Phase II Multi-Ctr, Prospective, Randomized, Double Blind, Active-Controlled Single Treatment Increasing Dose Trial to Study Safety & Duration of Effect of 40U of PrabotulinumtoxinA-xvfs in Adult Subjects for Treatment of Glabellar Lines
Phase: PHASE2
Conditions: Glabellar Frown Lines
Sponsor: Evolus, Inc.

NCT05320393 
STUDY PROTOCOL 
EVOLUS-CLIN201 
A Phase II Multi-Center, Prospective, Randomized, Double Blind, 
Active-Controlled, Single Treatment, Increasing Dose Trial to Study the 
Safety and Duration of Effect of 40U of PrabotulinumtoxinA-xvfs in 
Adult Subjects for Treatment of Moderate-to-Severe Glabellar Lines  
Phase II 
Version 2.0 
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STUDY PROTOCOL 
 
 
 
EVOLUS-CLIN201 
 
A Phase II Multi-Center, Prospective, Randomized, Double Blind, 
Active-Controlled, Single Treatment, Increasing Dose Trial to Study the 
Safety and Duration of Effect of 40U of PrabotulinumtoxinA-xvfs in 
Adult Subjects for Treatment of Moderate-to-Severe Glabellar Lines  
 
 
 
 
Phase II 
 
Version 2.0 
23-Nov-2022 
 
 
 
Study Sponsor 
Evolus, Inc. 
520 Newport Center Drive, Suite 1200 
Newport Beach, California 92660 
 
 
 
Clinical Research Organization 
ethica CRO Inc. 
3551 St. Charles Blvd, Suite 501 
Kirkland, Quebec H9H 3C4 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is provided in confidence. It is 
understood that this information will not be disclosed to others without prior 
agreement with the Sponsor, except to other study personnel and to the extent 
necessary to obtain informed consent from participating subject. 
 

   
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PROTOCOL VERSION HISTORY 
Version and Date 
Description 
v.1.0; 22-Jan-2022 
Final protocol 
v.1.1; 21-Feb-2022 
The following administrative amendments were incorporated into 
the study protocol in address to conditions placed on the study 
during the 08-Feb-2022 review by the central IRB: 
 Additional pregnancy testing: Additional requirement of a 
negative UPT at Visit 2 (Inclusion Criterion 2) 
 Additional information regarding Confidentiality: Section 3.4 
Confidentiality was added to provide additional details 
regarding confidentiality safeguards. 
 Information regarding participant recruitment: Specifics on 
participant recruitment were added to Section 5. Study Subject 
Selection and Identification. 
 Informed consent process: Clarification was added to Section 
13.1 Informed Consent to specific that the study coordinator 
will lead the participant consenting process. 
v.2.0; 23-Nov-2022 
The following amendments were incorporated into the study 
protocol: 
 Interim analysis will be conducted (Section 12.8) 
 The Protocol Clarification Letters dated on March 7th,2022 
and April 27th,2022   
 
 
 

   
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PROTOCOL APPROVAL SIGNATURE PAGE 
 
The following individuals approve this version of Protocol EVOLUS-CLIN201. These signatures, 
in conjunction with the signature of the investigator, confirms the agreement of all parties that the 
clinical study will be conducted in accordance with the protocol and all applicable laws and 
regulations including, but not limited to, the International Conference on Harmonization (ICH) 
Guideline for Good Clinical Practice (GCP), the Code of Federal Regulations (CFR), the ethical 
principles that have their origins in the Declaration of Helsinki, and applicable privacy laws. 
 
 
 
Accepted for the Sponsor – Evolus, Inc.: 
 
 
 
 
 
 
 
_______________________________________________________________________   
Rui Avelar, Chief Medical Officer  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DATE 
 
 
 
 
 
 
 
 
 
Accepted for the CRO – ethica CRO, Inc.: 
 
 
 
 
 
 
 
_______________________________________________________________________   
Murray Jensen, Managing Director  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DATE 
 
 
 
 
 
 
06-Dec-2022 | 14:13:35 EST
06-Dec-2022 | 16:12:56 EST

   
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INVESTIGATOR SIGNATURE PAGE 
My signature, in conjunction with the signature of the sponsor, confirms the agreement of all 
parties that the clinical study will be conducted in accordance with the protocol and all applicable 
laws and regulations including, but not limited to, the International Conference on Harmonization 
(ICH) Guideline for Good Clinical Practice (GCP), the Code of Federal Regulations (CFR), the 
ethical principles that have their origins in the Declaration of Helsinki, and applicable privacy 
laws. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations. 
By my signature below, I hereby attest that I have read, understood, and agree to abide by all 
conditions, instructions and restrictions contained in Evolus, Inc., Newport Beach, CA, Protocol 
Number: EVOLUS-CLIN201. 
 
 
 
____________________________________________________________________________   
Principal Investigator (Print Name)  
 
Signature  
 
 
 
 
 
 
Date 
 
 
 
 

   
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SYNOPSIS 
Version 
Version 2.0 (23-Nov-2022) 
Investigational 
Therapy 
PrabotulinumtoxinA 40 Units 
Study Number 
EVOLUS-CLIN201 
Phase 
Phase II 
Control Therapies 
PrabotulinumtoxinA 20 Units 
OnabotulinumtoxinA 20 Units 
Indication 
Moderate-to-severe glabellar lines 
Study Sites 
5 sites (US) 
Title 
A Phase II Multi-Center, Prospective, Randomized, Double Blind, Active-Controlled, Single 
Treatment, Increasing Dose Trial to Study the Safety and Duration of Effect of 40U of 
PrabotulinumtoxinA-xvfs in Adult Subjects for Treatment of Moderate-to-Severe Glabellar 
Lines  
Sponsor 
Evolus, Inc. 
Study Duration 
per Subject 
Up to 379 days 
Sample Size 
150 subjects 
Study Design 
This is a multicenter, prospective, randomized, double-blind, active-controlled, single-
treatment, increasing dose design. 
Up to one hundred and fifty subjects will be randomized 1:1:1, to either 20U 
onabotulinumtoxinA, 20U prabotulinumtoxinA-xvfs, or 40U prabotulinumtoxinA-xvfs. 
Subjects with moderate or severe glabellar lines at maximum frown on the 4-point validated 
Glabellar Line Scale, as judged by the investigator and the subject, will be eligible. 
Safety and effectiveness will be assessed on days 3, 7, and 30, then every 30 days up to 365 
days or until the subject has returned to Baseline as assessed by the Investigator, at which point 
the subject will exit the study. 
Duration of effect will be estimated by Kaplan-Meier analysis and will be based on the number 
of days from Treatment Day (Baseline) to the day that GLS severity (Investigator assessment) 
at maximum frown returns to the Baseline value (i.e., the treatment will be considered to remain 
effective for the amount of time during which GLS severity at maximum frown has not returned 
to Baseline severity). 
The Evaluating Investigator (i.e., Blinded Investigator) will be responsible for managing the 
subject, monitor for related and unrelated adverse effects, and carrying out the evaluations. 
Injections of study drug will be performed by an “Unblinded Injector” (i.e., physician or nurse 
practitioner appropriately skilled in injecting botulinum toxin into the glabellar area and not 
responsible for subject follow-up). 
Hypothesis 
The general form of duration of effect hypotheses will be: 
Ho: β = 0 
HA: β < 0 
where exp(β) is the hazard ratio (experimental treatment / comparator treatment) for loss of 
effect. The study is not powered for formal hypothesis testing and any analyses presented will 
be for interpretation purposes only. 
Primary 
Objectives 
The primary objectives of this study are to demonstrate the safety and duration of effect of 40U 
of prabotulinumtoxinA-xvfs in providing temporary improvement in the appearance of 
moderate to severe glabellar lines associated with corrugators and/or procerus muscle activity 
in adult subjects. 
Inclusion 
Criteria 
1. Outpatient, male or female of any race, 18 years of age or older. 
2. Female subjects of childbearing potential must have a negative UPT during Visit 1 
(Screening), Visit 2 (if applicable) and practice a reliable method of contraception for the 
duration of the study. 
3. Moderate to severe glabellar lines (i.e., score of 2 or 3) on maximum frown as assessed by 

   
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the investigator using the GLS. 
4. Subject has moderate to severe glabellar lines (i.e., score of 2 or 3) at maximum frown as 
assessed by the subject using the GLS. 
5. Able to follow study instructions and likely to complete all required visits. 
6. Sign the IRB-approved ICF prior to any study-related procedures being performed. 
Exclusion 
Criteria 
1. Female subjects who are pregnant, breast-feeding, or of childbearing potential and not 
practicing reliable birth control. 
2. Known hypersensitivity or previous allergic reaction to any constituent of the IP or control. 
3. Any active infection in the area of the injection sites. 
4. Inability to substantially lessen glabellar frown lines even by physically spreading them 
apart. 
5. Marked facial asymmetry (Investigator discretion). 
6. Ptosis of eyelid and/or eyebrow, or history of eyelid and/or eyebrow ptosis. 
7. History of facial nerve palsy. 
8. Excessive dermatochalasis, deep dermal scarring, thick sebaceous skin (Investigator 
discretion). 
9. Medical condition that may affect neuromuscular function (e.g., myasthemia gravis, Eaton-
Lambert syndrome, amyotrophic lateral sclerosis). 
10. Previous treatment with botulinum toxin of any serotype above the level of the lateral 
canthus within the last 6 months. 
11. Planned treatment with botulinum toxin of any serotype below the level of the lateral 
canthus during the study period. 
12. Previous treatment with any facial aesthetic procedure (e.g., injection with biodegradable 
fillers, chemical peeling, photo rejuvenation) in the glabellar area within the last 12 months. 
13. Previous insertion of permanent material in the glabellar area. 
14. Any previous energy based or cryotherapy-based treatment of facial muscles superior to 
the lateral canthus. 
15. Any other planned facial aesthetic procedure during the trial period, superior to the level of 
the lateral canthus (can continue with their usual skin care routine). 
16. Any surgery in the glabellar area including surgical removal of the corrugator, procerus, or 
depressor supercilii muscles, or a combination of these, or scars in the glabellar area and 
the surrounding areas (including eyebrow). 
17. Medical or psychiatric conditions that may increase the risk associated with study 
participation or may interfere with the interpretation of study results and, in the judgment 
of the Investigator, would make the subject inappropriate for entry into this study. 
18. Evidence of recent alcohol or drug abuse (Investigator discretion). 
19. History of poor cooperation or unreliability. 
20. Planning to move out of the area prior to study completion. 
21. Subjects who are investigational site staff members or family members of such employees. 
22. Exposure to any other investigational drug/device within 30 days prior to Visit 1. 
Drug 
Administration 
20U of onabotulinumtoxinA (control): prepared by reconstituting with 1.25 ml of 0.9% 
sterile, non-preserved saline solution in a 50U vial for a final dilution of 4 U/0.1 ml. After 
reconstitution, a total of 0.5ml will be drawn up into a 0.5ml syringe. 
20U of prabotulinumtoxinA (control): prepared by reconstituting with 2.5 ml of 0.9% sterile, 
non-preserved saline solution for a final dilution of 4 U/0.1 ml. After reconstitution, a total of 
0.5ml will be drawn up into a 0.5ml syringe. 

