------+-----------------------+

[Predictive analysis]{.underline}

The sponsor has done an analysis of the covariates in order to discern
those variables that may be associated with an unfavorable or favorable
outcome.

According to the analysis favorable outcome was predictive with a
positive femoral stretch test. Whether this is clinically useful is not
clear. Patients with co-morbid conditions and higher blood loss were
negatively correlated with out comes. This finding is not uncommon with
a surgical intervention. Worse baseline scores on the ZCQ physical
function score were predictive of a positive outcome. Patients who were
employed, had involvement at L4 -L5 or had used narcotics for pain prior
to enrollment were weakly correlated with a positive outcome. Patients
with worse symptoms and scores in the SF-36 and had greater range of
motion preoperatively were weakly correlated with a positive outcome.
Those who were older and had back pain were weakly correlated with a
worse outcome. No conclusions can be accurately drawn from these weak
associations. The usefulness of this analysis in selecting appropriate
patients for treatment is not clear.

Gender, symptom duration and number of operated levels were not
predictors of outcome in this analysis. This finding does not follow
what is generally known for this spinal diagnosis. .

In the secondary endpoint analysis, mean improvement scores over
baseline were significantly better in the X-stop group for the SF-36
except for general health, while there were no statistically significant
improvement in the mean scores in any SF-36 domain in the control group.
In the X-Stop group, there was mean improvement scores in the frequency
and severity of back and leg pain while sitting, standing or walking
were significantly better in the X-stop group except for back pain while
sitting. In comparison there was no significant improvement in the mean
scores in the control group in the frequency and severity of back and
leg pain while sitting, standing, or walking.

Although the overall results show that the X-stop group achieved better
results than the control group, there were several trends that deserve
attention. In the X-stop treated group, a trend of immediate relief in
the first six months for pain and function was observed, but this relief
was not sustained in all patients and over time, the mean scores and
number of patients with improvement decreased with out a great decrease
in the numbers of patients that was seen in the control group. In
approximately 15% of patients treated by X-stop who showed improvement
in pain scores, treatment offered only temporary pain relief by 24
months. In approximately 10% of patients treated by X-stop who showed
initial improvement in function scores, this improvement was not
sustained through 24 months.

# Safety Evaluation

Adverse events were determined by the investigators as to the
relationship of the event to the device. Adverse events that were
related to the device or device implantation are described as implant
related or operative site related. Adverse events related to the
patients disease, occurred in the perioperative period or were
associated with epidural injections were described as LSS disease,
surgery or treatment related. Adverse events were designated as systemic
if they had no relation ship to the implant or procedures.

## [Adverse Event Rates]{.underline}

**[Implant related adverse events]{.underline}**

As a result of the implant related events, the sponsor has modified
inclusion/exclusion, and surgical techniques and labeling for the
device.

Three implant related events (3%) were described by the sponsor. These
include dislodgement of the device following a fall from a chair 11 days
after surgery, which required removal; spinous process fracture, noted
on follow-up radiograph at 6 months. Because it was felt that the device
was initially not stable after placement due to facet hypertrophy, the
surgical technique and device labeling were modified.

The second patient had an asymptomatic spinous process fracture noted at
the 6 month visit radiograph, not seen on the 6 week radiograph. Because
healing was noted at subsequent radiographs, no other intervention
occurred. This patient did meet the success criteria at 24 months.

The third patient had a double level implantation and at the 6 week
visit, the investigator noted that the intraoperative radiographs show
that the implant had been positioned too far posteriorly. This patient
did not meet the success criteria at 24 months.

## [Deaths]{.underline}

There were 4 deaths in each treatment group. No death was linked to the
specific treatment the patient received according to the sponsor.
However, in one X-stop patient, (0508) death occurred 2 days after
surgery due to pulmonary edema and FDA believes it should be considered
procedure related. Other deaths in the X-Stop group occurred at 4
months, and 1.5 years post operatively. In the control group, deaths
occurred in two patients 1.5 years after enrollment but associated with
additional surgery. Two other patients in the control group died at 5
months and 2 years after treatment.

**[Intraoperative complications]{.underline}**

There were no device related intraoperative adverse events in that
surgeons were able to implant the device in all patients, no cases were
abandoned and none were converted intraoperatively to laminectomy. One
patient, who was supposed to have two-level implantation, only had one
level implanted because of respiratory distress during implantation.

There were 3 patients (3%) who experienced intraoperative complications.
One patient was unable to tolerate the epidural injection procedure.
Intraoperatively, in the X stop group, one patient each had respiratory
distress, an ischemic coronary episode and technical difficulty passing
the probe dilator.

In the control group, 6 adverse events occurred during epidural
injection. Three events occurred at the first injection. Four occurred
during injection, one post injection and one day after injection. These
included a reaction resulting in pain, aborting of the procedure, an
exacerbation of symptoms, two patients with paresthesias during
injection which resolved, and an Myocardial Infarction 3days following
the injection. One patient in the control group was unable to tolerate
the epidural injections, the procedure was terminated and the patient
withdrew from the study.

