**Clinical Review -- Restylane (P020023)**

**Introduction**

The basis of pre-marketing application P020023 is the outcome of a
prospective Pivotal Clinical Study performed in the US under
investigational device exemption along with an open label extension.

P020023 also contains an uncontrolled copy of the report of a
non-randomized an unmasked study of 112 patients that was conducted in
Sweden during 1995-6 with an earlier formulation of Restylane. The
cohort in this non-randomized and uncontrolled study included
non-pregnant and non-lactating patients with depressed cutaneous scars
and one to three facial wrinkles up to 4mm in depth; patients were
excluded if other local wrinkle therapy had been administered within 6
months prior to study due to potential confounding of Restylane's safety
and effectiveness. Of this cohort, 20 patients were randomly selected
for follow-up at 52 weeks. As the device has been re-formulated, data
from this non-randomized, uncontrolled, and unmasked study is included
only in discussion of device safety.

**Pivotal Study**

-   ***Devices***

Investigational: Restylane is a stabilized, bacterium -- generated
(non-animal) hylauronic acid suspended in physiologic buffer at pH = 7
and concentration of 20mg/ml, intended for use to correct contour
deformities, e.g., naso-labial wrinkles. Delivered during study via 0.7
cc syringe and 30 gauge x 1/2\'" needle. Maximum dose / treatment
session: 1.5 ml.

Control: Zyplast cross-linked collagen Implant is purified bovine dermal
collagen cross linked with glutaraldehyde, dispersed in phosphate
buffered saline and 0.3% lidocaine, indicated for the correction of
contour deficiencies of soft tissue. Delivered during study via 1.0 cc
syringe and fine gauge needle. Maximum dose Zyplast / year: 30 ml.

Zyderm, the non-crosslinked collagen implant analog, was used for
pre-treatment skin testing for hypersensitivity to bovine collagen.

-   ***Design***

***Highlights***

The pivotal study was a 1 to 1 randomized, prospective study conducted
at 6 US centers to compare Restylane and Zyplast in a within patient
control model of augmentation correction of bilateral nasal labial
folds: the randomized side was treated with Restylane; the opposite side
was treated with Control. Treatment was considered to be complete when
optimal correction as determined by treating physician discretion, not
by a pre-determined change in objective measure, was found to be
sustained for 2 weeks after injection. This follow-up 2 weeks
post-initial or touch-up injection began the 'Baseline' for 6, 9 and 12
month follow-up. Effectiveness was studied with 6 month follow-up from
'baseline'. Safety was studied from initial treatment and touch-up as
needed to achieve optimal correction that was sustained for 2 weeks,
through 12 month post- 'baseline' follow-up.

***Masking Plan***

-   Patient: partially masked

-   Evaluating physician: independent and masked

-   Treating physician: unmasked

***Primary Objectives***

The pivotal study primary objective was to evaluate the safety and
effectiveness of Restylane compared to Control in patients seeking
augmentation correction of bilateral nasal labial folds that met study
criteria.

-   [Effectiveness]{.underline}: the primary objective was to evaluate
    differences in effect of Restylane and Control on the visual
    severity of the nasolabial folds, as assessed by an Evaluating
    Investigator at 6 months post-'baseline'.

Optimal correction was defined to be the best cosmetic result obtainable
with 2 injectable implants as determined by the evaluating physician; a
specific objective score or goal for optimal correction was not defined.
The evaluation parameter was the Wrinkle Severity Rating Scale (SRS)
Score:

1.  Absent: no visible fold; continuous line

2.  Mild: shallow but visible fold with slight indentation; minor facial
    feature.

3.  Moderate: moderately deep fold; clear facial feature visible at
    normal appearance but not when stretched. Excellent correction
    expected.

4.  Severe: very long and deep; prominent facial feature; less than 2mm
    visible fold when stretched.

5.  Extreme: extremely deep and long folds; 2-4mm visible v-shaped fold
    when stretched; detrimental to appearance; unlikely to have
    satisfactory correction with injectable implant alone.

This scoring system was validated per review of 30 non-study photos by
Evaluating Investigators. Based on this photo review, an SRS change = 1
was considered to be clinically significant. Validation was not
confirmed by evaluation of pivotal study photos.

-   [Safety]{.underline}: the pivotal study primary objective was
    evaluation of adverse events recorded by

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-   Patient Diary: intensity and duration of pain, tenderness, swelling,
    redness, bruising and itching for 14 days post-treatment.

-   Follow-up by the unmasked treating investigator from treatment
    through 12 months.

Hypersensitivity reaction was considered as to Restylane and Control.
Pre-screening skin testing for sensitivity to the cross-linked collagen
Control, Zyplast, was performed using the non-crosslinking analog,
Zyderm. Pre-screening skin test for sensitivity to the bacterial source
hyaluronate, Restylane was not performed due to low suspicion of
hypersensitivity. No anti-body titers were drawn pre-treatment to
collagen or to hyaluronate. Post-treatment adverse event skin testing
was planned to evaluate sensitivity to hyaluronate and collagen in case
hypersensitivity reaction was suspected by the unmasked treating
investigator during follow-up. Criteria with protocol details are listed
in Appendix 1.

***Secondary objectives***

-   SRS score assessed at 2, 4, and 6 months post-'baseline' by the
    evaluating investigator and by the subject.

-   Number of treatment sessions needed to achieve optimal cosmesis.

-   Global Aesthetic Improvement (GAI): a subjective, non-validated
    scale assessed at 2, 4, and 6 months by the evaluating investigator
    and by the subject:

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-   Very much improved

-   Much improved /

-   Improved

-   No change

-   Worse

***Study Population Criteria***

Highlights:

-   Non-pregnant, non-lactating adults seeking augmentation correction
    of bilateral nasolabial folds.

-   SRS 3 or 4 at pre-treatment evaluation

-   Willing to abstain during the study from exclusion procedures, e.g.:
    Laser or chemical re-surfacing, Botox injections, aesthetic facial
    surgery, concurrent facial wrinkle treatments, immuno-modulary
    therapy, desensitization injections to meat products.

-   Without active skin disease within 6 months of study entry, known
    connective tissue disease or immunosuppressive therapy.

-   Without any aesthetic facial therapy within 6 months of study entry.

-   Without coagulopathy or known allergy / hypersensitivity or planned
    desensitization to device components or meat products.

Inclusion and Exclusion Criteria with protocol details are in Appendix
2.

***Study Procedure***

The pivotal study procedure consisted of 2 phases:

During the Treatment Phase, device doses were provided as required to
achieve optimal cosmetic result, within maximum limits per device.
Patients were re-evaluated every two weeks with touch-up if correction
was sub-optimal on follow-up. The 'baseline,' i.e.: post-treatment
baseline, began at the visit at which optimal correction had been
maintained for 2 weeks since last treatment.

Follow-up occurred by two schedules:

-   Effectiveness: At 2, 8, 16 and 24 weeks after 'baseline'

-   Safety: At 2, 8, 16, 24, 36 and 52 weeks after 'baseline'

***Sample Size***

Sample size determination was based on the hypothesis that three times
as many Restylane treated sites would remain superior compared to
control at 6 months after 'baseline'. Superiority per patient was
defined as a difference of at least 1 in the SRS score in favor of one
of the treatments. At any time, SRS per patient is determined in whole
units of SRS as the Wrinkle SRS is an integer scale. An SRS score
difference or change = 1 was considered to be clinically significant
based on the non-study photo validation study.

Minimum enrollment, accounting for potential loss to follow-up, was
statistically determined to be N = 130 patients.

-   **[Pivotal Study Outcomes]{.underline}**

***Demographics***

On the basis of this design, the study enrolled a population of
predominately healthy, female, Caucasian non-smokers with minimal sun
exposure. There were few men or other racial / ethnic groups; few
smokers or patients with extensive sun exposure. Reference: Table 11.2,
P020023, p895.

