Clinical Trial to Evaluate ET-01 in Subjects With Lateral Canthal Lines
Phase: PHASE2
Conditions: Lateral Canthal Lines, LCL, Crow's Feet
Sponsor: Eirion Therapeutics Inc.

The confidential and proprietary information in this document is provided to you as a Principal Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee or duly 
authorized representatives of the U.S. Food and Drug Administration under the condition that they are requested to 
keep it confidential. Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without authorization from the Sponsor, Eirion Therapeutics, Inc. 
 
 
 
 
 
 
 
Clinical Trial to Evaluate ET-01 in Subjects with Lateral Canthal Lines 
 
 
 
 
 
 
Protocol No.: ET-01-LCL-209 
 
 
 
 
 
January 18, 2019 
 
 
 
 
 
 
 
 
 
 
Eirion Therapeutics, Inc.  
25-K Olympia Ave., Suite 200 
Woburn, MA 01801 
Tel: 215-356-7532 
 
 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 2 of 42 
 
 
Confidential  
 
TABLE OF CONTENTS 
ABBREVIATIONS ................................................................................................................................... 5 
1 
INTRODUCTION AND BACKGROUND .......................................................................................... 6 
2 
STUDY OBJECTIVES AND PURPOSE .......................................................................................... 7 
3 
STUDY DESIGN ............................................................................................................................. 7 
3.1 
Overall Design....................................................................................................................... 7 
3.2 
Treatment Groups / Sample Size .......................................................................................... 7 
3.3 
Efficacy Parameters and Timing .......................................................................................... 7 
3.4 
Safety Parameters and Timing ............................................................................................. 7 
3.4.1 
Vital signs ......................................................................................................................... 8 
3.4.2 
Muscle Weakness or Paralysis ........................................................................................ 8 
3.4.3 
Hematology ....................................................................................................................... 8 
3.4.4 
Clinical Chemistry ............................................................................................................ 8 
3.4.5 
ECG Testing ...................................................................................................................... 9 
3.4.6 
Immunogenicity ................................................................................................................ 9 
3.4.7 
Photography ..................................................................................................................... 9 
3.4.8 
Treatment Procedure ........................................................................................................ 9 
3.5 
Study Visits and Procedures .............................................................................................. 10 
3.6 
Measures to Minimize/Avoid Bias ...................................................................................... 10 
4 
MEDICATION AND DOSING ........................................................................................................ 11 
4.1 
Dose Rationale .................................................................................................................... 11 
4.2 
Treatment of Subjects ........................................................................................................ 11 
4.3 
Drug Storage and Drug Accountability .............................................................................. 14 
4.3.1 
Drug Storage ................................................................................................................... 14 
4.3.2 
Drug Accountability ........................................................................................................ 14 
5 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS .......................................................... 15 
5.1 
Inclusion Criteria................................................................................................................. 15 
5.2 
Exclusion Criteria ............................................................................................................... 15 
5.3 
Concomitant Medication..................................................................................................... 16 
5.4 
Subject Withdrawal or Removal From Study ..................................................................... 17 
5.4.1 
Subject Unblinding Procedures ..................................................................................... 17 
6 
STUDY PROCEDURES ................................................................................................................ 17 
6.1.1 
Baseline (Qualifying) Visit .............................................................................................. 17 
6.1.2 
Week 1 Visit (+/- 2 days) ................................................................................................. 19 
6.1.3 
Week 2 Visit (+/- 3 days) ................................................................................................. 19 
6.1.4 
Week 4 Visit (+/- 4 days) ................................................................................................. 20 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 3 of 42 
 
 
Confidential  
 
6.1.5 
Week 8 Visit (+/- 7 days) ................................................................................................. 20 
6.1.6 
Week 12 Visit (+/- 7 days) ............................................................................................... 21 
6.1.7 
Week 18 Visit (+/- 7 days) ............................................................................................... 21 
6.1.8 
Week 26 Visit (+/- 7 days) ............................................................................................... 22 
6.1.9 
Study Exit / Early Termination........................................................................................ 22 
6.1.10 
Unscheduled Visits..................................................................................................... 22 
7 
STUDY DURATION AND CONDUCT ........................................................................................... 23 
7.1 
Conduct of Study ................................................................................................................ 23 
7.2 
Duration of Study ................................................................................................................ 23 
7.3 
Stopping Rules ................................................................................................................... 23 
7.4 
Monitoring for subject compliance .................................................................................... 24 
8 
ADVERSE EVENT REPORTING .................................................................................................. 24 
8.1 
Definitions ........................................................................................................................... 25 
8.1.1 
Relationship to Study Drug ............................................................................................ 25 
8.1.2 
Adverse Event Severity .................................................................................................. 26 
8.1.3 
Serious Adverse Events ................................................................................................. 26 
8.1.4 
Unanticipated Problems Involving Risk to Subjects or Others .................................... 27 
8.2 
Adverse Event Follow-up ................................................................................................... 28 
8.2.1 
Pregnancy ....................................................................................................................... 28 
9 
STATISTICAL PLAN .................................................................................................................... 28 
9.1 
Subject Population(s) for Analysis .................................................................................... 28 
9.1.1 
Sample size ..................................................................................................................... 28 
9.1.2 
ITT and PP population .................................................................................................... 28 
9.2 
Statistical Methods ............................................................................................................. 29 
9.2.1 
Study Population ............................................................................................................ 29 
9.2.2 
Primary Efficacy Analysis .............................................................................................. 29 
9.2.3 
Secondary Efficacy Analyses ........................................................................................ 30 
9.2.4 
Safety Analysis ............................................................................................................... 30 
9.2.5 
Interim Analysis .............................................................................................................. 31 
9.3 
Significance ........................................................................................................................ 31 
9.4 
Termination Criteria ............................................................................................................ 31 
9.5 
Deviation Reporting ............................................................................................................ 31 
10 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ......................................................... 31 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................... 32 
12 
ETHICAL CONSIDERATIONS ...................................................................................................... 32 
13 
DATA HANDLING AND RECORD KEEPING ............................................................................... 33 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 4 of 42 
 
 
Confidential  
 
14 
FINANCE ...................................................................................................................................... 34 
15 
INVESTIGATOR’S AGREEMENT ................................................................................................. 34 
16 
REFERENCES ............................................................................................................................. 35 
APPENDIX A: CROW’S FEET WRINKLE SCALE ................................................................................ 36 
APPENDIX B: SIGNS OF BOTULINUM TOXIN SPREAD ..................................................................... 38 
APPENDIX C: PROCEDURE FOR COLOR PHOTOGRAPHY .............................................................. 39 
APPENDIX D: IRRITATION SCORING ................................................................................................. 41 
APPENDIX E: PREPARATION OF STUDY DRUG ............................................................................... 42 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 5 of 42 
 
 
Confidential  
 
ABBREVIATIONS 
 
AE 
 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA  
Analysis Of Variance 
BoNTA 
Botulinum toxin, Type A  
CFW  
Crow’s Feet Wrinkle (scale) 
eCRF  
Case Report Form 
ECG  
Electrocardiogram 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
ICH 
 
International Conference on Harmonization 
IGA 
 
Investigator's Global Assessment score 
IGA-C  
Investigator's Global Assessment score on Contraction 
IGA-R  
Investigator's Global Assessment score at Rest 
IRB 
 
Institutional Review Board 
ITT  
 
Intent-to-Treat 
IUD 
 
Intra-Uterine Device 
LCL 
 
Lateral Canthal Lines 
LOCF  
Last Observation Carried Forward 
PP 
 
Per-Protocol 
SAE  
Serious Adverse Event 
SSA  
Subject Self-Assessment 
SSA-C 
Subject Self-Assessment on Contraction 
SSA-R 
Subject Self-Assessment at Rest 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 6 of 42 
 
 
Confidential  
 
1 
INTRODUCTION AND BACKGROUND  
Over time, the actions of the facial musculature, coupled with loss of skin elasticity and a 
reduction in subcutaneous tissue, result in the development of facial lines. With the 
decrease in skin elasticity, repeated facial expressions can become permanent lines1. 
The periorbital area is one of the first places on the face to show signs of aging, in the 
form of lateral canthal lines or Crow’s Feet. Genetic differences and environmental toxins, 
predominantly ultraviolet light exposure and cigarette smoking, may alter the rate of this 
normal aging process2. 
 