**[Device/procedure related complications]{.underline}**

The following table lists possible device or procedure related
complications (from table 11.1, Vol 7, p. 1534)

  ------------------------------------- ----------------- ---------------
  Event                                 X-Stop            Control

  **Laminectomy**                       **7**             **26**

  Pain/Stenosis                         6                 26

  **Device removal**                    **7**             **0**

  **Epidural injection Reaction**       **0**             **4**

  Cardiovascular event after treatment  1                 1

  CHF/PE post operative death           1                 0

  **Device Migration/dislodgement**     **1**             **0**

  Lung edema                            1                 0

  Failed epidural injection             0                 1

  Incisional pain                       1                 0

  **Malpositioned implant**             **1**             **0**

  Pain & progressive neurologic deficit 0                 1

  Worsening pain in low back            1                 0

  Respiratory distress during surgery   1                 0

  **Spinous process fracture**          **1**             **0**

  **Surgical site hematoma**            **1**             **0**

  **Wound dehiscence**                  **1**             **0**

  **Wound Swelling**                    **1**             **0**
  ------------------------------------- ----------------- ---------------

Patients with 2-level implantation had less complications
postoperatively when compared to patients with 1 level
implantations**.**

**[Operative Site Related Adverse Events]{.underline}**

Four X-stop patients had operative site adverse events including wound
swelling, dehiscence, hematoma and incisional pain. Three of these
required additional intervention for treatment. Although the wound was
aspirated in patient #0340, no information is provided on the
result**.**

**[Details of other adverse events:]{.underline}**

[Pain]{.underline}

One patient in each treatment group experienced worsening pain in the
follow-up period. The patient treated with a series of nerve root blocks
and still did not meet the criteria for success. The X-stop patient is a
protocol deviation. The control patient had increasing pain, progressive
neurologic deficit and loss of sexual function less than 2 weeks after
epidural injection but was not treated by laminectomy until 66 days
following this injection. What the sponsor terms "stenosis pain" is the
complication that led 6 X-stop and 26 control patients to go on to
laminectomy., however not all patients who were treatment failures went
on to laminectomy. The protocol does not describe what criteria were set
for progression to laminectomy in either group.

Two additional patients in the control group had laminectomy following
their 24 month visits.

## [Neurologic Adverse Events]{.underline}

A total of 9 neurological events occurred in X-Stop group patients (7)
compared to 2 events in Control group patients. These included headache
(1), Neurological disorder (1,1) neuropathy (4) stroke (1,1) and
neuropsychological disorder (5, 10) respectively.

**[Musculoskeletal Adverse Events]{.underline}**

There were 67 events in 43 patients in the X-stop group and 22 events in
16 patients in the control group.

## The majority of these were considered as unrelated to treatment. These included epidural injection reaction (3 control), incisional pain (1 X-stop), back (3,0), hip (11,3), lower back(17, 7), lower extremity(13,3), rib(1), upper back (4) and upper extremities (4,2), groin pain (3), wound swelling (1). The high incidence of lower extremity and back events suggests that treatment may have been incomplete for both groups, although there is a greater incidence in the X stop group. Included in these patients were some of the patients who underwent secondary procedures. Some of the increased problems are due to the increase in activity after successful resolution of symptoms. The sponsor proposes that the dwindling numbers in the control group as the study progressed contributed to the difference in the incidence of these events, however the rate of events is so significantly different, this seems unlikely. 

## Alternatively, it is possible that this is due to the population not completely defined had multiple co morbid and/or arthritic conditions accounting for the pain. Whether the patients and the ZCQ was able to discern the difference between the pain caused by stenosis or other etiology is not clear by the results.