-   Gender

Male: 9 (6.6%)

Female: 128 (93.4%)

-   Ethnicity

Caucasian: 122 (89.0%)

Black: 2 (1.5%)

Asian: 2 (1.5%)

Hispanic: 11 (8.0%)

-   Tobacco use

Non-smoking: 118 (86.1%)

Smokers: 19 (13.9%)

-   Sun Exposure

None: 83 (60.6%)

Natural Sun: 52 (38.0%)

Artificial: 2 ( 1.5%)

A total of 48 patients (35.0%) had not had any previous facial aesthetic
procedures; data was missing for 6 patients; 83 patients (60.6%) had had
prior facial aesthetic procedures.

Reference: Table 11.4 & 5, P020023, p897.

-   Collagen injection 59 (43.1%)

-   Botulinum toxin injection 32 (23.4%)

-   Face-lift 16 (11.7%)

-   Laser Resurfacing 15 (11%)

-   Chemical resurfacing 12 (8.8%)

-   Autologous fat transplant 5 (3.6%)

-   Other 23 (16.8%)

***Patient Disposition***

Number of Subjects presenting at each follow-up time point:

-   Pre-treatment 138

-   'Baseline'\* 138

-   6 months 134\*\*

-   9 months 125 for safety\*\*\*

-   12 months 125 for safety

\*'Baseline' defined as the 2 week follow-up point at which optimal
correction has been maintained for 2 weeks.

\*\* 4 Patients were withdrawn / lost to follow-up before 6 months.

\*\*\* 9 Patients were withdrawn / lost to follow-up before 9 months

***Evaluating Investigator & Patient Masking Assessment***

Evaluating investigator & patient masking assessment found that the
incidence of correct guess as to treatment, for both the evaluating
investigator and patients, increased during the study from approximately
60% correct guess at baseline to 70% correct guess at 6 month follow-up.
Masking was found to vary significantly by center. An incidence of
correct guess greater than 50% is considered to suggest incomplete
masking. Therefore study masking was incomplete from baseline and
progressively less effective during the trial. Reference: Table 12.12 --
13, P020023, p915-18.

[Evaluating Investigator]{.underline} [Patient]{.underline}

Baseline Correct ***88 (64.2%) 82 (59.8%)***

Not correct 47 (34.3%) 46 (33.6%)

Total reporting 135 (98.5%) 128 (93.4%)

Month 2 Correct ***91 (66.4%) 82 (59.8%)***

Not correct 38 (27.7%) 41 (29.9%)

Total reporting 129 (94.2%) 123 (89.8%)

Month 6 Correct ***96 (70.1%) 93 (67.9%)***

Not correct 37 (27.0%) 38 (27.7%)

Total reporting 133 (97.1%) 131 (95.6%)

***Primary Effectiveness***

Comparative SRS per patient at 6 months as determined

By the evaluating investigator:

N = 137

Restylane lower (better) than Control: 80

Restylane equal to Control: 44

Restylane higher (worse) than Control: 13

Reference: P020023 A5, tab11, response to Question 10 (Appendix 3 of
this review)

With both treatments, Restylane and Control, a mean 1.5 unit improvement
of SRS was made from pre-treatment to establish optimal correction:
post-treatment 'baseline' or month 0.

SRS: Pre-treatment to Optimal: 0month 2month 4month 6month

N = 137 137 137 137 137

Restylane 0 1.5 1.25 1.01 0.93

Control 0 1.52 0.94 0.54 0.36

Difference 0 0.02 0.31 0.47 0.57

Reference: P020023 A3, appendix 25

Mean SRS Score

By evaluating investigator:

N Restylane Control Absolute Difference\*

Pre-treatment 138 3.29 3.31 0.02

Baseline 137 1.80 1.79 0.01

6 months 134 2.36 2.94 0.58

\*between Restylane and Control

Reference: P020023 A5, tab11, response to Question 10 (Appendix 3 of
this review)

Data demonstrates that while there was essentially no difference between
Restylane and Control treated cohort sides at pre-treatment (0.02 Units
SRS) and baseline (0.01 Units SRS), for the cohort of 134 patients,
there was a difference of 0.58 units of SRS at 6 months.

The difference in treatment effect for the cohort of 134 to 138 patients
based on SRS plateaus at about 0.58 at 6 months post 'baseline'. A
difference in SRS of 1 is considered to be clinically significant per
pre-study validation of the SRS scale.

***Secondary Objectives***

-   Comparative SRS per patient at 6 months as determined

By Patients

N = 137

Restylane greater (worse) than Control: 8

Restylane lower (better) than Control: 76

Restylane equal to Control: 53

Reference: P020023 A5, tab11, response to Question 10 (Appendix 3 of
this review)

-   Mean SRS Score

By Patients

N Restylane Control Absolute

Difference

Pre-treatment 138 3.33 3.37 0.04

Baseline 138 1.96 1.97 0.01

6 months 134 2.44 3.01 0.57

Reference: P020023 A5, tab11, response to Question 10 (Appendix 3 of
this review)

-   Global Aesthetic Improvement

By Evaluating Investigator

Follow-up: 0month 2month 4month 6month

N 134 136 137 137

%Restylane \> Control 3.6 38.7 56.9 62

%Restylane = Control 89 52.6 34.3 29.9

%Restylane \< Control 5.1 8 8.8 8

Reference: P020023, Table 12.9, p913

By Patient Evaluation

Follow-up: 0month 2month 4month 6month

N 133 136 137 137

%Restylane \> Control 11.7 34.3 43.1 55.5

%Restylane = Control 75.9 55.5 47.4 36.5

%Restylane \< Control 9.5 9.5 9.5 8

Reference: P020023, Table 12.11, p914

With time post-optimal cosmesis, comparing Restylane and Control, report
of the global aesthetic improvement score favoring Restylane increased.
This trend was similar for data by evaluating investigators and
patients.

-   Number of treatment sessions to achieve optimal cosmesis was
    evaluated.

For both Restylane and Control, optimal cosmesis required 1 to 3
treatments.

Optimal Cosmesis with initial treatment alone:

-   Restylane: n = 89 (65.0%)

-   Control: n = 85 (62.0%)

Optimal Cosmesis requiring 3 treatments:

-   Restylane: n = 7 (5.1%)

-   Control: n = 3 (2.2%)

Overall, no statistically significant different numbers of treatments
were required to achieve Optimal Cosmesis with Restylane or Control.

***Safety***

-   *Restylane:* Basic criteria used for some of the more frequent types
    of reaction observed after treatment with Restylane were as follows.
    Reference: P020023, p965; P020023 A3, p6.

[Hypersensitivity]{.underline}: inflammatory reaction with swelling,
redness, tenderness, induration and rarely acneform papules at the
injection site with an onset of one to several weeks after the initial
treatment in individuals not previously treated, and in \< 7 days
following treatment in patients known to have been previously exposed.
Average duration 2 weeks.

[Injection site reaction:]{.underline} a mix of different types of
reactions that do not fit with other classifications: mainly short-term
inflammatory symptoms starting early after treatment and with \< 7 days
duration.

-   *Control*: Basic criteria used for some of the more frequent
    treatment responses reported in Labeling for Control were as
    follows. Reference: P020023, p999-1000.

[Hypersensitivity]{.underline}: reactions have occurred in 1 -- 2% of
treated patients: erythema, swelling, induration, and / or urticaria at
implant sites. Typically reactions persist between 1 and 9 months;
average duration of 4 months.