Over the past two decades, there has been increasing demand for aesthetic procedures 
to reverse the effects of aging, particularly in the facial area, and treatment of Crow's Feet 
is among the most frequent of corrective treatment requests. A number of techniques 
have been developed to meet the increasing demand for aesthetic procedures to reverse 
the signs of aging. These include: incisional and excisional surgery, various resurfacing 
procedures, and the use of temporary or semi-permanent, injectable dermal fillers such 
as allogeneic or xenogeneic collagen, hyaluronic acid, and autologous fat cells. Topical 
agents, such as retinoic acids, glycolic acids and lactic acids, are other common methods 
to minimize Crow’s Feet and other facial wrinkles.  
 
Injection of botulinum toxin type A (BoNTA) is now one of the most common aesthetic 
procedures performed and there is a considerable body of medical literature 
demonstrating its safety and efficacy in aesthetic indications3. On a molecular level, 
botulinum toxin prevents the release of preformed mediators, such as acetylcholine, from 
motor nerve endings leading to a flaccid paralysis. 
 
BoNTA is an effective treatment for Crow’s Feet and is associated with high subject 
satisfaction. However, the treatment requires multiple injections into a well innervated, 
sensitive area that is prone to bleeding and bruising and close to delicate organs such as 
the eyes and lachrymal glands. In addition, misplacement of injection can lead to 
unwanted effects in non-target areas. Therefore, a topical dermatological formulation to 
deliver the active ingredient, avoiding the discomforts and potential side effects of 
injections, would be highly desirable.   
 
Several studies have been conducted assessing the dose-response of the topical 
botulinum product, ET-014, in the treatment of Crow’s Feet. The product was well 
tolerated. This current clinical trial seeks to expand on the existing work. 
                                            
1 Ascher, B et al. Dermatol Surg 35:1478-1486, 2009 
2 Carruthers, A et. al. Dermatol Surg 2008; 34:S173–S178 
3 Coté, T. et al. J. Am. Acad. Dermatol. 2005;53:407-15 
4 ET-01 was previously studied under Anterios’ code ANT-1207 and ANT-1401 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 7 of 42 
 
 
Confidential  
 
 
2 
STUDY OBJECTIVES AND PURPOSE 
In two previous studies ET-01 was applied at doses of up to 1,150 U after skin pre-
conditioning with microneedle arrays of the type AdminStamp. The purpose of this 
Phase 2 study is to continue with the previously employed AdminStamp for skin pre-
conditioning while advancing dose exploration. 
 
3 
STUDY DESIGN 
3.1 Overall Design 
The study will be an out-patient, prospectively randomized, double-blind, vehicle-
controlled, two-armed, parallel dose group, multi-center clinical trial.  
3.2 Treatment Groups / Sample Size 
The following dose groups and sample sizes are planned:  
 
Dose Group 
Vehicle 1,600 U ∑ Total 
Sample Size N = 
20 
20 
40 
 
The treatment area will be preconditioned with a microneedle array, AdminStamp 600, 
that features microneedles 0.5 mm in length. ET-01 will be applied immediately after pre-
conditioning. 
3.3 Efficacy Parameters and Timing 
Efficacy will be assessed using the Crow’s Feet Wrinkle Scale (CFW), which is a 
published validated, photo-numeric guide that grades severity of lateral canthal lines into 
one of the five categories of 0=none, 1=minimal, 2=mild, 3=moderate, and 4=severe. (see 
Appendix A for details). Using the same scale, assessments will be made by both, the 
investigator (IGA) and the subjects (SSA). Assessments are made “static” to avoid recall 
bias.  
 
The IGA and SSA are recorded separately for the right and left canthal areas, both “at 
rest” and “on contraction”. The IGA and SSA will be recorded at each visit.  
3.4 Safety Parameters and Timing 
Safety will be assessed during the study by collection of study events, review of 
concomitant treatments and laboratory data. Clinical adverse event reporting will be 
conducted at each visit. 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 8 of 42 
 
 
Confidential  
 
 
All laboratory measurements will be performed by a central laboratory using appropriate 
and validated methods. Values will be reported to the Investigator and the Sponsor. 
Laboratory reference range values will be described in the laboratory manual. 
Investigators will assess all out of range values as being clinically significant or not.  
3.4.1 Vital signs 
Weight, height (Screening visit only) temperature, resting pulse, blood pressure, and 
respiration rate. Vital signs will be recorded at every visit. 
3.4.2 Muscle Weakness or Paralysis  
Participants will be monitored for potential signs of botulinum induced muscle weakness 
or paralysis. Subjects will be evaluated for Signs of Botulinum Toxin Spread (muscle 
weakness - ocular and the extremities) or difficulty swallowing or breathing (cranial nerve 
assessment, Appendix B). 
 
The neurologic assessments are made at Baseline, Week 1, 2, and Week 4. 
3.4.3 Hematology 
Non-fasting clinical hematology evaluations are: 
hemoglobin, hematocrit, red blood cell count, white blood cell count, with a differential, 
and a platelet count.  
 
Non-fasting clinical hematology evaluations will be performed at Week 0 (Baseline), 
Week 4, and Week 26/End of Study. 
3.4.4 Clinical Chemistry 
A standard non-fasting chemistry panel will be performed which will include the following 
parameters: 
glucose, uric acid, calcium, sodium, potassium, phosphorus, chloride, alkaline 
phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, 
bicarbonate, creatinine, blood urea nitrogen, lactate dehydrogenase, total protein, 
albumin. 
 
The chemistry panel will be performed at Baseline (Week 0), Week 4, and Week 26/End 
of Study. A urine pregnancy test will be performed for women of child-bearing potential at 
Baseline and the Week 4 visit.  

Study #: ET-01-LCL-209 
January 18, 2019 
Page 9 of 42 
 
 
Confidential  
 
3.4.5 ECG Testing 
A 12-lead ECG will be recorded measuring the RR, PR, QRS, and QT interval durations 
prior to treatment application at Baseline and at Week 2. 
3.4.6 Immunogenicity 
Plasma samples will be banked for future analysis of anti-botulinum serum antibodies as 
a safety parameter for possible immunization against botulinum.  
 
Samples will be taken at Baseline, Week 4, and Week 26. 
3.4.7 Photography 
Color photographs will be taken at every visit. Five pictures will be taken as described in 
Appendix C. 
3.4.8 Treatment Procedure 
To capture the level of comfort or discomfort caused by the skin pre-treatment with the 
AdminStamps and subsequent rubbing in of the study medication subjects will be asked 
to rate their experience on a scale from “-5” (very bad) to “+5” (very good). 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 10 of 42 
 
 
Confidential  
 
3.5 Study Visits and Procedures 
A schematic study diagram is shown below: 
 
Procedure 
Scr./BL 
W 1 
W 2 
W 4 
W 8 
W 12 
W 18 
W 26 
 
 
Day  
0 
± 0 
Day 
 7 
± 2 
Day 
14 
± 3 
Day 
28 
± 4 
Day 
56 
± 7 
Day 
84 
± 7 
Day 
126 
± 7 
Day 
182 
± 7 
End of 
Study# 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Assess Eligibility & 
Medical History 
X 
 
 
 
 
 
 
 
 
Review Con-meds 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight and Vital 
Signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Signs of Botulinum 
Spread 
X 
X 
X 
X 
 
 
 
 
 
Hematology and 
Chemistry 
X 
 
 
X 
 
 
 
 
X 
Anti-Botulinum 
Antibodies 
X 
 
 
X 
 
 
 
 
X 
Urine Pregnancy 
test (WOCBP) 
X 
 
 
X 
 
 
 
 
 
ECG 
X 
 
X 
 
 
 
 
 
 
IGA Score 
X 
X 
X 
X 
X 
X 
X 
X 
 
Subject Self-
Assessment (SSA) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Photography 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Apply Study 
Medication 
X 
 
 
 
 
 
 
 
 
# also for early termination 
 
The study will consist of up to 8 office visits. 
3.6 Measures to Minimize/Avoid Bias 
To minimize bias, subjects will be randomly allocated to one of the two treatment groups, 
i.e. vehicle (group A) vs. active dose (group B). Neither subjects nor investigators will be 
aware of the treatment allocation.  
 