> Summary of Adverse Events Associated with Musculoskeletal or Nervous
> Systems

<table>
<colgroup>
<col style="width: 18%" />
<col style="width: 19%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"><strong>Type of Adverse Event/Complication</strong></td>
<td colspan="2"><strong>Surgery/ Discharge</strong></td>
<td colspan="2"><p><strong>6</strong></p>
<p><strong>Weeks</strong></p></td>
<td colspan="2"><p><strong>6</strong></p>
<p><strong>Months</strong></p></td>
<td colspan="2"><strong>12 Months</strong></td>
<td colspan="2"><strong>24 Months</strong></td>
<td colspan="2"><strong>Total</strong></td>
</tr>
<tr class="even">
<td colspan="2"><strong>Treatment Group</strong> (X = X STOP; C =
Control)</td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td rowspan="2"><strong>X</strong></td>
<td rowspan="2"><strong>C</strong></td>
</tr>
<tr class="odd">
<td colspan="2"><strong># Pts Evaluated at Each F/U Interval
Visit</strong></td>
<td><strong>100</strong></td>
<td><strong>91</strong></td>
<td><strong>94</strong></td>
<td><strong>70</strong></td>
<td><strong>88</strong></td>
<td><strong>64</strong></td>
<td><strong>88</strong></td>
<td><strong>69</strong></td>
<td><strong>88</strong></td>
<td><strong>58</strong></td>
</tr>
<tr class="even">
<td><strong>System</strong></td>
<td><strong>Code/Event</strong></td>
<td colspan="12"></td>
</tr>
<tr class="odd">
<td rowspan="3"><strong>Musculoskeletal</strong></td>
<td>Lower Back</td>
<td></td>
<td></td>
<td>3</td>
<td></td>
<td>5</td>
<td>2</td>
<td>5</td>
<td>3</td>
<td>8</td>
<td>2</td>
<td>21</td>
<td>7</td>
</tr>
<tr class="even">
<td>Lower Extremity</td>
<td></td>
<td></td>
<td>1</td>
<td>2</td>
<td>6</td>
<td>1</td>
<td>6</td>
<td>2</td>
<td>3</td>
<td></td>
<td>16</td>
<td>5</td>
</tr>
<tr class="odd">
<td>Upper Back</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td></td>
<td>4</td>
<td></td>
</tr>
<tr class="even">
<td rowspan="3"><strong>Neurological</strong></td>
<td>Neurological Disorder</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
</tr>
<tr class="odd">
<td>Neuropathy</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>2</td>
<td></td>
<td></td>
<td></td>
<td>4</td>
<td></td>
</tr>
<tr class="even">
<td>Stroke</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td></td>
<td>1</td>
<td>1</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>TOTAL# of Events</strong></td>
<td><strong>0</strong></td>
<td><strong>0</strong></td>
<td><strong>4</strong></td>
<td><strong>2</strong></td>
<td><strong>15</strong></td>
<td><strong>4</strong></td>
<td><strong>15</strong></td>
<td><strong>6</strong></td>
<td><strong>12</strong></td>
<td><strong>2</strong></td>
<td><strong>47</strong></td>
<td><strong>14</strong></td>
</tr>
</tbody>
</table>

## [Systemic Adverse Events]{.underline}

There was a higher incidence of cardiovascular , endocrine,
gastrointestinal, genitourinary, hematologic, hepatobiliary,
immunological, accidental injury, respiratory disorders and infections
in the X-stop group. X-stop patients were at higher risk than the
controls for \"systemic events\" without any seeming explanation. There
shouldn't be any difference given the outpatient nature and local used
for most procedures. This is detailed in Table 50 (Vol. 1. page 87).

## [Infection Adverse Events]{.underline}

No events related to infection are reported except the three wound
problems reported as secondary re-operations.

[Vascular Adverse Events.]{.underline}

There was one event in one X-stop patient.

## [Cancer]{.underline}

There were 4 patients in the X-stop group and 1 patient in the control
group diagnosed with cancer during the study. Patients with malignancies
were not excluded from this study.

**[Secondary Surgical Procedures]{.underline}**

This table summarized the time course of the secondary surgical
interventions in both study groups.

<table style="width:100%;">
<colgroup>
<col style="width: 34%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="13"><strong>SECONDARY SURGICAL INTERVENTIONS</strong></td>
</tr>
<tr class="even">
<td><strong>Type of Adverse Event/Complication***</strong></td>
<td colspan="2"><strong>Surgery/ Discharge</strong></td>
<td colspan="2"><strong>6 Weeks</strong></td>
<td colspan="2"><strong>6 Months</strong></td>
<td colspan="2"><strong>12 Months</strong></td>
<td colspan="2"><strong>24 Months</strong></td>
<td colspan="2"><strong>Total</strong></td>
</tr>
<tr class="odd">
<td><p><strong>Treatment Group</strong></p>
<p>(X = X STOP; C = Control)</p></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
</tr>
<tr class="even">
<td><strong># of Patients at Each Follow-up Interval</strong></td>
<td><strong>100</strong></td>
<td><strong>91</strong></td>
<td><strong>100</strong></td>
<td><strong>91</strong></td>
<td><strong>99</strong></td>
<td><strong>91</strong></td>
<td><strong>98</strong></td>
<td><strong>89</strong></td>
<td><strong>98</strong></td>
<td><strong>83</strong></td>
<td><strong>100</strong></td>
<td><strong>91</strong></td>
</tr>
<tr class="odd">
<td>Aspiration of wound swelling</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
</tr>
<tr class="even">
<td>Debridement and secondary wound closure</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
</tr>
<tr class="odd">
<td>Drainage of hematoma</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
</tr>
<tr class="even">
<td>Implant removal without laminectomy</td>
<td></td>
<td></td>
<td>1*</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
</tr>
<tr class="odd">
<td>Laminectomy**</td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td>2</td>
<td>11</td>
<td>1</td>
<td>3</td>
<td>2</td>
<td>9</td>
<td>6</td>
<td>24</td>
</tr>
<tr class="even">
<td><strong>TOTAL</strong></td>
<td></td>
<td></td>
<td><strong>5</strong></td>
<td><strong>1</strong></td>
<td><strong>2</strong></td>
<td><strong>11</strong></td>
<td><strong>1</strong></td>
<td><strong>3</strong></td>
<td><strong>2</strong></td>
<td><strong>9</strong></td>
<td><strong>10</strong></td>
<td><strong>24</strong></td>
</tr>
</tbody>
</table>

\* This patient reportedly underwent laminectomy between 18-24 months
following X STOP removal and study withdrawal.