Rarely, reactions resolve in 1 or 2 weeks, or last more than 1 year.
Rarely, abscess formation occurs, in some cases associated with elevated
anti-bovine collagen antibodies, weeks to months following injections
and may cause induration and / or scarring. Most have occurred in
patients who became sensitized to collagen implants at some point during
treatment.

[Injection site reaction]{.underline}: minimal swelling, redness, and
discomfort will probably occur immediately following implantation.
Temporary palpable lumpiness or visible material (white papules or
milia-like yellow) may occur.

-   Maximal intensity: After the initial session

Reference: P020023, Table 13.9, p 930

<table style="width:100%;">
<colgroup>
<col style="width: 11%" />
<col style="width: 13%" />
<col style="width: 13%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td><blockquote>
<p>Restylane</p>
</blockquote></td>
<td>Zyplast side</td>
<td colspan="4">Restylane side</td>
<td colspan="4">Zyplast side</td>
</tr>
<tr class="even">
<td></td>
<td><blockquote>
<p>side</p>
</blockquote></td>
<td></td>
<td colspan="4"></td>
<td colspan="4">_</td>
</tr>
<tr class="odd">
<td></td>
<td><strong>Total reporting</strong></td>
<td><strong>Total reporting</strong></td>
<td><blockquote>
<p><strong>None</strong></p>
</blockquote></td>
<td><strong>Mild</strong></td>
<td><blockquote>
<p><strong>Mode-</strong></p>
</blockquote></td>
<td><strong>Severe</strong></td>
<td><strong>None</strong></td>
<td><strong>Mild</strong></td>
<td><strong>Mode-</strong></td>
<td><strong>Severe</strong></td>
</tr>
<tr class="even">
<td></td>
<td><blockquote>
<p><strong>symptoms</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>symptoms</strong></p>
</blockquote></td>
<td></td>
<td></td>
<td><strong>rate</strong></td>
<td></td>
<td></td>
<td></td>
<td><blockquote>
<p><strong>rate</strong></p>
</blockquote></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td><blockquote>
<p><strong>n (%)</strong></p>
</blockquote></td>
<td><strong>n %~</strong></td>
<td><blockquote>
<p><strong>n (%)</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>n %~</strong></p>
</blockquote></td>
<td><blockquote>
<p><strong>n</strong> (<sup>o</sup>/~~</p>
</blockquote></td>
<td>n (%)</td>
<td>n (%)</td>
<td><blockquote>
<p>n (%)</p>
</blockquote></td>
<td>n %~</td>
<td>n (%)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Bruising</p>
</blockquote></td>
<td><blockquote>
<p>72 (52.2)</p>
</blockquote></td>
<td><blockquote>
<p>67 (48.6)</p>
</blockquote></td>
<td>63</td>
<td>32</td>
<td>35</td>
<td>5</td>
<td>68</td>
<td>43</td>
<td><blockquote>
<p>23</p>
</blockquote></td>
<td>1</td>
</tr>
<tr class="odd">
<td></td>
<td><blockquote>
<p>-</p>
<p>--</p>
</blockquote></td>
<td></td>
<td><blockquote>
<p>(45.6)</p>
</blockquote></td>
<td><blockquote>
<p>(23.2)</p>
</blockquote></td>
<td><blockquote>
<p>(25.4)</p>
</blockquote></td>
<td>(3.6)</td>
<td>(493)</td>
<td><blockquote>
<p>(31.2)</p>
</blockquote></td>
<td>(16.7)</td>
<td>(0.7)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Redness</p>
</blockquote></td>
<td>% l l7 (84.8)1 ;</td>
<td><blockquote>
<p>117 (84.8)</p>
</blockquote></td>
<td>17</td>
<td>56</td>
<td>54</td>
<td>7</td>
<td>17</td>
<td>72</td>
<td><blockquote>
<p>37</p>
</blockquote></td>
<td>8</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td><blockquote>
<p>(12.3)</p>
</blockquote></td>
<td><blockquote>
<p>(40.6)</p>
</blockquote></td>
<td><blockquote>
<p>(39.1)</p>
</blockquote></td>
<td>(5.1)</td>
<td>(12.3)</td>
<td><blockquote>
<p>(52.2)</p>
</blockquote></td>
<td>(26.8)</td>
<td>(5.8)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Swelling</p>
</blockquote></td>
<td><blockquote>
<p>120 (87.0)</p>
</blockquote></td>
<td><blockquote>
<p>102 (73.9)</p>
</blockquote></td>
<td>14</td>
<td>54</td>
<td>61</td>
<td>5</td>
<td>32</td>
<td>65</td>
<td><blockquote>
<p>35</p>
</blockquote></td>
<td>2</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td><blockquote>
<p>(10.1)</p>
</blockquote></td>
<td><blockquote>
<p>(39.1)</p>
</blockquote></td>
<td><blockquote>
<p>(44.2)</p>
</blockquote></td>
<td>(3.6)</td>
<td>(23.2)</td>
<td><blockquote>
<p>(47.1)</p>
</blockquote></td>
<td>(25.4)</td>
<td>(1.4)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Pain</p>
</blockquote></td>
<td><blockquote>
<p>79 (57.2)</p>
</blockquote></td>
<td><blockquote>
<p>58 (42.0)</p>
</blockquote></td>
<td>55</td>
<td>40</td>
<td>34</td>
<td>5</td>
<td>76</td>
<td>46</td>
<td><blockquote>
<p>10</p>
</blockquote></td>
<td>2</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td><blockquote>
<p>(39.9)</p>
</blockquote></td>
<td><blockquote>
<p>(29.0)</p>
</blockquote></td>
<td><blockquote>
<p>(24.6)</p>
</blockquote></td>
<td>(3.6)</td>
<td>(55.1)</td>
<td><blockquote>
<p>(33.3)</p>
</blockquote></td>
<td>(7.2)</td>
<td>(1.4)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Tendernesss</p>
</blockquote></td>
<td><blockquote>
<p>107 (77.5)</p>
</blockquote></td>
<td><blockquote>
<p>89 (64.5)</p>
</blockquote></td>
<td>27</td>
<td>60</td>
<td>43</td>
<td>4</td>
<td>45</td>
<td>70</td>
<td><blockquote>
<p>17</p>
</blockquote></td>
<td>2</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td><blockquote>
<p>(19.6)</p>
</blockquote></td>
<td><blockquote>
<p>(43.5)</p>
</blockquote></td>
<td><blockquote>
<p>(31.2)</p>
</blockquote></td>
<td>(2.9)</td>
<td>(32.6)</td>
<td><blockquote>
<p>(50.7)</p>
</blockquote></td>
<td>(12.3)</td>
<td>(1.4)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Itching</p>
</blockquote></td>
<td><blockquote>
<p>42 (30.4)</p>
</blockquote></td>
<td><blockquote>
<p>33 (23.9)</p>
</blockquote></td>
<td>91</td>
<td>31</td>
<td>11</td>
<td>0</td>
<td>101</td>
<td>27</td>
<td><blockquote>
<p>6</p>
</blockquote></td>
<td>0</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td><blockquote>
<p>(65.9)</p>
</blockquote></td>
<td><blockquote>
<p>(22.5)</p>
</blockquote></td>
<td><blockquote>
<p>(8.0)</p>
</blockquote></td>
<td>(0.0)</td>
<td>(73.2)</td>
<td><blockquote>
<p>(19.6)</p>
</blockquote></td>
<td>(4.4)</td>
<td>(0.0)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Other</p>
</blockquote></td>
<td><blockquote>
<p>34 (24.6)</p>
</blockquote></td>
<td><blockquote>
<p>33 (23.9)</p>
</blockquote></td>
<td>93</td>
<td>14</td>
<td>15</td>
<td>5</td>
<td>94</td>
<td>20</td>
<td><blockquote>
<p>10</p>
</blockquote></td>
<td>3</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td><blockquote>
<p>(67.4)</p>
</blockquote></td>
<td><blockquote>
<p>(10.1)</p>
</blockquote></td>
<td><blockquote>
<p>(10.9)</p>
</blockquote></td>
<td>(3.6)</td>
<td>(68.1)</td>
<td><blockquote>
<p>(14.5)</p>
</blockquote></td>
<td>(7.2)</td>
<td>(2.2)</td>
</tr>
</tbody>
</table>

Data indicate that there was an increased incidence of bruising,
swelling, pain, tenderness and itching after first treatment with
Restylane compared to Control.

