Lidocaine Comparison Trial Full

NTL4
The Next Generation Topical Anesthetic
Optimized Topical Lidocaine 4% in a Unique Nano
Technology Delivery System
Results of Clinical Trials Comparing NTL4 to LMX4
Protocols N°
10025
10025.1
Center for Clinical and Cosmetic Research (CCCR), Aventura,
Florida
Mark S. Nestor, M.D., Ph.D.

 NTL4 is an experimental topical Anesthetic owned by
Innovatech, Inc.
 LMX4 is a commercially available topical anesthetic
owned by Ferndale Laboratories
 Clinical studies results in this presentation are
preliminary and confidential and protected under existing
CDA
 Studies preformed at CCCR in Aventura, Florida and
Manhattan Beach, California. Mark S. Nestor, M.D.,
Ph.D., Principle Investigator, Glynis Ablon, M.D., Co
Investigator
 Funding provided by a Research Grant from Innovatech,
Inc.
Disclosure

 The successful reduction of pain is one of the primary
goals of medical care.
 The medical management of pain encompasses pain
related to injury, medical conditions and surgical
procedures
 The use of topical anesthetics (TA) is an important part
of the management of pain both by physicians and
consumers
 In a recent study TA were prescribed or used 3.8 million
times by physicians over a 5 year study interval and yet
accounted for only a small fraction of the overall
consumer use of TA
 At the present time Dermatologists represent only a
small fraction of physicians that use of TA, primarily
using TA for minor surgical and cosmetic procedures
Introduction
Yentzer BA et al.: Utilization of Topical Anesthetics By Dermatologists in the
US. Cosmetic Derm 22, 238 2009.

 TA are classified as RX, OTC or pharmacy compounded
medications and contain a variety of ingredients from benzocaine to
lidocaine to cocaine. Worldwide market estimated at over $5 billion
in sales.
 OTC Lidocaine (LMX4) is the most commonly used and prescribed
TA by physicians
 Important characteristics of TA include efficacy, onset and safety
 The ideal TA would have the ability to provide a significant
anesthetic effect shortly after application (5 – 10 minutes), have an
excellent safety profile and be available to patients and physicians
OTC
 TA efficacy and onset limited by difficulty in drugs penetrating the
skin barrier
 Optimized drug delivery system can dramatically improve TA
effectiveness, and onset and allow the use of safe, OTC strength
compounds
Topical Anesthetics
Yentzer BA et al.: Utilization of Topical Anesthetics By Dermatologists in the
US. Cosmetic Derm 22, 238 2009.

Topical Drug Delivery
 The skin is a formidable barrier against
environmental assaults as well as topical drug
delivery
 A variety of active compounds have significant
activity in the skin, subcutaneous tissue or muscle
but cannot adequately permeate the intact skin
 The use of topical anesthetics is limited based on
the difficulty that Lidocaine and other topical
anesthetics to penetrate the skin
 Ionic Nano Particle Technology (InParT) is a novel
and unique delivery system that can be utilized to
assist the transport topical anesthetics and of a
variety of active compounds to target sites in the
skin and beyond

InParT Drug Delivery System
Ionic Nano Particle Technology I
Novel, commercially viable trans
dermal non-invasive drug delivery
technology that enables delivery
and absorption of active
compounds through the stratum
corneum and throughout the skin
and sub cutaneous tissue without
any cutaneous toxicity

Ionic Nano Particle Technology II
 Nano particles are made from combinations of
micelles (surfactants and protein solubilizers), coated
with lipid molecules
 Nano particles size; less than 1-10 nano meters
smaller than the skin pores
 Nano Particles physically entraps active molecules
without any changes in their chemical composition
 Stabilizes the actives: shelf stable at room
temperature for extended period of time without
refrigeration
 Uses all FDA approved ingredients

Ionic Nano Particle Technology III
 INParT technology is highly adaptable to
most high molecular weight drugs, proteins,
peptides and insoluble hydrophobic
molecules
 Capable of delivering more than one
therapeutic agent at a time
 The technology is easily scalable to any
size

SEM-Photograph- 250x SEM-Photograph- 1000x

 NTL4 is a unique 4% lidocaine TA based on the INParT
drug delivery system
 The INParT drug delivery system allows for rapid and
efficient transfer of the lidocaine through the stratum
cornenum, epidermis and dermis to sensory nerves
 4% lidocaine is ideal because of it’s OTC FDA indication
 Clinical trails were conducted to test efficacy and safety
of NTL4 as a TA in patients receiving Restylane
injections in the NLF. The trails utilized LMX4 (the
market leader in commercially available 4% lidocaine) on
the contra lateral NLF as an active control
 The initial trial investigated the efficacy and safety
comparing a 20 minute application of both products
 A second trial accessed early onset efficacy at 5, 10, and
15 minute application of both products
NTL4

CCCR Protocol 10025
Double Blind, Randomized, Split-Face Study
to Evaluate the Efficacy, Safety and Subject
Satisfaction of Pain Management Utilizing
NTL4 (Topical 4% Lidocaine in a Novel Nano
Technology Delivery System) vs. LMX 4 (4%
Lidocaine cream) During and After
Restylane® Dermal Filler Injections for the
Correction of Nasolabial Folds

Study Design: Protocol 10025
 Two-center, randomized, split-face, double-blind pilot trial to evaluate
the effectiveness of a test product NTL4 versus L-M-X4® topical
anesthetic immediately post, one and three hours after Restylane®
injections in the NLF.
 2-day study
 30 patients total for 2 sites randomized left and right to NLT4 or
LMX4, respectively, randomly applied (20 second massage) to each
NLF for 20 minutes and removed
 Investigator and patient assessments completed at screening
/injection immediately upon injection, at 1 hour and 3 hours at visit 1
 Follow-up assessments completed at Visit 2 (next day)
 AE and concomitant medication review / update at each visit
AE, adverse event.