   
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40U of prabotulinumtoxinA (study drug): prepared by reconstituting with 0.625 ml of 0.9% 
sterile, non-preserved saline solution for a final dilution of 8U/0.05 ml. After reconstitution, a 
total of 0.25ml will be drawn up into a 0.3ml. 
Using the preloaded syringe with a 30G needle, the subject will be injected intra-muscularly 
into a total of five sites, the mid-line of the procerus, the inferomedial aspect of each corrugator 
muscle and the superior middle aspect of each corrugator, at least 1 cm above the bony orbital 
rim. Both controls (i.e., 20U of prabotlinumtoxinA, 20U of onabotulinumtoxinA) will be 
injected with 0.1 ml (4U) per site, for a total of 20 U and 0.5 ml. The study drug (i.e., 40U 
prabotulinumtoxinA) will be injected with 0.05 ml (8U) per site, for a total of 40 U and 0.25 
ml. 
Blinding 
An “Unblinded Injector” (i.e., physician or nurse practitioner appropriately skilled in injecting 
botulinum toxin into the glabellar area and not responsible for subject follow-up) will have 
access to the Randomization Schedule, be aware of treatment assignment, will prepare syringes 
of reconstituted IP, and will administer injections of study drug to study subjects. 
The Unblinded Injector will be a different individual than the Blinded Evaluator. The Blinded 
Evaluator and the study coordinators responsible for subject assessment and follow-up, as well 
as study subjects, will remain blinded to which study treatment was injected. 
Primary 
Effectiveness 
Endpoint 
The primary effectiveness endpoint will be duration of effect, defined as the number of days 
from Treatment Day (Baseline) to the day that GLS severity (Investigator assessment) at 
maximum frown returns to the Baseline value. The treatment will be considered to remain 
effective for the amount of time during which GLS severity at maximal frown has not returned 
to Baseline severity. Duration of effect will be estimated by Kaplan–Meier analysis. 
Although the trial is not powered for inferential analysis, this will be the most influential 
outcome in the overall assessment of the effectiveness of prabotulinumtoxinA 40 Units, 
compared to prabotulinumtoxinA 20 Units, in treating moderate to severe glabellar lines.  
Secondary 
Effectiveness 
Endpoints 
Secondary effectiveness endpoints will be used to provide additional evidence of 
prabotulinumtoxinA 40 Units superiority to prabotulinumtoxinA 20 Units. Secondary 
endpoints, in order of importance, will be: 
1. Duration of effect, defined as the number of days from Treatment Day (Baseline) to the 
day that GLS severity (subject assessment) at maximum frown returns to the Baseline 
value. 
2. Duration of effect in GAIS responders (score of 2 or 1) as assessed by Investigator. 
3. Duration of effect in GAIS responders (score of 2 or 1) as assessed by subject. 
4. Duration of effect in SSS responders (score of 2 or 1) as assessed by subjects. 
Tertiary 
Effectiveness 
Endpoints 
Tertiary effectiveness endpoints will be used to compare prabotulinumtoxinA 40 Units to 
onabotulinumtoxinA 20 Units, as well prabotulinumtoxinA 20 Units to onabotulinumtoxinA 20 
Units. Tertiary endpoints, in order of importance, will be: 
1. Duration of effect, defined as the number of days from Treatment Day (Baseline) to the 
day that GLS severity (Investigator assessment) at maximum frown returns to the Baseline 
value. 
2. Duration of effect, defined as the number of days from Treatment Day (Baseline) to the 
day that GLS severity (subject assessment) at maximum frown returns to the Baseline 
value. 
3. Duration of effect in GAIS responders (score of 2 or 1) as assessed by Investigator. 
4. Duration of effect in GAIS responders (score of 2 or 1) as assessed by subject. 
5. Duration of effect in SSS responders (score of 2 or 1) as assessed by subjects. 
Exploratory 
Effectiveness 
Endpoints 
Exploratory effectiveness endpoints will be evaluated for signals of effectiveness to explore 
whether any should be elevated in importance for subsequent trials. Comparisons will be made 
between all treatment groups. Exploratory endpoints will be: 

   
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1. GLS score of 0 or 1 (maximum frown) as assessed by Investigator and subject at each visit. 
2. GAIS response (score of 2 or 1) as assessed by Investigator and subject at each visit. 
3. SSS response (score of 2 or 1) as assessed by subjects at each visit. 
4. 1-point or greater, 2-point or greater, and 3-point or greater improvement on the GLS 
(maximum frown) as assessed by Investigator at each visit. 
5. 1-point or greater, 2-point or greater, and 3-point or greater improvement on the GLS 
(maximum frown) as assessed by subject at each visit. 
6. Duration of effect in responders with a 1-point or greater, 2-point or greater, and 3-point or 
greater improvement on the GLS (maximum frown) as assessed by Investigator at each 
visit. 
7. Duration of effect in responders with a 1-point or greater, 2-point or greater, and 3-point or 
greater improvement on the GLS (maximum frown) as assessed subject at each visit. 
8. Duration of effect in GLS responders (responder = ≥1-point improvement on GLS at Day 
30) as assessed by Investigator. 
9. Duration of effect in GLS responders (responder = ≥1-point improvement on GLS at Day 
30) as assessed by subject. 
10. Onset of effect as assessed by subjects through the 7-Day Subject Diary. 
Safety 
Endpoints 
1. Adverse Events 
2. Concomitant Medications 
3. Physical Exam 
4. Vital Signs: blood pressure, respiratory rate, heart rate 
5. Clinical Safety Laboratory Tests: hematology, chemistry, urinalysis, botulinum antibodies 
6. 12-Lead ECG 
7. Urine Pregnancy Test 
8. Directed Questionnaire: review of problems regarding speaking, swallowing, breathing, 
headaches, eyelid or eyebrow drooping. 
9. Directed Review of Systems: review of the following systems: Head and Neck, 
Respiratory, Cardiovascular, Neurological, Musculoskeletal, Dermatological. 
Sample Size 
A total of 150 subjects will be randomized to the study, 50 subjects in each of the three treatment 
arms; 20U onabotulinumtoxinA, 20U prabotulinumtoxinA and 40U prabotulinumtoxinA. 
Assuming 50 subjects per treatment group, exponential distributions for failure and censoring 
times, a median duration of effect of 4 months in the reference group, and an annual censoring 
rate of 10%, the study will have 80% power to detect a hazard ratio of 0.47 based on a one-
sided hypothesis test of the primary effectiveness endpoint with alpha = 0.025. As such, it is the 
opinion of the study Sponsor that 50 subjects per group (total sample size n=150) will be 
sufficient to address the objectives of this study. 
Statistical 
Methods 
Analysis Populations: The Modified Intent-to-Treat (mITT) Population is defined as all 
subjects who were randomized, received their injection of IP, and have at least one post-dosing 
assessment for the primary effectiveness endpoint. Subjects will be summarized and analyzed 
according to randomized treatment. 
Per Protocol (PP) Population is defined as treated subjects who complete the entire study up to 
the final visit with no protocol deviations that could affect effectiveness assessments. 
Safety (SAFT) Population will consist of all randomized subjects who received treatment with 
the IP and will be analyzed as per treatment received. 
Primary Effectiveness Endpoint: Duration of effect will be described by Kaplan-Meier curves 
and the respective median times with associated 2-sided 95% confidence interval (CI) for each 
treatment group. Statistical analyses of treatment group differences will be done using Cox 
proportional hazards regression with time to return to Baseline as the dependent variable, 
treatment group as the independent variable, and age, gender, and Baseline GLS score 

   
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(Investigator assessment) at maximum frown as covariates. Statistical significance will be 
established at the 0.025 level with one-sided hypothesis testing. Analysis will be performed 
using the modified Intent-To-Treat (mITT) population. 
Secondary Effectiveness Endpoints: As duration of effect outcomes, secondary endpoints will 
be assessed as described above for the primary endpoint. The mITT population will be used for 
summaries and comparisons.  
Tertiary Effectiveness Endpoints: As duration of effect outcomes, tertiary endpoints will be 
assessed as described above for the primary endpoint. The mITT population will be used for 
summaries and comparisons. 
Exploratory Effectiveness Endpoints: Exploratory endpoints will be assessed using either 
logistic regression (for binary endpoints) or survival analysis-type methods as described above. 
Comparisons will be made between all treatment groups. Chi-square tests of association or 
Fisher’s exact tests will be used to compare treatment group differences in proportion of subjects 
returning to Baseline at each time point in the study. The mITT population will be used for 
summaries and comparisons. 
Safety Assessments will be summarized for the SAFT population using descriptive statistics: 
frequencies and percentages for categorical assessments, and means, variability, and ranges for 
continuous assessments. 
 
 

   
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TABLE 1.  SCHEDULE OF EVENTS AND PROCEDURES 
Visit Number 
V1 1 
Screening 
V2 1 
V3 
V4         
(phone f/u) 
V5 to V15 2 
V16 3               
(or Final Visit, or ET) 
Unscheduled 
Visit 11 
Day/Week/Month 
≤ 14D 
Tx Day 
48Hr 
D7 
D30 to D330      
Monthly Visits 
D365 
 
Visit Windows 
-- 
-- 
-- 
±1 Day 
D30 ±3D, ≥D60 ±7D 
±14D 
 
Assessment and Procedures 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Inc/Excl Criteria 
X 
 
 
 
 
 
 
Demographics, Med Hx 
X 
 
 
 
 
 
 
Randomization to Study Tx  4 
 
X 
 
 
 
 
 
Effectiveness - Investigator 
 
 
 
 
 
 
 
Glabellar Line Scale 5 
X 
X 
X 
 
X 
X 
X 
Global Aesthetic Improvement 
 
 
X 
 
X 
X 
X 
Effectiveness - Subject 
 
 
 
 
 
 
 
Glabellar Line Scale 5 
X 
X 
X 
 
X 
X 
X 
7-Day Subject Diary 
 
X  
 
 
 
 
 
Global Aesthetic Improvement 
 
 
X 
 
X 
X 
X 
Subject Satisfaction Score 
 
 
X 
 
X 
X 
X 
Clinical Interview 6 
 
 
 
 
D30 only 
X 
X 
Safety Evaluations 
 
 
 
 
 
 
 
Directed Questionnaire 7 
X 
 
X 
 
X 
X 
X 
Directed Review of Systems 
X 
 
X 
 
X 
X 
X 
Vital Signs 8 
X 
 
X 
 
X 
X 
X 
Physical Exam 9 
X 
 
X 
 
X 
X 
X 
UPT (as applicable) 
X 
X 
 
 
 
X 
 
Clinical Laboratory Tests 10 
X 
 
 
 
 
X 
X 
ECG 
X 
 
 
 
 
X 
X 
Safety Assessment Phone Call 
 
 
 
X 
 
 
 
Brow Area Photography 
X 
X 
X 
 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
 
1. 
Screening and treatment visit can take place the same day, at the discretion of the investigator 
2. 
Subjects will be followed monthly until their Glabellar Line Scale score is back to Baseline (Investigator assessment) 
3. 
Subject exits study once their Glabellar Line Scale Score has returned to Baseline (Investigator assessment) 
4. 
IP may be administered same day as Screening 
5. 
Glabellar Line Scale at Maximum Frown, 0=none, 1=mild, 2=moderate, 3=severe 
6. 
Clinical Interview Questions 
 
What did you like about the treatment (clinically or other feedback)? 
 