-   Maximal intensity: After touch-ups

Reference: P020023, Table 13.10, p 931

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2"><blockquote>
<p>Res lane side</p>
</blockquote></td>
<td colspan="2"><blockquote>
<p>Z plast side</p>
</blockquote></td>
<td colspan="4"><blockquote>
<p>Restylane side</p>
</blockquote></td>
<td colspan="4">Zyplast side ,</td>
</tr>
<tr class="even">
<td></td>
<td><blockquote>
<p>Total</p>
</blockquote>
<p>reporting</p>
<p>n</p></td>
<td><p>Not</p>
<p>reporting</p>
<p>n</p></td>
<td><p>Total</p>
<p>reporting</p>
<blockquote>
<p>n</p>
</blockquote></td>
<td><p>Not</p>
<p>reporting</p>
<p>n</p></td>
<td><p>None</p>
<blockquote>
<p>n</p>
</blockquote></td>
<td><p>Mild</p>
<blockquote>
<p>n</p>
</blockquote></td>
<td><p>Mode-</p>
<blockquote>
<p>rate</p>
<p>n</p>
</blockquote></td>
<td><p>Severe</p>
<p>n</p></td>
<td><p>None</p>
<blockquote>
<p>n</p>
</blockquote></td>
<td><p>Mild</p>
<blockquote>
<p>n</p>
</blockquote></td>
<td><p>Mode-</p>
<blockquote>
<p>rate</p>
<p>n</p>
</blockquote></td>
<td><p>Severe</p>
<p>n</p></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Bruisin</p>
</blockquote></td>
<td>43</td>
<td>6</td>
<td>44</td>
<td>9</td>
<td><blockquote>
<p>24</p>
</blockquote></td>
<td><blockquote>
<p>11</p>
</blockquote></td>
<td><blockquote>
<p>6</p>
</blockquote></td>
<td>2</td>
<td><blockquote>
<p>25</p>
</blockquote></td>
<td><blockquote>
<p>11</p>
</blockquote></td>
<td><blockquote>
<p>6</p>
</blockquote></td>
<td>2</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Redness</p>
</blockquote></td>
<td>43</td>
<td>6</td>
<td><u>44</u></td>
<td>9</td>
<td><blockquote>
<p>8</p>
</blockquote></td>
<td><blockquote>
<p>16</p>
</blockquote></td>
<td><blockquote>
<p>14</p>
</blockquote></td>
<td>5</td>
<td><blockquote>
<p>5</p>
</blockquote></td>
<td><blockquote>
<p>18</p>
</blockquote></td>
<td><blockquote>
<p>17</p>
</blockquote></td>
<td>4</td>
</tr>
<tr class="odd">
<td><blockquote>
<p><u>Swelling</u></p>
</blockquote></td>
<td>43</td>
<td>6</td>
<td>44</td>
<td>9</td>
<td><blockquote>
<p>8</p>
</blockquote></td>
<td><blockquote>
<p>18</p>
</blockquote></td>
<td><blockquote>
<p>14</p>
</blockquote></td>
<td>3</td>
<td><blockquote>
<p>9</p>
</blockquote></td>
<td><blockquote>
<p>23</p>
</blockquote></td>
<td><blockquote>
<p>10</p>
</blockquote></td>
<td>2</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Pain</p>
</blockquote></td>
<td>43</td>
<td>6</td>
<td>44</td>
<td>9</td>
<td><blockquote>
<p>21</p>
</blockquote></td>
<td><blockquote>
<p>14</p>
</blockquote></td>
<td><blockquote>
<p>7</p>
</blockquote></td>
<td>1</td>
<td><blockquote>
<p>29</p>
</blockquote></td>
<td><blockquote>
<p>7</p>
</blockquote></td>
<td><blockquote>
<p>7</p>
</blockquote></td>
<td>1</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Tenderness</p>
</blockquote></td>
<td>43</td>
<td>6</td>
<td>44</td>
<td>9</td>
<td><blockquote>
<p>9</p>
</blockquote></td>
<td><blockquote>
<p>19</p>
</blockquote></td>
<td><blockquote>
<p>13</p>
</blockquote></td>
<td>2</td>
<td><blockquote>
<p>16</p>
</blockquote></td>
<td><blockquote>
<p>19</p>
</blockquote></td>
<td><blockquote>
<p>8</p>
</blockquote></td>
<td>1</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Itching</p>
</blockquote></td>
<td>43</td>
<td>6</td>
<td>44</td>
<td>9</td>
<td><blockquote>
<p>34</p>
</blockquote></td>
<td><blockquote>
<p>5</p>
</blockquote></td>
<td><blockquote>
<p>2</p>
</blockquote></td>
<td>2</td>
<td><blockquote>
<p>31</p>
</blockquote></td>
<td><blockquote>
<p>6</p>
</blockquote></td>
<td><blockquote>
<p>5</p>
</blockquote></td>
<td>2</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Other</p>
</blockquote></td>
<td>41</td>
<td>8</td>
<td>44</td>
<td>9</td>
<td><blockquote>
<p>36</p>
</blockquote></td>
<td><blockquote>
<p>3</p>
</blockquote></td>
<td><blockquote>
<p>2</p>
</blockquote></td>
<td>0</td>
<td><blockquote>
<p>38</p>
</blockquote></td>
<td><blockquote>
<p>0</p>
</blockquote></td>
<td><blockquote>
<p>6</p>
</blockquote></td>
<td>0</td>
</tr>
</tbody>
</table>

The incidence of most reactions was lower for both treatments after the
touch-up injections, than after the initial injection.

P-values for difference between treatments after initial session and
after all touch-ups comparing Restylane and Control categories:
none/mild and moderate/severe.

Reference: P020023 A3, Tab 11, response to Question 3b.

[After initial session]{.underline} [After all touch-ups]{.underline}

N Control, n = 138 Control, n = 53 Restylane, n = 138 Restylane, n = 49

Bruising 0.0025 1.000

Redness 0.0139 1.000

Swelling \<0.0001 0.125

Pain \<0.0001 1.000

Tenderness \<0.0001 0.125

Itching 0.0625 0.2500

Other 0.1185 0.2500

This table presents p-values for difference between Restylane and
Control reports of 2 groups: those with none or mild symptoms, and those
with moderate or severe symptoms, and demonstrates that there was a
statistically significant difference between treatments as to maximal
symptom intensity for bruising, redness, swelling, pain and tenderness,
as well as a trend towards a statistically significant difference for
itching.