\*\* All X STOP patients had device(s) removed at time of laminectomy;
two control patients underwent laminectomy following their 24 month
follow-up visits.

> \*\*\* Time intervals for this and other tables in this response are
> defined as follows: 6 weeks = 1-42 days; 6 months = 43-182 days; 12
> months = 183-365 days; 24 months ≥ 366 days

One patient had removal of the X-stop device which dislodged 13 days
after surgery following a fall 11 days after surgery His device was
removed and replaced but he did not undergo laminectomy. Six other
patients failed X-stop therapy, and underwent removal followed by
laminectomy. In the control group, 26 patients had laminectomy
procedures. Three X-stop patients underwent minor procedures classified
as re-operations for drainage of a hematoma, aspiration of the
incisional site, secondary wound closure after dehiscence. It appears
that 5/6 patients who had secondary surgery had two level implants.

The following table describes 7 X STOP patients in whom the device was
explanted. Five patients had one-level implantation and 2 patients had
two-level implantation of the device. At the time of laminectomy surgery
all devices were explanted with the exception of one patient (#1401),
who withdrew from the study after the device was removed 11 days
post-implantation and, reportedly, underwent laminectomy surgery
approximately 18 months later.

> **Summary of Explanted Devices**

  ----------- ---------------- -------------- ------------- ----------------- ----------------------------
  **Patient   **X STOP                        **\# Devices  **Laminectomy**   
  ID**        Implantation**                  Explanted**                     

              **\# Levels**    **Location**                 **\# Levels**     **Location**

  0213        1                L4-5           1             1                 L4-5 (fusion)

  0218        1                L4-5           1             2                 L4-5, L5-S1 (instrumented
                                                                              fusion)

  0320        1                L4-5           1             1                 L4-5

  0344        2                L3-4, L4-5     2             3                 L2-3, L3-4, L4-5 (fusion)

  0819        2                L3-4, L4-5     2             2                 L3-4, L4-5

  1009        1                L4-5           1             3                 L3-4, L4-5, L5-S1 (R
                                                                              foraminotomy @ L5-S1)

  1401        1                L4-5           1             N/A               Not performed at time of
                                                                              explant
  ----------- ---------------- -------------- ------------- ----------------- ----------------------------

> The number of levels at which laminectomy was performed in those
> patients in both the X STOP and control groups who underwent
> laminectomy is summarized in the table below. Two of 6 (33%) X STOP
> patients had single-level laminectomy performed. Similarly, in the
> control group, 7 of 24 patients (29%) underwent single-level
> laminectomy. More patients required (approximately 2/3 of the patient
> who failed initial treatment) more than one level decompression than
> single level decompression in both study groups suggesting that those
> patients who failed had greater involvement than perhaps originally
> thought.
>
> **Number of Levels at which Laminectomy was Performed -- X STOP vs.
> Control Patients**

  ----------------------- ----------------------- -----------------------
  **Laminectomy: \# of    **\# of X STOP          **\# of Control
  Levels**                Patients**              Patients**

  1                       2                       7

  2                       2                       6

  3                       2                       4

  4                       0                       2

  5                       0                       1

  Unknown\*               0                       4\*

  **TOTAL**               **6**                   **24**
  ----------------------- ----------------------- -----------------------

> \* Laminectomy surgeries performed at location other than
> investigative site; additional information regarding \# of levels not
> available.
>
> Explant retrieval analysis is provided in Amendment 3, Attachment E.
> All explant analyses include spacer assembly assessment, surface wear
> analysis, and release torque if applicable. The explant surgical
> reports did not contain any notations regarding the status of the
> surrounding tissue or implant appearance. Postoperative pathology was
> not performed.

