Lidocaine Comparison Trial Full

NTL4The 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

10025.1Center 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 SystemIonic 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

InParT Drug Delivery SystemIonic 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

InParT Drug Delivery SystemIonic 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]

Results

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. DeviationStd. ErrorMean

Efficacy Results: Subjective VAS

N=30 N=30 N=30

p=0.04 p=0.01 p=0.06

d=0.48 (Medium)

X Axis: Time After InjectionY Axis: VAS Scale

0

1

2

3

4

5

Immediate 1 Hour 3 Hour

NTL4

LMX4

Subject Satisfaction DataSubjective 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_Levelof_Pain

% of Total

Count

Expected Count



% of Total

Count

Expected Count



% of Total

(A) NTL4

(B) LMX4

Randomization

Total

No Pain Minimal Pain Mild PainModerate

Pain Severe Pain

Subject_Level_of_Pain

Total

Subject Satisfaction DataSubjective Level of Pain

P=0.22

(B) LMX4(A) NTL4

Randomization

20

15

10

5

0

Co

un

t

Severe PainModerate PainMild PainMinimal PainNo Pain


Bar Chart

Subject Satisfaction DataOverall 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 Preference

% of Total

Count

Expected Count


% within Preference

% of Total

NTL4

LMX

Product_Randomization

Total

Yes NoNo

Preference

Preference

Total

Subject Satisfaction DataOverall 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 NoPreference

Subject Preference

P=0.002Preference 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



% of Total

Count

Expected Count



% of Total

(A) NTL4

(B) LMX4

Randomization

Total

No Pain Slight PainModerate

Pain Severe Pain

Investigator_Rating

Total

Blinded Investigator’s Evaluation of Pain


Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


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

Co

un

t

Severe Pain

Moderate Pain

Slight Pain

No PainInvestigator_Rating

Bar Chart

Blinded Investigator’s Overall Satisfaction of Topical Anesthetic


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)

General disorders and administrative site reactions Chest pain

0

1 (<1)

1 (<1)

Infections and infestations Appendicitis

0

1 (<1)

1 (<1)

Injury, poisoning, and procedural complications Burns second degree Burns third degree Thermal burn

1 (1) 1 (1) 1 (1)

0 0 0

1 (<1) 1 (<1) 1 (<1)

Nervous system disorders 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



% of Total

Count

Expected Count



% 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

Co

un

t

Not SatisfiedSatisfied


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.

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]

Results

Efficacy Results: Subjective VAS 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

Product_RandomizationNTL4

LMX4

NTL4

LMX4

NTL4

LMX4

VAS_Immediate

VAS_1_Hour

VAS_3_Hour

N Mean Std. DeviationStd. Error

Mean

Efficacy Results: Subjective VAS Early Onset Groups Combined (N=20)

N=20 N=20 N=20

p<0.001 p=0.242 p=0.161

d=0.37 d=0.45 (Medium)


0

1

2

3

4

5


NTL4

LMX4

Efficacy Results: Subjective VAS 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

N Mean Std. Deviation

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)


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


LMX4

NTL4

LMX4

NTL4

LMX4

VAS_Immediate

VAS_1_Hour

VAS_3_Hour


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)


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


LMX4

NTL4

LMX4

NTL4

LMX4

VAS_Immediate

VAS_1_Hour

VAS_3_Hour


Mean


N=6 N=6 N=6

p=0.045 p=0.309 p=0.643

d=0.61 (Large) d=0.27 (Small)


0

1

2

3

4

5


NTL4

LMX4

Subjective Level of Pain Early Onset Groups Combined

(N=20)Product_Randomization * Subject_Level_of_Pain Crosstabulation

2 14 2 2 0 201.0 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%

CountExpected Count% within Product_Randomization% within Subject_Level_of_Pain% of TotalCountExpected Count% within Product_Randomization% within Subject_Level_of_Pain% of TotalCountExpected Count% within Product_Randomization% within Subject_Level_of_Pain% of Total

NTL4

LMX4


Total


Pain Severe Pain


Total

Subjective Level of Pain Early Onset Groups Combined (N=20)

P<0.001

LMX4NTL4


14

12

10

8

6

4

2

0

Co

un

t

Severe Pain

Moderate Pain

Mild Pain

Minimal Pain

No PainSubject_Level_of_Pain

Bar Chart

Subjective Level of Pain Early Onset (15 Minutes) (N=6)

