**SUMMARY OF SAFETY AND EFFECTIVENESS DATA**

Spectranetics Corporation

2 September 2003

***[L]{.underline}ASER [A]{.underline}NGIOPLASTY FOR
[C]{.underline}RITICAL LIMB [I]{.underline}SCHEMIA***

***LACI***

TABLE OF CONTENTS:

I. General Information [3](#i.-general-information)

II\. Intended Use/Indications [3](#ii.-intended-useindications)

III\. Device Description [3](#iii.-device-description)

IV\. Contraindications, Warnings, and Precautions
[4](#iv.-contraindications-warnings-and-precautions)

Contraindications:
......................................................................
[4](#contraindications)

Warnings:
.................................................................................
[4](#warnings)

Precautions:
...........................................................................\...
[5](#precautions)

V. Alternative Practices and Procedures
[6](#v.-alternative-practices-and-procedures)

VI\. Marketing History [8](#vi.-marketing-history)

VII\. Potential Adverse Effects of the Device on Health
[8](#vii.-potential-adverse-effects-of-the-device-on-health)

VIII\. Summary of Pre-Clinical Studies
[9](#viii.-summary-of-pre-clinical-studies)

Biocompatibility:
.........................................................................
[9](#biocompatibility)

Bench Testing:
........................................................................\...
[9](#bench-testing)

IX\. Summary of Clinical Studies [10](#ix.-summary-of-clinical-studies)

Design:
....................................................................................
[10](#design)

Methods:
..................................................................................
[10](#methods)

Patient Population and Demographics:
...........................................
[11](#patient-population-and-demographics)

Data Analysis and Results:
...........................................................
[15](#data-analysis-and-results)

Figure 4: Adjudicated serious adverse events, Registry Group

vs. Control Group
.........................................................
[16](#figure-4-adjudicated-serious-adverse-events-registry-group-vs.-control-group)

Device Failures and Replacements:
.............................................\...
[19](#device-failures-and-replacements)

X. Conclusions Drawn from the LACI Phase 2 Clinical Trial
[19](#x.-conclusions-drawn-from-the-laci-phase-2-clinical-trial)

Protocol Endpoints:
..................................................................\...
[19](#protocol-endpoints)

Risk Benefit Statement for LACI as Alternative CLI Treatment:
............
[20](#risk-benefit-statement-for-laci-as-alternative-cli-treatment)

REFERENCES [20](#references)

ATTACHMENT Risk Management Table [23](#attachment)

**SUMMARY OF SAFETY AND EFFECTIVENESS DATA**

**Spectranetics Corporation**

draft 27 August 2003

**[L]{.underline}ASER [A]{.underline}NGIOPLASTY FOR
[C]{.underline}RITICAL LIMB [I]{.underline}SCHEMIA - LACI**

# I. General Information

+-------------------------+--------------------------------------------+
| Device Generic Name:    | Laser Catheter                             |
+-------------------------+--------------------------------------------+
|                         |                                            |
+-------------------------+--------------------------------------------+
| Device Trade Names:     | Vitesse Catheters                          |
|                         |                                            |
|                         | Models 110-003, 114-009, 117-016, 120-009  |
+-------------------------+--------------------------------------------+
|                         | Vitesse E Catheter                         |
|                         |                                            |
|                         | Model 120-008                              |
+-------------------------+--------------------------------------------+
|                         | Extreme Catheters                          |
|                         |                                            |
|                         | Models 110-001, 110-002, 114-001, 220-001, |
|                         | 222-005, 225-004                           |
+-------------------------+--------------------------------------------+
|                         | Extreme II Catheters                       |
|                         |                                            |
|                         | Models 220-006, 223-001, and 225-010       |
+-------------------------+--------------------------------------------+
|                         |                                            |
+-------------------------+--------------------------------------------+
| Applicant's Name and    | Spectranetics Corporation                  |
| Address:                |                                            |
|                         | 96 Talamine Court                          |
|                         |                                            |
|                         | Colorado Springs, Colorado 8097            |
+-------------------------+--------------------------------------------+
|                         |                                            |
+-------------------------+--------------------------------------------+
| PMA Application Number: | PMA P910001 / Supplement 022               |
+-------------------------+--------------------------------------------+
|                         |                                            |
+-------------------------+--------------------------------------------+

# II. Intended Use/Indications

Facilitation of limb salvage in patients with critical limb ischemia
(associated with Rutherford Categories 4, 5 and 6) who have
angiographically evident culprit stenoses and/or occlusions in the SFA,
popliteal and/or infrapopliteal arteries, who are poor surgical
candidates, and who are acceptable candidates for revascularization.