Treatment
 Topical NTL4 and LMX4
were randomly applied (20
second massage) to each
NLF for 20 minutes and
removed
 Restylane was injected in
the nasolabial fold area up
to 1.5 ML per side on
Injection Visit/ Visit 1.

Patient Assessments & Scale
 Upon first needle stick of each of the NLF injections, the patient
assessed the amount of pain associated with the procedure by
completing a Visual Analog Scale (VAS) for the respective injection
time:
 Immediately after injection [1.0-10]
 1 Hour after injection [1.0-10]
 3 Hours after injection [1.0-10]
 VAS: The patient drew a hash mark to indicate the degree of pain
on a 10 cm line. The mark was measured in cm as a quantification
of perceived pain:
A separate evaluation will be performed for each side of the face at each time point.
_____________________________________________________________________
No pain The worst pain you can imagine

Patient Assessments & Scale
 1 Hour following injection, subjects were asked to complete
a satisfaction survey addressing their assessment of the
pain management options utilized.
 Secondary endpoints obtained from this survey included:
 Level of pain experienced on Left/Right Side when
injected:
 No Pain [0]
 Slight Pain [1]
 Moderate Pain [2]
 Severe Pain [3]
 Which topical anesthetic cream did you prefer?
 Right [1]
 Left [2]
 No Preference [3]

Investigator Assessments
 Upon injection, investigator completed a
immediate assessment to evaluate severity of
the patient’s pain using a 4-point scale
 Upon injection, investigator completed a
immediate assessment to evaluate the overall
impression of the topical anesthetics
(Investigator assessments were completed
independent of patient assessment)
 Facial photographs were obtained immediately
following injection, 3 hours after injection and the
next day.

Investigator Scale
 The severity of the patient’s perceived pain during the
procedure was scored on a 4-point grading system:
 No Pain [0]
 Slight Pain [1]
 Moderate Pain [2]
 Severe Pain [3]
 The evaluation the overall impression of the topical
anesthetics was scored using a 2-point system:
 Did the Right/Left Side Topical provide adequate
anesthesia for the dermal filler procedure?
 Yes [1]
 No [2]

Efficacy Results: Subjective VAS
Group Statistics
30 1.997 1.5736 .2873
30 3.087 2.4329 .4442
30 .217 .3086 .0563
30 .747 1.1227 .2050
30 .070 .1535 .0280
30 .313 .6942 .1267
Randomization
(A) NTL4
(B) LMX4
(A) NTL4
(B) LMX4
(A) NTL4
(B) LMX4
VAS_Immediate
VAS_1_Hour
VAS_3_Hour
N Mean Std. Deviation
Std. Error
Mean

N=30 N=30 N=30
p=0.04 p=0.01 p=0.06
d=0.48 (Medium)
X Axis: Time After Injection
Y Axis: VAS Scale
0
1
2
3
4
5
Immediate 1 Hour 3 Hour
NTL4
LMX4

Subject Satisfaction Data
Subjective Level of Pain
Randomization * Subject_Level_of_Pain Crosstabulation
2 18 7 2 1 30
1.0 15.0 9.0 3.5 1.5 30.0
6.7% 60.0% 23.3% 6.7% 3.3% 100.0%
100.0% 60.0% 38.9% 28.6% 33.3% 50.0%
3.3% 30.0% 11.7% 3.3% 1.7% 50.0%
0 12 11 5 2 30
1.0 15.0 9.0 3.5 1.5 30.0
.0% 40.0% 36.7% 16.7% 6.7% 100.0%
.0% 40.0% 61.1% 71.4% 66.7% 50.0%
.0% 20.0% 18.3% 8.3% 3.3% 50.0%
2 30 18 7 3 60
2.0 30.0 18.0 7.0 3.0 60.0
3.3% 50.0% 30.0% 11.7% 5.0% 100.0%
100.0% 100.0% 100.0% 100.0% 100.0% 100.0%
3.3% 50.0% 30.0% 11.7% 5.0% 100.0%
Count
Expected Count
% within Randomization
% within Subject_Level
of_Pain
% of Total
Count
Expected Count
of_Pain
% of Total
Count
Expected Count
of_Pain
% of Total
(A) NTL4
(B) LMX4
Randomization
Total
No Pain Minimal Pain Mild Pain
Moderate
Pain Severe Pain
Subject_Level_of_Pain
Total

P=0.22
(B) LMX4(A) NTL4
Randomization
20
15
10
5
0
Count
Severe Pain
Moderate Pain
Mild Pain
Minimal Pain
No Pain
Bar Chart

Overall Preference
Product_Randomization * Preference Crosstabulation
18 6 6 30
12.0 12.0 6.0 30.0
60.0% 20.0% 20.0% 100.0%
75.0% 25.0% 50.0% 50.0%
30.0% 10.0% 10.0% 50.0%
6 18 6 30
12.0 12.0 6.0 30.0
20.0% 60.0% 20.0% 100.0%
25.0% 75.0% 50.0% 50.0%
10.0% 30.0% 10.0% 50.0%
24 24 12 60
24.0 24.0 12.0 60.0
40.0% 40.0% 20.0% 100.0%
100.0% 100.0% 100.0% 100.0%
40.0% 40.0% 20.0% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
NTL4
LMX
Product_Randomization
Total
Yes No
No
Preference
Preference
Total