Product_Randomization * Subject_Level_of_Pain Crosstabulation

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 Subject_Level_of_Pain

% of Total

Count

Expected Count



% of Total

Count

Expected Count

% within Product_Randomization% within Subject_Level_of_Pain% of Total

NTL4

LMX4


Total

Minimal Pain Mild PainModerate

Pain


Total


P=0.01

LMX4NTL4


5

4

3

2

1

0

Co

un

t

Moderate PainMild PainMinimal 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



% of Total

Count

Expected Count



% of Total

Count

Expected Count



% 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

Co

un

t

Severe PainMild PainMinimal PainNo Pain


Bar Chart



Placebo n=100

Dysport 50 U n=200

Total N=300


1 (1)

4 (2)

5 (2)


0

1 (<1)

1 (<1)


1 (1)

0

1 (<1)


0

1 (<1)

1 (<1)


0

1 (<1)

1 (<1)


1 (1) 1 (1) 1 (1)

0 0 0

1 (<1) 1 (<1) 1 (<1)


0

1 (<1)

1 (<1)


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%

CountExpected Count

% within Product_Randomization% within Subject_Level_of_Pain

% of TotalCount

Expected Count% within Product_Randomization


% of Total

CountExpected Count



% of Total

NTL4

LMX4


Total


Pain


Total



Dysport 50 U n=200

Total N=300


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

Co

un

t

Moderate PainMild PainMinimal PainNo Pain


Bar Chart

Subject Satisfaction Data: Overall PreferenceEarly Onset Groups Combined (N=20)


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 Preference

% of Total

Count

Expected Count


% within Preference

% of Total

Count

Expected Count


% within Preference

% of Total

NTL4

LMX


Total

Yes No

Preference

Total

Subject Satisfaction Data: Overall PreferenceEarly Onset Groups Combined (N=20)


Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

0

5

10

15

20


Subject Preference

P<0.001Preference Rates:NTL4 = 85% (17/20)LMX4 = 15% (3/20)No Preference = 0% (0/20)

Subject Satisfaction Data: Overall Preference Early Onset (15 Minutes) (N=6)


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 Preference

% of Total

Count

Expected Count


% within Preference

% of Total

Count

Expected Count


% within Preference

% of Total

NTL4

LMX


Total

Yes No

Preference

Total



Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

0

1

2

3

4

5

6


Subject Preference




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 Preference

% of Total

Count

Expected Count


% within Preference

% of Total

Count

Expected Count


% within Preference

% of Total

NTL4

LMX


Total

Yes No

Preference

Total



Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

0

1

2

3

4

5

6

7

8


Subject Preference




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 Preference

% of Total

Count

Expected Count


% within Preference

% of Total

Count

Expected Count


% within Preference

% of Total

NTL4

LMX


Total

Yes No

Preference

Total



Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

0

1

2

3

4

5

6


Subject Preference


Blinded Investigator’s Evaluation of PainEarly Onset Groups Combined (N=20)


Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

P<0.001

LMX4NTL4


12

10

8

6

4

2

0

Co

un

t



Bar Chart

Blinded Investigator’s Overall Impression Early Onset Groups Combined (N=20)


Placebo n=100

Dysport 50 U n=200

Total N=300


1 (1)

4 (2)

5 (2)


0

1 (<1)

1 (<1)


1 (1)

0

1 (<1)


0

1 (<1)

1 (<1)


0

1 (<1)

1 (<1)


1 (1) 1 (1) 1 (1)

0 0 0

1 (<1) 1 (<1) 1 (<1)


0

1 (<1)

1 (<1)


0

1 (<1)

1 (<1)

Product_Randomization * Overall_Impression_of_Anesthetic Crosstabulation

20 0 2015.0 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%

CountExpected Count% within Product_Randomization% within Overall_Impression_of_Anesthetic% of TotalCountExpected Count% within Product_Randomization% within Overall_Impression_of_Anesthetic% of TotalCountExpected Count% within Product_Randomization% within Overall_Impression_of_Anesthetic% of Total

NTL4

LMX4


Total



Total

Blinded Investigator’s Evaluation of PainEarly Onset (15 Minutes) (N=6)


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



% of Total

Count

Expected Count



% of Total

Count

Expected Count



% of Total

NTL4

LMX4


Total

No Pain Minimal Pain Mild Pain


Total



Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

P=0.02

LMX4NTL4


4

3

2

1

0

Co

un

t

Mild PainMinimal PainNo 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



% of Total

Count

Expected Count



% of Total

Count

Expected Count



% of Total

NTL4

LMX4


Total


Pain


Total



Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

P=0.112

LMX4NTL4


5

4

3

2

1

0

Co

un

t



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



% of Total

Count

Expected Count



% of Total

Count

Expected Count



% of Total

NTL4

LMX4


Total

No Pain Minimal Pain Mild Pain


Total



Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

P=0.076

LMX4NTL4


4

3

2

1

0

Co

un

t

Mild PainMinimal PainNo Pain


Bar Chart

Blinded Investigator’s Overall Impression Early Onset Groups Combined (N=20)


Dysport 50 U n=200

Total N=300


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

Co

un

t



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.