**[Time course of Adverse events]{.underline}**

**[Table 1.2: Adverse Events Summary]{.underline}**[^1]

<table style="width:100%;">
<colgroup>
<col style="width: 17%" />
<col style="width: 17%" />
<col style="width: 5%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2" rowspan="2"><strong>Type of Adverse
Event/Complication</strong></td>
<td colspan="2" rowspan="2"><strong>Surgery/ Discharge</strong></td>
<td colspan="2" rowspan="2"><p><strong>6</strong></p>
<p><strong>Week</strong></p></td>
<td colspan="2" rowspan="2"><strong>6 Months</strong></td>
<td colspan="2" rowspan="2"><strong>12 Months</strong></td>
<td colspan="2" rowspan="2"><strong>24 Months</strong></td>
<td colspan="4"><strong>Overall</strong></td>
</tr>
<tr class="even">
<td colspan="2"><strong># Events</strong></td>
<td colspan="2"><strong># Patients</strong></td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Treatment Group</strong> (X = X STOP; C =
Control)</td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
<td><strong>X</strong></td>
<td><strong>C</strong></td>
</tr>
<tr class="even">
<td colspan="2"><strong># of Patients at Each Follow-up
Interval</strong></td>
<td><strong>100</strong></td>
<td><strong>91</strong></td>
<td><strong>100</strong></td>
<td><strong>91</strong></td>
<td><strong>99</strong></td>
<td><strong>91</strong></td>
<td><strong>98</strong></td>
<td><strong>89</strong></td>
<td><strong>98</strong></td>
<td><strong>83</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="16"><strong>ADVERSE EVENTS RELATED TO LSS, SURGERY OR
EPIDURAL INJECTION</strong></td>
</tr>
<tr class="even">
<td colspan="2">Coronary episode, ischemic</td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td colspan="2">Heart attack</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>1</td>
</tr>
<tr class="even">
<td colspan="2">Epidural injection reaction</td>
<td></td>
<td>1</td>
<td></td>
<td>2</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>4</td>
<td>0</td>
<td>4</td>
</tr>
<tr class="odd">
<td colspan="2">Epidural injection failed</td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>1</td>
</tr>
<tr class="even">
<td colspan="2">Hematoma at surgical site</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td colspan="2">Incisional pain</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td colspan="2">Pain and progressive neurological deficit</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>1</td>
</tr>
<tr class="odd">
<td colspan="2">Pain worsening in low back</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td colspan="2">Pain, stenosis</td>
<td></td>
<td>2</td>
<td></td>
<td>3</td>
<td>3</td>
<td>9</td>
<td>1</td>
<td>4</td>
<td>2</td>
<td>8</td>
<td>6</td>
<td>26</td>
<td>6</td>
<td>26</td>
</tr>
<tr class="odd">
<td colspan="2">Pulmonary edema</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td colspan="2">Respiratory distress</td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td colspan="2">Wound dehiscence</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td colspan="2">Wound swelling</td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td colspan="16"><strong>DEVICE RELATED ADVERSE EVENTS</strong></td>
</tr>
<tr class="even">
<td colspan="2">Device migration/dislodgement</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td colspan="2">Malpositioned implant</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td colspan="2">Spinous process fracture</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td colspan="16"><strong>SYSTEMIC EVENTS*</strong></td>
</tr>
<tr class="even">
<td><strong>System</strong></td>
<td><strong>Code/Event</strong></td>
<td colspan="14"></td>
</tr>
<tr class="odd">
<td rowspan="4"><strong>Body as a Whole</strong></td>
<td>Cancer</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>2</td>
<td></td>
<td>2</td>
<td></td>
<td>4</td>
<td>1</td>
<td>4</td>
<td>1</td>
</tr>
<tr class="even">
<td>Death</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td>1</td>
<td></td>
<td>1</td>
<td>2</td>
<td>2</td>
<td>4</td>
<td>4</td>
<td>4</td>
<td>4</td>
</tr>
<tr class="odd">
<td>Injury, Accidental</td>
<td></td>
<td></td>
<td>3</td>
<td></td>
<td>2</td>
<td>2</td>
<td>6</td>
<td>2</td>
<td>3</td>
<td></td>
<td>14</td>
<td>4</td>
<td>11</td>
<td>4</td>
</tr>
<tr class="even">
<td>Weight Gain</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td><strong>Cardiovascular</strong></td>
<td>CV Disorder</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>2</td>
<td></td>
<td>4</td>
<td>0</td>
<td>4</td>
<td>0</td>
</tr>
<tr class="even">
<td><strong>Endocrine</strong></td>
<td>Diabetes</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td><strong>Gastrointestinal</strong></td>
<td>GI Disorder</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td></td>
<td>4</td>
<td>0</td>
<td>3</td>
<td>0</td>
</tr>
<tr class="even">
<td rowspan="3"><strong>Genitourinary</strong></td>
<td>Chronic Renal Failure</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td>GU Infection</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td>Pain, Groin</td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td>0</td>
<td>2</td>
<td>0</td>
</tr>
<tr class="odd">
<td><strong>Hematological</strong></td>
<td>Anemia</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td><strong>Hepatobiliary</strong></td>
<td>Gallstones</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td><strong>Immunological</strong></td>
<td>Allergy</td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td rowspan="9"><strong>Musculoskeletal</strong></td>
<td>Back, Unspecified</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td></td>
<td>3</td>
<td>0</td>
<td>3</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Hip</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>4</td>
<td></td>
<td>4</td>
<td>1</td>
<td>5</td>
<td>2</td>
<td>13</td>
<td>3</td>
<td>11</td>
<td>3</td>
</tr>
<tr class="even">
<td>Lower Back</td>
<td></td>
<td></td>
<td>3</td>
<td></td>
<td>5</td>
<td>2</td>
<td>5</td>
<td>3</td>
<td>8</td>
<td>2</td>
<td>21</td>
<td>7</td>
<td>16</td>
<td>7</td>
</tr>
<tr class="odd">
<td>Lower Extremity</td>
<td></td>
<td></td>
<td>1</td>
<td>2</td>
<td>6</td>
<td>1</td>
<td>6</td>
<td>2</td>
<td>3</td>
<td></td>
<td>16</td>
<td>5</td>
<td>13</td>
<td>3</td>
</tr>
<tr class="even">
<td>Rib</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Upper Back</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td></td>
<td>4</td>
<td>0</td>
<td>4</td>
<td>0</td>
</tr>
<tr class="even">
<td>Upper Extremity</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>2</td>
<td>1</td>
<td>4</td>
<td>2</td>
<td>4</td>
<td>2</td>
</tr>
<tr class="odd">
<td>Unspecified</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td>Pain, Groin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td>1</td>
<td></td>
<td></td>
<td>1</td>
<td>2</td>
<td>1</td>
<td>2</td>
</tr>
<tr class="odd">
<td rowspan="4"><strong>Neurological</strong></td>
<td>Headache</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="even">
<td>Neurological Disorder</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1</td>
</tr>
<tr class="odd">
<td>Neuropathy</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>2</td>
<td></td>
<td></td>
<td></td>
<td>4</td>
<td>0</td>
<td>4</td>
<td>0</td>
</tr>
<tr class="even">
<td>Stroke</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>1</td>
<td></td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1</td>
</tr>
<tr class="odd">
<td><strong>Neuropsychological</strong></td>
<td>NP Disorder</td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td>1</td>
<td>3</td>
<td></td>
<td>5</td>
<td>1</td>
<td>5</td>
<td>1</td>
</tr>
<tr class="even">
<td><strong>Peripheral Vascular</strong></td>
<td>PV Disorder</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>0</td>
</tr>
<tr class="odd">
<td rowspan="2"><strong>Respiratory</strong></td>
<td>Respiratory Infection</td>
<td></td>
<td></td>
<td>2</td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>3</td>
<td>0</td>
<td>3</td>
<td>0</td>
</tr>
<tr class="even">
<td>Respiratory Disorder</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>1</td>
<td></td>
<td></td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>1</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>TOTAL # of Events</strong></td>
<td><strong>4</strong></td>
<td><strong>4</strong></td>
<td><strong>22</strong></td>
<td><strong>10</strong></td>
<td><strong>32</strong></td>
<td><strong>18</strong></td>
<td><strong>40</strong></td>
<td><strong>17</strong></td>
<td><strong>38</strong></td>
<td><strong>16</strong></td>
<td><strong>136</strong></td>
<td><strong>65</strong></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