Overall Preference
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Patients with any adverse event 43 (43) 104 (52) 147 (49)
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
General disorders and administrative site reactions
Injection site pain
Injection site hemorrhage
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Infections and Infestations
Nasopharyngitis
Upper respiratory tract infection
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Injury, poisoning, and procedural complications
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Nervous system disorders
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
0
5
10
15
20
25
30
NTL4 LMX4 No
Preference
Subject Preference
P=0.002
Preference Rates:
NTL4 = 60% (18/30)
LMX4 = 20% (6/30)
No Preference = 20% (6/30)

Blinded Investigator’s Evaluation
of Pain
Randomization * Investigator_Rating Crosstabulation
11 17 2 0 30
6.0 17.5 5.0 1.5 30.0
36.7% 56.7% 6.7% .0% 100.0%
91.7% 48.6% 20.0% .0% 50.0%
18.3% 28.3% 3.3% .0% 50.0%
1 18 8 3 30
6.0 17.5 5.0 1.5 30.0
3.3% 60.0% 26.7% 10.0% 100.0%
8.3% 51.4% 80.0% 100.0% 50.0%
1.7% 30.0% 13.3% 5.0% 50.0%
12 35 10 3 60
12.0 35.0 10.0 3.0 60.0
20.0% 58.3% 16.7% 5.0% 100.0%
100.0% 100.0% 100.0% 100.0% 100.0%
20.0% 58.3% 16.7% 5.0% 100.0%
Count
Expected Count
% within Investigator_
Rating
% of Total
Count
Expected Count
Rating
% of Total
Count
Expected Count
Rating
% of Total
(A) NTL4
(B) LMX4
Randomization
Total
No Pain Slight Pain
Moderate
Pain Severe Pain
Investigator_Rating
Total

Blinded Investigator’s Evaluation
of Pain
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
P=0.002
(B) LMX4(A) NTL4
Randomization
20
15
10
5
0
Count
Severe Pain
Moderate Pain
Slight Pain
No Pain
Investigator_Rating
Bar Chart

Blinded Investigator’s Overall
Satisfaction of Topical Anesthetic
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Patients reporting serious treatment-emergent
adverse events: n (%) 1 (1) 4 (2) 5 (2)
Cardiac disorders
Cardiac flutter 0 1 (<1) 1 (<1)
Gastrointestinal disorders
Intestinal obstruction 1 (1) 0 1 (<1)
Chest pain 0 1 (<1) 1 (<1)
Infections and infestations
Appendicitis 0 1 (<1) 1 (<1)
Burns second degree
Burns third degree
Thermal burn
1 (1)
1 (1)
1 (1)
0
0
0
1 (<1)
1 (<1)
1 (<1)
Facial paresis 0 1 (<1) 1 (<1)
Pregnancy, puerperium, and perinatal conditions
Pregnancy 0 1 (<1) 1 (<1)
Randomization * Overall_Impression_of_Anesthetic Crosstabulation
28 2 30
21.0 9.0 30.0
93.3% 6.7% 100.0%
66.7% 11.1% 50.0%
46.7% 3.3% 50.0%
14 16 30
21.0 9.0 30.0
46.7% 53.3% 100.0%
33.3% 88.9% 50.0%
23.3% 26.7% 50.0%
42 18 60
42.0 18.0 60.0
70.0% 30.0% 100.0%
100.0% 100.0% 100.0%
70.0% 30.0% 100.0%
Count
Expected Count
% within Overall_
Impression_of_
Anesthetic
% of Total
Count
Expected Count
% within Overall_
Impression_of_
Anesthetic
% of Total
Count
Expected Count
% within Overall_
Impression_of_
Anesthetic
% of Total
(A) NTL4
(B) LMX4
Randomization
Total
Satisfied Not Satisfied
Overall_Impression_of_
Anesthetic
Total

Blinded Investigator’s Overall
Satisfaction of Topical Anesthetic
Preferred Term, n (%) Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eyelid edema
Probable
Eyelid ptosis
Probable
Possible
Asthenopia
Probable
Possible
Vision blurred
Possible
Photopsia
Probable
0
0
0
0
0
0
0
3 (2)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
3 (1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
P<0.001
(B) LMX4(A) NTL4
Randomization
30
25
20
15
10
5
0
Count
Not Satisfied
Satisfied
Overall_Impression_of_Anesthetic
Bar Chart

Results: AE’s
 AE’s were all classified as minor and
included tenderness, bruising and
edema all of which were considered to
be related to the Restylane injections
 There were no apparent differences in
the injection related AE’s for either
NTL4 or LMX4

Results Summary: Protocol 10025
 Subjective mean VAS scores for the 30 subjects indicated
significantly less pain upon injection (p=0.04), one hour
after injection (p< 0.01) and trend at 3 hours (p=0.06)
favoring NTL4 over LMX4
 Subjective assessment of level of pain indicated clear but
trend favoring NTL4 over LMX4
 Subjects preference of topical anesthetic significantly
favored NTL4 over LMX4 (p=0.002)
 Blinded investigator assessment of pain indicated
significantly less pain on the NTL4 treated vs. LMX4
treated side (p=0.002)
 Blinded investigators overall satisfaction (adequate
anesthesia) significantly favored NTL4 over LMX4 (p<
0.001)

Results Summary: Protocol 10025
 AE’s were all classified as minor and
included tenderness, bruising and
edema all of which were considered to
be related to the Restylane injections
 There were no apparent differences in
the injection related AE’s for either
NTL4 or LMX4

CCCR Protocol 10025.1
Double Blind, Randomized, Split-
Face Study to Evaluate the Onset
of Topical 4% Lidocaine in a Novel
Nano Technology Delivery System
vs. LMX 4 (4% Lidocaine cream)
During and After Restylane®
Dermal Filler Injections for the
Correction of Nasolabial Folds

Study Design: Protocol 10025.1
 Two-center, randomized, split-face, double-blind pilot trial to evaluate
the onset and effectiveness of a test product NTL4 versus L-M-X4®
topical anesthetic immediately post, one and three hours after
Restylane® injections in the NLF.
 2-day study
 20 patients total for 2 sites randomized left and right to NLT4 or
LMX4, respectively
 3 group randomization for onset of effectiveness: 15, 10 and 5 minute
duration of topical cream prior to injection
 Investigator and patient assessments completed at
screening/injection Immediately upon injection, at 1 hour and 3 hours
at Visit 1
 Follow-up assessments completed at Visit 2 (next day)
 AE and concomitant medication review / update at each visit
AE, adverse event.