 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 11 of 42 
 
 
Confidential  
 
4 
MEDICATION AND DOSING 
4.1 Dose Rationale  
Finding evidence of a safe and effective dose is the purpose of this study. In previous 
clinical studies doses of up to 2,000 U per treatment area were applied under occlusion 
and were well tolerated. In studies LCL-206 and LCL-207, that also employed 
AdminStamp microneedle skin preconditioning, doses of up to 1,150 U were applied 
safely. To further explore the dose-response relationship, this study plans to cautiously 
increase the administered dose by factor 1.4 to a total of 1600 U per treatment area. This 
dose is still well below the 2,000 U per treatment area applied before. 
4.2 Treatment of Subjects 
The study preparation or vehicle consists of a milky, white lotion of low viscosity. The drug 
product and diluents will be provided in kits containing 3 mL dropper bottles that contain 
either ET-01 or Vehicle.  
 
The following dose groups and sample sizes are planned: 
 
Dose Group 
Vehicle 1,600 U ∑ Total 
Sample Size N = 
20 
20 
40 
 
Randomization to a treatment group, i.e. ET-01 or Vehicle, will be obtained following a 
randomization list prepared by the Sponsor. Allocation to a dose level will be driven by 
sequence of enrollment. 
 
The study medication will be applied TOPICALLY and only to subject’s canthal areas. 
The site will be instructed to make sure no syringes or needles are present in the 
treatment room before study medication is brought into the room. 
 
The treatment area is the periorbital region in the distribution of the muscles responsible 
for the Crow’s Feet wrinkles. The muscle being treated to reduce the Crow’s Feet wrinkle 
– the orbicularis oculi – is illustrated Figure 1.  
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 12 of 42 
 
 
Confidential  
 
Figure 1: M. orbicularis oculi  
 
 
In general, the treatment region begins on the bony rim of the orbit, extending laterally to 
approximately one centimeter from the exterior edge of the hairline, 1 - 1.5 cm above and 
1.5 – 2 cm below a horizontal line emanating from the lateral canthus to the hairline. This 
area of application is illustrated by the black outline in the picture below:  
 
Figure 2: Treatment Area 
 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 13 of 42 
 
 
Confidential  
 
As a guide to treatment, it is helpful to have the subject contract the orbicularis oculi 
muscle by asking the subject to produce a maximal smile so that the muscular extension 
can be visualized for that subject’s treatment. In no case, however, should ET-01 ever be 
applied within the area circumscribed by the interior edge of the orbital rim. 
 
The treatment area will be pre-conditioned by pressing the AdminStamp firmly, applying 
approximately 3-4 pounds of pressure, to the skin. The location of the areas of pre-
conditioning are illustrated by the red circles in Figure 2. There will be three (3) 
impressions made along the bony rim of the orbital cavity and one (1) impression distal 
and inferior to the horizontal mid-line. After all four impressions have been made, the 
micro-needle array will be rotated by approximately 90° and the process is repeated.  
 
Immediately thereafter, using a gloved finger, the investigator will massage 5 drops of the 
topical treatment into the skin of the treatment area. 
 
The medication is of low viscosity and administered one drop at a time to avoid run-off. 
As an additional precaution, the subject will be positioned on an examination table or fully 
reclined examination chair such that his/her temple will slightly slant backwards and to 
the side, directing any run-off away from the eyes and into the hairline.  
 
There are 3 phases that the study drug will go through before it is completely absorbed 
into the skin. The clinical investigator will be instructed to make sure to visually observe 
all 3 phases during application process before additional small aliquots of Test Article are 
applied as listed below:  
 
Phase 1: Gelling  
the sample becomes clear in color and flowable. 
Phase 2: Creaming  
the sample becomes more viscous, is white in color, and 
sticky. 
Phase 3: Absorption  
the sample becomes clear in color and has a glossy smooth 
finish. There is no visible residue left on the skin after 
absorption. 
 
The process of treatment application will take at least 5 and up to 10 minutes each to 
complete for each periorbital region. After the last drop as been applied to the skin, it is 
critical that the product is continually rubbed onto the skin until all 3 phases have been 
observed for the last time, especially the creaming phase. This procedure will be 
completed when there is no liquid visible on the surface of the skin.  
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 14 of 42 
 
 
Confidential  
 
This procedure will be employed for both, the right and left periorbital regions. The start 
and finish time will be recorded in the eCRF. The study medication kit drug label will be 
completed and peeled-off for application in the subject’s Case Report Form.  
 
4.3 Drug Storage and Drug Accountability 
4.3.1 Drug Storage 
The investigator will ensure that the investigational product is stored in appropriate 
conditions in a secure, locked refrigerator with controlled access. Until ready for 
dispensing, the investigational product will be stored at a controlled temperature of +5°C. 
Temperature logs will be maintained to document that the storage temperature has not 
deviated from the recommended range. Should a deviation occur in the storage 
temperature of unopened investigational product kits, the investigator will complete and 
submit an Investigational Product Deviation Report form by e-mail to the Sponsor. The 
Sponsor will review the information submitted and will provide direction regarding further 
use of the applicable kit/s. 
4.3.2 Drug Accountability 
The principal investigator at each site is responsible for maintaining accurate records of 
the receipt and application of all investigational materials. The investigator may apply the 
investigational drug only to eligible subjects enrolled in the study. All applications of the 
investigational drug will be conducted at the study sites. 
 
Eirion Therapeutics will provide drug accountability forms to assist the investigator in 
maintaining current and accurate inventory records covering receipt, application, and the 
return of investigational drug supplies. When a shipment is received, the investigator or 
designee will verify the quantities received. The Case Report Form includes the 
identification of the person to whom the drug is applied, the date of application, and any 
returned or unused drug. These records will be readily available for inspection by the 
Sponsor or a monitor and are open to any other regulatory authority inspection at any 
time. 
 
When the supplies are returned, the investigator, designee, or monitor signs the 
investigational drug return log to verify that all used, unused, or partially used supplies 
have been returned, and that no study supplies remain in the investigator’s possession. 
One copy of all inventory records and the return statement are retained by the investigator 
for the study files. 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 15 of 42 
 
 
Confidential  
 
At study termination, unless otherwise specified, all used, unused, and partially used drug 
supplies should be returned to the distribution center. The study drug return form will be 
returned to Eirion Therapeutics, Inc., and a copy will be maintained on site. 
 
5 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS 
The study will enroll adult female subjects diagnosed with mild to severe Crow’s Feet. 
5.1 Inclusion Criteria 
• able to understand and give written informed consent  
• females 25 - 65 years of age 
• willing to have facial pictures taken per protocol 
• minimal to moderate Crow's Feet wrinkles (IGA 1-3) at rest 
• moderate to severe Crow’s Feet (IGA 3-4) on contraction 
• moderate to severe Crow’s Feet (SSA 3-4) on contraction 
• Have adequate vision without the use of eyeglasses to assess facial wrinkles in a 
mirror (contact lenses are OK) 
• willingness to refrain from the use of facial fillers, retinoids, botulinum toxins, laser 
treatments, or any product affecting skin remodeling or that might cause an active 
dermal response during the course of the study 
• female subjects of child bearing potential must have a negative urine pregnancy 
test and be non-lactating at the Baseline visit 
• female subjects of child bearing potential must utilize one of the following methods 
of birth control throughout the study: IUD, diaphragm, a condom, a spermicidal gel 
or foam, oral contraceptives (provided subject has been utilizing this method for at 
least 3 months prior to baseline and has not changed the brand within this period), 
or patch, injectable, implantable, or vaginal ring contraceptives. Subjects may also 
participate if they are surgically sterilized (tubal sterilization or hysterectomy) or 
are in menopause. 
• subjects should be in good general health as determined by the investigator and 
free of any disease that may interfere with study evaluations or the Investigational 
Product 
5.2 Exclusion Criteria 
• history of adverse reactions to any prior botulinum toxin treatments  
• history of vaccination with botulinum toxin 
• history of non-response to any prior botulinum toxin treatments 
• any botulinum toxin treatment in the prior 6 months  
• history of periocular surgery, brow lift or related procedures 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 16 of 42 
 
 
Confidential  
 
• soft tissue augmentation or any procedures affecting the lateral canthal region in 
the prior 12 months 
• dermabrasion or laser treatment in the periocular region in the last 6 months  
• topical prescription-strength retinoids in the prior 3 months to the treatment area 
• application of any topical prescription medication to the treatment area within 
14 days prior to treatment  
• subjects on clinically significant, concomitant drug therapy (See section 5.3 below). 
• present or history of neuromuscular disease, eyelid ptosis, muscle weakness or 
paralysis 
• present or history of “dry eye”  
• systemic aminoglycoside use in the week prior to treatment application 
• participation in another investigational drug trial or receiving any investigational 
treatment(s) within 30 days of Baseline 
• alcohol or drug abuse within the past 3 years 
• female subjects who are pregnant or are nursing a child 
• psychiatric disease interfering with the subject’s ability to give informed consent 
• refusal or inability to comply with the requirements of the protocol for any reason 
5.3 Concomitant Medication 
Any prescription or over-the-counter medication taken during the study will be recorded 
in the appropriate section of the Case Report Form. 
 