Symptom Duration: after initial session

Reference: P020023, Table 13.11, p 932

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td>!~</td>
<td colspan="2">Restylane</td>
<td colspan="2"><blockquote>
<p>Zyplast</p>
</blockquote></td>
<td colspan="4">Restylane side</td>
<td colspan="4"><blockquote>
<p>Zyplast side</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">side</td>
<td colspan="2">side</td>
<td colspan="4"></td>
<td colspan="4"></td>
</tr>
<tr class="odd">
<td></td>
<td>Total</td>
<td>Not</td>
<td><blockquote>
<p>Total</p>
</blockquote></td>
<td>Not</td>
<td></td>
<td><blockquote>
<p>Number</p>
</blockquote></td>
<td>of days</td>
<td></td>
<td></td>
<td><blockquote>
<p>Number</p>
</blockquote></td>
<td>of days</td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>repor</td>
<td>repor</td>
<td><blockquote>
<p>repor</p>
</blockquote></td>
<td>repor</td>
<td>1</td>
<td>2-7</td>
<td>8-13</td>
<td><blockquote>
<p>14-</p>
</blockquote></td>
<td><blockquote>
<p>1</p>
</blockquote></td>
<td><blockquote>
<p>2-7</p>
</blockquote></td>
<td><blockquote>
<p>8-13</p>
</blockquote></td>
<td><blockquote>
<p>14-~</p>
</blockquote></td>
</tr>
<tr class="odd">
<td></td>
<td>-tin-,</td>
<td>-frog</td>
<td><blockquote>
<p>-tmg</p>
</blockquote></td>
<td>-tine</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>n</td>
<td>n</td>
<td><blockquote>
<p>n</p>
</blockquote></td>
<td>n</td>
<td>n (%)</td>
<td><blockquote>
<p>n (%)</p>
</blockquote></td>
<td>n (%)</td>
<td><blockquote>
<p>n (%)</p>
</blockquote></td>
<td><blockquote>
<p>n (%)</p>
</blockquote></td>
<td><blockquote>
<p>n (%)</p>
</blockquote></td>
<td><blockquote>
<p>n</p>
</blockquote></td>
<td></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Bruising</p>
</blockquote></td>
<td>135</td>
<td>3</td>
<td><blockquote>
<p>135</p>
</blockquote></td>
<td>3</td>
<td>7</td>
<td>56</td>
<td>6</td>
<td><blockquote>
<p>3</p>
</blockquote></td>
<td><blockquote>
<p>7</p>
</blockquote></td>
<td><blockquote>
<p>53</p>
</blockquote></td>
<td>5</td>
<td><blockquote>
<p>2</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>(5.1)</td>
<td>(40.6)</td>
<td>(4.4)</td>
<td><blockquote>
<p>(2.2)</p>
</blockquote></td>
<td><blockquote>
<p>(5.1)</p>
</blockquote></td>
<td><blockquote>
<p>(38.4)</p>
</blockquote></td>
<td>(3.6)</td>
<td>(1.4)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Redness</p>
</blockquote></td>
<td>134</td>
<td>4</td>
<td><blockquote>
<p>134</p>
</blockquote></td>
<td>4</td>
<td>19</td>
<td>68</td>
<td>18</td>
<td><blockquote>
<p>12</p>
</blockquote></td>
<td><blockquote>
<p>19</p>
</blockquote></td>
<td><blockquote>
<p>71</p>
</blockquote></td>
<td>15</td>
<td><blockquote>
<p>12</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>(13.8)</td>
<td>(49.3)</td>
<td>(13.0)</td>
<td><blockquote>
<p>(8.7)</p>
</blockquote></td>
<td><blockquote>
<p>(13.8)</p>
</blockquote></td>
<td><blockquote>
<p>(51.4)</p>
</blockquote></td>
<td>(10.9)</td>
<td>(8.7)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Swelling</p>
</blockquote></td>
<td>134</td>
<td>4</td>
<td><blockquote>
<p>134</p>
</blockquote></td>
<td>4</td>
<td>16</td>
<td>84</td>
<td>16</td>
<td><blockquote>
<p>4</p>
</blockquote></td>
<td><blockquote>
<p>14</p>
</blockquote></td>
<td><blockquote>
<p>70</p>
</blockquote></td>
<td>16</td>
<td><blockquote>
<p>2</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>(11.6)</td>
<td>60.9)</td>
<td>(11.6)</td>
<td><blockquote>
<p>(2.9)</p>
</blockquote></td>
<td><blockquote>
<p>(10.1)</p>
</blockquote></td>
<td><blockquote>
<p>(50.7)</p>
</blockquote></td>
<td>(11.6)</td>
<td>(1.4)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Pain</p>
</blockquote></td>
<td>134</td>
<td>4</td>
<td><blockquote>
<p>134</p>
</blockquote></td>
<td>4</td>
<td>29</td>
<td>48</td>
<td>2</td>
<td colspan="2"><blockquote>
<p>0 31</p>
</blockquote></td>
<td><blockquote>
<p>25</p>
</blockquote></td>
<td>1</td>
<td><blockquote>
<p>1</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>(21.0)</td>
<td>(34.8)</td>
<td>(1.4)</td>
<td colspan="2"><blockquote>
<p>(0.0) (22.5)</p>
</blockquote></td>
<td><blockquote>
<p>(18.1)</p>
</blockquote></td>
<td>(0.7)</td>
<td>(0.7)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Tenderness</p>
</blockquote></td>
<td>134</td>
<td>4</td>
<td><blockquote>
<p>134</p>
</blockquote></td>
<td>4</td>
<td>21</td>
<td>78</td>
<td>6</td>
<td colspan="2"><blockquote>
<p>2 27</p>
</blockquote></td>
<td><blockquote>
<p>54</p>
</blockquote></td>
<td>6</td>
<td><blockquote>
<p>2</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>(15.2)</td>
<td>(56.5)</td>
<td>(4.4)</td>
<td colspan="2"><blockquote>
<p>(1.4) (19.6)</p>
</blockquote></td>
<td><blockquote>
<p>(39.1)</p>
</blockquote></td>
<td>(4.4)</td>
<td>(1.4)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Itching</p>
</blockquote></td>
<td>133</td>
<td>5</td>
<td><blockquote>
<p>134</p>
</blockquote></td>
<td>4</td>
<td>' 11</td>
<td>25</td>
<td>6</td>
<td colspan="2"><blockquote>
<p>0 8</p>
</blockquote></td>
<td><blockquote>
<p>22</p>
</blockquote></td>
<td>3</td>
<td><blockquote>
<p>0</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>(8.0)</td>
<td>(18.1)</td>
<td>(4.4)</td>
<td colspan="2"><blockquote>
<p>(0.0) (5.8)</p>
</blockquote></td>
<td><blockquote>
<p>(15.9)</p>
</blockquote></td>
<td>(2.2)</td>
<td>(0.0)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Other</p>
</blockquote></td>
<td>127</td>
<td>11</td>
<td colspan="2"><blockquote>
<p>127 11</p>
</blockquote></td>
<td>7</td>
<td>23</td>
<td>3</td>
<td colspan="2"><blockquote>
<p>1 10</p>
</blockquote></td>
<td><blockquote>
<p>15</p>
</blockquote></td>
<td>6</td>
<td><blockquote>
<p>2</p>
</blockquote></td>
</tr>
<tr class="even">
<td></td>
<td></td>
<td></td>
<td colspan="2"></td>
<td>(5.1)</td>
<td>(16.7)</td>
<td>(2.2)</td>
<td colspan="2"><blockquote>
<p>(0.7) (7.2)</p>
</blockquote></td>
<td><blockquote>
<p>(10.9)</p>
</blockquote></td>
<td>(4.4)</td>
<td>(1.4)</td>
</tr>
</tbody>
</table>