# III. Device Description

Spectranetics Excimer Laser Atherectomy (ELA) catheters consist of a
bundle of optical fibers, arranged around a guidewire lumen. Two (2)
basic types of ELA catheters have been evaluated regarding Laser
Angioplasty for Critical Limb Ischemia (LACI): Extreme^®^ brand
catheters are over-the-wire (OTW) models; Vitesse^®^ brand catheters are
rapid exchange (Rx) models. All models consist of a proximal length,
which couples exclusively with the Spectranetics CVX 300 Excimer Laser,
and a distal portion having direct patient contact. In Extreme models, a
bifurcation at the juncture of the proximal and distal catheter portions
permits insertion of an appropriately sized guidewire (between 0.014"
and 0.035" diameter) through the lumen of the catheter. In Vitesse
models, the guidewire lumen begins 9 cm from the distal tip, to
facilitate speedier removal of the laser catheter.

Within the Extreme catheter family, the Extreme catheter models are OTW
devices originally designed for coronary applications. The Extreme II
catheter models comprise larger-diameter OTW devices (from 2.0 mm to 2.5
mm diameter) with increased pushability requested by physicians for use
in the legs. All catheters in the Extreme family have a fiber bundle
that is concentrically and symmetrically disposed around the guidewire
lumen at the distal tip.

Within the Vitesse catheter family, all models are rapid exchange, but
models with specific features can be distinguished. Catheters with the
simple name \"Vitesse\" have a fiber bundle that is concentrically and
symmetrically disposed around the guidewire lumen at the distal tip. The
Vitesse-E model has an eccentrically arranged fiber bundle at the distal
tip; the guidewire exits the distal tip in an off-center position.
Vitesse E models are equipped with a torque wire extending through the
distal portion of the catheter. A torque handle controls rotation of the
distal catheter tip through a full 360° arc, around the eccentrically
positioned guidewire lumen.

All ELA catheters conduct pulsed 308 nm laser light, from the CVX 300
laser source to the atherosclerotic lesion within an artery. The
ultraviolet pulses ablate and debulk the lesion as the catheter tip is
slowly advanced through the blockage, without thermal damage to
surrounding tissues. Thus, ELA has the ability to traverse long complex
vascular lesions, transforming them into treated arteries more amenable
to further intervention.

# IV. Contraindications, Warnings, and Precautions

## Contraindications:

-   No known contraindications

## Warnings:

> Spectranetics Excimer Laser Catheters require CVX-300^®^ software
> version 3.7 or higher.
>
> When the laser catheter is in the body, it should be manipulated only
> while it is under fluoroscopic observation with radiographic equipment
> that provides high quality images.

## 

The use of the CVX-300^®^ Excimer Laser System is restricted to
physicians who are trained in angioplasty, Percutaneous Transluminal
Angioplasty (PTA) and who meet the training requirements listed below.
These requirements include, but are not limited to:

1\. Training of laser safety and physics.

2\. Review of patient films of lesions that meet the indications for
use.

3\. A review of cases demonstrating the CLiRpath technique in lesions
that meet the indications for use.

4\. A review of laser operation followed by a demonstration of the
CVX-300^®^ Excimer Laser System.

5\. Hands on training with the CVX-300^®^ Excimer Laser System and
appropriate model.

6.  A fully trained Spectranetics representative will be present to
    assist for a minimum of the first three cases.

7.  Following the formal training session, Spectranetics will make
    available additional training if so requested by the physician,
    support personnel, the institution or Spectranetics.

## Precautions:

> This catheter has been sterilized using Ethylene Oxide and is supplied
> STERILE. The device is designated and intended for **SINGLE USE ONLY**
> and must not be resterilized and/or reused.
>
> Store in a cool, dry place. Protect from direct sunlight and high
> temperatures *(greater than 60°C or 140°F)*.
>
> The sterility of the product is guaranteed only if the package is
> unopened and undamaged. Prior to use, visually inspect the sterile
> package to ensure that the seals have not been broken. Do not use the
> catheter if the integrity of the package has been compromised. Do not
> use catheter product if its "Use Before Date," found on package
> labeling, has been passed.
>
> Before use, examine carefully all of the equipment to be used in the
> procedure for defects. Do not use any equipment if it is damaged.
>
> After use, dispose of all equipment in accordance with applicable
> specific requirements relating to hospital waste, and potentially
> biohazardous materials.
>
> Read the Operator's Manual (7030-0035 or 7030-0068) thoroughly before
> operating the Excimer Laser System. Pay particular attention to the
> Warnings and Responsibility section of the manual which explains
> Notes, Cautions, and Warnings to be followed to ensure safe operation
> of the CVX-300^®^.
>
> During the procedure, appropriate anticoagulant and vasodilator
> therapy must be provided to the patient per the institution's PTA
> protocol.

# V. Alternative Practices and Procedures

Unrelieved Critical Limb Ischemia (CLI) most often leads to amputation.
Up to 500,000 individuals suffer from CLI, with approximately 80,000
amputations performed annually in the United States (1). Surgical bypass
presents doctors and patients with an alternative, which is more
successful when autologous vein grafts are used than when synthetic
grafts are used (2-5). However, for the large portion of the CLI patient
population that presents with multiple profound comorbid conditions, the
option of surgical intervention carries an unacceptable risk. Renal
dysfunction, advanced cardiac disease, and a lack of veins suitable as
bypass grafts may all contribute to a patient's lack of surgical
candidacy. What are the treatment plan options for these CLI patients
presenting in ASA Class 4 or higher?