What did you dislike about the treatment (clinically or other feedback)? 
 
If treated with botulinum toxin before this study, which treatment did you prefer, the study treatment or the previous treatment? 
7. 
Directed Questionnaire: Have you noticed any problems with speaking, swallowing, or breathing? Have you had any headaches, eyelid 
or eyebrow drooping? 
8. 
Blood pressure, heart rate, respiration rate 
9. 
Physical exam to be based on the Investigator judgment as a response to the Medical History, Questionnaire, Review of Systems, and any 
other relevant information. Neurological exam includes extraocular movement, cranial nerve and muscle weakness assessment 
10. Clinical Laboratory Tests: 
 
Hematology: Hemoglobin, Hematocrit, RBC, WBC, WBC differential, Platelets 
 
Serum: ALP, BUN, Creatinine, ALT, AST, Alb, total protein, UA, Glucose, Na, K, Cl, Ca, anti-botulinum toxin antibodies 
 
Urinalysis: Specific Gravity, pH, Protein, Glucose, WBC, Blood 
11. Unscheduled Visit: May occur at any time during the study to complete missed study procedures, assess AEs, or assess ongoing unresolved 
drug-related AEs after study exit. During a visit, some or all of the safety and effectiveness evaluations may be performed. 

   
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TABLE OF CONTENTS 
PROTOCOL VERSION HISTORY ....................................................................................................................... 2 
PROTOCOL APPROVAL SIGNATURE PAGE .................................................................................................. 3 
INVESTIGATOR SIGNATURE PAGE ................................................................................................................. 4 
SYNOPSIS ................................................................................................................................................................. 5 
TABLE OF CONTENTS ....................................................................................................................................... 11 
ABBREVIATIONS ................................................................................................................................................. 14 
1 
BACKGROUND AND RATIONALE ....................................................................................................... 15 
1.1 
Clinical Review ................................................................................................................................... 15 
1.2 
Rationale for Study .............................................................................................................................. 20 
1.3 
Hypothesis ........................................................................................................................................... 20 
2 
STUDY OBJECTIVE ................................................................................................................................. 21 
3 
COMPLIANCE STATEMENT ................................................................................................................. 22 
3.1 
Variations to the Protocol .................................................................................................................... 22 
3.2 
Investigational Sites ............................................................................................................................. 22 
3.3 
Medical Monitor .................................................................................................................................. 22 
3.4 
Confidentiality ..................................................................................................................................... 22 
4 
STUDY DESIGN AND TREATMENT ..................................................................................................... 24 
4.1 
Study Design ........................................................................................................................................ 24 
4.2 
Primary Endpoint ................................................................................................................................. 24 
5 
STUDY SUBJECT SELECTION AND IDENTIFICATION .................................................................. 25 
5.1 
Inclusion Criteria ................................................................................................................................. 25 
5.2 
Exclusion Criteria ................................................................................................................................ 26 
6 
SUBJECT NUMBERING, RANDOMIZATION AND BLINDING ....................................................... 27 
6.1 
Subject Numbering .............................................................................................................................. 27 
6.2 
Subject Randomization ........................................................................................................................ 27 
6.3 
Blinding ............................................................................................................................................... 27 
6.4 
Unblinding ........................................................................................................................................... 27 
7 
INVESTIGATIONAL PRODUCT MANAGEMENT .............................................................................. 29 
7.1 
Study Drug ........................................................................................................................................... 29 
7.2 
Labeling, Packaging and Storage ......................................................................................................... 29 
7.3 
Investigational Product Supply and Accountability ............................................................................. 29 
8 
STUDY TREATMENT ............................................................................................................................... 30 
8.1 
Concomitant Medications .................................................................................................................... 30 
8.1.1 
Prohibited and Restricted Medications ........................................................................................... 31 
9 
DATA COLLECTION ................................................................................................................................ 32 
9.1 
Electronic Case Report Form ............................................................................................................... 32 
9.2 
Coding ................................................................................................................................................. 32 
10 
STUDY EVALUATIONS ........................................................................................................................... 33 
10.1 
Informed Consent ................................................................................................................................ 33 
10.2 
Visit Procedures ................................................................................................................................... 33 
10.2.1 
Visit 1 (Screening Visit; ≤14 Days) ................................................................................................ 33 
10.2.2 
Visit 2 (Treatment Day) .................................................................................................................. 33 
10.2.3 
Visit 3 (Safety and Effectiveness Follow-up; 48hrs ±0 day)........................................................... 34 
10.2.4 
Visit 4 (Phone Follow-up; Day 7 ±1 day) ....................................................................................... 34 
10.2.5 
Visits 5 to 15 (Visits each 30 Days; V5 ±3 days, V6 to V15 ±7 days) ........................................... 34 
10.2.6 
Visit 16 (Final Visit or ET Visit; Day 365 ±14 days) ..................................................................... 34 
10.3 
Effectiveness Assessments .................................................................................................................. 36 
10.3.1 
Glabellar Lines Scale (GLS) ........................................................................................................... 36 
10.3.2 
Global Aesthetic Improvement Scale (GAIS) ................................................................................. 36 
10.3.3 
Subject Satisfaction Scale (SSS) ..................................................................................................... 36 
10.3.4 
Brow Area Photography .................................................................................................................. 36 

   
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10.3.5 
Clinical Interview (Day 30, Final Visit/Early Termination, and Unscheduled Visit) ..................... 36 
10.3.6 
7-Day Subject Diary........................................................................................................................ 37 
10.4 
Safety Assessments .............................................................................................................................. 37 
10.4.1 
Directed Questionnaire ................................................................................................................... 37 
10.4.2 
Directed Review of Systems ........................................................................................................... 37 
10.4.3 
Vital Signs ....................................................................................................................................... 37 
10.4.4 
Physical Exam ................................................................................................................................. 37 
10.4.5 
Urine Pregnancy Test ...................................................................................................................... 37 
10.4.6 
Clinical Safety Laboratory Tests ..................................................................................................... 37 
10.4.7 
12-Lead ECG .................................................................................................................................. 38 
10.4.8 
Safety Assessment Phone Call ........................................................................................................ 38 
10.4.9 
Concomitant Medications ............................................................................................................... 38 
10.4.10 Pregnancy and Contraception ......................................................................................................... 38 
10.5 
Adverse Events .................................................................................................................................... 38 
10.5.1 
Definition of an Adverse Event ....................................................................................................... 38 
10.5.2 
Serious Adverse Events (SAEs) ...................................................................................................... 39 
10.5.3 
Unexpected Adverse Drug Reaction (UADR) ................................................................................ 39 
10.5.4 
Causality Assessment ...................................................................................................................... 39 
10.5.5 
Severity Assessment ....................................................................................................................... 40 
10.5.6 
Safety Reporting ............................................................................................................................. 40 
10.5.6.1 
All Adverse Events ................................................................................................................ 41 
10.5.6.2 
Serious Adverse Events (SAEs) ............................................................................................ 41 
10.5.6.3 
Adverse Events of Special Interest (AESI) Reporting ........................................................... 42 
10.5.6.4 
Unexpected Adverse Drug Reaction (UADR) Reporting ...................................................... 42 
10.5.6.5 
Other Reportable Information ............................................................................................... 43 
10.5.7 
Pregnancy ........................................................................................................................................ 43 
11 
STUDY COMPLETION / SUBJECT COMPLETION / WITHDRAWAL ............................................ 44 
11.1 
Study Completion ................................................................................................................................ 44 
11.2 
Subject Completion.............................................................................................................................. 44 
11.3 
Withdrawal .......................................................................................................................................... 44 
11.4 
Termination of Study ........................................................................................................................... 45 
11.4.1 
Termination by Sponsor .................................................................................................................. 45 
11.4.2 
Termination by Investigator ............................................................................................................ 45 
12 
STATISTICAL METHODS ....................................................................................................................... 46 
12.1 
Primary Endpoint ................................................................................................................................. 46 
12.2 
Secondary Endpoints ........................................................................................................................... 46 
12.3 
Tertiary Endpoints ............................................................................................................................... 46 
12.4 
Exploratory Effectiveness Endpoints ................................................................................................... 47 
12.5 
Safety Endpoints .................................................................................................................................. 47 
12.5.1 
Adverse Events (AEs) ..................................................................................................................... 47 
12.5.2 
Laboratory Variables ....................................................................................................................... 48 
12.5.3 
Vital Signs ....................................................................................................................................... 48 
12.5.4 
12-Lead Electrocardiograms ........................................................................................................... 48 
12.6 
Analysis Populations............................................................................................................................ 48 
12.6.1 
Modified Intent-to-Treat Population ............................................................................................... 48 
12.6.2 
Per Protocol Population .................................................................................................................. 48 
12.6.3 
Safety Population ............................................................................................................................ 49 
12.7 
Sample Size Considerations ................................................................................................................. 49 
12.8 
General Considerations ........................................................................................................................ 49 
13 
ETHICAL ASPECTS .................................................................................................................................. 50 
13.1 
Informed Consent ................................................................................................................................ 50 
13.2 
Health Authorities and IRBs ................................................................................................................ 50 
13.3 
Confidentiality Regarding Study Subjects ........................................................................................... 50 
14 
STUDY MANAGEMENT & ADMINISTRATION ................................................................................. 51 
14.1 
Protocol Amendments.......................................................................................................................... 51 

   
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14.2 
Monitoring and Quality Assurance ...................................................................................................... 51 
14.2.1 
Information to Study Personnel ...................................................................................................... 51 
14.2.2 
Study Monitoring ............................................................................................................................ 51 
14.2.3 
Audit and Inspection ....................................................................................................................... 52 
14.3 
Protocol Deviations.............................................................................................................................. 52 
14.4 
COVID-19 and Potential Study Interruption ....................................................................................... 53 
15 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 54 
15.1 
Source Data .......................................................................................................................................... 54 
15.2 
Case Report Form ................................................................................................................................ 55 
15.3 
Archiving of Study Documentation ..................................................................................................... 55 
16 
FINANCING AND INSURANCE .............................................................................................................. 56 
17 
REPORTING AND PUBLICATION OF RESULTS ............................................................................... 57 
18 
REFERENCES ............................................................................................................................................ 58 
19 
APPENDICES ............................................................................................................................................. 59 
APPENDIX A: ADJUSTMENT OF VISITS AND ASSESSMENTS DUE TO COVID-19 ............................. 59 
APPENDIX B: DECLARATION OF HELSINKI ............................................................................................... 63 
APPENDIX C: GLABELLAR LINE SCALE (GLS) AT MAXIMUM FROWN ............................................. 67 
APPENDIX D: GLOBAL AESTHETIC IMPROVEMENT SCALE (GAIS) ................................................... 68 
APPENDIX E: SUBJECT SATISFACTION SCALE (SSS) ............................................................................... 68 
 