-   Symptom Duration: after all touch-ups

Reference: P020023, Table 13.12, p 932

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 17%" />
<col style="width: 16%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td>R<u>estyla</u>ne <u>side</u></td>
<td>Zyplast_sidee</td>
<td colspan="4">Restylane _side _</td>
<td colspan="4">Zy<u>plast side</u></td>
</tr>
<tr class="even">
<td></td>
<td>Total reporting</td>
<td>Total reporting</td>
<td colspan="4">Number of days</td>
<td colspan="4">Number of da s</td>
</tr>
<tr class="odd">
<td></td>
<td><p>symptoms</p>
<blockquote>
<p>n</p>
</blockquote></td>
<td><p>symptoms</p>
<p>n</p></td>
<td><p>1</p>
<p>n</p></td>
<td><blockquote>
<p>2-7</p>
<p>n</p>
</blockquote></td>
<td><p>8-13</p>
<p>n</p></td>
<td><p>14-</p>
<p>n</p></td>
<td><p>1</p>
<p>n</p></td>
<td><p>2-7</p>
<p>n</p></td>
<td><p>8-13</p>
<p>n</p></td>
<td><p>14­</p>
<p>n</p></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Bruising</p>
</blockquote></td>
<td><blockquote>
<p>19</p>
</blockquote></td>
<td>19</td>
<td>3</td>
<td><blockquote>
<p>12</p>
</blockquote></td>
<td>3</td>
<td>1</td>
<td>2</td>
<td>14</td>
<td>1</td>
<td>2</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Redness</p>
</blockquote></td>
<td><blockquote>
<p>35</p>
</blockquote></td>
<td>39</td>
<td>4</td>
<td><blockquote>
<p>18</p>
</blockquote></td>
<td>6</td>
<td>7</td>
<td>6</td>
<td>15</td>
<td>6</td>
<td>12</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Swellimv</p>
</blockquote></td>
<td><blockquote>
<p>35</p>
</blockquote></td>
<td>35</td>
<td>4</td>
<td><blockquote>
<p>24</p>
</blockquote></td>
<td>4</td>
<td>3</td>
<td>8</td>
<td>20</td>
<td>4</td>
<td>3</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Pain</p>
</blockquote></td>
<td><blockquote>
<p>22</p>
</blockquote></td>
<td>15</td>
<td>11</td>
<td><blockquote>
<p>10</p>
</blockquote></td>
<td>! 1</td>
<td>0</td>
<td>6</td>
<td>9</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Tenderness</p>
</blockquote></td>
<td><blockquote>
<p>34</p>
</blockquote></td>
<td>28</td>
<td>6</td>
<td><blockquote>
<p>26</p>
</blockquote></td>
<td>2</td>
<td>0</td>
<td>7</td>
<td>16</td>
<td>5</td>
<td>0</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Itching</p>
</blockquote></td>
<td><blockquote>
<p>9</p>
</blockquote></td>
<td>13</td>
<td>3</td>
<td>3</td>
<td>3</td>
<td>0</td>
<td>2</td>
<td>6</td>
<td>3</td>
<td>2</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Other</p>
</blockquote></td>
<td><blockquote>
<p>5</p>
</blockquote></td>
<td>6</td>
<td>1</td>
<td>3</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>2</td>
<td>2</td>
<td>2</td>
</tr>
</tbody>
</table>

Clinical trials have not evaluated anti-body titers before or after
treatment with Restylane to allow correlation of symptoms with immune
response, and so to objectively characterize the symptom profile
associated with immune response to Restylane. The overlap of symptom
profiles for Restylane hypersensitivity and injection site reactions,
and lack of correlation of symptoms with anti-body titers, may have
confounded diagnosis of hypersensitivity reaction to the investigational
device during the pivotal trial.

**[Open Label Extension]{.underline}**

-   ***Design***

The open label extension of the pivotal trial allowed study participants
to receive uni-lateral or bilateral re-treatment with Restylane at the 6
or 9 month visits, while continuing accrual of safety data for the
pivotal trial.

-   For patients who were re-treated, efficacy was assessed before
    re-treatment, not after re-treatment.

-   For patients who were not re-treated, no efficacy assessment was
    made beyond 6 months.

Hypotheses:

Efficacy: Restylane is superior to Zyplast 3 times as frequently as
Zyplast is superior to Restylane.

Safety: pivotal protocol continued.

-   ***Outcomes***

Number of Patients: for Safety for Effectiveness Re-treated

Pre-treatment 138 138

Baseline 138 138

6 months 134\* 134 100

9 months 125 for safety\*\* 34 28

12 months 125 for safety 7

Assessment of Pivotal Study treatment effectiveness at 9 or 12 months is
limited as

100 of 138: 72.5 % of Pivotal Study patients were re-treated at 6
months.

34 of 138: 24.6 % of Pivotal Study patients presented for effectiveness
at 9 months.

7 of 138: 5.0 % of Pivotal Study patients presented for effectives at 12
months.

\* 4 patients withdrawn / lost to follow-up before 6 months

\*\* 9 patients withdrawn / lost to follow-up before 9 months

[**Overall Summary**\
]{.underline}Effectiveness

-   Optimal correction is achievable with both Restylane and Control by
    a mean 1.5 unit SRS increase, in a comparable number of sessions.

-   Wrinkle SRS assessment that 1 unit is a clinically significant
    change was not confirmed on study photos.

-   SRS at 6 months was clinically significantly (1 unit, minimum)
    higher for Restylane than Control in 59.7% patients, but less than
    clinically significantly higher (0.6 unit) for the overall cohort.

-   SRS at 9 and 12 months post-treatment is limited as most (72.5%)
    patients were re-treated at 6 months.

Safety

-   Hypersensitivity reaction to Restylane is reported to vary in onset
    and symptom presentation, possibly representing different mechanisms
    of reaction.

    -   Symptoms of inflammation within 14 days post-treatment were of
        statistically significantly higher intensity after initial
        treatment with Restylane compared to Control.

    -   Two papule / nodule lesions reported with onset at more than 40
        days post treatment.

-   Injection reaction and early hypersensitivity symptom profile
    overlap and may confound diagnosis of hypersensitivity reaction to a
    new product: hypersensitivity reaction may have been unrecognized.

-   Anti-body titer not evaluated; symptom profiles have not been
    correlated to immunologic change.

Appendix 1

Reference: P020023, p965 - 966

*Hypersensitivity Reactions*

Reactions thought to be of a hypersensitivity nature have been reported
in about one in every 2,000 subjects treated with Restylane®, and up to
3% of subjects treated with Zyplast® (who had a negative skin test).

In the case of Restylane® these reactions consist of swelling and
induration at the implant site, sometimes with edema in the surrounding
tissues. Erythema, tenderness and rarely acneiform papules may also
occur. The reactions started either shortly after injection or after a
delay of 2-4 weeks and were described as mild to moderate.,
self-limiting with an average duration of 2 weeks. In pronounced cases a
short course of oral steroids may prove effective.

Similar reactions have occurred in subjects receiving ZyplastO as well
as more severe systemic reactions.

If an adverse reaction occurred indicating a hypersensitivity etiology,
the subject was to be followed-up according to the schedule below:

1\. When the subject had been free of symptoms for at least two weeks, a
volume of 0.1 mL of Restylane® was implanted intradermally on the volar
aspect of the left forearm, and a Collagen Test Implant on the volar
aspect of the right forearm. The subject was to be instructed to
visually inspect the test site for reactions (see below) and to be
especially observant during the following three days.

Note: the subject was also to be instructed not to aggravate: the test
site by scratching or repeatedly touching it. On the third day following
the test injection, the Investigator was to inspect the injection site.

2\. A positive test response was defined as: any change in the original
welt (such as increased erythema, induration, tenderness or swelling)
with or without accompanying pruritus, which persisted for more than six
hours and appeared more than 2.4 hours after implantation.

3\. The readings were scored as follows:

-   No reaction

-   Doubtful reaction

-   Weak reaction (erythematous and maybe papular)

-   Strong reaction (erythematous and edematous or vesicular)

If the test response was judged to be doubtful, a second test dose was
to be administered at this same visit on the opposite arm and
evaluated/scored as described above.