Reviewing literature data on CLI patients, one can see that there have
been three (3) options historically available to poor surgical
candidates with complex CLI. LACI does not appear as a historical
option. Treatment options appear as parallel pathways in Figure 1.

Considering each of the three (3) alternatives to LACI, for non-surgical
candidates:

*Primary amputation*, among ASA class 4 and higher patients, not only
results in a reduced perceived quality of life (6), the literature also
reports longer hospital stays of about 3 weeks for amputees (7, 8, 9)
compared to 2.6 days for LACI patients. Perioperative deaths were as
high as 11% (8) among amputees, whereas LACI intervention resulted in no
perioperative deaths. Reintevention risk was 19% for amputees (7, 8),
including conversions from below-the-knee to above-the-knee surgeries,
compared to 15% for LACI, and up to 11% of the amputations resulted in
non-healing wounds (8).

*Medication* for CLI, referred to as "conservative" treatment, has
reportedly resulted in rates for major amputation and death equal to
between 37% and 38% (10, 11), and 8% to 42% (10, 11, 12) respectively.
These rates for LACI were only 14% and 6%, respectively, for Registry
Group patients in surgical class ASA 4 or higher. In spite of the known
high risk, the literature reports that 11% of conservatively treated CLI
patients still underwent bypass surgery.

*Percutaneous transluminal angioplasty (PTA)*, using balloons and
stents, have shown promising results in some cases (13, 14, 15).
However, in other studies certain patterns of CLI disease were
identified that are not well suited to PTA (16, 17). In cases of diffuse
lesions plaque remodeling tends to mitigate the effects of PTA. When
disease extends throughout the legs, and many sites in the
femoral-popliteal-tibial-pedal arch are blocked, PTA at a few local
sites is ineffective in establishing sufficient blood flow to help the
patient. Even when PTA is applied among CLI patients with less complex
stenotic disease patterns, LACI shows only a marginally higher
reintevention rate of 15%, compared to between 9% and 12% reported in
the literature (18, 19, 20, 21) for follow-up intervals in the 6 - 12
month range. LACI showed noticeably lower rates for bypass surgery and
major amputation (2% and 7% respectively), compared to 6-15% bypass (19,
20, 21, 22), and 9% to 21% major amputations in PTA patients.

Finally, CLI patients who underwent *bypass surgery*, in spite of
predictions that surgery would be high risk, experienced reintervention
in as many as 19% of the cases (23), and death rates of 1% to 2% within
30 days (24, 25, 26), while all LACI patients survived for at least 30
days.

The alternative treatments for CLI patients with high surgical risks are
all indicated as either unacceptable, or inferior to LACI, according to
literature references. Therefore, acknowledging there are some CLI
patients (approximately 10%) whose advanced condition leaves primary
amputation as the best alternative (27), and eliminating the portion of
the CLI population for whom PTA may be effective due to simple lesion
morphology, there remains a large segment of the CLI population without
a limb-saving treatment alternative, other than LACI.

Figure 2 depicts the revised treatment alternatives for CLI patients,
including LACI, based on the above arguments and literature data.

# VI. Marketing History

None of the Spectranetics catheter models have been previously marketed
in the USA for critical limb ischemia. Two models (the Extreme
catheters, model numbers 222-005 and 225-004) are currently CE Marked,
and have been commercially marketed in Europe since November, 1996,
without any significant complaints that required a vigilance report to
any Notified Body or Competent Authority.

# VII. Potential Adverse Effects of the Device on Health

> Use of the Spectranetics CVX-300^®^ Excimer Laser System may
> contribute to the following complications:

  ------------------------------------- ---------------------------------
  Dissection of the arterial wall       Embolization

  Acute reclosure                       Spasm

  Aneurysm formation                    Thrombus

  Nerve Injury                          Arrhythmia

  Perforation                           Hematoma

  AV fistula formation                  Death
  ------------------------------------- ---------------------------------

No long term adverse effects of peripheral excimer laser atherectomy are
known at this time.

# VIII. Summary of Pre-Clinical Studies

## Biocompatibility: 

Spectranetics has tested all of the materials used in the manufacture of
laser catheters, and shown that they conform to the provisions of ISO
10993-1, with reference to Bluebook memo G95-1. Vitesse catheter models,
previously marketed only for coronary applications, collectively
represent all of the materials used in the new models. Thus, there is no
reason to suspect detectable toxicity, or any lack of biocompatibility,
in either the previously approved, or re-designed, catheter models
suitable for LACI.