The following medications are prohibited: 
• Botulinum toxin containing products for the course of the study 
• The use of any facial fillers, laser treatments, or any product affecting skin 
remodeling for the course of the study 
• Dermabrasion or laser treatment in the periocular region for the course of the study 
• Topical prescription-strength retinoids in the periocular region for the course of the 
study 
• Tanning booths or sun exposure for the treatment day and the following 2 days  
• Any topical medications applied to the treatment area for the day of treatment and 
5 days following treatment. Toiletry and make-up are permitted. 
• Systemic aminoglycosides for the day of treatment and 7 days following the 
treatment application at the Baseline Visit 
• Investigational medications or treatments within 30 days of Baseline and during 
the course of the study 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 17 of 42 
 
 
Confidential  
 
5.4 Subject Withdrawal or Removal From Study 
As stated in the Informed Consent, all subjects reserve the right to withdraw from the 
study at any time. An effort will be made to determine why a subject discontinues the 
study prematurely. The reason for study discontinuation will be recorded in the eCRF. All 
subjects who terminate the study early and have completed the Baseline Visit will be 
encouraged to complete Week 26/End of Study procedures.  
 
Any subject found to have entered the study in violation of this protocol may be withdrawn 
from the study after discussion with the sponsor. Any subject who requires the use of an 
unacceptable concomitant medication may be withdrawn from the study. The investigator 
will discontinue any subject from the study if, in the investigator’s opinion, it is not in the 
subject’s best interest to continue.  
 
If the reason for withdrawal is an AE/ SAE, the specific event will be recorded, and every 
effort will be made by the Investigator to document the outcome. The date that the subject 
is withdrawn from the study and the reason for discontinuation will be recorded on the 
Case Report Form. Subjects who discontinue from the study or who are lost to follow up 
will not be replaced.  
 
5.4.1 Subject Unblinding Procedures 
Randomization lists will be maintained by the sponsor. In case of serious adverse events 
or other medical emergencies that make it necessary to unblind the treatment code for a 
specific subject, the investigator will, after consultation with the sponsor, submit a written 
request for unblinding to the Medical Monitor. The request will be documented, and the 
applicable information will be sent to the investigator via fax or e-mail. Unblinded subjects 
will be discontinued from the study. 
 
6 
STUDY PROCEDURES 
6.1.1 Baseline (Qualifying) Visit  
Prior to participating in any aspect of the study, each subject will be fully informed, both 
verbally and in writing, of the conduct and consequences of the study. Each subject must 
sign the written Informed Consent prior to the conduct of the Baseline (Qualifying) 
evaluation.  
 
The investigator will assign a unique identification code to each subject being evaluated 
for participation in the trial. The following procedures will be conducted: 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 18 of 42 
 
 
Confidential  
 
• using the rating guide provided in Appendix A, record right and left Investigator’s 
Global Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• using the same rating guide provided in Appendix A, record right and left Subject's 
Self-Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• record medical history and concomitant diseases 
• record concomitant medication usage  
• record history of botulinum use 
• female subjects of child-bearing potential will be given a urine pregnancy test 
• assess eligibility according to the Inclusion and Exclusion criteria in 5.1 and 5.2  
 
If the subject is deemed eligible to participate in the study, the subject will be randomized 
and treated. 
 
• record vital signs (weight, height, temperature, resting pulse and blood pressure, 
and respiration rate) 
• collect non-fasting blood samples for laboratory safety testing 
• record and transmit a 12-lead ECG 
• take color photographs (see Appendix C for photograph procedure)  
• evaluate for muscle weakness (ocular and the extremities) or difficulty swallowing 
or breathing (Signs of Botulinum Toxin Spread, Appendix B) 
• provide the study medication with the lowest available Kit No. to the investigator.  
• apply skin-preconditioning using the AdminStamp 
• Investigator will apply the topical treatment to the left and right lateral canthal areas  
• record subject’s experience with the application process 
• evaluate for topical adverse event reactions 30 minutes after application using the 
Irritation Score in Appendix D 
• instruct the subject to avoid sun exposure or tanning beds for two days after 
treatment 
• instruct the subject to avoid strenuous activities on the day of application which will 
cause them to perspire 
• instruct the participant not to touch or let others touch the treatment area until the 
treatment area is washed with soap and water 
• instruct the participant to wash the treatment areas with soap and water no sooner 
than 12 hours after treatment application but no later than 24 hours after treatment 
application 
• schedule follow-up appointment for the next office visit  

Study #: ET-01-LCL-209 
January 18, 2019 
Page 19 of 42 
 
 
Confidential  
 
6.1.2 Week 1 Visit (+/- 2 days) 
The Week 1 visit will occur one week post Baseline (+/- 2 days): 
 
• ask the open ended “How Do You Feel” question and document answer in the 
electronic Case Report Form 
• if the subject noted any change in well-being since last investigator contact, 
document details on the Adverse Event eCRF 
• record changes in medication usage from the Baseline (Qualifying) visit 
• record vital signs (weight, temperature, resting pulse and blood pressure, and 
respiration rate) 
• ask if the subject experienced weakness, lethargy, or difficulty swallowing or 
breathing 
• evaluate for muscle weakness (ocular and the extremities) or difficulty swallowing 
or breathing (Appendix B) 
• using the rating guide provided in Appendix A, record right and left Investigator’s 
Global Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• using the same rating guide provided in Appendix A, record right and left Subject's 
Self-Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• take color photographs (see Appendix C for photograph procedure) 
• schedule the subject for the next office visit 
6.1.3 Week 2 Visit (+/- 3 days) 
The Week 2 visit will occur two weeks post Baseline (+/- 3 days). 
 
• ask a non-leading “How Do You Feel” question and document answer in the 
electronic Case Report Form  
• if subject noted any change in well-being since last investigator contact, document 
details on the Adverse Event eCRF 
• record changes in medication usage 
• record vital signs (weight, temperature, resting pulse and blood pressure, and 
respiration rate) 
• ask if the subject experienced weakness, lethargy, or difficulty swallowing or 
breathing 
• evaluate for muscle weakness (ocular and the extremities) or difficulty swallowing 
or breathing (Appendix B) 
• record and transmit a 12-lead ECG 
• using the rating guide provided in Appendix A, record right and left Investigator’s 
Global Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  

Study #: ET-01-LCL-209 
January 18, 2019 
Page 20 of 42 
 
 
Confidential  
 
• using the same rating guide provided in Appendix A, record right and left Subject's 
Self-Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• take color photographs (see Appendix C for photograph procedure)  
• schedule subject for the next office visit  
6.1.4 Week 4 Visit (+/- 4 days) 
The Week 4 visit will occur 4 weeks post Baseline +/- 4 days. 
 
• ask a non-leading “How Do You Feel” question and document answer in the 
electronic Case Report Form  
• if subject noted any change in well-being since last investigator contact, document 
details on the Adverse Event Form 
• record changes in medication usage 
• record vital signs (weight, temperature, resting pulse and blood pressure, and 
respiration rate) 
• ask if the subject experienced weakness, lethargy, or difficulty swallowing or 
breathing 
• evaluate for muscle weakness (ocular and the extremities) or difficulty swallowing 
or breathing (Appendix B) 
• using the rating guide provided in Appendix A, record right and left Investigator’s 
Global Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• using the same rating guide provided in Appendix A, record right and left Subject's 
Self-Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• take color photographs (see Appendix C for photograph procedure)  
• collect non-fasting blood samples for laboratory safety testing 
• female subjects of child-bearing potential will be given a urine pregnancy test 
• schedule subject for the next office visit 
6.1.5 Week 8 Visit (+/- 7 days) 
The Week 8 visit will occur 8 weeks post Baseline +/- 7 days. 
 
• ask a non-leading “How Do You Feel” question and document answer in the 
electronic Case Report Form  
• if subject noted any change in well-being since last investigator contact, document 
details on the Adverse Event Form 
• record changes in medication usage 
• record vital signs (weight, temperature, resting pulse and blood pressure, and 
respiration rate) 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 21 of 42 
 
 
Confidential  
 
• using the rating guide provided in Appendix A, record right and left Investigator’s 
Global Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• using the same rating guide provided in Appendix A, record right and left Subject's 
Self-Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• take color photographs (see Appendix C for photograph procedure)  
• schedule subject for the next office visit 
6.1.6 Week 12 Visit (+/- 7 days) 
The Week 12 visit will occur 12 weeks post Baseline +/- 7 days. 
 