Treatment
 Topical NTL4 and LMX4
were randomly applied (30
second massage) to each
NLF for 15, 10 or 5 minutes
and removed
 Restylane was injected in
the nasolabial fold area up
to 1.5 ML per side on
Injection Visit/ Visit 1.

Early Onset Groups Combined (N=20)
Group Statistics
20 1.520 1.0191 .2279
20 3.860 2.2763 .5090
20 .550 1.1963 .2675
20 1.120 1.7828 .3987
20 .380 .6978 .1560
20 1.025 1.8948 .4237
NTL4
LMX4
NTL4
LMX4
NTL4
LMX4
VAS_Immediate
VAS_1_Hour
VAS_3_Hour
Std. Error
Mean

N=20 N=20 N=20
p<0.001 p=0.242 p=0.161
d=0.37 d=0.45 (Medium)
Y Axis: VAS Scale
0
1
2
3
4
5
NTL4
LMX4

Early Onset (15 Minutes) (N=6)
Group Statistics
6 1.917 1.1873 .4847
6 4.667 1.3721 .5602
6 .217 .2401 .0980
6 .983 .9517 .3885
6 .117 .2401 .0980
6 1.667 2.8884 1.1792
NTL4
LMX4
NTL4
LMX4
NTL4
LMX4
VAS_Immediate
VAS_1_Hour
VAS_3_Hour
Std. Error
Mean

N=6 N=6 N=6
p<0.004 p=0.085 p=0.22
d=1.1 (Large) d=0.75 (Large)
Y Axis: VAS Scale
0
1
2
3
4
5
NTL4
LMX4

Group Statistics
8 1.075 .8311 .2938
8 3.000 2.6306 .9301
8 .213 .4155 .1469
8 .863 1.5802 .5587
8 .525 .8137 .2877
8 .713 1.2287 .4344
NTL4
LMX4
NTL4
LMX4
NTL4
LMX4
VAS_Immediate
VAS_1_Hour
VAS_3_Hour
Std. Error
Mean

N=8 N=8 N=8
p=0.068 p=0.279 p=0.724
d=0.98 (Large) d=0.56 (Medium) d=0.18 (Small)
Y Axis: VAS Scale
0
1
2
3
4
5
NTL4
LMX4

Group Statistics
6 1.717 1.0088 .4118
6 4.200 2.4528 1.0013
6 .767 1.2533 .5116
6 2.167 2.9419 1.2010
6 .450 .8620 .3519
6 .800 1.5735 .6424
NTL4
LMX4
NTL4
LMX4
NTL4
LMX4
VAS_Immediate
VAS_1_Hour
VAS_3_Hour
Std. Error
Mean

N=6 N=6 N=6
p=0.045 p=0.309 p=0.643
d=0.61 (Large) d=0.27 (Small)
Y Axis: VAS Scale
0
1
2
3
4
5
NTL4
LMX4

Early Onset Groups Combined
(N=20)
Product_Randomization * Subject_Level_of_Pain Crosstabulation
2 14 2 2 0 20
1.0 7.5 6.0 5.0 .5 20.0
10.0% 70.0% 10.0% 10.0% .0% 100.0%
100.0% 93.3% 16.7% 20.0% .0% 50.0%
5.0% 35.0% 5.0% 5.0% .0% 50.0%
0 1 10 8 1 20
1.0 7.5 6.0 5.0 .5 20.0
.0% 5.0% 50.0% 40.0% 5.0% 100.0%
.0% 6.7% 83.3% 80.0% 100.0% 50.0%
.0% 2.5% 25.0% 20.0% 2.5% 50.0%
2 15 12 10 1 40
2.0 15.0 12.0 10.0 1.0 40.0
5.0% 37.5% 30.0% 25.0% 2.5% 100.0%
100.0% 100.0% 100.0% 100.0% 100.0% 100.0%
5.0% 37.5% 30.0% 25.0% 2.5% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
NTL4
LMX4
Total
Moderate
Pain Severe Pain
Total

P<0.001
LMX4NTL4
14
12
10
8
6
4
2
0
Count
Severe Pain
Moderate Pain
Mild Pain
Minimal Pain
No Pain
Bar Chart

5 0 1 6
2.5 1.0 2.5 6.0
83.3% .0% 16.7% 100.0%
100.0% .0% 20.0% 50.0%
41.7% .0% 8.3% 50.0%
0 2 4 6
2.5 1.0 2.5 6.0
.0% 33.3% 66.7% 100.0%
.0% 100.0% 80.0% 50.0%
.0% 16.7% 33.3% 50.0%
5 2 5 12
5.0 2.0 5.0 12.0
41.7% 16.7% 41.7% 100.0%
100.0% 100.0% 100.0% 100.0%
41.7% 16.7% 41.7% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
NTL4
LMX4
Total
Minimal Pain Mild Pain
Moderate
Pain
Total