## Bench Testing:

Extreme Catheter Models -- Bench testing, for mechanical integrity, was
performed separately for the 2.2 mm and 2.5 mm Extreme catheters, which
are manufactured with metal bands at the distal catheter tip, one on the
outside diameter of the catheter, and one at the inner diameter
surrounding the guidewire lumen.

2.2 mm Extreme catheters (222-005): Testing showed 2.2 Extreme laser
catheters maintained physical integrity after fatigue, and tension in
excess of the acceptable lower limit. The distal tips of test units
showed no deterioration after artificial fatigue, and separation forces
for the metal band exceeded 5 pounds. Pull tests on the inner lumen
showed that the bond strength to the inner lumen at the catheter tip
exceeded 2 pounds, and the bond strength between the inner band and the
epoxy-bound fiber array exceeded 5 pounds. All tests exceeded the
acceptable lower limits for strength.

2.5 mm Extreme catheters ( 225-004): Tensile strength testing indicated
that tubing-to-tubing fuse had tensile strengths in excess of that
measured for the tubing alone. Fatigue and pull tests on the 2.5 mm
Extreme catheters showed that, again, the separation forces for the
outer band, inner tubing bond, and inner band-to-epoxy junctures were
\>5 pounds, \>2 pounds, and \>5 pounds, respectively, which exceeded the
acceptable lower limits for strength.

Extreme II Catheter Models (220-006, 223-001, and 225-010) -- Bench
testing for both mechanical integrity and tissue ablation interactions
were conducted on the 2.0 mm, 2.3 mm, and 2.5 mm Extreme II laser
catheters. Tissue ablation, using porcine aorta as a substrate, showed
comparable performance, and tip wear, when Extreme and Extreme II
catheters were compared. The cross-sectional ablation areas were equal
to, or greater than, the diameter of the catheter tip in each case. All
three (3) catheter sizes were able to negotiate through the iliac arch
of a model, held at 37° C, without binding

or prolapsing an appropriately sized guidewire. Finally, the mechanical
integrity of each tubing-to-tubing, or tubing-to-band, or
epoxy-to-metal, bond was checked using tensile strength as per ISO
10555-1. All bonds exceed either the 5 Newton limit for tubing with
diameters between 0.75 mm and 1.15 mm, or the 15 Newton limit for tubing
with diameters \>1.85 mm.

#  IX. Summary of Clinical Studies

## Design: 

The LACI Phase 2 (LACI 2) trial was a multicenter prospective registry
of patients, who were poor surgical candidates with critical limb
ischemia (CLI) categorized as Rutherford class 4, 5, or 6 (10). The
registry group was compared to the ICAI (Ischemia Cronica Critica degli
Arti Inferior) Study Group's historical control cohort for a randomized
trial of prostaglandin E~1~ (alprostadil-alpha-cyclodextrine, Schwarz
Pharma Italia, Milan), treatment of CLI (11). The ICAI control group
thus received standard treatment for CLI, including both invasive and
noninvasive interventions, but not prostaglandins. Thus, the ICAI
control group served as a well balanced reference to currently available
treatments for CLI.

## Methods: 

Patients were screened at twelve (12) clinical sites in the United
States and three (3) sites in Germany. Up to (3) patients at new LACI
sites[^1] were enrolled as training cases, and data was compiled
separately for the training group.

Key inclusion criteria were Rutherford class 4, 5, or 6 CLI, which had
been stable for two (2) weeks, angiographically identifiable
arterosclerotic lesions in the superficial femoral artery (SFA),
popliteal, infrapopliteal or tibial arteries, and poor surgical
candidacy. Poor surgical candidates were those with an absence of veins
suitable as autologous grafts, absence of vessels suitable as a bypass
site, and high risk of surgical complications including death. Upon
study completion, there were five (5) instances in which patients who
did not meet inclusion criteria were treated with LACI. These five (5)
patients, who presented in Rutherford class 3 without ulcers or rest
pain, were pooled into the training group at the recommendation of the
LACI Steering Committee.

The primay efficacy endpoint was limb salvage (that is, freedom from
amputation at or above the ankle) at six months, and the primary safety
endpoint was survival at 6 months. Secondary endpoints included
procedural and radiographic outcomes, and serious adverse events (SAEs).
Although the protocol did not specify that reintervention

during the follow-up period would be an SAE, the results were tabulated
as if they were, at the direction of the Data Safety Monitoring
Committee.

After recording relevant medical history, a clinician photographed
ischemia-associated ulcerations, using a digital camera with a 3x3 cm (9
cm^2^) reference target visible in the picture. Each patient leg to be
treated was angiographed and the locations of lesions, with their
percent stenoses, were recorded. Recanalization via laser atherectomy at
the target lesion(s), began with the choice of a laser catheter sized
with respect to the target vessel's diameter. In some cases, the use of
a smaller catheter was followed by a second pass with a larger laser
catheter, in order to optimize the reopening of the diseased artery.
Standard catheter insertion techniques were used, beginning with sheath
insertion. Contralateral or ipsilateral antegrade approach, in the same
direction as blood flow, was recommended in the study protocol, but not
required if other approaches were indicated. Saline infusion was
recommended, to flush blood and contrast media from the field of
laser-lesion interaction.