• ask a non-leading “How Do You Feel” question and document answer in the 
electronic Case Report Form  
• if subject noted any change in well-being since last investigator contact, document 
details on the Adverse Event Form 
• record changes in medication usage 
• record vital signs (weight, temperature, resting pulse and blood pressure, and 
respiration rate) 
• using the rating guide provided in Appendix A, record right and left Investigator’s 
Global Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• using the same rating guide provided in Appendix A, record right and left Subject's 
Self-Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• take color photographs (see Appendix C for photograph procedure)  
• schedule subject for the next office visit 
6.1.7 Week 18 Visit (+/- 7 days) 
The Week 18 visit will occur 18 weeks post Baseline +/- 7 days. 
 
• ask a non-leading “How Do You Feel” question and document answer in the 
electronic Case Report Form  
• if subject noted any change in well-being since last investigator contact, document 
details on the Adverse Event Form 
• record changes in medication usage 
• record vital signs (weight, temperature, resting pulse and blood pressure, and 
respiration rate) 
• using the rating guide provided in Appendix A, record right and left Investigator’s 
Global Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• using the same rating guide provided in Appendix A, record right and left Subject's 
Self-Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• take color photographs (see Appendix C for photograph procedure)  

Study #: ET-01-LCL-209 
January 18, 2019 
Page 22 of 42 
 
 
Confidential  
 
• schedule subject for the next office visit 
6.1.8 Week 26 Visit (+/- 7 days) 
The Week 26 visit will occur 26 weeks post Baseline +/- 7 days. 
 
• ask a non-leading “How Do You Feel” question and document answer in the Case 
Report Form  
• if subject noted any change in well-being since last investigator contact, document 
details on the Adverse Event Form 
• record changes in medication usage 
• record vital signs (weight, temperature, resting pulse and blood pressure, and 
respiration rate) 
• using the rating guide provided in Appendix A, record right and left Investigator’s 
Global Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• using the same rating guide provided in Appendix A, record right and left Subject's 
Self-Assessment score of Crow’s Feet, both, “at rest” and “on contraction”  
• take color photographs (see Appendix C for photograph procedure)  
6.1.9 Study Exit / Early Termination 
The scheduled Study Exit is at Week 26. However, if a subject should discontinue 
prematurely, the following will be performed in addition to the procedures scheduled for 
the patient’s terminating visit: 
 
• collect non-fasting blood samples for laboratory safety testing  
6.1.10 Unscheduled Visits  
The subject may contact the investigator or may be called in for additional unscheduled 
visits due to safety reasons or at the discretion of the investigator or Sponsor. All 
unscheduled visits will describe the reason for the visit in the electronic Case Report 
Form. Some of the procedures that may be completed at an Unscheduled Study Visit are 
as follows:  
 
• Review of adverse events and concomitant medications 
• Vital signs 
• Collection of blood samples for laboratory safety testing  
• Urine pregnancy testing 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 23 of 42 
 
 
Confidential  
 
7 
STUDY DURATION AND CONDUCT 
7.1 Conduct of Study 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board and according to Good Clinical Practice standards. No intentional deviation 
from the protocol will be implemented without the prior review and approval of the IRB 
except where it may be necessary to eliminate an immediate hazard to a research subject. 
In such case, the deviation will be reported to the IRB as soon as possible. 
7.2 Duration of Study 
Subject enrollment will take approximately one month. The total study duration will be 
approximately 7-8 months. 
 
Each subject will participate for up to 26 weeks. There will be a (Qualifying) Baseline Visit 
on Week 0 and seven in-office visits at Week 1, 2, 4, 8, 12, 18, and 26. 
7.3 Stopping Rules 
The study is designed as a sequential, overlapping cohort, dose-escalation trial. 
Enrollment will be halted after each cohort until a safety review has been completed.  
 
• Enrollment will be halted in the event that one serious adverse event (SAE), 
considered to be probably or definitely related to the administration of study 
medication, is observed. 
 
• Enrollment will be halted in the event that one AE is observed considered to be 
indicative of distant spread of study medication or unintended exposure to other 
beings.  
 
• The Sponsor may stop the study in its entirety or discontinue individual study 
centers at its discretion for any reason or, e.g. if it is observed that the protocol or 
sound clinical practices are not being followed, or for any other reasons. 
 
The study protocol calls for only one single application of study medication at Baseline 
(Week 0). Since there is no continuous treatment, no stopping rules for subjects are 
applicable and subjects will be encouraged to participate in the study until the scheduled 
termination visit at Week 26. 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 24 of 42 
 
 
Confidential  
 
7.4 Monitoring for subject compliance 
In this study, a single application of study medication at Day 0 is planned. The study 
medication will be applied by the Investigator or a designated healthcare professional 
thereby ensuring compliance with the study application procedure. 
 
Subjects will be queried with regards to concomitant medication at all study visits. 
 
8 
ADVERSE EVENT REPORTING 
Adverse event reporting will be handled in accordance with the IRB requirements and the 
requirements of other regulatory authorities that may apply, e.g. the Food and Drug 
Administration. 
 
Adverse Events reporting will be solicited by non-leading "How Do You Feel" questions. 
Subtle symptoms of local or systemic spread of toxin effect would be unlikely to be 
recognized by the subjects as related to treatment. Therefore, study participants will be 
asked if they experienced weakness, lethargy, or difficulty swallowing or breathing. In 
addition, information derived from change in concomitant medications, laboratory 
analyses, and clinical observations will be evaluated for possible indications for side 
effects. Adverse events resulting from concurrent illnesses or reactions to concurrent 
medications will also be recorded. The Investigator must monitor the condition of the 
subject throughout the study from the time of obtaining informed consent until the final 
study visit.  
 
Any adverse event, including both observed and volunteered problems, complaints, and 
symptoms, will be recorded on the Adverse Event pages of the electronic Case Report 
Form. When an adverse event occurs, the following information and assessments should 
be recorded in the adverse event section of the eCRF: 
 
• The signs, symptoms or diagnosis or the event, 
• The date and time of onset of the event using the 24-hour clock where midnight is 
00:00 and noon is 12:00. Onset is the date when the first sign or symptoms were first 
noted.  
• Date of recovery/ resolution 
• The adverse event severity/ intensity using the criteria outlined in Section 8.1.2 
• The relationship of the event to the study drug as outlined in Section 8.1.1  
• Any other actions required such as therapy, medication, treatment or diagnostic 
procedure 
• Seriousness of the event using the criteria outlined in Section 8.1.3 
• Outcome (recovered, recovered with sequelae, not yet recovered, death) 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 25 of 42 
 
 
Confidential  
 
 
Follow-up of a subject should be conducted until resolution of the adverse event or until 
the medical condition is stable. The investigator is responsible for the appropriate medical 
management of all adverse events.  
 
Adverse events will be analyzed and reported after unblinding of the treatment code within 
the clinical study report. Serious Adverse Events (SAEs) will be reported by the Sponsor 
within 10 working days to the IRB as well as the regulatory agency, FDA. In addition, any 
unanticipated problems involving risk to subjects or others, which in the opinion of the 
local investigator was unanticipated, serious AND at least possibly related to the research 
procedures will be reported by the Sponsor to the IRB within 10 working days. 
8.1 Definitions 
An adverse event is an undesirable or unintentional event affecting the well-being of a 
subject that occurs during use of the study drug, whether or not considered related to the 
drug; this includes accidental injuries, reasons for any change in medication (drug and/or 
dose), and reasons for surgical procedures. It is to be noted that procedures are not 
adverse events. Abnormal laboratory values or clinically significant changes in laboratory 
values are not adverse events, but the underlying reasons are. Regardless of the severity 
or relationship to the investigational drug, all adverse events occurring during the study 
period must be recorded in the subject’s eCRF.  
 
An unexpected adverse event is one that has not been previously observed, or one that 
is of a specificity or severity not consistent with the current Investigator Brochure.  
8.1.1 Relationship to Study Drug 
The following definitions to assess the causal relationship between an adverse event 
and the study drug should be used:  
 
Not Related: 
The event is clearly related to other factors such as a subject’s 
clinical state, therapeutic interventions or concomitant medications. 
 