P=0.01
LMX4NTL4
5
4
3
2
1
0
Count
Moderate Pain
Mild Pain
Minimal Pain
Bar Chart

1 6 1 0 8
.5 3.0 4.0 .5 8.0
12.5% 75.0% 12.5% .0% 100.0%
100.0% 100.0% 12.5% .0% 50.0%
6.3% 37.5% 6.3% .0% 50.0%
0 0 7 1 8
.5 3.0 4.0 .5 8.0
.0% .0% 87.5% 12.5% 100.0%
.0% .0% 87.5% 100.0% 50.0%
.0% .0% 43.8% 6.3% 50.0%
1 6 8 1 16
1.0 6.0 8.0 1.0 16.0
6.3% 37.5% 50.0% 6.3% 100.0%
100.0% 100.0% 100.0% 100.0% 100.0%
6.3% 37.5% 50.0% 6.3% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
NTL4
LMX4
Total
No Pain Minimal Pain Mild Pain Severe Pain
Total

P=0.006
LMX4NTL4
7
6
5
4
3
2
1
0
Count
Severe Pain
Mild Pain
Minimal Pain
No Pain
Bar Chart

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
adverse events: n (%) 1 (1) 4 (2) 5 (2)
Cardiac disorders
Chest pain 0 1 (<1) 1 (<1)
Burns second degree
Burns third degree
Thermal burn
1 (1)
1 (1)
1 (1)
0
0
0
1 (<1)
1 (<1)
1 (<1)
Pregnancy 0 1 (<1) 1 (<1)
1 4 1 0 6
.5 2.5 1.0 2.0 6.0
16.7% 66.7% 16.7% .0% 100.0%
100.0% 80.0% 50.0% .0% 50.0%
8.3% 33.3% 8.3% .0% 50.0%
0 1 1 4 6
.5 2.5 1.0 2.0 6.0
.0% 16.7% 16.7% 66.7% 100.0%
.0% 20.0% 50.0% 100.0% 50.0%
.0% 8.3% 8.3% 33.3% 50.0%
1 5 2 4 12
1.0 5.0 2.0 4.0 12.0
8.3% 41.7% 16.7% 33.3% 100.0%
100.0% 100.0% 100.0% 100.0% 100.0%
8.3% 41.7% 16.7% 33.3% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
NTL4
LMX4
Total
Moderate
Pain
Total

n=100
Dysport 50 U
n=200
Total
N=300
Eyelid edema
Probable
Eyelid ptosis
Probable
Possible
Asthenopia
Probable
Possible
Vision blurred
Possible
Photopsia
Probable
0
0
0
0
0
0
0
3 (2)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
3 (1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
P=0.079
LMX4NTL4
4
3
2
1
0
Count
Moderate Pain
Mild Pain
Minimal Pain
No Pain
Bar Chart

Subject Satisfaction Data: Overall Preference
17 3 20
10.0 10.0 20.0
85.0% 15.0% 100.0%
85.0% 15.0% 50.0%
42.5% 7.5% 50.0%
3 17 20
10.0 10.0 20.0
15.0% 85.0% 100.0%
15.0% 85.0% 50.0%
7.5% 42.5% 50.0%
20 20 40
20.0 20.0 40.0
50.0% 50.0% 100.0%
100.0% 100.0% 100.0%
50.0% 50.0% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
NTL4
LMX
Total
Yes No
Preference
Total

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
0
5
10
15
20
NTL4 LMX4 No
Preference
Subject Preference
P<0.001
Preference Rates:
NTL4 = 85% (17/20)
LMX4 = 15% (3/20)

6 0 6
3.0 3.0 6.0
100.0% .0% 100.0%
100.0% .0% 50.0%
50.0% .0% 50.0%
0 6 6
3.0 3.0 6.0
.0% 100.0% 100.0%
.0% 100.0% 50.0%
.0% 50.0% 50.0%
6 6 12
6.0 6.0 12.0
50.0% 50.0% 100.0%
100.0% 100.0% 100.0%
50.0% 50.0% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
NTL4
LMX
Total
Yes No
Preference
Total

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
0
1
2
3
4
5
6
NTL4 LMX4 No
Preference
Subject Preference
P=0.001
Preference Rates:
NTL4 = 100% (6/6)
LMX4 = 0% (0/6)

6 2 8
4.0 4.0 8.0
75.0% 25.0% 100.0%
75.0% 25.0% 50.0%
37.5% 12.5% 50.0%
2 6 8
4.0 4.0 8.0
25.0% 75.0% 100.0%
25.0% 75.0% 50.0%
12.5% 37.5% 50.0%
8 8 16
8.0 8.0 16.0
50.0% 50.0% 100.0%
100.0% 100.0% 100.0%
50.0% 50.0% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
NTL4
LMX
Total
Yes No
Preference
Total

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
0
1
2
3
4
5
6
7
8
NTL4 LMX4 No
Preference
Subject Preference
P=0.046
Preference Rates:
NTL4 = 75% (6/8)
LMX4 = 25% (2/8)

5 1 6
3.0 3.0 6.0
83.3% 16.7% 100.0%
83.3% 16.7% 50.0%
41.7% 8.3% 50.0%
1 5 6
3.0 3.0 6.0
16.7% 83.3% 100.0%
16.7% 83.3% 50.0%
8.3% 41.7% 50.0%
6 6 12
6.0 6.0 12.0
50.0% 50.0% 100.0%
100.0% 100.0% 100.0%
50.0% 50.0% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
NTL4
LMX
Total
Yes No
Preference
Total

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
0
1
2
3
4
5
6
NTL4 LMX4 No
Preference
Subject Preference
P=0.02
Preference Rates:
NTL4 = 83% (5/6)
LMX4 = 16% (1/6)