Upon completion of any adjunctive balloon angioplasty and/or stent
deployment, the final percent stenosis in any target lesion was visually
assessed and recorded. Follow-up visits were scheduled at 1, 3, and 6
months post-treatment. Follow-up visits included digital photography,
Rutherford classification, ankle-brachial blood pressure measurement,
records of any reinterventions including amputation since the last
visit, and general examination. Serious adverse events were reported at
the time of occurrence.

## Patient Population and Demographics: 

The LACI Registry Group contained 145 patients with 155 limbs treated,
and the Training Group contained 15 patients with 15 limbs treated. A
total of 160 patients were accounted for in both groups, with a total of
170 limbs treated. The ICAI historical control group contained 789
individuals.

The Registry Group patient descriptors were similar to the Control Group
in more than one statistic, including age, and past history of smoking.
(See Table 1.)

However, more women and more comorbidities were noted in the Registry
Group, including more hypertension, prior stroke, prior myocardial
infarction, diabetes, hypercholesterolemia, obesity, and high surgical
risk. More current smokers were treated in the Control Group. None of
these variables correlated with mortality or major amputation. Overall
the Registry Group was a more morbid patient group; the difference
between 46% of Registry Patients in ASA class 4 or higher 11% of the
Control Group (see page 415 of the ICAI paper) in a similar category has
statistical significance.

Table 1: *Baseline patient characteristics, Registry Group vs. Control
Group; Training Group*

<table style="width:100%;">
<colgroup>
<col style="width: 27%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 11%" />
<col style="width: 15%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 10%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2"><p><strong>Registry Group</strong></p>
<p>n= 145</p></td>
<td colspan="2"><strong>Control Group</strong> n=789</td>
<td></td>
<td></td>
<td></td>
<td colspan="2"><p><strong>Training</strong></p>
<p><strong>Group</strong></p>
<p>n=15</p></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td><strong>Difference</strong></td>
<td><strong>95% CI in Difference</strong></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>Age</td>
<td colspan="2"><p>72 ± 10</p>
<p>(45 - 91)</p></td>
<td colspan="2">71 ± 10</td>
<td>1</td>
<td>-0.8 to 2.8</td>
<td></td>
<td colspan="2"><p>73 ± 12</p>
<p>(52 – 91)</p></td>
</tr>
<tr class="even">
<td></td>
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td><strong>n</strong></td>
<td><strong>%</strong></td>
<td><strong>Difference</strong></td>
<td><strong>95% CI in Difference</strong></td>
<td></td>
<td><strong>n</strong></td>
<td><strong>%</strong></td>
</tr>
<tr class="odd">
<td><em><strong>Gender:</strong></em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Male</td>
<td>77</td>
<td>53%</td>
<td>572</td>
<td>72%</td>
<td>-19.4%</td>
<td>-28.5% to –10.3%</td>
<td></td>
<td>6</td>
<td>40%</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><em><strong>Previous Cardiovascular Illness:</strong></em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Stroke (CVA)</td>
<td>30</td>
<td>21%</td>
<td>92</td>
<td>12%</td>
<td>9.0%</td>
<td>1.7% to 16.4%</td>
<td></td>
<td>2</td>
<td>13%</td>
</tr>
<tr class="even">
<td>Myocardial Infarction (MI)</td>
<td>33</td>
<td>23%</td>
<td>120</td>
<td>15.%</td>
<td>7.5%</td>
<td>1.9% TO 16.1%</td>
<td></td>
<td>2</td>
<td>13%</td>
</tr>
<tr class="odd">
<td>Coronary Artery Disease (CAD)</td>
<td>72</td>
<td>50%</td>
<td>DNA</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>7</td>
<td>47%</td>
</tr>
<tr class="even">
<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><em><strong>Previous Surgical Interventions:</strong></em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Coronary Artery Bypass (CABG)</td>
<td>24</td>
<td>17%</td>
<td>DNA</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>4</td>
<td>27%</td>
</tr>
<tr class="odd">
<td>Coronary Angioplasty (PCTA)</td>
<td>21</td>
<td>14%</td>
<td>DNA</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td>13%</td>
</tr>
<tr class="even">
<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></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><em><strong>Risk Factors Present at Enrollment:</strong></em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Diabetes</td>
<td>95</td>
<td>66%</td>
<td>309</td>
<td>39%</td>
<td>26.4%</td>
<td>17.5% to 35.2%</td>
<td></td>
<td>7</td>
<td>47%</td>
</tr>
<tr class="even">
<td>Hypertension</td>
<td>121</td>
<td>83%</td>
<td>384</td>
<td>49%</td>
<td>34.8%</td>
<td>27.4% to 42.2%</td>
<td></td>
<td>12</td>
<td>80%</td>
</tr>
<tr class="odd">
<td>Hypercholesterolemia</td>
<td>81</td>
<td>56%</td>
<td>126</td>
<td>16%</td>
<td>39.9%</td>
<td>31.0% to 48.8%</td>
<td></td>
<td>8</td>
<td>53%</td>
</tr>
<tr class="even">
<td>Obesity</td>
<td>51</td>
<td>35%</td>
<td>53</td>
<td>7%</td>
<td>28.5%</td>
<td>20.1% to 36.8%</td>
<td></td>
<td>3</td>
<td>20%</td>
</tr>
<tr class="odd">
<td>Smoking Past</td>
<td>57</td>
<td>39%</td>
<td>352</td>
<td>45%</td>
<td>-5.3%</td>
<td>-14.4% to 38%</td>
<td></td>
<td>5</td>
<td>33%</td>
</tr>
<tr class="even">
<td>Smoking Current</td>
<td>20</td>
<td>14%</td>
<td>201</td>
<td>25%</td>
<td>-11.7%</td>
<td>-18.5% TO –4.9%</td>
<td></td>
<td>3</td>
<td>20%</td>
</tr>
<tr class="odd">
<td>Other</td>
<td>21</td>
<td>14%</td>
<td>DNA</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>0</td>
<td>0%</td>
</tr>
<tr class="even">
<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><em><strong>Renal Function:</strong></em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Creatinine (144)</td>
<td colspan="2">1.7 ± 1.9 (0.4 – 11)</td>
<td colspan="2">DNA</td>
<td></td>
<td></td>
<td></td>
<td colspan="2"><p>1.5 ± 1.2</p>
<p>(0.6 – 4.5)</p></td>
</tr>
<tr class="odd">
<td>BUN (140)</td>
<td colspan="2">34.0 ± 22.1 (7 – 139)</td>
<td colspan="2">DNA</td>
<td></td>
<td></td>
<td></td>
<td colspan="2"><p>26.0 ± 13.3</p>
<p>(6 – 48)</p></td>
</tr>
<tr class="even">
<td><em><strong>Poor Surgical Candidate:</strong></em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>High Surgical Risk</td>
<td>66</td>
<td>46%</td>
<td>84</td>
<td>11%</td>
<td>35%</td>
<td>27% to 44%</td>
<td></td>
<td>2</td>
<td>13%</td>
</tr>
<tr class="even">
<td>Absence of Venous Autologous Graft</td>
<td>47</td>
<td>32%</td>
<td>DNA</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>3</td>
<td>20%</td>
</tr>
<tr class="odd">
<td>Poor/No Distal</td>
<td>98</td>
<td>68%</td>
<td>DNA</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>12</td>
<td>80%</td>
</tr>
<tr class="even">
<td>Any two Reasons</td>
<td>48</td>
<td>33%</td>
<td>DNA</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>2</td>
<td>13%</td>
</tr>
<tr class="odd">
<td>Any three Reasons</td>
<td>9</td>
<td>6%</td>
<td>DNA</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>0</td>
<td>0%</td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