\* Systemic events are defined as those events unrelated to device or
study-related procedures

As reported in the PMA (Vol 1, Tables 49 and 50, pp. 86-87), there were
no statistically significant differences between the study groups in any
single category of adverse events, with two exceptions: 1) the incidence
of lower extremity disorders was significantly higher in the X STOP
group (13/100 vs. 3/91; p = 0.018) and 2) the incidence of stenosis pain
was significantly higher in the control group (26/91 vs. 6/100; p \<
0.001).

**[Subgroup analysis]{.underline}**

Patients with longer duration of symptoms had greater numbers of adverse
events due to systemic and surgical procedure or stenosis, however the
results did not reach statistical significance..

A total of 55 adverse events occurred among the subgroup of 43 X STOP
patients who had stenosis symptoms for 2 years or less prior to study
entry (55/43; 1.3 events per patient). A total of 81 adverse events
occurred among the subgroup of 57 X STOP patients who had stenosis
symptoms for more than 2 years prior to study entry (81/57; 1.4 events
per patient). No statistically significant differences between the two
subgroups were observed overall or in any single adverse event category.
Similarly, no significant differences were noted between the subgroups
of control patients based on symptom duration.

> **Summary of Adverse Events by Symptom Duration ≤ 2 Years vs*.* \> 2
> Years --**
>
> **X STOP Group and Control Groups**