 
 

   
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ABBREVIATIONS 
AE 
Adverse Event 
BLA 
Biologic License Application 
BP 
Blood Pressure 
CFR 
U. S. Code of Federal Regulations 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
ECG 
Electrocardiogram 
ET 
Early Termination 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GAIS 
Global Aesthetic Improvement Scale 
GLS 
Glabellar Line Scale (0=none, 1=mild, 2=moderate, 3=severe) 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
PI 
Principal Investigator 
PP 
Per protocol 
SAE 
Serious Adverse Event 
SAFT 
Safety 
SAP 
Statistical Analysis Plan 
SMMP 
Safety and Medical Monitoring Plan 
SOC 
System Organ Class 
SSS 
Subject Satisfaction Scale 
TRAE 
Treatment Related Adverse Event 
UADR 
Unanticipated Adverse Drug Reaction 
ULN 
Upper Limit of Normal 
UPT 
Urine Pregnancy Test 
US 
United States 
 
 

   
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1 
BACKGROUND AND RATIONALE 
Botulinum toxin type A, now manufactured by several pharmaceutical/biotechnology companies, 
has been approved for the temporary improvement in the appearance of moderate to severe 
glabellar lines associated with corrugator and/or procerus muscle activity in adult subjects. 
The clinical study designs that have supported the New Drug Applications for these products have 
generally followed the same pattern in that they were all multicenter, randomized, double-blind, 
placebo-controlled studies that assessed the efficacy of the product to reduce the severity of 
glabellar lines at 30 days following injection of the targeted glabellar muscles. 
More recently, approved botulinum toxins approved in the US have investigated the effect of 
increasing dose on duration of effect (REF 1). In this clinical investigation, the dose of 
prabotulinumtoxinA will be increased and the safety and duration of effect will be studied. 
1.1 
Clinical Review 
PrabotulinumtoxinA was approved by the FDA in the US in 2019, it is also approved for use in 
Canada and Europe. In 2014, a comprehensive five-study prabotulinumtoxinA clinical 
development program was initiated in the United States, EU, and Canada to meet the regulatory 
requirements for a BLA in the United States, a MAA in the EU, and a NDS in Canada, for the 
treatment of moderate to severe glabellar lines. The program, included three multicenter, 
randomized, double-blinded, controlled, single dose Phase III studies titled EV-001, EV-002 and 
EVB-003. Each Phase III study lasted 150 days. It also included two open-label, multiple dose, 
long-term Phase II studies titled EV-004 and EV-006, each lasting one year. Between September 
2014 and August 2016, over 2,100 adult male and female subjects with moderate to severe 
glabellar lines at maximum frown participated in this program. 
Subjects received intramuscular injections in five target sites; the midline of the procerus, the 
inferomedial aspect of each corrugator, and the superior middle aspect of each corrugator. Each of 
the five target sites was injected with 0.1mL for a total of 0.5mL. Subjects assigned (in the open 
label studies) or randomized (in the controlled studies) to prabotulinumtoxinA received a total of 
20 units per treatment, administered as 4 units per 0.1 mL and those subjects who were randomized 
to the placebo group received 0.5 mL saline. In our EVB-003 Phase III trial, the only study of the 
five with both a placebo and active control arm, subjects randomized to the active control received 
a total of 20 units of onabotulinumtoxinA administered as 4 units per 0.1 mL. In the multiple dose 
studies, eligible subjects could receive up to four treatments of 20 units of prabotulinumtoxinA 
each. 
Phase III U.S. Based Clinical Trials 
The two identical U.S. Phase III studies, EV-001 and EV-002, enrolled subjects who were selected 
from a population of healthy adults, at least 18 years of age, who had moderate to severe glabellar 
lines at maximum frown (REF 2). Eligible subjects were randomly assigned in a 3:1 ratio to receive 
a single treatment of either prabotulinumtoxinA or placebo. Subjects were followed for 150 days. 
The primary efficacy endpoint was defined as the proportion of subjects classified as responders 
on Day 30. This was a composite endpoint in which a responder was a subject with a 2-point 
improvement or greater on the GLS from Day 0 to Day 30 at maximum frown, only if 
independently agreed by both investigator and subject assessment. 
Both studies met the primary endpoint of superiority over placebo. The percentages of responders 
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composite improvement, in each of the two controlled single dose studies were: 
 EV-001: 1.2% placebo, 67.5% prabotulinumtoxinA, with an absolute difference between 
the groups of 66.3%, 95% CI (59.0, 72.4). 
 EV-002: 1.3% placebo, 70.4% prabotulinumtoxinA, with an absolute difference between 
the groups of 69.1%, 95% CI (61.5, 75.1). 
 
U.S. Phase III Primary Endpoint - Composite Score ≥ 2 Point GLS Improvement at 
 Maximum Frown on Day 30 
 
 
In the EV-001 study, analysis of the secondary endpoints investigated the response at maximum 
frown beyond Day 30 using a two-point composite score. A subject was considered a responder 
only if a ≥2 point improvement had occurred on the GLS at maximum frown from Day 0, by both 
investigator and subject assessment: 
 At Day 90 (post hoc), the percentage of responders was 1.3% in the placebo group and 
26.5% in the prabotulinumtoxinA group with an absolute difference of 25.2%, p<0.001. 
 At Day 120, the percentage of responders was 1.3% in the placebo group and 8.3% in the 
prabotulinumtoxinA group with an absolute difference of 7.0%, p=0.023.  
 At Day 150 or early termination, the percentage of responders was 0.0% in the placebo 
group and 4.6% in the prabotulinumtoxinA group. The absolute difference of 4.6% 
between the groups remained statistically significant for the composite endpoint, p=0.041. 
The 2-point composite score results were similar in the EV-002 study to the EV-001 study for the 
secondary endpoints: 
 At Day 90 (post hoc), the percentage of responders was 0.0% in the placebo group and 
25.8% in the prabotulinumtoxinA group with an absolute difference of 25.8%, p<0.001.  
 At Day 120, the percentage of responders was 0.0% in the placebo group and 12.4% in the 
prabotulinumtoxinA group, with an absolute difference of 12.4%, p<0.001. 
 At Day 150 or early termination, the percentage of responders was 0.0% in the placebo 
group and 4.6% in the prabotulinumtoxinA group. The absolute difference of 4.6% 
between the groups remained statistically significant for the composite endpoint, p=0.047. 

   
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EV-002 Subject - Glabellar Lines at Maximum Frown 
 
In the EV-001 study, the AE rate was 32.1% in the placebo group and 38.2% in the 
prabotulinumtoxinA group. Placebo and prabotulinumtoxinA groups were similar in the overall 
incidence of subjects who experienced one or more AEs. Three prabotulinumtoxinA subjects 
(3/246, 1.2%) experienced SAEs, but none were assessed as study drug related. Placebo and 
prabotulinumtoxinA groups were also similar in the percentages of subjects who experienced AEs 
assessed by the investigator as study drug related: 13.1% of placebo subjects and 15.4% of 
prabotulinumtoxinA subjects. The eyelid and eyebrow ptosis rates, the drooping of an upper eyelid 
or eyebrow, respectively, in the prabotulinumtoxinA group was 0.8% and 0.4%, respectively. 
In the EV-002 study, the AE rate was 26.9% in the placebo group and 28.5% in the 
prabotulinumtoxinA group. Placebo and prabotulinumtoxinA groups were similar in the overall 
incidence of subjects who experienced one or more AEs. Four prabotulinumtoxinA subjects 
(4/246, 1.6%) experienced a SAE, but none were assessed as study drug related. Placebo and 
prabotulinumtoxinA groups were also similar in the percentages of subjects who experienced an 
AE assessed by the investigator as study drug related: 7.7% of placebo subjects and 9.8% of 
prabotulinumtoxinA subjects. The eyelid and eyebrow ptosis rates in the prabotulinumtoxinA arm 
were 1.2% and 0.4% respectively. Overall, AEs with an incidence of 1% or greater were headache 
at 9.3% in the prabotulinumtoxinA groups and 7.6% in the placebo groups and eyelid ptosis at 1% 
in the prabotulinumtoxinA groups and 0% in the placebo groups. 
U.S. Phase III Trials - Adverse Event Rate Summary 
 
Phase III European Clinical Trial for Glabellar Lines 
The EVB-003 study was the third Phase III safety and efficacy study in the prabotulinumtoxinA 
clinical development program and was conducted in Europe and Canada (REF 3). 540 subjects 

   
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with moderate to severe glabellar lines, or a GLS score of 2 or 3, as assessed by the investigator at 
maximum frown, were eligible to be enrolled provided that subjects also felt their glabellar lines 
had an important psychological impact, such as on their mood, anxiety, or depressive symptoms. 
On Day 0, eligible subjects were randomly assigned in a 5:5:1 ratio to receive a single treatment 
of 20 units of prabotulinumtoxinA, 20 units of onabotulinumtoxinA or placebo. 
The primary efficacy endpoint was defined as the proportion of subjects classified as responders 
on Day 30. A responder was a subject with a GLS score of 0 or 1, as assessed by the investigator 
at maximum frown. The primary analysis of the primary efficacy endpoint in the EVB-003 study 
showed prabotulinumtoxinA’s superiority over placebo, and established prabotulinumtoxinA’s 
non-inferiority to BOTOX. The percentages of responders for the primary efficacy endpoint were: 
 4.2% in the placebo group, 95% CI (0.0, 9.8); 
 82.8% in the onabotulinumtoxinA group, 95% CI (78.1, 87.5); and 
 87.2% in the prabotulinumtoxinA group, 95% CI (83.0, 91.5). 
The absolute differences between the treatment groups were: 
 83.1% between prabotulinumtoxinA and placebo groups, 95% CI (70.3, 89.4), (p<0.001), 
indicating prabotulinumtoxinA was superior to placebo; and 
 4.4% between prabotulinumtoxinA and onabotulinumtoxinA groups, 95% CI (-1.9, 10.8), 
with non-inferiority of prabotulinumtoxinA versus onabotulinumtoxinA concluded based 
on the lower bound of the 95% CI for the absolute difference exceeding -10.0%. 
EU Phase III Primary Endpoint - Responder Rates at 
Maximum Frown on Day 30 (GLS = 0 or 1) by 
Investigator Assessment 
 
EU Phase III Primary Endpoint - Non-Inferiority, at 
Maximum Frown on Day 30 by Investigator 
Assessment 
 
 
 
As presented in the table below, within each group, 32.7% of placebo subjects, 41.9% of 
onabotulinumtoxinA subjects and 37.6% of prabotulinumtoxinA subjects experienced AEs. One 
placebo subject (1/49, 2.0%), one onabotulinumtoxinA subject (1/246, 0.4%) and three 
prabotulinumtoxinA subjects (3/245, 1.2%) experienced a total of 11 SAEs and none were assessed 
as study drug related. The eyelid ptosis rates were 1.6% in the prabotulinumtoxinA arm and 0% in 
the onabotulinumtoxinA arm and the eyebrow ptosis rates were 0% in the prabotulinumtoxinA 
arm and 0.4% in the onabotulinumtoxinA arm. 