Blinded Investigator’s Evaluation of Pain
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
P<0.001
LMX4NTL4
12
10
8
6
4
2
0
Count
Moderate Pain
Mild Pain
Minimal Pain
No Pain
Bar Chart

Blinded Investigator’s Overall Impression
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
adverse events: n (%) 1 (1) 4 (2) 5 (2)
Cardiac disorders
Chest pain 0 1 (<1) 1 (<1)
Burns second degree
Burns third degree
Thermal burn
1 (1)
1 (1)
1 (1)
0
0
0
1 (<1)
1 (<1)
1 (<1)
Pregnancy 0 1 (<1) 1 (<1)
Product_Randomization * Overall_Impression_of_Anesthetic Crosstabulation
20 0 20
15.0 5.0 20.0
100.0% .0% 100.0%
66.7% .0% 50.0%
50.0% .0% 50.0%
10 10 20
15.0 5.0 20.0
50.0% 50.0% 100.0%
33.3% 100.0% 50.0%
25.0% 25.0% 50.0%
30 10 40
30.0 10.0 40.0
75.0% 25.0% 100.0%
100.0% 100.0% 100.0%
75.0% 25.0% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Overall_
Impression_of_
Anesthetic
% of Total
Count
Expected Count
% within Product_
Randomization
% within Overall_
Impression_of_
Anesthetic
% of Total
Count
Expected Count
% within Product_
Randomization
% within Overall_
Impression_of_
Anesthetic
% of Total
NTL4
LMX4
Total
Anesthetic
Total

3 3 0 6
1.5 2.5 2.0 6.0
50.0% 50.0% .0% 100.0%
100.0% 60.0% .0% 50.0%
25.0% 25.0% .0% 50.0%
0 2 4 6
1.5 2.5 2.0 6.0
.0% 33.3% 66.7% 100.0%
.0% 40.0% 100.0% 50.0%
.0% 16.7% 33.3% 50.0%
3 5 4 12
3.0 5.0 4.0 12.0
25.0% 41.7% 33.3% 100.0%
100.0% 100.0% 100.0% 100.0%
25.0% 41.7% 33.3% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
NTL4
LMX4
Total
Total

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
P=0.02
LMX4NTL4
4
3
2
1
0
Count
Mild Pain
Minimal Pain
No Pain
Bar Chart

3 5 0 0 8
1.5 5.0 1.0 .5 8.0
37.5% 62.5% .0% .0% 100.0%
100.0% 50.0% .0% .0% 50.0%
18.8% 31.3% .0% .0% 50.0%
0 5 2 1 8
1.5 5.0 1.0 .5 8.0
.0% 62.5% 25.0% 12.5% 100.0%
.0% 50.0% 100.0% 100.0% 50.0%
.0% 31.3% 12.5% 6.3% 50.0%
3 10 2 1 16
3.0 10.0 2.0 1.0 16.0
18.8% 62.5% 12.5% 6.3% 100.0%
100.0% 100.0% 100.0% 100.0% 100.0%
18.8% 62.5% 12.5% 6.3% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
NTL4
LMX4
Total
Moderate
Pain
Total

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
P=0.112
LMX4NTL4
5
4
3
2
1
0
Count
Moderate Pain
Mild Pain
Minimal Pain
No Pain
Bar Chart

2 4 0 6
1.0 3.5 1.5 6.0
33.3% 66.7% .0% 100.0%
100.0% 57.1% .0% 50.0%
16.7% 33.3% .0% 50.0%
0 3 3 6
1.0 3.5 1.5 6.0
.0% 50.0% 50.0% 100.0%
.0% 42.9% 100.0% 50.0%
.0% 25.0% 25.0% 50.0%
2 7 3 12
2.0 7.0 3.0 12.0
16.7% 58.3% 25.0% 100.0%
100.0% 100.0% 100.0% 100.0%
16.7% 58.3% 25.0% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
Count
Expected Count
% within Product_
Randomization
% within Subject_
Level_of_Pain
% of Total
NTL4
LMX4
Total
Total

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
P=0.076
LMX4NTL4
4
3
2
1
0
Count
Mild Pain
Minimal Pain
No Pain
Bar Chart

n=100
Dysport 50 U
n=200
Total
N=300
Eyelid edema
Probable
Eyelid ptosis
Probable
Possible
Asthenopia
Probable
Possible
Vision blurred
Possible
Photopsia
Probable
0
0
0
0
0
0
0
3 (2)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
3 (1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
1 (<1)
P<0.001
LMX4NTL4
20
15
10
5
0
Count
Not Satisfied
Satisfied
Bar Chart

Results: AE’s
 AE’s were all classified as minor and included
tenderness, bruising and edema all of which were
considered to be related to the Restylane
injections. One patient (15 minute) demonstrated
erythema and edema lasting 4 days, initially
bilateral and then unilateral (NTL4 side). Cleared
with topical cortisone. Thought to be reaction to
Lidocaine.