<table>
<colgroup>
<col style="width: 19%" />
<col style="width: 19%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2" rowspan="2"><strong>Type of Adverse
Event/Complication</strong></td>
<td colspan="5"><strong>X STOP</strong></td>
<td colspan="5"><strong>Control</strong></td>
</tr>
<tr class="even">
<td colspan="2"><p><strong>≤ 2Yrs</strong></p>
<p><strong>(N = 43)</strong></p></td>
<td colspan="2"><strong>&gt; 2 Years (N = 57)</strong></td>
<td rowspan="2"><strong>p-value</strong></td>
<td colspan="2"><p><strong>≤ 2 Yrs</strong></p>
<p><strong>(N =36)</strong></p></td>
<td colspan="2"><strong>&gt; 2 Years (N =55)</strong></td>
<td rowspan="2"><strong>p-value</strong></td>
</tr>
<tr class="odd">
<td colspan="2"><p>(N = # of pts with reported event;</p>
<p>n = total # of reported events)</p></td>
<td><strong>n</strong></td>
<td><strong>N</strong></td>
<td><strong>n</strong></td>
<td><strong>N</strong></td>
<td><strong>n</strong></td>
<td><strong>N</strong></td>
<td><strong>n</strong></td>
<td><strong>N</strong></td>
</tr>
<tr class="even">
<td colspan="12"><strong>ADVERSE EVENTS RELATED TO SURGERY, TREATMENT OR
LSS</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Coronary episode, ischemic</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td colspan="2">Heart attack</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
</tr>
<tr class="odd">
<td colspan="2">Epidural injection reaction</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>0.647</td>
</tr>
<tr class="even">
<td colspan="2">Epidural injection failed</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
</tr>
<tr class="odd">
<td colspan="2">Hematoma at surgical site</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td colspan="2">Incisional pain</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td colspan="2">Pain and progressive neurological deficit</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.396</td>
</tr>
<tr class="even">
<td colspan="2">Pain worsening in low back</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td colspan="2">Pain, stenosis</td>
<td>3</td>
<td>3</td>
<td>3</td>
<td>3</td>
<td>1.000</td>
<td>11</td>
<td>11</td>
<td>15</td>
<td>15</td>
<td>0.814</td>
</tr>
<tr class="even">
<td colspan="2">Pulmonary edema</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td colspan="2">Respiratory distress</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td colspan="2">Wound dehiscence</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td colspan="2">Wound swelling</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td colspan="2"><strong>DEVICE RELATED ADVERSE EVENTS</strong></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">Device migration/dislodgement</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td colspan="2">Malpositioned implant</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td colspan="2">Spinous process fracture</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td colspan="2"><strong>SYSTEMIC EVENTS*</strong></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>System</strong></td>
<td><strong>Code/Event</strong></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td rowspan="4"><strong>Body as a Whole</strong></td>
<td>Cancer</td>
<td>1</td>
<td>1</td>
<td>3</td>
<td>3</td>
<td>0.632</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.396</td>
</tr>
<tr class="odd">
<td>Death</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>1.000</td>
<td>3</td>
<td>3</td>
<td>1</td>
<td>1</td>
<td>0.297</td>
</tr>
<tr class="even">
<td>Injury, Accidental</td>
<td>7</td>
<td>5</td>
<td>7</td>
<td>6</td>
<td>1.000</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>0.647</td>
</tr>
<tr class="odd">
<td>Weight Gain</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td><strong>Cardiovascular</strong></td>
<td>CV Disorder</td>
<td>1</td>
<td>1</td>
<td>3</td>
<td>3</td>
<td>0.632</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td><strong>Endocrine</strong></td>
<td>Diabetes</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td><strong>Gastrointestinal</strong></td>
<td>GI Disorder</td>
<td>2</td>
<td>1</td>
<td>2</td>
<td>2</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td rowspan="3"><strong>Genitourinary</strong></td>
<td>Chronic Renal Failure</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td>GU Infection</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Pain, Groin</td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td><strong>Hematological</strong></td>
<td>Anemia</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td><strong>Hepatobiliary</strong></td>
<td>Gallstones</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td><strong>Immunological</strong></td>
<td>Allergy</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td rowspan="9"><strong>Musculoskeletal</strong></td>
<td>Back, Unspecified</td>
<td>0</td>
<td>0</td>
<td>3</td>
<td>3</td>
<td>0.257</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td>Hip</td>
<td>3</td>
<td>3</td>
<td>10</td>
<td>8</td>
<td>0.343</td>
<td>1</td>
<td>1</td>
<td>2</td>
<td>2</td>
<td>1.000</td>
</tr>
<tr class="odd">
<td>Lower Back</td>
<td>8</td>
<td>5</td>
<td>13</td>
<td>11</td>
<td>1.000</td>
<td>2</td>
<td>2</td>
<td>5</td>
<td>5</td>
<td>0.699</td>
</tr>
<tr class="even">
<td>Lower Extremity</td>
<td>7</td>
<td>5</td>
<td>9</td>
<td>8</td>
<td>0.773</td>
<td>5</td>
<td>3</td>
<td>0</td>
<td>0</td>
<td>0.059</td>
</tr>
<tr class="odd">
<td>Rib</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td>Upper Back</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Upper Extremity</td>
<td>3</td>
<td>3</td>
<td>1</td>
<td>1</td>
<td>0.312</td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
</tr>
<tr class="even">
<td>Unspecified</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Pain, Groin</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.430</td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
</tr>
<tr class="even">
<td rowspan="4"><strong>Neurological</strong></td>
<td>Headache</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Neurologic Disorder</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
</tr>
<tr class="even">
<td>Neuropathy</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>2</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Stroke</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
</tr>
<tr class="even">
<td><strong>Neuropsychological</strong></td>
<td>NP Disorder</td>
<td>4</td>
<td>4</td>
<td>1</td>
<td>1</td>
<td>0.162</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0.396</td>
</tr>
<tr class="odd">
<td><strong>Peripheral Vascular</strong></td>
<td>PV Disorder</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="even">
<td rowspan="2"><strong>Respiratory</strong></td>
<td>Respiratory Infection</td>
<td>0</td>
<td>0</td>
<td>3</td>
<td>3</td>
<td>0.257</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
</tr>
<tr class="odd">
<td>Respiratory Disorder</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>-</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>1.000</td>
</tr>
<tr class="even">
<td colspan="2"><strong>TOTAL</strong></td>
<td><strong>55</strong></td>
<td></td>
<td><strong>81</strong></td>
<td></td>
<td></td>
<td><strong>31</strong></td>
<td></td>
<td><strong>34</strong></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