   
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EU Phase III Trial - Adverse Event Rate Summary 
 
Phase II Repeat Dose Clinical Trial for Glabellar Lines 
The primary objective of the Phase II EV-004 study was to demonstrate the safety of 
prabotulinumtoxinA in adult subjects receiving repeat doses of prabotulinumtoxinA of the course 
of a year for the treatment of moderate to severe glabellar lines (REF 4). 
The test product in this study was different from all the other studies because each vial contained 
lyophilized prabotulinumtoxinA, while all the other studies used vials containing vacuum dried 
prabotulinumtoxinA. 
Over the course of the one year study, the 352 subjects in the study received a median total dose 
of 60 units, or 3 treatments. 
Total AEs 
 148 subjects (148/352, 42.0%) experienced a total of 265 AEs. 
 7 subjects (7/352, 2.0%) experienced a total of 9 SAEs, none assessed as study drug related. 
Study Drug Related AEs 
 51 subjects (51/352, 14.5%) experienced a total of 59 AEs (59/265 events, 22.3%) assessed 
by the investigator as study drug related. 
 39 subjects (39/352, 11.1%) experienced a study drug related AE following the initial 
treatment visit, representing 76.5% of all subjects who experienced study drug related AEs 
(39/51). Progressively lower percentages of subjects experienced study drug related AEs 
following each repeat treatment: 3.4% (11/319) after the first repeat treatment, 1.5% 
(4/262) after the second repeat treatment, and none after the third repeat treatment. 
The primary objective of the phase II EV-006 study objective was also to demonstrate the safety 
of prabotulinumtoxinA in adult subjects receiving repeat doses of prabotulinumtoxinA over the 
course of a year for the treatment of moderate to severe glabellar lines (REF 5). 
Over the course of the one-year study, the 570 subjects in the study received a median total dose 
of 60 units, or 3 treatments. 
Total AEs 
 235 subjects (235/570, 41.2%) experienced a total of 475 AEs. 
 Seven subjects (7/570, 1.2%) experienced eight SAEs, none of the SAEs were assessed as 
study drug related. One death (1/570, 0.2%) was reported during the study, a SAE, this 
event was not related to the study drug. 

   
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Study Drug Related AEs 
 61 subjects (61/570, 10.7%) experienced a total of 91 AEs (91/473 events, 19.2%) assessed 
by the investigator as study drug related. 
 37 subjects (37/570, 6.5%) experienced 46 study drug related AEs following the initial 
treatment visit, representing 60.7% of all subjects who experienced study drug related AEs 
(37/61). Progressively lower percentages of subjects experienced study drug related AEs 
following each repeat treatment: 3.6% (19/524) after the first repeat treatment, 3.2% 
(14/431) after the second repeat treatment, and 1.9% (4/214) after the third repeat 
treatment. 
The combined eyelid ptosis rate for the EV-004 and EV-006 studies was 0.9%. 
1.2 
Rationale for Study 
PrabotulinumtoxinA, using a total dose of 20 Units (i.e., 4 Units injected into five sites of the 
glabellar complex muscles), has been approved by the FDA for the treatment of moderate to severe 
glabellar lines. The current study will explore the safety and effectiveness of injecting 40 Units of 
prabotulinumtoxinA into the glabella and determine if the duration of effect of 
prabotulinumtoxinA 40 Units is superior to that of prabotulinumtoxinA 20 Units. 
Exploratory analyses will determine if the duration of effect of prabotulinumtoxinA 40 Units is 
superior to that of onabotulinumtoxinA 20 Units, as well as if the duration of effect of 
prabotulinumtoxinA 20 Units is superior to that of onabotulinumtoxinA 20 Units. 
1.3 
Hypothesis 
The general form of duration of effect hypotheses will be: 
Ho: β = 0 
HA: β < 0 
where exp(β) is the hazard ratio (experimental treatment / comparator treatment) for loss of effect. 
The study is not powered for formal hypothesis testing and any analyses presented will be for 
interpretation purposes only. 

   
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2 
STUDY OBJECTIVE 
The primary objectives of this study are to demonstrate the safety and duration of effect of 40U of 
prabotulinumtoxinA-xvfs in providing temporary improvement in the appearance of moderate to 
severe glabellar lines associated with corrugators and/or procerus muscle activity in adult subjects. 
 

   
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3 
COMPLIANCE STATEMENT 
This clinical study will be conducted in accordance with the U.S. Code of Federal Regulations 
governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical 
Investigators (21 CFR 54), Institutional Review Boards (21 CFR 56), Investigational New Drug 
(21 CFR 312), and Electronic Records; Electronic Signatures (21 CFR Part 11), as appropriate. As 
such, these sections of U.S. Title 21 CFR are commonly known as Good Clinical Practices (GCPs), 
which are consistent with the Declaration of Helsinki.  
The sites’ Principal Investigator (PI) is responsible for ensuring the privacy, safety, and welfare of 
the subjects during and after the study and must ensure that site personnel are appropriately trained. 
The PI must be familiar with the background and requirements of the study and with the properties 
of the IP as described in the Investigator Brochure. The PI at each site has the overall responsibility 
for the conduct and administration of the study at their site, contact with study site management, 
as well as the Institutional Review Board (IRB) and local authorities. 
3.1 
Variations to the Protocol 
No changes from the final approved (signed) protocol will be initiated without the prior approval 
of the FDA and the IRB except 1) when necessary to eliminate immediate hazards to the subjects 
or when the change involves only logistics or administration, or 2) minor administrative or 
typographical corrections. The sites’ PIs and the Sponsor must sign any protocol amendments. 
While a protocol or ICF change intended to eliminate an apparent immediate risk to subjects may 
be implemented immediately, the change must be documented in an amendment and reported to 
the IRB within 5 working days and be submitted to the appropriate regulatory agency in the 
required time frame. 
All protocol amendments must be reviewed and approved following the same process as the 
original protocol. The version number and date of amendments shall be documented, and a 
justification statement shall be included with each amended section of the document. 
3.2 
Investigational Sites 
Approximately five (5) investigational sites in the U.S. will participate in this study. Each site will 
obtain written approval from an appropriate IRB prior to recruitment and enrollment of any subject 
into the study. Any changes to the study procedures must be made with the mutual agreement of 
the PI and the Sponsor, documented in an amendment to the protocol, and approved by the 
reviewing IRB. 
3.3 
Medical Monitor 
A Medical Monitor will provide safety oversight for this clinical study. The Medical Monitor, in 
consultation with the Sponsor’s team, will review and evaluate AEs and SAEs on a regular basis, 
review safety reports, and will provide consultation and recommendations with regard to 
inclusion/exclusion criteria, concomitant medications/treatments, and subject discontinuations. 
The Medical Monitor will follow the Safety Management Plan and report the trends of AEs and 
SAEs with the Sponsor. 
3.4 
Confidentiality 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 

   
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for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored by ethica CRO Inc. using a 21 CFR Part 11 compliant eCRF 
housed on a secure server. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by clinical 
sites and by ethica CRO Inc. research staff will be secured and password protected. At the end of 
the study, all study databases will be archived at ethica CRO Inc. and the study Sponsor. 
The electronic diary will housed on the same 21 CFR Part 11 compliant eCRF and will ensure the 
research participants’ privacy and confidentiality, does not share data with third parties or link data 
with data from other sources, or use research participants’ data in any other way or for any other 
purpose than mentioned in this study protocol and the informed consent documentation. 
 

   
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4 
STUDY DESIGN AND TREATMENT 
4.1 
Study Design 
The study is a multicenter, prospective, randomized, double-blind, active-controlled, single-
treatment, increasing dose design. 
Up to one hundred and fifty subjects will be randomized 1:1:1, to either 20U onabotulinumtoxinA, 
20U prabotulinumtoxinA-xvfs, or 40U prabotulinumtoxinA-xvfs. Subjects with moderate or 
severe glabellar lines at maximum frown on the 4-point validated Glabellar Line Scale (GLS, 
0=none, 1= mild, 2=moderate, 3=severe), as judged by the investigator and the subject, will be 
eligible. See Section 5 for a full description of the inclusion and exclusion criteria. 
Safety and effectiveness will be assessed on days 3, 7, and 30, then every 30 days up to 365 days 
or until the subject has returned to Baseline as assessed by the Investigator, at which point the 
subject will exit the study. 
Duration of effect will be estimated by Kaplan-Meier analysis and will be based on the number of 
days from Treatment Day (Baseline) to the day that GLS severity (Investigator assessment) at 
maximum frown returns to the Baseline value (i.e., the treatment will be considered to remain 
effective for the amount of time during which GLS severity at maximum frown has not returned 
to Baseline severity). 
The Evaluating Investigator (i.e., Blinded Investigator) will be responsible for managing the 
subject, monitor for related and unrelated adverse effects, and carrying out the evaluations. Ideally, 
the same Evaluating Investigator will perform assessments for a given subject during the entire 
trial. Injections of study drug will be performed by an “Unblinded Injector” (i.e., physician or 
nurse practitioner appropriately skilled in injecting botulinum toxin into the glabellar area and not 
responsible for subject follow-up). 
After exiting the study, subjects are eligible for a treatment of their glabellar lines at no cost 
provided that the investigator deems it appropriate.  
4.2 
Primary Endpoint 
The primary effectiveness endpoint will be duration of effect, defined as the number of days from 
Treatment Day (Baseline) to the day that GLS severity (Investigator assessment) at maximum 
frown returns to the Baseline value. The treatment will be considered to remain effective for the 
amount of time during which GLS severity at maximum frown has not returned to Baseline 
severity. Duration of effect will be estimated by Kaplan–Meier analysis. 
Although the trial is not powered for inferential analysis, this will be the most influential outcome 
in the overall assessment of the effectiveness of prabotulinumtoxinA 40 Units, compared to 
prabotulinumtoxinA 20 Units, in treating moderate to severe glabellar lines.  