ResultsCombined Trials

Efficacy Results: Subjective VAS 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


Mean

Efficacy Results: Subjective VAS Overall Combined (N=50)

N=50 N=50 N=50

p<0.001 p=0.02 p=0.04

0

1

2

3

4

5


NTL4

LMX4


Subjective Level of PainOverall Combined (N=50)

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



% of Total

Count

Expected Count



% of Total

Count

Expected Count



% of Total

(A) NTL4

(B) LMX4

Randomization

Total


Pain Severe Pain


Total

Subjective Level of PainOverall Combined (N=50)

P<0.001

(B) LMX4(A) NTL4

Randomization

40

30

20

10

0

Co

un

t

Severe PainModerate PainMild PainMinimal PainNo Pain


Bar Chart

Subject Satisfaction Data: Overall Preference Overall Combined (N=50)


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 Preference

% of Total

Count

Expected Count


% within Preference

% of Total

Count

Expected Count


% within Preference

% of Total

NTL4

LMX


Total

Yes NoNo

Preference

Preference

Total

Subject Satisfaction Data: Overall Preference Overall Combined (N=50)


Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


13 (13) 9 (9)

29 (15) 22 (11)

42 (14) 31 (10)

0

10

20

30

40

50


Subject Preference

P<0.001Preference Rates:NTL4 = 70% (35/50)LMX4 = 18% (9/50)No Preference = 12% (6/50)

Blinded Investigator’s Evaluation of PainOverall Combined (N=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



% of Total

Count

Expected Count



% of Total

Count

Expected Count



% of Total

(A) NTL4

(B) LMX4

Randomization

Total

No Pain Slight PainModerate

Pain Severe Pain

Investigator_Rating

Total

Blinded Investigator’s Evaluation of PainOverall Combined (N=50)


Placebo n=100

Dysport 50 U n=200

Total N=300


0 0

15 (8) 6 (3)

15 (5) 6 (2)


10 (10) 1 (1) 3 (3)

28 (14) 7 (4) 3 (2)

38 (13) 8 (3) 6 (2)


20 (20) 4 (4) 5 (5)

45 (23) 16 (8) 8 (4)

65 (22) 20 (7) 13 (4)


8 (8) 3 (3)

10 (5) 2 (1)

18 (6) 5 (2)


2 (2) 1 (1)

8 (4) 6 (3)

10 (3) 7 (2)


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

Co

un

t

Severe PainModerate PainSlight PainNo Pain

Investigator_Rating

Bar Chart

Blinded Investigator’s Overall Impression Overall Combined (N=50)


Placebo n=100

Dysport 50 U n=200

Total N=300


1 (1)

4 (2)

5 (2)


0

1 (<1)

1 (<1)


1 (1)

0

1 (<1)


0

1 (<1)

1 (<1)


0

1 (<1)

1 (<1)


1 (1) 1 (1) 1 (1)

0 0 0

1 (<1) 1 (<1) 1 (<1)


0

1 (<1)

1 (<1)


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



% of Total

Count

Expected Count



% of Total

Count

Expected Count



% of Total

(A) NTL4

(B) LMX4

Randomization

Total



Total

Blinded Investigator’s Overall Impression Overall Combined (N=50)

P<0.001

(B) LMX4(A) NTL4

Randomization

50

40

30

20

10

0

Co

un

t



Bar Chart

VAS Comparison: OnsetImmediate 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=6p=0.044 p=0.004 p=0.068 p=0.045

d=0.98 (Large)X Axis: Duration of ApplicationY Axis: VAS Scale

VAS Comparison: OnsetOne Hour Post Injection

N=30 N=6 N=8 N=6p=0.016 p=0.085 p=0.279 p=0.309

d=1.1 (Large) d=0.56 (Medium) d=0.27 (Small)X Axis: Duration of ApplicationY Axis: VAS Scale

0

1

2

3

4

5


NTL4

LMX4

VAS Comparison: OnsetThree 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

X Axis: Duration of ApplicationY 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)

Date post:	22-Jan-2015
Category:	Business
Upload:	pankaj-modi
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