Notes: DNA = Data was not available for Control

Other (Risk Factors) = History of Infection, Neuropathy, Limb Pain, and
Interventions in Limbs

CLI presentation was similar between the Registry Group and the Control
Group, with the same ratios of Rutherford Category 4 (rest pain without
ulcers) and Category 5-6. (See Table 2.) The recruited LACI Registry
Group showed a noticeable similarity to the ICAI historical control
group.

Table 2: *Baseline Patient characteristics, Registry Group vs. Control
Group*

![](media/image1.wmf)

Final enrollment and patient accountability data are summarized in
Figure 3 below. ICAI control group data were extracted from the
reference paper.

Figure 3: *Patient flow in LACI Phase 2 Group and Control Group*

## Data Analysis and Results:

The fact ten (10) patients in the Registry Group had both legs treated
necessitated analysis on a per patient basis for Serious Adverse Events
such as death, myocardial infarction, and stroke. Other analyses,
including the primary endpoint, limb salvage at 6 months, were done on
per limb basis.

The primary endpoint was limb salvage (freedom from amputation above the
ankle), a short-term efficacy endpoint. Secondary endpoints, to
establish safety, included death, persistent CLI, frequency of bypass
surgery, and other events. Limb salvage rates may be calculated using
two different bases for the LACI Registry Group, either the number of
patients or the number of limbs. Also, rates may be calculated on either
an intent to treat basis, counting all Registry and Control enrollees,
or on a basis censored for deaths, lost-to-follow-up, cases with
unreliable or incomplete data, and drop outs. Tables 5 and 6 show that
limb salvage was higher for the Registry Group, regardless of basis. The
difference between Registry and control limb salvage rates is
significant (α=0.05) when the basis is all limbs (Table 3), but
insignificant based on the censored cohort (Table 4).