   
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5 
STUDY SUBJECT SELECTION AND IDENTIFICATION 
The Institutional Review Board (IRB) must review and approve the protocol and informed consent 
form before any subjects provide consent. Each subject must participate in the informed consent 
process, sign and date an informed consent form for this protocol before any protocol-required 
procedures are performed. 
If informed consent has not been obtained, no protocol required procedures are to be performed 
on the subject and no subject data are to be recorded and transferred to the sponsor. Documentation 
of informed consent must be recorded in the source documents for each subject. Subjects who are 
unable to provide informed consent will not be able to participate in the study. 
Study participants will be identified and recruited from advertising (e.g., social media, newspapers, 
posters, flyers) and from established site lists of potential study participants who have expressed 
interest in participating in future clinical trials. The study coordinator will present study specifics 
to potential participants and will lead the consenting process. The study Investigator and study 
coordinator will assess and confirm inclusion/exclusion criteria. 
In order to be eligible for enrollment in the study, the subject must meet all of the following 
inclusion criteria and none of the exclusion criteria. 
5.1 
Inclusion Criteria 
A subject must meet the following key criteria in order to be eligible for enrollment in the study: 
1. Outpatient, male or female of any race, 18 years of age or older. 
2. Female subjects of childbearing potential must have a negative UPT during Visit 1 
(Screening), Visit 2 (if applicable) and practice a reliable method of contraception for the 
duration of the study. 
A female is considered of childbearing potential unless she is: 
- 
postmenopausal for ≥12 months prior to study treatment administration; 
- 
without a uterus and/or both ovaries; or 
- 
has been surgically sterile for ≥6 months prior to study treatment administration.  
Reliable methods of contraception are: 
- 
hormonal methods (contraceptive pill or implant) or IUD in use ≥90 days prior to enrolment; 
- 
barrier methods (e.g., diaphragm w/ spermicide or condom w/ spermicide in use ≥14 days prior to 
study treatment administration; or 
- 
partner vasectomized ≥3 months (or confirmed ‘0’ sperm count) prior to enrolment. 
[Exception: Females of childbearing potential who are not sexually active are not required to practice a 
reliable method of contraception. These subjects may be enrolled at Investigator’s discretion if they are 
counseled to remain sexually inactive during the study or agree to use an approved method of contraception 
should they become sexually active and understand the possible risks in getting pregnant during the study.] 
3. Moderate to severe glabellar lines (i.e., score of 2 or 3) on maximum frown as assessed 
by the investigator using the GLS. 
4. Subject has moderate to severe glabellar lines (i.e., score of 2 or 3) at maximum frown 
as assessed by the subject using the GLS. 
5. Able to follow study instructions and likely to complete all required visits. 
6. Sign the IRB-approved ICF prior to any study-related procedures being performed. 

   
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5.2 
Exclusion Criteria 
A subject is ineligible to enroll in the study if he/she meets any of the following key criteria: 
1. Female subjects who are pregnant, breast-feeding, or of childbearing potential and not 
practicing reliable birth control. 
2. Known hypersensitivity or previous allergic reaction to any constituent of the IP or 
control. 
3. Any active infection in the area of the injection sites. 
4. Inability to substantially lessen glabellar frown lines even by physically spreading them 
apart. 
5. Marked facial asymmetry (Investigator discretion). 
6. Ptosis of eyelid and/or eyebrow, or history of eyelid and/or eyebrow ptosis. 
7. History of facial nerve palsy. 
8. Excessive dermatochalasis, deep dermal scarring, thick sebaceous skin (Investigator 
discretion). 
9. Medical condition that may affect neuromuscular function (e.g., myasthemia gravis, 
Eaton-Lambert syndrome, amyotrophic lateral sclerosis). 
10. Previous treatment with botulinum toxin of any serotype above the level of the lateral 
canthus within the last 6 months. 
11. Planned treatment with botulinum toxin of any serotype below the level of the lateral 
canthus during the study period. 
12. Previous treatment with any facial aesthetic procedure (e.g., injection with biodegradable 
fillers, chemical peeling, photo rejuvenation) in the glabellar area within the last 12 
months. 
13. Previous insertion of permanent material in the glabellar area. 
14. Any previous energy based or cryotherapy-based treatment of facial muscles superior to 
the lateral canthus. 
15. Any other planned facial aesthetic procedure during the trial period, superior to the level 
of the lateral canthus (can continue with their usual skin care routine). 
16. Any surgery in the glabellar area including surgical removal of the corrugator, procerus, 
or depressor supercilii muscles, or a combination of these, or scars in the glabellar area 
and the surrounding areas (including eyebrow). 
17. Medical or psychiatric conditions that may increase the risk associated with study 
participation or may interfere with the interpretation of study results and, in the judgment 
of the Investigator, would make the subject inappropriate for entry into this study. 
18. Evidence of recent alcohol or drug abuse (Investigator discretion). 
19. History of poor cooperation or unreliability. 
20. Planning to move out of the area prior to study completion. 
21. Subjects who are investigational site staff members or family members of such 
employees. 
22. Exposure to any other investigational drug/device within 30 days prior to Visit 1. 

   
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6 
SUBJECT NUMBERING, RANDOMIZATION AND BLINDING 
6.1 
Subject Numbering 
In order to maintain confidentiality, the subject will be identified by his/her Subject Number and 
initials, and every effort will be made to ensure the confidentiality of this subject information.  
All subjects will receive a 3-digit subject number, starting at 001. Subject numbers will be assigned 
at site level and in ascending order and will be coupled with the site identification number for 
unique identification of each subject. The subject number will be used to identify the subject 
throughout the study. Subject Numbers will not be reassigned or reused for any reason. Subjects 
withdrawn from the study will retain their subject number; new subjects will be allocated a new 
subject number. 
Subjects who do not meet eligibility criteria will be deemed screen failures. Screen Failures will 
not be entered in the eCRF. However, these subjects may be re-screened at a later date. 
6.2 
Subject Randomization 
At Visit 2/Treatment Day, subjects will be randomized to a study group utilizing hardcopy 
computer generated “Randomization Schedules” that will link treatment assignment to each 
Subject Number. The Randomization Schedule will be maintained by the “Unblinded Injector” 
(Section 6.3). 
The Randomization Schedules will provide for equal randomization (1:1:1 ratio) to treatment with 
either 20U onabotulinumtoxinA, 20U prabotulinumtoxinA-xvfs, or 40U prabotulinumtoxinA-
xvfs. 
Subjects will be randomized using a blocked randomization scheme that will be stratified by the 
following factors: 
 Baseline GLS: moderate vs. severe 
 Age group: <65 vs. >65 within each stratum 
 Gender: female vs male 
6.3 
Blinding 
To maintain study blind, the “Unblinded Injector” (i.e., physician or nurse practitioner 
appropriately skilled in injecting botulinum toxin into the glabellar area and not responsible for 
subject follow-up) will have access to the Randomization Schedule, be aware of treatment 
assignment, will prepare syringes of reconstituted IP, and will administer injections of study drug 
to study subjects. 
The Unblinded Injector will be a different individual than the Blinded Evaluator. The Blinded 
Evaluator and the study coordinators responsible for subject assessment and follow-up, as well as 
study subjects, will remain blinded to which study treatment was injected. 
6.4 
Unblinding 
The treatment assignments for all enrolled subjects will be unblinded only after the conclusion of 
the study. Specifically, the blind will be broken only after all data are verified, entered into the 
database and validated, and the database is locked. 
If it is medically imperative to know what study treatment was injected, the Investigator or 
authorized person will contact the Unblinded Injector to obtain the treatment assignment for that 

   
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subject. Prior to unblinding, the investigator should attempt to contact the Medical Monitor and 
ethica CRO Inc. to discuss the rationale for unblinding. The rationale for breaking the code must 
be recorded in the subjects’ medical record and eCRF. 
The Sponsor’s pharmacovigilance staff or designee may unblind the treatment assignment for any 
subject with a treatment-related SAE. If the SAE requires that an expedited regulatory report be 
sent to one or more regulatory agencies, a copy of the report, identifying the subject’s treatment 
assignment, may be sent to clinical investigators in accordance with local regulations and/or 
Sponsor policy. 
Any subject who is unblinded should be withdrawn from the study. An exception may be granted 
in cases where there are ethical reasons to have the subject remain in the study. In these rare cases, 
the investigator must obtain documented approval from the Sponsor to allow the subject to 
continue in the study. 
 

   
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7 
INVESTIGATIONAL PRODUCT MANAGEMENT 
7.1 
Study Drug 
PrabotulinumtoxinA-xvfs (Jeuveau®): Each vial of JEUVEAU (prabotulinumtoxinA-xvfs) for 
injection contains 100 Units of botulinum toxin type A neurotoxin complex, human serum albumin 
(0.5 mg), and sodium chloride (0.9 mg) in a sterile, vacuum-dried form without a preservative.  
OnabotulinumtoxinA (Botox® Cosmetic): Each vial of BOTOX contains 50 Units of 
Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of 
sodium chloride in a sterile, vacuum-dried form without a preservative.  
7.2 
Labeling, Packaging and Storage 
Vials of IP will be provided to the sites in bulk (i.e., individual kits per subject will not be 
provided). It is forbidden to use IP for purposes other than defined in this protocol. 
IP is to be stored refrigerated (2°C to 8°C) in a secure restricted area; avoid freezing. IP will be 
shipped to sites in controlled temperature shipments with a temperature monitor. Appropriate 
temperature records will be filed at the site and in the eTMF. It is the responsibility of the PI to 
verify that IP is within its expiry date before being used. 
The external packaging of IP will be labeled with study information (i.e., study number, study 
Sponsor, name and address of Evolus, Inc., quantity, “CAUTION: Investigational Drug. Limited 
by Federal law to investigational use”, etc.). 
The Investigator Brochure will provide all relevant contraindications, hazards, AEs, warnings, and 
precautions. 
7.3 
Investigational Product Supply and Accountability 
In accordance with 21 CFR Part 312.140 (a) (2), the investigator must maintain accurate records 
of receipt, use or disposition of a drug that relate to:  
 The type and quantity of the drug, the dates of its receipt, and the drug identification (lot 
number, batch number or code mark); 
 The names of all persons who received, used, or disposed of each drug; 
 Why and how many units of the drug have been returned to the sponsor or otherwise 
disposed of. 
The sponsor must notify the FDA and IRB of any request that an Investigator return or dispose of 
any IP. The notice must be made within 30 working days after the request is made and must state 
why the request was made. 
In addition, accurate records will be kept regarding when and how much test article is dispensed 
and used by each subject in the study. Reasons for departure from the expected dispensing regimen 
must also be recorded. At the completion of the study, to satisfy regulatory requirements regarding 
drug accountability, all study drug will be reconciled and retained or destroyed according to 
applicable regulations. 
Unless otherwise confirmed in writing, all used and unused study drug will be returned to 
Sponsor/designee for destruction at the conclusion of the study. The site monitor will be provided 
access to the study IP and records for periodic review. 