Results Summary I: Protocol 10025.1
 Subjective mean VAS scores for the 20 subjects
(combined early onset) indicated significantly less
pain upon injection (p<0.001), with trends at one
hour after injection and trend at 3 hours favoring
NTL4 over LMX4. VAS immediate injection score
were lower for NTL4 in early onset trial vs original
20 minute trial (1.57 vs 1.99) but higher for the
LMX4 (3.86 vs 3.02) .Mean Individual onset
groups: significantly less pain favoring NTL4 over
LMX4 for 15 minute and 5 minute incubations
(p=0.04) with trend favoring NTL4 at 10 minutes.
Trends favoring NTL4 at one and three hours in
all groups

Results Summary II: Protocol 10025.1
 Subjective assessment for the 20 subjects (combined early onset) of
level of pain indicated significant less pain on NTL4 over LMX4
(p<0.001). Individual onset groups: significantly less pain favoring
NTL4 over LMX4 for 15 minute and 5 minute incubations (p=0.01,
p=0.006) with trend favoring NTL4 at 10 minutes.
 Subjects preference of topical anesthetic for the 20 subjects
(combined early onset) significantly favored NTL4 over LMX4
(p=0.002). Individual onset groups: significant preference favoring
NTL4 over LMX4 for 15 minute 10 minute and 5 minute incubations
(p=0.001, p= 0.05, p=0.02)
 Blinded investigator assessment of pain for the 20 subjects
(combined early onset) indicated significantly less pain on the NTL4
treated vs. LMX4 treated side (p=0.001) Individual onset groups:
significantly less pain favoring NTL4 over LMX4 for 15 minute
(p=0.02) with trends favoring NTL4 for the10 minute and 5 minute
incubations

Results Summary III: Protocol 10025.1
 Blinded investigators overall satisfaction (adequate
anesthesia) for the 20 subjects (combined early onset)
significantly favored NTL4 over LMX4 (p<0.001).
Individual onset groups: significant preference favoring
NTL4 over LMX4 for 15 minute 10 minute and 5 minute
incubations (p= 0.05)
 AE’s were all classified as minor and included tenderness,
bruising and edema all of which were considered to be
related to the Restylane injections. One patient (15
minute) demonstrated erythema and edema lasting 4
days, initially bilateral and then unilateral (NTL4 side).
Cleared with topical cortisone. Thought to be reaction to
Lidocaine.

Overall Combined (N=50)
Group Statistics
50 1.806 1.3870 .1962
50 3.396 2.3788 .3364
50 .350 .7990 .1130
50 .896 1.4187 .2006
50 .194 .4757 .0673
50 .598 1.3422 .1898
Randomization
(A) NTL4
(B) LMX4
(A) NTL4
(B) LMX4
(A) NTL4
(B) LMX4
VAS_Immediate
VAS_1_Hour
VAS_3_Hour
Std. Error
Mean

N=50 N=50 N=50
p<0.001 p=0.02 p=0.04
0
1
2
3
4
5
NTL4
LMX4
Y Axis: VAS Scale

Randomization * Subject_Level_of_Pain Crosstabulation
4 32 9 4 1 50
2.0 22.5 15.0 8.5 2.0 50.0
8.0% 64.0% 18.0% 8.0% 2.0% 100.0%
100.0% 71.1% 30.0% 23.5% 25.0% 50.0%
4.0% 32.0% 9.0% 4.0% 1.0% 50.0%
0 13 21 13 3 50
2.0 22.5 15.0 8.5 2.0 50.0
.0% 26.0% 42.0% 26.0% 6.0% 100.0%
.0% 28.9% 70.0% 76.5% 75.0% 50.0%
.0% 13.0% 21.0% 13.0% 3.0% 50.0%
4 45 30 17 4 100
4.0 45.0 30.0 17.0 4.0 100.0
4.0% 45.0% 30.0% 17.0% 4.0% 100.0%
100.0% 100.0% 100.0% 100.0% 100.0% 100.0%
4.0% 45.0% 30.0% 17.0% 4.0% 100.0%
Count
Expected Count
% within Subject_Level_
of_Pain
% of Total
Count
Expected Count
of_Pain
% of Total
Count
Expected Count
of_Pain
% of Total
(A) NTL4
(B) LMX4
Randomization
Total
Moderate
Pain Severe Pain
Total

P<0.001
(B) LMX4(A) NTL4
Randomization
40
30
20
10
0
Count
Severe Pain
Moderate Pain
Mild Pain
Minimal Pain
No Pain
Bar Chart

35 9 6 50
22.0 22.0 6.0 50.0
70.0% 18.0% 12.0% 100.0%
79.5% 20.5% 50.0% 50.0%
35.0% 9.0% 6.0% 50.0%
9 35 6 50
22.0 22.0 6.0 50.0
18.0% 70.0% 12.0% 100.0%
20.5% 79.5% 50.0% 50.0%
9.0% 35.0% 6.0% 50.0%
44 44 12 100
44.0 44.0 12.0 100.0
44.0% 44.0% 12.0% 100.0%
100.0% 100.0% 100.0% 100.0%
44.0% 44.0% 12.0% 100.0%
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
Count
Expected Count
% within Product_
Randomization
% within Preference
% of Total
NTL4
LMX
Total
Yes No
No
Preference
Preference
Total

Subject Satisfaction Data: Overall
Preference Overall Combined (N=50)
System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
0
10
20
30
40
50
NTL4 LMX4 No
Preference
Subject Preference
P<0.001
Preference Rates:
NTL4 = 70% (35/50)
LMX4 = 18% (9/50)

Randomization * Investigator_Rating Crosstabulation
19 29 2 0 50
10.0 28.5 9.5 2.0 50.0
38.0% 58.0% 4.0% .0% 100.0%
95.0% 50.9% 10.5% .0% 50.0%
19.0% 29.0% 2.0% .0% 50.0%
1 28 17 4 50
10.0 28.5 9.5 2.0 50.0
2.0% 56.0% 34.0% 8.0% 100.0%
5.0% 49.1% 89.5% 100.0% 50.0%
1.0% 28.0% 17.0% 4.0% 50.0%
20 57 19 4 100
20.0 57.0 19.0 4.0 100.0
20.0% 57.0% 19.0% 4.0% 100.0%
100.0% 100.0% 100.0% 100.0% 100.0%
20.0% 57.0% 19.0% 4.0% 100.0%
Count
Expected Count
Rating
% of Total
Count
Expected Count
Rating
% of Total
Count
Expected Count
Rating
% of Total
(A) NTL4
(B) LMX4
Randomization
Total
No Pain Slight Pain
Moderate
Pain Severe Pain
Investigator_Rating
Total