The number of patient limbs reaching the primary endpoint was
significantly higher in the Registry Group when compared to the
historical control. (See Table 3.) It should be noted that limb salvage
in 118, out of the 130 patients living 6 months after LACI, equals a 93%
limb salvage rate in non-morbid patients.

Table 3: Limb Salvage Rate Intent to Treat Analysis

  ------------ ------------------- -------------------- -------------------
               **LACI Registry     **Control Group**    **Difference \[95%
               Group**                                  CI\]**

  Limb salvage 76% (118/155) limbs 63% (501/789)        13% \[5%, 20%\]
                                   patients             

  Limb salvage 76% (110/145)       63% (501/789)        13% \[5%, 20%\]
               patients            patients             
  ------------ ------------------- -------------------- -------------------

Table 4: Limb Salvage Rate Censored Population Analysis

  ------------ ------------------- -------------------- -------------------
               **LACI Registry     **Control Group**    **Difference \[95%
               Group**                                  CI\]**

  Limb salvage 93% (118/127) limbs 87% (494/570)        6% \[0.5%, 12%\]
                                   patients             

  Limb salvage 92% (110/119)       87% (494/570)        6% \[-0.2%, 12%\]
               patients            patients             
  ------------ ------------------- -------------------- -------------------

The overall SAE rate for the Registry Group, including a 17% rate
(24/145 patients) for reinterventions, was 35% based on 155 legs, or 38%
(55/145) based on 145 patients. The overall SAE rate for the literature
Control Group was 30% (239/789) including 4% (34/789) reinterventions.
Death, stroke, and complication rates were either equivalent or lower
for the Registry Group when compared to the historical control. Bypass
surgery was rare in the Registry Group (2.1%), but deemed necessary in
almost one third (29.7%) of the control group. Refer to Figure 4.

Furthermore, LACI treatment led to shorter hospital stays, 3 days on the
average, for CLI patients, than that observed for the control group, 23
days on the average.

## Figure 4: Adjudicated serious adverse events, Registry Group vs. Control Group 

## ![](media/image2.wmf){width="7.295138888888889in" height="3.547222222222222in"}

## 

## 

## 

## 

## 

## 

## 

## ![](media/image3.wmf)

## 

## 

LACI treatment reduced wound areas in 41 out of 109 ulcers, for which
baseline wound area measurements were available. Eighteen (18) of the 41
improved wounds healed completely. Wound areas were measured using a
validated, software based, technique in which the areas were calculated
from digital ulcer images internally calibrated to the 9 cm^2^ target
included in each image. Most of the healing, as measured by wound area,
occurred within the first 3 months after LACI, as indicated by the small
difference between a cumulative frequency plot of ulceration size at 3
months vs. that at 6 months. For instance, Figure 5 shows that the
percentage of wounds ≤ 5 cm^2^ in area increased from a baseline of 65%
to 80% within 3 months. That is 15% of wounds observed during LACI
screening procedures healed to an area of ≤ 5 cm^2^, during the first
half of the follow-up period. The percentage of wounds ≤ 5 cm^2^ in size
increased to 82% in the time period between 3 and 6 months
post-treatment, a differential of only 2%.

Figure 5: *Cumulative Frequency of Ulceration (Wound) Areas at Baseline,
3 Months, and 6 Months*

![](media/image4.wmf){width="6.448611111111111in"
height="4.313194444444444in"}

The data presented in Table 5 indicate that the average wound area
decreased 44% within 3 months, and 50% within 6 months. In 7 cases,
wound size increased, and there were 8 cases in which wounds were lost
to amputation, totaling 15 cases in which no wound healing was
documented with certainty. Additionally, there were wounds for which the
6-month status was indeterminate. In spite of the incomplete data set,
Spectranetics is compelled to point out that many ulcerations, but not
all, heal after LACI treatment.

Table 5: *Wound Mean Areas at Baseline, 3 Months, and 6 Months, for 109
ulcers with known baseline areas*

  ---------------- ------------------ ------------------ -----------------
  *Ulcer Areas:*                                         

                                                         

                   Mean Area cm^2^ ±  Range cm^2^        Mean % Healed vs.
                   Standard Deviation                    Baseline

  Wound area at    7 ± 21             0 to 263 cm^2^     0%
  Baseline                                               

  Wound area at 3  4 ± 8              0 to 40 cm^2^      44%
  months                                                 

  Wound area at 6  3 ± 9              0 to 51 cm^2^      50%
  months                                                 

  *Numbers of                                            
  Ulcers showing                                         
  Changes after 6                                        
  Months:*                                               

                   Number of Wounds =                    
                   N                                     

  Improved         23                                    

  Healed 100%      18                                    

  Worse            7                                     

  Amputated        8                                     
  ---------------- ------------------ ------------------ -----------------

## 

## 

## 

##  

## Device Failures and Replacements:

No device failures, which required product replacement, were recorded
during the LACI Phase 2 clinical study.