   
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8 
STUDY TREATMENT 
Subjects will be treated either with the study drug 40U of prabotulinumtoxinA or one of the two 
controls; 20U of prabotulinumtoxinA or 20U of onabotulinumtoxinA. 
The study drug and active controls will be prepared, reconstituted, and loaded into the syringes by 
an appropriate and protocol trained person at the site (i.e., study nurse or other designee). The 
reconstitution and syringe preparations will be done in a double-blinded fashion. 
Using a 25G needle each vial will be constituted, gently, without shaking: 
 20U of onabotulinumtoxinA (control) will be prepared by reconstituting with 1.25 ml of 
0.9% sterile, non-preserved saline solution in a 50U vial for a final dilution of 4 U/0.1 ml. 
After reconstitution, a total of 0.5ml will be drawn up into a 0.5ml syringe. 
 20U of prabotulinumtoxinA (control) will be prepared by reconstituting with 2.5 ml of 
0.9% sterile, non-preserved saline solution for a final dilution of 4 U/0.1 ml. After 
reconstitution, a total of 0.5ml will be drawn up into a 0.5ml syringe. 
 The study drug, 40U of prabotulinumtoxinA will be prepared by reconstituting with 0.625 
ml of 0.9% sterile, non-preserved saline solution for a final dilution of 8U/0.05 ml. After 
reconstitution, a total of 0.25ml will be drawn up into a 0.3ml. 
Using the preloaded syringe with a 30G needle, the subject is to be injected intra-muscularly into 
a total of five sites, the mid-line of the procerus, the inferomedial aspect of each corrugator muscle 
and the superior middle aspect of each corrugator, at least 1 cm above the bony orbital rim 
(Diagram 1). Both controls (i.e., 20U of prabotlinumtoxinA, 20U of onabotulinumtoxinA) will be 
injected with 0.1 ml (4U) per site, for a total of 20 U and 0.5 ml. The study drug (i.e., 40U 
prabotulinumtoxinA) will be injected with 0.05 ml (8U) per site, for a total of 40 U and 0.25 ml. 
Topical anesthesia is allowed if required; the type(s) used is to be recorded as a concomitant 
medication. 
 
Diagram 1: Injection Sites 
8.1 
Concomitant Medications 
All treatment/procedures received by the subject within 14 days prior to Visit 2 (Treatment Day) 
and throughout the treatment period, including the name of the treatment/procedure, must be 
recorded in the eCRF with start date, stop date, dosage, frequency and indication, if applicable. 

   
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Medications that may interfere with neuromuscular transmission (e.g., aminoglycosides, curare-
like agents) or muscle relaxants need to be observed closely since botulinum toxin may potentiate 
the effects. Botulinum toxin may also potentiate the systemic anticholinergic effects of 
anticholinergic drugs. If any of these medications are taken, the Investigator will ensure that all 
appropriate therapy and follow-up for the subject is provided. 
If prohibited therapies and/or procedures are administered during the study, the Medical Monitor 
will be contacted to discuss details of the event. At a minimum, the event will be documented by 
the site staff as a protocol deviation, as instructed by the Medical Monitor. Depending upon the 
nature of the prohibited therapy and the timing relative to the determination of the primary 
endpoint, the Medical Monitor may decide to discontinue the subject. 
The decision to administer a prohibited medication/treatment is done with the study subjects’ 
safety as the primary consideration. If permissibility of a medication/treatment is in question, the 
Medical Monitor should be contacted before the prohibited medication/treatment is administered. 
8.1.1 
Prohibited and Restricted Medications 
As per Exclusion Criteria (Section 5.2), subjects are prohibited from using various medications or 
undergo various procedures while enrolled in the study from Visit 1 until study exit. 
The following medications/procedures have either restriction for usage and/or are prohibited 
during the course of the study, and appropriate washout periods noted below must be respected: 
 
Treatment/Procedure 
Washout 
During Study 
Botulinum toxin injections (any serotype) above the level of the lateral 
canthus 
≥6 months 
Prohibited 
Botulinum toxin injections (any serotype) in any other body region 
below the level of the lateral canthus 
n/a 
Prohibited 
Any facial aesthetic procedure (e.g., injection with biodegradable fillers, 
chemical peeling, photo rejuvenation, etc.) in the glabellar area 
≥12 months 
Prohibited 
Insertion of permanent material in the glabellar area 
Any previous use 
prohibited 
Prohibited 
Energy based or cryotherapy-based treatment of facial muscles superior 
to the lateral canthus 
Any previous use 
prohibited 
Prohibited 
Surgery in the glabellar area including surgical removal of the 
corrugator, procerus, or depressor supercilii muscles, or a combination of 
these, or scars in the glabellar area and the surrounding areas (including 
eyebrow) 
Any previous 
surgery prohibited 
Prohibited 
Any planned facial aesthetic procedure superior to the level of the lateral 
canthus (can continue with their usual skin care routine) 
n/a 
Prohibited 
Exposure to any other investigational drug/device  
≥30 days  
Prohibited 
 
 
 

   
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9 
DATA COLLECTION 
9.1 
Electronic Case Report Form 
Treatment and follow-up of subjects will be recorded in a 21 CFR part 11 compliant eCRF. Data 
will be first recorded into the medical record and study specific source document worksheets prior 
to entry into the eCRF. The study coordinator will refer to these worksheets in conjunction with 
the medical record in order to complete data entry into the eCRF. 
In order to review and electronically sign the eCRF, the PI will have an individual login password 
that will allow him/her to view data that has been generated. The PI must ensure that he/she 
electronically signs for completed eCRFs on a timely basis. 
9.2 
Coding 
Adverse Events will be coded using the current MedDRA dictionary. Concomitant medications 
will be coded using the current WHODrug dictionary. 

   
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10 STUDY EVALUATIONS 
10.1 
Informed Consent 
The PI (or designate) will explain the benefits and risks of study participation to each subject. 
Written informed consent must be obtained prior to any study related procedure. 
10.2 
Visit Procedures 
10.2.1 
Visit 1 (Screening Visit; ≤14 Days) 
Subjects can be treated any day after initial screening (within 14 days), including the day of 
screening at the discretion of the Investigator. The following screening assessments will be 
conducted at Visit 1: 
 Written informed consent 
 Inclusion / exclusion criteria 
 Demographics and medical history (including previous use of botulinum toxins) 
 Brow Area Photography (Section 10.3.4) 
 Effectiveness Evaluations - Investigator (Blinded Evaluator) 
- 
GLS (max frown) (Section 10.3.1) 
 Effectiveness Evaluations - Subject 
- 
GLS (max frown) 
 Safety Assessments 
- 
Directed Questionnaire (Section 10.4.1) 
- 
Directed Review of Systems (Section 10.4.2) 
- 
Vital Signs (Section 10.4.3) 
- 
Physical Exam (Section 10.4.4) 
- 
UPT (if female subject of childbearing potential) (Section 10.4.5) 
- 
Clinical Laboratory Tests (Section 10.4.6) 
- 
ECG (Section 10.4.7) 
- 
Concomitant Medications (Section 10.4.9) 
10.2.2 
Visit 2 (Treatment Day) 
Subjects who successfully complete screening and sign the informed consent will be treated with 
20U onabotulinumtoxinA, 20U prabotulinumtoxinA, or a 40U prabotulinumtoxinA. At the 
discretion of the Investigator, the screening visit and first treatment visit may take place on the 
same day. The following assessments and procedures will be conducted at Visit 2: 
 UPT (if female subject of childbearing potential) 
 Brow Area Photography 
 Effectiveness Evaluations - Investigator (Blinded Evaluator) 
- 
GLS (max frown) prior to injection 
 Effectiveness Evaluations - Subject 
- 
GLS (max frown) prior to injection 
 Randomization to study treatment and IP injections (Unblinded Injector) 
 Effectiveness Evaluations - Subject 
- 
7-Day Subject Diary (Section 10.3.5) 
 Safety Assessments - Investigator (Blinded Evaluator) 
- 
Concomitant Medications 
- 
Adverse Events (Section 10.5) 

   
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10.2.3 
Visit 3 (Safety and Effectiveness Follow-up; 48hrs ±0 day) 
 Brow Area Photography 
 Effectiveness Evaluations - Investigator (Blinded Evaluator) 
- 
GLS (max frown) 
- 
GAIS (Section 10.3.2) 
 Effectiveness Evaluations - Subject 
- 
GLS (max frown) 
- 
GAIS 
- 
Subject Satisfaction (Section 10.3.3) 
- 
7-Day Subject Diary 
 Safety Assessments - Investigator (Blinded Evaluator) 
- 
Directed Questionnaire 
- 
Directed Review of Systems 
- 
Vital Signs 
- 
Physical Exam 
- 
Concomitant Medications 
- 
Adverse Events 
10.2.4 
Visit 4 (Phone Follow-up; Day 7 ±1 day) 
 Safety Assessments 
- 
Safety Assessment Phone Call (Section 10.4.8) 
- 
Concomitant Medications 
- 
Adverse Events 
10.2.5 
Visits 5 to 15 (Visits each 30 Days; V5 ±3 days, V6 to V15 ±7 days) 
Subjects will continue to be monitored for safety and effectiveness at one-month intervals. On and 
after Day 90, subjects are eligible to exit the study once their GLS score at maximum frown has 
returned to Baseline (Investigator assessment). Subjects will return for monthly assessments until 
they reach their Baseline GLS score (Investigator assessment). Assessment procedures include: 
 Brow Area Photography 
 Effectiveness Evaluations - Investigator (Blinded Evaluator) 
- 
GLS (max frown) 
- 
GAIS 
 Effectiveness Evaluations - Subject 
- 
GLS (max frown) 
- 
GAIS 
- 
Subject Satisfaction 
- 
Clinical Interview (Visit 5; Day 30 only) (Section 10.3.4) 
 Safety Assessments - Investigator (Blinded Evaluator) 
- 
Directed Questionnaire 
- 
Directed Review of Systems 
- 
Vital Signs 
- 
Physical Exam 
- 
Concomitant Medications 
- 
Adverse Events 
10.2.6 
Visit 16 (Final Visit or ET Visit; Day 365 ±14 days) 
The Final visit (or ET visit) will take place when subjects GLS score (Investigator assessment) has 
returned to Baseline. Subjects may withdraw from participation in the study at any time for any 

   
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reason. If withdrawal occurs, the subject should be asked to complete a follow-up or early 
termination visit, if possible. During the final or early termination visit, both safety and 
effectiveness evaluations will be performed as follows: 
 Brow Area Photography 
 UPT (if female subject of childbearing potential) 
 Effectiveness Evaluations - Investigator (Blinded Evaluator) 
- 
GLS (max frown) 
- 
GAIS 
 Effectiveness Evaluations - Subject 
- 
GLS (max frown) 
- 
GAIS 
- 
Subject Satisfaction 
- 
Clinical Interview 
 Safety Assessments - Investigator (Blinded Evaluator) 
- 
Directed Questionnaire 
- 
Directed Review of Systems 
- 
Vital Signs 
- 
Physical Exam 
- 
Clinical Laboratory Tests 
- 
ECG 
- 
Concomitant Medications 
- 
Adverse Events 
10.2.7 Unscheduled Visit  
An unscheduled in-office visit may occur at any time during the study to complete missed study 
procedures, assess adverse events, or assess ongoing unresolved drug-related adverse events after 
study exit. During the visit, some or all of the safety and effectiveness evaluations may be 
performed as follows: 
 Brow Area Photography 
 Effectiveness Evaluations - Investigator (Blinded Evaluator) 
- 
GLS (max frown) 
- 
GAIS 
 Effectiveness Evaluations - Subject 
- 
GLS (max frown) 
- 
GAIS 
- 
Subject Satisfaction 
- 
Clinical Interview 
 Safety Assessments - Investigator (Blinded Evaluator) 
- 
Directed Questionnaire 
- 
Directed Review of Systems 
- 
Vital Signs 
- 
Physical Exam 
- 
Clinical Laboratory Tests 
- 
ECG 
- 
Concomitant Medications 
- 
Adverse Events 
 