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
Eye disorders
Eyelid edema
0
0
15 (8)
6 (3)
15 (5)
6 (2)
Injection site pain
10 (10)
1 (1)
3 (3)
28 (14)
7 (4)
3 (2)
38 (13)
8 (3)
6 (2)
Nasopharyngitis
20 (20)
4 (4)
5 (5)
45 (23)
16 (8)
8 (4)
65 (22)
20 (7)
13 (4)
Postprocedural pain
8 (8)
3 (3)
10 (5)
2 (1)
18 (6)
5 (2)
Investigations
Blood urine present
2 (2)
1 (1)
8 (4)
6 (3)
10 (3)
7 (2)
Headache
13 (13)
9 (9)
29 (15)
22 (11)
42 (14)
31 (10)
P<0.001
(B) LMX4(A) NTL4
Randomization
30
25
20
15
10
5
0
Count
Severe Pain
Moderate Pain
Slight Pain
No Pain
Investigator_Rating
Bar Chart

System Organ Class
Preferred Term
Placebo
n=100
Dysport 50 U
n=200
Total
N=300
adverse events: n (%) 1 (1) 4 (2) 5 (2)
Cardiac disorders
Chest pain 0 1 (<1) 1 (<1)
Burns second degree
Burns third degree
Thermal burn
1 (1)
1 (1)
1 (1)
0
0
0
1 (<1)
1 (<1)
1 (<1)
Pregnancy 0 1 (<1) 1 (<1)
Randomization * Overall_Impression_of_Anesthetic Crosstabulation
48 2 50
36.0 14.0 50.0
96.0% 4.0% 100.0%
66.7% 7.1% 50.0%
48.0% 2.0% 50.0%
24 26 50
36.0 14.0 50.0
48.0% 52.0% 100.0%
33.3% 92.9% 50.0%
24.0% 26.0% 50.0%
72 28 100
72.0 28.0 100.0
72.0% 28.0% 100.0%
100.0% 100.0% 100.0%
72.0% 28.0% 100.0%
Count
Expected Count
% within Overall_
Impression_of_
Anesthetic
% of Total
Count
Expected Count
% within Overall_
Impression_of_
Anesthetic
% of Total
Count
Expected Count
% within Overall_
Impression_of_
Anesthetic
% of Total
(A) NTL4
(B) LMX4
Randomization
Total
Anesthetic
Total

P<0.001
(B) LMX4(A) NTL4
Randomization
50
40
30
20
10
0
Count
Not Satisfied
Satisfied
Bar Chart

VAS Comparison: Onset
Immediate Post Injection
0
1
2
3
4
5
20 minutes 15 minutes 10 minutes 5 minutes
NTL4
LMX4
N=30 N=6 N=8 N=6
p=0.044 p=0.004 p=0.068 p=0.045
d=0.98 (Large)
X Axis: Duration of Application
Y Axis: VAS Scale

One Hour Post Injection
N=30 N=6 N=8 N=6
p=0.016 p=0.085 p=0.279 p=0.309
d=1.1 (Large) d=0.56 (Medium) d=0.27 (Small)
Y Axis: VAS Scale
0
1
2
3
4
5
NTL4
LMX4

Three Hours Post Injection
N=30 N=6 N=8 N=6
p=0.066 p=0.22 p=0.724 p=0.643
d=0.48 (Medium) d=0.75 (Large) d=0.18 (Small) d=0.27 (Small)
0
1
2
3
NTL4
LMX4
Y Axis: VAS Scale

Results Summary Combined Trials
 All evaluations categories both subjective
and investigator assessed for combined
trials (n=50) demonstrated significantly less
pain and significantly favored the NTL4 vs.
LMX4 (p<0.01 or better)
 VAS scores for NTL4 similar and
independent of incubation time (20, 15, 10,
5 minutes) at immediate, one hour and
three hours

Discussion I
 Trails compared subjective and blinded investigator assessment pain,
as well as preference following Restylane injections in the NLF
comparing a novel 4 % lidocaine in nano technology delivery system
(NTL4) to commercially available LMX4
 Results indicate that NTL4 is significantly superior to LMX4 according
to blinded subjective bilateral comparisons and blinded investigator
observations. Results consistent at one hour and three hours after
injection and is related to both half life of lidocaine and decreased
initial pain
 NTL4 appears to have significant efficiency with extremely short
incubation (15,10 and 5 minutes) after 30 second massage
application. Variations in significance of individual onset groups
secondary to small n in each group. Differences between initial and
early onset study (apparent enhanced effect of NTL4 may be due to
30 vs 20 second application massage)

Discussion II
 Significant effectiveness of NTL4 demonstrated in trials against
active compound (LMX4) not placebo
 AE’s mild and appear associated with injections except for one
subject. Erythema and edema started bilaterally and continued in
NTL4 treatment side. Probable cause is topical lidocaine sensitivity.
 NTL4 show significant promise as a next generation topical
anesthetic having significantly enhanced effect and early onset ability
 Nano technology allows for enhanced rapid penetration of lidocaine
through the stratum corneum, epidermis and dermis to the sensory
nerves
 4% lidocaine allows for OTC status: both as a physician used
(dispensed) and general consumer use
 Short incubation times (early onset) will be very attractive to
dermatologists and pediatricians
 Commercial launch of OTC within months (just need stability testing)

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