4\. In case of a positive test response (weak or strong reaction) to the
Restylane® test dose, a skin sample was obtained from the test site with
a punch biopsy (2 mm). The tissue specimen was then placed in a standard
buffered formaldehyde fixative and sent to a pathologist (local
laboratory) for immuno-histochemical examination with the differential
diagnosis \"cell-mediated hypersensitivity reaction.\"

[Appendix 2]{.underline}

Reference: P020023, p857 - 9

All inclusion and none of the exclusion criteria were to be met at the
treatment visit, before the treatment was given to the subject.

*9.4.1 Inclusion Criteria*

1\. subjects who were males or non-pregnant, non-breast-feeding
females\' aged 18 years or older; and

2\. were outpatients seeking augmentation therapy for correction of
bilateral nasolabial folds. The subjects should have a score of 3 or 4
on the Severity Rating Scale; and

3\. had the ability to understand and comply with the requirements of
the study; and

4\. were willing to abstain from exclusionary procedures (e.g., further
augmentation therapy.. laser or chemical resurfacing; Botox(k
injections; facelift) for the duration of the study; and

5\. gave written informed consent to participate in the study.

9.4.2 Exclusion Criteria

Subjects with any of the following criteria were to be excluded from the
study:

1.  subjects with active skin disease, inflammation or related
    conditions, such as infection, psoriasis and herpes zoster near or
    on the nasolabial folds

2.  subjects that had undergone procedures based on active dermal
    response (e.g. laser and chemical peeling procedures) below the
    level of the lower orbital rim, within 6 months prior to
    randomization ^2^

3.  use of any facial tissue augmenting therapy or aesthetic facial
    surgical therapy effecting areas below the level of the lower
    orbital rim, within six (6) months prior to randomization, e.g.
    injection or other form of implantation of tissue augmenting
    substances, Botox® injections or facelift

4.  use of facial wrinkle therapies, including Accutane® or Renova®
    within six (6) months prior to study entry

5.  concomitant anticoagulant therapy, antiplatelet therapy, or a
    history of bleeding disorders

6.  a history of allergies to any bovine collagen products or a positive
    response to the Collagen Test Implant (administered at screening)

7.  a history of severe allergies manifested by a history of
    anaphylaxis, or a history or presence of

8.  multiple severe allergies

9.  known lidocaine hypersensitivity

10. known latex allergy

11. subjects undergoing or planning to undergo desensitization
    injections to meat products, as these

12. injections can contain bovine collagen

13. a presence or history of connective tissue diseases (e.g.,
    rheumatoid arthritis, juvenile rheumatoid arthritis, scleroderma, or
    systemic lupus erythematosus)

14. subjects on immunosuppressive therapy

\' Women of childbearing potential had to use a medically acceptable
method of birth control, and had to have a negative urine pregnancy test
at Visit 2, prior to treatment.

Appendix 3

**Efficacy results up to 12 months**

Question 10

ITT population at 6 months, n=137 ITT population at 9 months, n=34 ITT
population at 12 months, n=7

+------------------+-------+---+-------+------+-------+---+------+------+
|                  | >     |   |       |      | > **S |   |      |      |
|                  |  **SR |   |       |      | RS-su |   |      |      |
|                  | S-eva |   |       |      | bject |   |      |      |
|                  | luato |   |       |      | >     |   |      |      |
|                  | r\_** |   |       |      | -\_** |   |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
|                  | **    |   | >     | *    | [Re   |   | >    |      |
|                  | [Rest |   | **[Co | *-** | styla |   |  Con |      |
|                  | ylane |   | n]{.u |      | ne]{. |   | trol |      |
|                  | ]{.un |   | nderl |      | under |   |      |      |
|                  | derli |   | ine}t |      | line} |   |      |      |
|                  | ne}** |   | rol** |      |       |   |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Pre-treat n    | 137   |   | 137   |      | 137   |   | 137  |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Mean           | 3.29  |   | 3.31  |      | 3.33  |   | 3.37 |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Median         | 3     |   | > 3   |      | 3     |   | 3    |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Range          | 2-4   |   | 2-4   |      | 2-5   |   | 2-5  |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| SD               | 0.54  |   | 0.54  |      | 0.54  |   | 0.56 |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Baseline n     | 137   |   | 137   |      | 137   |   | 137  |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Mean           | 1.80  |   | 1.79  | >    | 1.96  |   | 1.97 | >    |
|                  |       |   |       | 0.84 |       |   |      | 0.70 |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Median         | 2     |   | > 2   |      | 2     |   | 2    |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Range          | 1-4   |   | 1-4   |      | 1-5   |   | 1-4  |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| j SD             | 0.68  |   | 0.66  |      | 0.81  |   | 0.79 |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > 6 months 11    | 137   |   | 137   |      | 137   |   | 137  |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Mean           | 2.36  |   | 2.94  | >    | 2.44  |   | 3.01 | >    |
|                  |       |   |       |  \<. |       |   |      |  \<. |
|                  |       |   |       | 0001 |       |   |      | 0001 |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Median         | 2     |   | > 3   |      | 2     |   | 3    |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Range          | 1-4   |   | 1-4   |      | 1-5   |   | 1-5  |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SD             | 0.78  |   | 0.76  |      | 0.80  |   | >    |      |
|                  |       |   |       |      |       |   | 0.75 |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Incidence of   |       |   |       |      |       |   |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 1 |       | >    |       | 8 |      | >    |
| > \> Control     |       | 3 |       |  \<. |       |   |      |  \<. |
|                  |       |   |       | 0001 |       |   |      | 0001 |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 8 |       |      |       | 7 |      |      |
| > \< Control     |       | 0 |       |      |       | 6 |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 4 |       |      |       | 5 |      |      |
| > = Control      |       | 4 |       |      |       | 3 |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > 9 months n     | 34    |   | 34    |      | 34    |   | 34   |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Mean           | >     |   | 3.12  | >    | 2.47  |   | >    | >    |
|                  |  2.44 |   |       |  \<. |       |   | 3.12 |  \<. |
|                  |       |   |       | 0001 |       |   |      | 0001 |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Median         | 2.5   |   | > 3   |      | 2     |   | 3    |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Range          | > 1-4 |   | 2-4   |      | 2-5   |   | >    |      |
|                  |       |   |       |      |       |   |  2-5 |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SD             | >     |   | 0.59  |      | 0.75  |   | >    |      |
|                  |  0.86 |   |       |      |       |   | 0.64 |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Incidence of   |       |   |       |      |       |   |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 0 |       | >    |       | 0 |      | >    |
| > \> Control     |       |   |       |  \<. |       |   |      |  \<. |
|                  |       |   |       | 0001 |       |   |      | 0001 |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 2 |       |      |       | 2 |      |      |
| > \< Control     |       | 1 |       |      |       | 0 |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 1 |       |      |       | 1 |      |      |
| > = Control      |       | 3 |       |      |       | 4 |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > 12 months n    | 1 3   |   | > 3   |      | 3     |   | 3    |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > miss           | 4     |   | > 4   |      | 4     |   | 4    |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Mean           | >     |   | 3.00  | >    | 2.00  |   | >    | >    |
|                  |  2.67 |   |       | N.A. |       |   | 2.67 | N.A. |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Median         | 3     |   | > 3   |      | 2     |   | 3    |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Range          | > 2-3 |   | 3-3   |      | 2-2   |   | >    |      |
|                  |       |   |       |      |       |   |  2-3 |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SD             | >     |   | > 0   |      | 0     |   | >    |      |
|                  |  0.58 |   |       |      |       |   | 0.58 |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > Incidence of   |       |   |       |      |       |   |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 0 |       | >    |       | 0 |      | >    |
| > \> Control     |       |   |       | N.A. |       |   |      | N.A. |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 1 |       |      |       | 2 |      |      |
| > \< Control     |       |   |       |      |       |   |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+
| > SRS Restylane  |       | 2 |       |      |       | [ |      |      |
| > = Control      |       |   |       |      |       | 1 |      |      |
|                  |       |   |       |      |       | ] |      |      |
|                  |       |   |       |      |       | { |      |      |
|                  |       |   |       |      |       | . |      |      |
|                  |       |   |       |      |       | u |      |      |
|                  |       |   |       |      |       | n |      |      |
|                  |       |   |       |      |       | d |      |      |
|                  |       |   |       |      |       | e |      |      |
|                  |       |   |       |      |       | r |      |      |
|                  |       |   |       |      |       | l |      |      |
|                  |       |   |       |      |       | i |      |      |
|                  |       |   |       |      |       | n |      |      |
|                  |       |   |       |      |       | e |      |      |
|                  |       |   |       |      |       | } |      |      |
+------------------+-------+---+-------+------+-------+---+------+------+

p-value for the mean: Student\'s paired t-test p-value for the
incidence: McNemar\'s test