Possibly Related:  The event has a reasonable temporal relationship to study drug 
administration and follows a known response pattern to the study 
drug. However, a potential alternate etiology may be responsible for 
the event.  
 
Related:  
The event follows a clear-cut temporal sequence from the time of 
drug administration and follows a known response pattern to the 
study drug and either occurs immediately following study drug 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 26 of 42 
 
 
Confidential  
 
administration, or improves on stopping the drug, or reappears on 
repeat exposure. 
8.1.2 Adverse Event Severity 
Mild: 
A mild adverse event is one that the symptoms are barely 
noticeable to a subject. It does not influence performance or prevent 
a subject from carrying on with normal life activities. 
 
Moderate:  
A moderate adverse event is one that the symptoms make the 
subject uncomfortable and causes some impairment to normal life 
activities. Treatment for symptom(s) may be required. 
 
Severe:  
A severe adverse event is one that the symptoms cause severe 
discomfort to the subject and severely limits the subject’s normal 
daily activities. Treatment for symptom(s) is given.  
 
Note that “serious” and “severe” are not synonymous. A serious 
adverse event must fulfill the requirements listed in the definition 
below, see section 8.1.3. 
 
When intensity changes or occurs more frequently than once a day, the maximum 
intensity for the event will be listed. If the intensity category changes over a number of 
days, then these mini-events or changes will be recorded separately (i.e., having distinct 
onset days). 
8.1.3 Serious Adverse Events 
A serious adverse event is an event that is:  
• fatal / results in death 
• life-threatening  
• results in persistent or significant disability/incapacity  
• requires or prolongs subject hospitalization or  
• is a congenital anomaly or birth defect 
 
Life Threatening is defined as an event in which a subject is at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death if 
it was more severe.  
Death: The death of an enrolled subject is not an event, but an outcome. It is the event 
that resulted in a fatal outcome that must be reported.  
Disability is defined as a substantial disruption of a person's ability to conduct normal life 
functions.  

Study #: ET-01-LCL-209 
January 18, 2019 
Page 27 of 42 
 
 
Confidential  
 
 
ANY SERIOUS ADVERSE EVENT, INCLUDING DEATH DUE TO ANY CAUSE, WHICH 
OCCURS DURING THIS INVESTIGATION, WHETHER OR NOT RELATED TO THE 
STUDY MEDICATION, MUST BE REPORTED IMMEDIATELY (DURING NORMAL 
BUSINESS HOURS, 9 AM TO 5 PM, ET) TO THE SPONSOR/MEDICAL MONITOR.  
 
Any serious adverse event should be reported to Eirion Therapeutics by telephone and/or 
e-mail within 24 hours of the event. The initial report should be followed-up with the 
completion of the written SAE report form within five days of receiving firsthand 
knowledge of the event. Full details of the event, any sequelae and an assessment of the 
relationship to the study drug must be provided in the report. Any serious adverse event 
must also be reported to the Institutional Review Board within 48 hours of receiving 
firsthand knowledge of the event and a copy of this SAE report must be sent to Eirion 
Therapeutics. The original SAE report form should be maintained in the Regulatory 
Binder. It is the Sponsor’s responsibility to fulfill reporting obligations to the FDA. 
 
Reports of serious adverse events should be made by e-mail and/or telephone to Eirion 
Therapeutics Clinical Development Department:  
 
klaus@eirionthera.com 
 
215-356-7532 
or 
 
karin@eirionthera.com 
 
610-247-6246 
 
Serious adverse events associated with the use of the study medication will be reported 
to appropriate regulatory agencies, investigators, and the IRB by the Sponsor. 
8.1.4 Unanticipated Problems Involving Risk to Subjects or Others 
Unanticipated problems involving risk to subjects or others are: 
• Any serious event (including on-site and off-site adverse events, injuries, side 
effects, deaths or other problems) which in the opinion of the local investigator was 
unanticipated, involved risk to subjects or others, and was possibly related to the 
research procedures. 
• Any serious accidental or unintentional change to the IRB-approved protocol that 
involves risk or has the potential to recur. 
• Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject. 
• Any breach in confidentiality that may involve risk to the subject or others. 
• Any other serious and possibly related event which in the opinion of the 
investigator constitutes an unanticipated risk. 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 28 of 42 
 
 
Confidential  
 
8.2 Adverse Event Follow-up 
Adverse events and Serious Adverse Events will be followed up until their resolution or 
until a stable outcome has emerged.  
8.2.1 Pregnancy 
Every effort must be made to avoid pregnancy during the study. If pregnancy does occur, 
Eirion Therapeutics must be informed immediately. The mother and fetus must be 
followed until the birth of the infant. In general, the follow up will include the course, 
duration, and outcome of the pregnancy, and the infant outcome. As the investigational 
product is applied only once during the study, subjects having a positive urine pregnancy 
test at or after the Week 4 Visit will be permitted to remain in the study. 
 
Medically accepted methods of birth control are surgical sterilization (tubal sterilization or 
hysterectomy), vaginal ring contraceptive, patch contraceptive, injectable contraceptive, 
implantable contraceptive, Intrauterine Device (IUD), diaphragm, condom, or spermicidal 
gel or foam. Oral contraceptives (prescribed birth control pill) are also acceptable 
provided this method has been used for at least 4 months prior to the qualifying visit with 
no change of the brand within this period.  
 
9 
STATISTICAL PLAN 
9.1 Subject Population(s) for Analysis 
9.1.1 Sample size 
This study is powered based on the interim results of studies LCL-206 and 207. 
9.1.2 ITT and PP population 
Statistical analysis of efficacy will be performed on the ITT population of all treated 
subjects with at least one post-baseline visit, including those for whom only incomplete 
data are available.  
 
Where data are missing due to subject discontinuation or other reasons, the last post-
baseline observation carried forward (LOCF) procedure will be used for each post-
baseline visit with missing data. The exception to this procedure will be the treatment of 
missing data only on one side of the face, as discussed below. Subjects who are lost to 
follow-up and who do not have at least one post-baseline visit will not be included in the 
analysis. 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 29 of 42 
 
 
Confidential  
 
An additional analysis may be performed in the per protocol population. Subjects will be 
considered “per protocol” if they complete the final visit evaluation without a major 
protocol violation. No data imputations will be made for this analysis. 
9.2 Statistical Methods 
9.2.1 Study Population 
Descriptive statistics will be used to summarize demographic characteristics (age, 
gender, race, height and weight) and background characteristics for all randomized 
subjects by treatment group. Past/coexistent medical history information for all 
randomized subjects will be presented in a by-subject listing. Baseline assessments of 
LCL severity will also be presented as background characteristics of the population and 
summarized by treatment group. 
 
Demographic data will be summarized using descriptive statistics. Categorical measures 
will be summarized by counts and percentages. Continuous measures will be 
summarized with means, standard deviations and ranges (min and max). 
 
Descriptive statistics will be used to summarize study medication compliance and 
exposure for all randomized subjects. Prior and concomitant medication information for 
all enrolled subjects will be presented in a by-subject listing. 
9.2.2 Primary Efficacy Analysis 
The IGA and SSA scores (Crow’s Feet Wrinkle scale) are evaluations performed by the 
investigator and the subject, respectively, measured both at rest and on contraction. For 
analysis purposes they will be averaged between left and right sides prior to analysis. In 
the event one side has missing data for a visit, the result from the side with non-missing 
data will be used instead of an average value. These scores will be treated as continuous 
measures for calculating means and performing ANOVA analyses, and they will be used 
as described below to derive binary indicators of treatment success, which will be 
analyzed as dichotomous measures. 
 
Efficacy analyses will be based on the assessments from the treatment areas, i.e. the 
lateral canthal area only. Alpha will be set at 0.05. The Crow’s Feet Wrinkle scale is an 
ordinal categorical scale ranging from 0 to 4. As described above, left- and right-side 
values will be averaged, and the averaged values will be used for analysis. 
 
The Investigator’s Global Assessment (IGA) is the primary efficacy parameter, and the 
evaluation of the active drug group vs. vehicle will be the primary comparisons. Results 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 30 of 42 
 
 
Confidential  
 
will be summarized for each treatment group and at each visit using frequency 
distributions.  
 