-   "Systemic events" are defined as those events that were determined
    to be unrelated to device or study-related procedures

**[Safety Conclusions]{.underline}**

The safety of the profile of the device is not remarkable. Device
related events are minor and few in number. However, the incidence of
what the sponsor calls "systemic" events particularly the
musculoskeletal and accidental events which are much higher in those
patients receiving the X-Stop implant. It is not clear if these events
are related to prior co-morbid conditions, lumbar stenosis symptoms
unrecognized preoperatively, or progressive symptoms as a result of
implantation and/or biomechanical changes due to a change in the
function of the spine and adjacent segments to the level of the implant.

**[Other Cohorts]{.underline}**

As of May 2004, 17 patients have been enrolled into the continued access
program(CAP), 10 patients have enrolled in the crossover program (COS)
and 2 patients have been implanted under compassionate use. Patients in
the COS and CAP have been followed to 6 months with some improvement.
Two level implantation outcome success was greater than one level.
Compassionate use patients had not reached the 6 week follow up yet. Two
adverse events UTI and spinal fracture were reported in the CAP patients
at 6 weeks. A vasomotor incident and malpositioned implant was noted in
the COS cohort at 6 weeks. There is one protocol deviation based on
inclusion symptoms.

**[Conclusions]{.underline}**

This minimally invasive surgically implanted device has shown to be
statistically superior to continued conservative care in patients
greater than 50 years old, with greater than 6 months duration in
symptoms associated with a diagnosis of lumbar spinal stenosis, who have
mild to moderate symptoms including claudication, who have failed
epidural injections, and who have comorbidities associated with their
health status. Although the device can be inserted with a minimally
invasive operative technique as an outpatient procedure with generally a
local anesthetic a decision as to the safety and effectiveness of this
device is based solely on 24 month data because information on the
patient outcomes after 24 months is not available. This information
becomes important when looking at pain relief and return to function.
Even though the goal of the study was accomplished showing a
significant, statistical difference between the investigational and
control groups, more patients report improvement at 12 months than at 24
months.

Contrary to what has been observed in spinal fusion studies, in this
study, a percentage of patients whose symptoms improved at 6 and 12
months show a trend of regression of pain and function symptoms toward
baseline levels.. There appears to be a trend with early pain relief but
the data suggests that in about 15% of patients initially successfully
treated by the X-stop had only temporary relief.

The sponsor continued to collect effectiveness results on patients after
they had failed treatment and had progressed to laminectomy. Then
provided a comparison of the outcomes of the treated laminectomy
patients, and patients undergoing laminectomy in a literature article
review to the outcomes of the successful X-stop group.

Overall the success of patients was less than 50% in the X-stop group
and less than 5% in the control group which is much lower than that
predicted in the pre-study stage based on the historical literature.
With such a low effectiveness result, the panel will be asked to comment
on the indications for the device and what population might benefit from
this device.

**[Labeling]{.underline}**

In the draft instructions for use, (Volume 2, Tab VIIIa., page 1/6,) the
section entitled "Mechanism of Action" describes the "biomechanical
effects on the implanted and adjacent levels," and provides values
describing the kinematics, spinal canal and foraminal dimensions,
intervertebral disc pressures, restoration of disc height, sagittal
balance and facet loads. This reference is found in Amendment 3,
Attachment J.

The sponsor has not made a link between the findings of the cadaveric
study and the clinical study with respect to the biomechanical effects
of the device. Data collected in the cadaveric study were different than
that collected in the clinical trial. Axial MRI images were obtained
from cadaver specimens, allowing for measurements of the area of the
spinal canal, while plain film radiographs were used in the Pivotal
Trial, from which this measurement cannot be made. Measurements made
from radiographs show no significant differences between the X STOP and
the control group in measurements of the L1-L5 coronal curve or the
L1-L5 angulation at 24 month follow-up. These data are included in Table
52 (Vol 1, p 91) of the PMA

Enclosure: The Zurich Claudication Questionnaire is attached.

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