# X. Conclusions Drawn from the LACI Phase 2 Clinical Trial

## Protocol Endpoints:

Primary Endpoint Efficacy-- The proportion of cases with clinical
success, i.e. limb salvage at 6 months, was nonsignificantly higher
among LACI patients than for the ICAI historical control group. The
intent-to-treat data in Table 3, of section IX above, lists clinical
success for 76% of LACI Registry Group limbs and 63% for ICAI control
group limbs. If the analysis is based on living limbs, (with the number
of deaths, cases lost follow-up, and/or cases without reliable data, are
subtracted prior to calculations) the 6-month values become 93% and 87%
for LACI patients and control patients, respectively. Even though not
statistically different, the odds of limb salvage are better after LACI.
This meets the standard for efficacy established in the LACI Phase 2
Study Protocol, in which it was hypothesized that limb salvage after
LACI would be as good as that for the ICAI control group.

Secondary Endpoints and Safety -- Rates of overall serious adverse
events (SAE's) were statistically equivalent for LACI patients vs. the
literature Control Group. The SAE rate for the Registry Group, as
reported in Figure 4 above, was 37.9%, slightly higher than the 30.3%
drawn from the ICAI publication for the Control Group. However, two (2)
mitigating points apply to the Registry Group's SAE rate. First,
post-procedural re-angioplasty was not considered a serious adverse
event according the LACI Phase 2 protocol approved under IDE #G981099.
In spite of this fact, re-interventions were tallied as part of the
reported 37.9% SAE rate. The reinterventions, representing on-going
potential for limb salvage, would likely have been impossible without
the associated original LACI success. Should reinterventions be excluded
as SAE's, the overall rate for LACI becomes significantly lower for the
Registry Group -- only 21.3%. Second, 46% of the LACI Registry Group
presented with combinations of medical conditions associated with high
risk of surgical mortality and morbidity (ASA class 4 or above), vs. 11%
in the Control Group. Significantly more comorbid conditions were
present in LACI patients, potentially leading to more adverse events
among the Registry Group. The statistically equivalent SAE rates
emphasize LACI's safety, even within a desperately ill population. Also,
the probability of surgical intervention, such as bypass and
endarterectomy, was low in the LACI Registry Group. Only 2.6% of the
Registry Group required either bypass or endarterectomy. This fact is
most significant in the CLI population, whose membership includes many
poor surgical candidates, having significant comorbidities.

Death rates were likewise statistically equivalent for the Registry and
Control Groups.

## Risk Benefit Statement for LACI as Alternative CLI Treatment:

CLI treatment plans available in the absence of LACI, as discussed in
Section V above, are all associated with higher serious adverse event
rates than is LACI, according to literature reports. Published data show
[primary amputation]{.underline} leads to more reintervention (19%) than
LACI (15.5%), not to mention the continued disease state represented by
non-healing wounds in 11% of amputees. CLI patients, treated
conservatively with [medications]{.underline}, show historical trends
toward higher rates for bypass (11%), amputation (38%), and even death
(42%), when compared to LACI. [Percutaneous Transluminal Angioplasty
(PTA),]{.underline} available only to the subset CLI patients with
relatively simple arterial lesion patterns, was associated with
amputation rates as high as 21%.

Therefore, considering three (3) points:

1)  The LACI alternative showed equivalency with the mixture of various
    treatment modes reported in the ICAI control publication, and cited
    in the approved study protocol (IDE G980199);

2)  LACI treatment presents CLI patients with improved adverse event
    rates, when specifically compared one-on-one to reported event rates
    for primary amputation, medication, and PTA; and

3)  The attached Risk Management Analysis Table, LACI presents no
    unacceptable risks, as evaluated by international standards;

then the benefits for LACI exceed the otherwise equivalent risks. The
decreased probability for serious adverse events, i.e. improved safety
when compared to literature reports for alternatives, combined with
formally equivalent efficacy data collected under the auspices of a
controlled clinical trial, fits the model for an acceptable risk/benefit
profile for a new medical device indication.

Therefore, Spectranetics believes that the results of the LACI Phase 2 ,
pivotal trial, show LACI to be both safe and efficacious. The company
furthermore believes LACI to be the best alternative treatment for CLI
patients, whose quality of life could be maintained through limb-saving
revascularization.

# REFERENCES

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3.  Whittemore A D; Autogenous saphenous vein versus PTFE bypass for
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# ATTACHMENT

**RISK MANAGEMENT TABLE**

**WITH REFERENCE TO ISO 14791**

![](media/image5.wmf){width="9.676388888888889in"
height="6.702083333333333in"}

![](media/image6.wmf)

![](media/image7.wmf){width="9.630555555555556in"
height="6.807638888888889in"}

[^1]: ^\*^ New LACI sites are those which did not participate in LACI
    Phase 1 feasibility trials.