For the primary efficacy analysis, "IGA on contraction" (IGA-C) data will be analyzed at 
each visit to evaluate the proportion of patients achieving treatment success (responder). 
For this analysis, a response will be defined as a reduction from baseline in IGA-C by at 
least 2 points. A separate chi-square test will be used to evaluate the effect of each dose 
of ET-01 compared to Vehicle. A chi-square test will also be performed evaluating the 
overall effect of active drug vs vehicle by collapsing the two active drug treatment groups 
for this analysis. In addition, a separate chi-square test will be used to compare the two 
active drug groups. The ITT population will be used for this analysis. 
9.2.3 Secondary Efficacy Analyses 
The ITT population will be used for the secondary analyses. As a secondary efficacy 
analysis, data will be analyzed at each post-baseline visit to evaluate the proportion of 
patients achieving a composite treatment success, defined as a response on both the 
IGA-C and SSA-C scales, where response for each parameter is defined as a reduction 
from baseline by at least 2 points. The analysis models for the primary efficacy analysis 
will be used. 
 
Treatment success based on the SSA alone will also be analyzed using the above 
definition and analysis models. 
 
In addition, mean change from Baseline IGA will be analyzed using an analysis of 
variance (ANOVA) model. The first model contrasts will be separate evaluations of the 
effect of each active group vs. vehicle. Additional contrasts will be performed comparing 
pooled active treatment groups vs. vehicle and comparing the two active treatment 
groups. Contrasts will be made within the ANOVA model using Least Squares Means and 
the appropriate pooled error term, with no alpha adjustment for multiple comparisons. An 
analysis of covariance (ANCOVA) model with baseline average IGA score as the 
covariate will be used if it yields greater sensitivity than the ANOVA model.  
 
A similar model will be used to analyze mean change from baseline SSA. 
 
Primary and secondary analyses will also be performed based on IGA and SSA 
evaluations made at rest. 
9.2.4 Safety Analysis 
The assessment of safety will be based mainly on the frequency of adverse events. Other 
safety data (e.g., vital signs and special tests) will be summarized as appropriate. 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 31 of 42 
 
 
Confidential  
 
Adverse events will be coded using a current MedDRA dictionary and summarized by 
presenting, for each treatment group, the number and percentage of subjects having any 
adverse event, having an adverse event in each body system (System Organ Class), and 
having each coded individual adverse event. Other adverse event information collected 
(e.g., severity/intensity or relationship to study medication) will be listed as appropriate. 
Data from other tests will be listed, notable values will be flagged, and any other 
information collected will be listed as appropriate. No inferential statistical tests are 
planned for safety data but may be performed on an ad-hoc basis to highlight any 
comparisons that may warrant further consideration. 
9.2.5 Interim Analysis 
Interim analyses for efficacy and safety may be conducted after all subjects have passed 
the Week 4 visit. As there is only one treatment at Baseline and, therefore, interim 
analyses will not alter the conduct of the trial, no alpha adjustment will be required. 
9.3 Significance 
Unless otherwise specified, all statistical tests will be conducted against a two-sided 
alternative hypothesis, employing a significance level of 0.05.  
9.4 Termination Criteria 
Enrollment into the study will be halted as described in section 7.3 Stopping Rules. No 
other type of interim analysis is planned that could trigger termination of the trial. 
9.5 Deviation Reporting 
A Statistical Analysis Plan will be created prior to the completion of the study and 
unblinding of the database. Any deviations from or additions to the statistical analyses 
specified in the protocol will be described and justified in the Statistical Analysis Plan. 
 
10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Data reflecting subject experience with the drug under investigation will be recorded on 
appropriate source documents and in the eCRF. The investigator understands that the 
office and hospital records of subjects entered in this study will be required to be available 
to copying and inspection if requested by a properly authorized employee of the Sponsor 
or the Department of Health and Human Services, under the supervision of the 
investigator or a designated representative and in accordance with Federal regulations. 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 32 of 42 
 
 
Confidential  
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
The investigator will allow Eirion Therapeutics or their designated affiliates to periodically 
audit, at mutually convenient times during the study and after the study has been 
completed, all source documents and corresponding portions of office, hospital, and 
laboratory records of each subject. The monitoring visits will provide Eirion Therapeutics 
with the opportunity to confirm the rights and safety of the subjects, ensure the 
confidentiality of the data and subject’s identification, evaluate the progress of the study, 
verify the accuracy and completeness of the eCRFs, assure compliance with protocol 
requirements, applicable FDA regulations, IRB and ICH-GCP Guidelines, confirm that 
investigator’s obligations are being fulfilled, and resolve any inconsistencies in the study 
records. The sponsor may stop the study if it is observed that the protocol or sound clinical 
practices are not being followed. 
 
12 ETHICAL CONSIDERATIONS 
This study must be approved by an IRB or other ethical approval body prior to subject 
enrollment. The governing IRB must comply with all the requirements set forth in 21 CFR 
§ 56. The IRB is responsible for the initial approval, any amendments, advertisements, 
and continuing review of the proposed clinical study. The IRB will review any written 
materials given to the subject and the Informed Consent Forms. The investigator must 
retain a copy of the approval letter that contains the study number, protocol title and 
identification of all documents approved. A copy of the letter must be sent to the sponsor 
prior to drug shipment to the investigator. 
 
The investigator agrees to promptly report to the IRB all unanticipated problems involving 
risks to human subjects or others. 
 
The investigator will ensure that this study is conducted in full conformity with the 
principles of the "Declaration of Helsinki" and with the laws and regulations of the 
participating countries, whichever affords the greater protection to the individual. It is the 
responsibility of the investigator to obtain informed consent in written form (according to 
local legal requirements) from each subject participating in this study. All subjects will be 
informed of the aims, methods, anticipated benefits, potential hazards and confidentiality 
of data. Candidates will also be told that they are free to refuse participation or withdraw 
from the study at any time. A consent form must be signed and dated by the subject 
before he/ she is exposed to any study-related procedure, including screening tests for 
eligibility. The subject will receive a copy of the signed consent. The subject should be 
informed if new information becomes available that may be relevant to his/ her willingness 
to continue participation in the study. Each subject will be informed that the monitor, in 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 33 of 42 
 
 
Confidential  
 
accordance with applicable regulatory requirements, may review his/ her medical records 
and data. 
 
Periodic status reports must be submitted at least yearly to the IRB. Within three months 
after completion or termination of the study, a final report should be submitted to the IRB 
and the Sponsor. The investigator must maintain an accurate and complete record of all 
submissions made to the IRB including a list of all reports and documents submitted. 
  
The investigator is responsible for maintaining all the records which enable the conduct 
of the study at the site to be fully understood in compliance with the ICH-GCP filing 
standard. The investigator is responsible for the completion and maintenance of the 
confidential subject identification code which provides the sole link between named 
subject source records and the eCRF data. The investigator must arrange for the 
retention of study records for 5 years after the completion of the study. No study site files 
may be destroyed without prior written agreement between the investigator and the 
sponsor. Should the investigator elect to assign the study documents to another party or 
move them to another location not noted on the FDA 1572 Form, the sponsor must be 
notified. 
 
13 DATA HANDLING AND RECORD KEEPING 
Data reflecting subject experience with the drug under investigation will be recorded in 
the eCRF. Sites may use a print-out of the eCRF or their own record keeping system as 
source documentation. After monitoring, source verification and authentication by the 
Principal Investigator, the eCRF will be locked. The study specific data in the eCRF are 
the sole property of the Sponsor.  
 
It is the Investigator’s responsibility to ensure completion and to review and approve all 
data in the eCRF and source documents. At all times, the Investigator has final 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered 
on the eCRF and source document. 
 
All fields and blanks must be completed or marked intentionally blank as appropriate 
following the instructions on the eCRF. eCRFs will be electronically signed and dated by 
the investigator or a designated representative. If an entry on an eCRF already submitted 
requires change, the Electronic Data Capture (EDC) system will capture the reason for 
the change and then the correction will be made according to the procedures dictated by 
the EDC system. 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 34 of 42 
 
 
Confidential  
 
The investigator will maintain adequate records for the study including subject’s eCRFs, 
medical records, laboratory reports, informed consent forms, drug accountability records, 
safety reports, information regarding subjects who discontinued, and any other pertinent 
data. 
 
14 FINANCE  
The study will be sponsored by Eirion Therapeutics, Inc. 
 
15 INVESTIGATOR’S AGREEMENT  
I have read Eirion Therapeutics’ protocol entitled: “Clinical Trial to Evaluate ET-01 in 
Subjects with Lateral Canthal Lines” in conjunction with the “Investigators Drug Brochure” 
which contains all information necessary to the conduct of the study. I agree to conduct 
the study as outlined therein and according to ICH Good Clinical Practice. 
 