No tests has been performed for 12 months data, since only 3 subjects
had values

Missing data at baseline, 2,4,6 and 9 months is substituted with tl,e
pre-treatment value

> May 27, 2003

+------------------+---------+------+------+---------+------+------+
| > ITT population |         |      |      |         |      |      |
| > at 6           |         |      |      |         |      |      |
| > ^,^months,     |         |      |      |         |      |      |
| > n=13 ;\'       |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > ITT population |         |      |      |         |      |      |
| > at 9 months,   |         |      |      |         |      |      |
| > n=34           |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > ITT population |         |      |      |         |      |      |
| > at 12 months,  |         |      |      |         |      |      |
| > r\_            |         |      |      |         |      |      |
| =[7]{.underline} |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| [SRS-evalua      |         |      |      | [SRS    |      |      |
| tor]{.underline} |         |      |      | -subj]{ |      |      |
|                  |         |      |      | .underl |      |      |
|                  |         |      |      | ine}ect |      |      |
+------------------+---------+------+------+---------+------+------+
|                  | Re      | Con  | ; p  | Re      | C    | p    |
|                  | stylane | trol |      | stylane | ontr |      |
|                  | -       |      |      |         | ol\_ |      |
+------------------+---------+------+------+---------+------+------+
| > Change from n  | 137;    |      |      | > 137   | 137  |      |
|                  | 137     |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > Pre-treatment  | > 1.50  |      | >    | > 1.37  | 1.40 | > 0  |
| > Mean           | > 1.52  |      | 0.55 |         |      | > 48 |
+------------------+---------+------+------+---------+------+------+
| to baseline      | > 1 1   |      |      | > 1     | 1    |      |
| Median           |         |      |      | > \...  |      |      |
+------------------+---------+------+------+---------+------+------+
| > Range Range    | 0-3 0-2 |      |      | -1 - 3  | -1 - |      |
|                  |         |      |      |         | 3    |      |
+------------------+---------+------+------+---------+------+------+
| > SD             | 0.67    | >    |      | > 0.82  | 0.75 |      |
|                  |         | 0.64 |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > Change from n  | 137     | > 13 |      | 137     | 137  |      |
|                  |         | >    |      |         |      |      |
|                  |         |  7\' |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > pre --         | 1.25    | >    | > \  | 1.08    | 0.89 | > 0. |
| > treatment Mean |         | 0.94 | <001 |         |      | 0019 |
+------------------+---------+------+------+---------+------+------+
| ^I^to 2 months   | 1       | l    |      | 1       | 1    |      |
| Median           |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| Range            | 0 -- 3  | 0 -  |      | -2 - 4  | -2 - |      |
|                  |         | 2    |      |         | 2    |      |
+------------------+---------+------+------+---------+------+------+
| > SD             | 0.67    | > 0  |      | > 092   | >    |      |
|                  |         | > 68 |      |         | 0.82 |      |
+------------------+---------+------+------+---------+------+------+
| > Change from n  | 137     | >    |      | 137     | 137  |      |
|                  |         |  137 |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > pre-treatment  | 1.01    | >    | >    | 0.83    | 0.56 | >    |
| > Mean j         |         | 0.54 |  \<. |         |      |  \<. |
|                  |         |      | 0001 |         |      | 0001 |
+------------------+---------+------+------+---------+------+------+
| > to 4 months    | 1       | 0    |      | 1       | 0    |      |
| > Median         |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > Range          | -1 - 2  | >    |      | > -1 -  | -1 - |      |
|                  |         | -1 - |      | > 3     | 3    |      |
|                  |         | > 2  |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > SD             | OAS     | > 0. |      | 0.90    | 0.-6 |      |
|                  |         | 6-\' |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > Change from n  | 137     | >    |      | 137     | 137  |      |
|                  |         |  137 |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > pre-treatment  | 0.93    | >    | >    | 0.89    | 0.36 | >    |
| > Mean Median    |         | 0.36 |  \<. |         |      |  \<. |
|                  |         |      | 0001 |         |      | OO0l |
+------------------+---------+------+------+---------+------+------+
| > to 6 months o  | 1       | 0    |      | 1       | 0    |      |
| > Median         |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > Range          | 0-3     | >    |      | 03      | -    |      |
|                  |         |  -10 |      |         | \~\_­ |      |
|                  |         |      |      |         |      |      |
|                  |         |      |      |         | 0\   |      |
|                  |         |      |      |         | ^7\" |      |
+------------------+---------+------+------+---------+------+------+
| > SD             | > 0.75  | >    |      | 0.87    | 0.77 |      |
|                  |         | 0.68 |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > Change from n  | 34      | 34   |      | > 34    | 34   |      |
+------------------+---------+------+------+---------+------+------+
| > pre-treatment  | > 0 65  | > -  | >    | > 0.71  | 0.09 | > \< |
| > Mean           |         | 0.03 |  \<0 |         |      | > 0  |
|                  |         |      | .OOl |         |      | 001: |
+------------------+---------+------+------+---------+------+------+
| > to 9 months    |         | 0    |      | i       | O    |      |
| > Median         |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > Range          | > 0-2   | >    |      | > -1-2  | -2-1 |      |
| >                |         | -1-0 |      |         |      |      |
| [\^]{.underline} |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > SD             | > 0.54  | >    |      | > 0.68  | 0.54 |      |
|                  |         | 0.17 |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > Change from n  | 3       | 3    |      | 3       | 3    |      |
+------------------+---------+------+------+---------+------+------+
| > pre-treatment  | 4       | -\*  |      | 4       | 4    |      |
| > \\ Miss        |         |      |      |         |      |      |
+------------------+---------+------+------+---------+------+------+
| > to 12 months   | > 0.33  | 0    | > n  | > 1.00  | 0.33 | >    |
| > Miss           |         |      | .a.. |         |      | n.a. |
+------------------+---------+------+------+---------+------+------+
| > Median         | 0       | 0    | > i  | 1       | 0    |      |
+------------------+---------+------+------+---------+------+------+
| > Range          | > 0-1   | 0    |      | 1       | 0-1  |      |
+------------------+---------+------+------+---------+------+------+
| >                | > [0.5  | [0]  |      | [       | [0   |      |
| [SD]{.underline} | 8]{.und | {.un |      | 0]{.und | .58] |      |
|                  | erline} | derl |      | erline} | {.un |      |
|                  |         | ine} |      |         | derl |      |
|                  |         |      |      |         | ine} |      |
+------------------+---------+------+------+---------+------+------+

p-value for the mean: Student\'s paired t-test

No tests has been performed for 1\'2 months data, since only 3 subjects
had values

Missing data at baseline. 2.4, 6 and 9 months is substituted with the
pre-treatment value