 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
 
 
 
 
 
 
January 18, 2019 
Sponsor's Signature 
 
Date 
Klaus Theobald, MD, PhD 
Chief R&D Officer 
Eirion Therapeutics, Inc. 
 
 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 35 of 42 
 
 
Confidential  
 
16 REFERENCES 
 
Ascher, Benjamin; Rzany, Berthold; Grover, Rajiv 
Efficacy and Safety of Botulinum Toxin Type A in the Treatment of Lateral Crow's Feet: 
Double-Blind, Placebo-Controlled, Dose-Ranging Study 
Dermatol Surg 35:1478-1486, 2009 
 
Carruthers, Alastair; Carruthers, Jean; Hardas, Bhushan; Kaur, Mandeep; 
Goertelmeyer, Roman; Jones, Derek; Rzany, Berthold; Cohen, Joel; Kerscher, Martina; 
Corcoran Flynn, Timothy; Maas, Corey; Sattler, Gerhard; Gebauer, Alexander; Pooth, 
Rainer; McClure, Kathleen; Simone-Korbel, Ulli; Buchner, Larry 
A Validated Grading Scale for Crow’s Feet 
Dermatol Surg 2008; 34:S173–S178 
 
Coté, Timothy; Mohan, Aparna; Polder, Jacquelyn; Walton, Marc; Braun, Miles 
Botulinum toxin type A injections: Adverse events reported to the US Food and Drug 
Administration in therapeutic and cosmetic cases 
J. Am. Acad. Dermatol. 2005;53:407-15 
 
 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 36 of 42 
 
 
Confidential  
 
Appendix A: Crow’s Feet Wrinkle Scale1 
 
The Crow’s Feet Wrinkle Scale (CFW) is a photonumeric guide that grades severity of 
lateral canthal lines according to one of the following five descriptions. 
 
Score 
Grade 
Description 
At Rest 
At Smile 
0 
Absent 
No visible wrinkles 
 
 
1 
Minimal 
Very fine wrinkles (that are 
barely visible) 
 
 
2 
Mild 
Fine wrinkles (that are shallow) 
 
 
3 
Moderate 
Moderate wrinkles (that are 
moderately deep) 
 
 
4 
Severe 
Severe wrinkles (that are 
severely deep) 
 
 
                                            
1 Carruthers et. al. A Validated Grading Scale for Crow’s Feet, Dermatol Surg 2008; 34:S173–S178 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 37 of 42 
 
 
Confidential  
 
Investigators and subjects will use the same scale. As a photo guide, the guidance 
pictures shown below will be presented as 11” x 17” laminated poster cards. 
 
 
Instructions for use: 
 
 
For Investigators: 
 
• “At Rest”: Ask the subject to make an expressionless face and indicate with a 
check mark the description that best describes his/her appearance. 
• “On Contraction”: Ask the subject to make a maximally exaggerated smile and 
indicate with a check mark the description that best describes his/her 
appearance.  
 
For Subjects: 
 
• Place the subject in front of a mirror or provide a hand-held mirror in a well-lit 
room 
• Provide subject with the photo guide 
• “At Rest”: Ask the subject to make an expressionless face and state the grade 
that best describes his/her appearance. Record in the eCRF. 
• “On Contraction”: Ask the subject to make a maximally exaggerated smile and 
using the provided scale state the grade that best describes his/her appearance. 
Record in the eCRF. 
 
 
 
 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 38 of 42 
 
 
Confidential  
 
Appendix B: Signs of Botulinum Toxin Spread 
 
 
 
1. Ask the subject to follow the examiner’s finger with his or her eyes without moving 
his or her head. At eye level, the examiner should move his or her finger to the 
right of the subject’s head and then to the left. Repeat this horizontal motion at the 
level of the subject’s forehead and chin. Note whether there is any abnormality in 
the form of any inability of the subject’s eyes to follow the finger. 
 
2. Ask the subject to raise his/her eyelids. Observe any indication for “drooping”. 
 
3. Ask the subject to swallow and note any difficulty doing so.  
 
4. Ask the subject to partially flex his or her arms at the elbow, with fist at shoulder 
level. Ask the subject to attempt to fully flex his or her arms against the resistance 
of the examiner pulling on the subject’s forearms. Note whether there is an 
abnormality in the form of any muscular weakness. 
 
5. Ask the subject to squat down and stand up again. Watch for any abnormalities or 
signs of weakness. 
 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 39 of 42 
 
 
Confidential  
 
Appendix C: Procedure for Color Photography 
 
 
Equipment: Digital Camera, Log Book,  Subject-Specific Index Card 
 
Procedure: 
In these clinical photographs, for the duration of the study, the only variable 
allowed to change is the skin condition itself. Therefore, anything 
extraneous to the condition (jewelry, makeup, clothing, furniture, walls, etc.) 
is to be eliminated from the fields to be photographed, from baseline through 
the final photographs. The necessity of good photos should be stressed to 
the subjects to ensure their cooperation. Camera, lighting, framing, and 
exposure must be held consistent. In the end, the pictures should read like 
a time-lapse movie. 
 
Ask the subject to stand against a light background, away from any window 
or other source of external light. The subject should hold a white index card 
with his/her identification number and initials. The photographer should 
stand about 1 foot away from the subject and set the camera for minimum 
zoom and take 5 photographs: 1 full frontal face photo, and one 45° view of 
each of the right and left periorbital region, both, “at rest” and “on 
contraction”.  
 
For the “at rest” pictures, ask the subject to have a relaxed, expressionless 
composure. In the frontal picture, the subject should hold an index card with 
subject ID, date and initials. The ID card is not required for the 45° views. 
For the “on contraction” pictures, ask the subject to produce a smile that is 
maximally exaggerated by exhorting the subject to make the biggest smile 
possible. An attempt should be made to consistently produce the same 
degree of smile in all photographs. This can be guided by observing the 
amount of teeth observable.  
 
Maintain a Log Book that includes the following information: 
• 
Protocol Number 
• 
Investigator Name 
• 
Subject Initials 
• 
Subject ID Number 
• 
Visit week  
• 
Date of Visit 
• 
Photographer’s Initials 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 40 of 42 
 
 
Confidential  
 
At monitoring visits, the Study Monitor will upload the pictures from the 
camera to a laptop computer. 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 41 of 42 
 
 
Confidential  
 
Appendix D: Irritation Scoring 
 
 
For the irritation assessment, the following scale will be utilized: 
 
Numeric Grades: 
0 = no evidence of irritation 
1 = minimal erythema, barely perceptible 
2 = definite erythema, readily visible; or minimal edema; or minimal papular 
response 
3 = erythema and papules 
4 = definite edema 
5 = erythema, edema, and papules 
6 = vesicular eruption 
7 = strong reaction spreading beyond test site 
 
All clinically significant skin responses observed with the test products or any score of 3 
or higher will be reported as an adverse event. 
 
 
 

Study #: ET-01-LCL-209 
January 18, 2019 
Page 42 of 42 
 
 
Confidential  
 
Appendix E: Preparation of Study Drug 
 
Study drug will be provided as a set of dropper bottles. The target strength of study drug 
will be prepared by dilution immediately prior to use following a randomization list 
provided by the sponsor. The bottles will be labeled “Active” or “Vehicle” and will be 
prefilled with 1 ml of ET-01 or Vehicle, respectively. The randomization list will consist of 
a set of envelopes marked with the four-digit medication number assigned to the study 
subject.  
 
The procedure to dilute the study medication is as follows: 
 
• open the envelope with the study medication number assigned to the subject and 
follow the instructions. Depending on treatment group, the instructions will read for: 
 
Vehicle: 
 
1. slowly invert bottle “Vehicle” 10 times to ensure resuspension of its content 
2. mask the bottle label with a secondary numbered label, and  
3. provide the bottle to the investigator for application 
 
Active: 
 
1. slowly invert bottle “Vehicle” 10 times to ensure resuspension of its content 
2. remove screw cap and dropper insert from bottle “Vehicle”  
3. remove bottle “Active” from its carton. Do NOT invert the bottle “Active”. 
4. remove screw cap and dropper insert from bottle “Active”  
5. using an adjustable pipette, transfer 0.22 ml (220 µl) from  
bottle “Vehicle”   ➔   bottle “Active” 
6. reinsert dropper tip into bottle “Active” and recap  
7. mask the bottle “Active” with a secondary numbered label 
8. slowly invert the masked bottle “Active” 10 times to ensure resuspension of its 
content, and  
9. provide the bottle to the investigator for application