   
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10.3 
Effectiveness Assessments 
10.3.1 
Glabellar Lines Scale (GLS) 
The severity of glabellar lines at “maximum frown” will be assessed by both the Investigator 
(Blinded Evaluator) and subjects using the validated 4-point GLS as per Table 2 and in Appendix 
C. The accompanying photonumeric guidance will be provided separate from this protocol. 
Table 2.  GLS at Maximum Frown 
Grade 
Score 
Description 
None 
0 
No lines 
Mild 
1 
Line seen, not sharp 
Moderate 
2 
Line sharper, deep, may see heaping of skin 
Severe 
3 
Deeper line, heaping of skin, skin may be opposed 
 
10.3.2 
Global Aesthetic Improvement Scale (GAIS) 
GAIS will be assessed by both the Investigator (Blinded Evaluator) and subjects using the 5-grade 
scale as per Table 3 below. Instruction for assessment: “Compare your pre-injection photograph 
to the photograph provided and rate the degree of aesthetic improvement by using the following 
scale”. Investigator and subject will assess using the same pre-injection photograph. 
Table 3.  GAIS 
Grade 
Score 
Description 
Much Improved 
2 
Marked improvement in appearance 
Improved 
1 
Improved in appearance, but would like more 
No Change 
0 
The appearance is essentially the same as the original condition 
Worse 
-1 
The appearance is worse than the original condition 
Much Worse 
-2 
The appearance is much worse that the original condition 
10.3.3 
Subject Satisfaction Scale (SSS) 
SSS will be assessed by the subject using the following 5-grade scale as detailed in Table 4 below. 
Subject will be instructed: “Rate your level of satisfaction with the effect of study treatment on 
your frown lines by using the following scale”: 
Table 4.  Subject Satisfaction Scale 
Grade 
Score 
Description 
Very Satisfied 
2 
I am very satisfied with the treatment 
Satisfied 
1 
I am satisfied with the treatment 
Indifferent 
0 
I am indifferent with the treatment 
Unsatisfied 
-1 
I am unsatisfied with the treatment 
Very Unsatisfied 
-2 
I am very unsatisfied with the treatment 
 
10.3.4 
Brow Area Photography 
Photos of the brow area will be collected at all visits except at Visit 4. A photography instruction 
manual will be provided separate from this protocol. 
10.3.5 
Clinical Interview (Day 30, Final Visit/Early Termination, and Unscheduled Visit) 
Subject opinion regarding study treatment will be assessed through a clinical interview employing 
the following questions: 
 
What did you like about the treatment (clinically or other feedback)? 

   
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 
What did you dislike about the treatment (clinically or other feedback)? 
 
If treated with botulinum toxin before this study, which treatment did you prefer, the study 
treatment or the previous treatment? 
10.3.6 
7-Day Subject Diary 
In the morning of the day after study treatment, subjects will be issued a 7-day electronic subject 
diary that will assess subjects’ opinion regarding onset of study treatment effect. Subjects will 
respond “Yes” or “No” to the following question: “Since being injected, have you noticed any 
effect on the appearance of your glabellar lines?” 
10.4 
Safety Assessments 
10.4.1 
Directed Questionnaire 
The following questions will be asked looking for signs of local or distant botulinum toxin spread 
and to set a baseline: 
 Have you noticed any problems with speaking, swallowing, or breathing? 
 Have you had any headaches, eyelid or eyebrow drooping? 
10.4.2 
Directed Review of Systems 
Directed Review of Systems will include review of the following systems: Head and Neck, 
Respiratory, Cardiovascular, Neurological, Musculoskeletal, Dermatological. 
10.4.3 
Vital Signs 
Blood pressure (systolic, diastolic), respiratory rate, and heart rate will be recorded. 
10.4.4 
Physical Exam 
Based on the response to the medical history, directed questions, directed reviews of systems, 
inclusion and exclusion criteria, an appropriate physical examination will be conducted by the 
Investigator. The neurological examination should include extraocular movement, cranial nerve 
and muscular weakness assessments.  This exam will also establish a baseline for the subject. 
10.4.5 
Urine Pregnancy Test 
Standard commercially available UPTs will be used to confirm pregnancy status at Screening 
(Visit 1), Visit 2 (if applicable) and end of study. The urine pregnancy test employed should have 
a sensitivity of at least 50 mIU/mL for human chorionic gonadotropin (hCG). 
10.4.6 
Clinical Safety Laboratory Tests 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry, 
and urinalysis) will be conducted as per the visit schedule. A designated central laboratory will 
analyze clinical laboratory samples. All tests and laboratory reports will be reviewed and signed 
by the Investigator. Any abnormal findings will be dealt with in a clinically appropriate manner, 
per the clinical judgment of the Investigator. Clinically significant results (Investigator opinion) 
will be reported as AEs. 
Approximately 12ml of blood will be drawn for each testing at Screening and end of the study (or 
early termination), for a total of 24ml for each subject. The following tests will be performed: 
 Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count 
 Chemistry: alkaline phosphate, urea nitrogen, creatinine, ALT, AST, albumin, total protein, 

   
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uric acid, glucose, sodium, potassium, chloride, calcium 
 Urinalysis: specific gravity, pH, protein, glucose, leukocytes, occult blood 
 Botulinum antibodies  
10.4.7 
12-Lead ECG 
12-lead ECGs will be at Screening and at the final study visit and will include heart rate, PR, QRS, 
QT, and QTc. ECG results will be interpreted by as Normal, Abnormal; not clinically significant 
(NCS), or Abnormal; clinically significant (CS). If Abnormal, details will be provided, and 
“Abnormal Clinically Significant” results (Investigator opinion) will be reported as AEs.” 
10.4.8 
Safety Assessment Phone Call 
General safety assessments above that can be conducted over the phone will be verbally 
administered. 
10.4.9 
Concomitant Medications 
All treatment/procedures received by the subject within 14 days prior to study treatment and 
throughout the treatment period, including the name of the treatment/procedure, must be recorded 
in the eCRF with end dates, if applicable.  
10.4.10 Pregnancy and Contraception 
All women of childbearing potential who participate in the study should be counseled on the need 
to practice adequate birth control and on the importance of avoiding pregnancy during study 
participation by using effective birth control methods (e.g., oral contraceptive, condom, IUD, 
injectable contraceptive, diaphragm, or vasectomized partner). Male subjects have no 
contraceptive restrictions. Women should be instructed to contact the PI or study staff immediately 
if pregnancy occurs or is suspected. 
Urine pregnancy testing (sensitivity of at least 50 mIU/mL for hCG) will be conducted at Screening 
(Visit 1), Visit 2 (if applicable), and at the end of the study on every woman of childbearing 
potential. A woman who is found to be pregnant at screening will be excluded from the study and 
considered to be a screen failure. 
Pregnancies will be recorded using the Unanticipated Problems Reporting Form and are not be 
considered AEs. 
10.5 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship to 
the study treatment will be recorded in the eCRF. Subjects will be questioned for the occurrence 
of any new or worsening signs or symptoms at each visit by the following methods: 
 Information volunteered by the subject 
 Open ended and non-leading questions such as: Have you had any health problems since 
your last visit? 
 Observation by the investigational team, other care providers or relatives 
10.5.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a subject administered the study treatment and 
which may, but does not necessarily, have a causal relationship with study treatment. An AE can 
therefore be any unfavorable or unintended sign (for example an abnormal laboratory finding), 

   
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symptom or disease temporally associated with the study treatment, whether or not considered 
related to the study treatment. 
AEs may include, but are not limited to, subjective or objective symptoms spontaneously offered 
by the subject, solicited via subject interviews, uncovered by review of concomitant medications 
or therapies, and/or observed by the site staff. A blinded Investigator will determine the description 
(sign, symptom, diagnosis), onset, resolution, seriousness, severity, cause, and action taken for any 
event.  
Disease signs and symptoms that existed prior to study enrolment are not considered AEs. 
Recurring symptoms associated with pre-existing conditions are not considered AEs unless they 
have a clinically significant increase in severity and/or frequency, as determined by the blinded 
Investigator. 
Clinically significant abnormal laboratory tests (if applicable) must be recorded as an AE. 
Changes resulting from normal growth and/or development occurring at a physiologically 
appropriate time that do not vary significantly from the frequency or severity expected, for 
example, the onset of menses or menopause, are not to be considered AEs. 
10.5.2 
Serious Adverse Events (SAEs) 
A SAE is defined as any unfavorable medical occurrence that meets any of the following:  
1. Results in death. 
2. Is life-threatening: “Life-threatening” refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event, which hypothetically might have 
caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization: Planned and 
routine hospital admissions for pre-existing conditions are not considered SAEs and do not 
require reporting as an AE unless the condition has worsened beyond what would reasonably 
be expected for that subject. If a subject experiences an additional AE that prolongs a pre-
planned hospitalization this is considered to be an SAE and should be reported as an SAE. 
Pre-planned admissions must be recorded in the subject’s source documentation.  
4. Results in persistent or significant disability/incapacity. 
5. Is a congenital anomaly or birth defect resulting from a pregnancy occurring during the study. 
6. Is an important medical even that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent one 
of the other outcomes listed above should usually be considered serious. 
10.5.3 
Unexpected Adverse Drug Reaction (UADR) 
A UADR is an adverse reaction where the nature or severity of which is not consistent with the 
applicable product information in the source documents (e.g., Investigator's Brochure.). 
10.5.4 
Causality Assessment 
A blinded Investigator’s assessment of an AE’s relationship to the study treatment is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. 
If there is any doubt as to whether a clinical observation is an AE, the event will be reported. A 
blinded Investigator will assign the causality assessment according to his/her clinical experience 
and the subject’s description of the event. The Sponsor will be responsible for the final causality 

   
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judgment. The causal relationship should be classified according to the following criteria (not all 
variables need to be present to be indicative of relationship to the treatment): 
Definitely related: 
 The temporal sequence of AE onset relative to study treatment is reasonable. 
 The AE is more likely explained by study treatment than by another cause. 
 The AE shows a pattern consistent with previous knowledge of study treatment. 
Probably related: 
 The temporal sequence of AE onset relative to study treatment is reasonable. 
 The AE is more likely explained by the study treatment than by another cause. 
Possibly related: 
 The temporal sequence of AE onset relative to study treatment is reasonable. 
 The AE could have been due to another equally likely cause. 
Probably not related: 
 There is another more likely cause of the AE. 
Definitely not related: 
 The temporal sequence of AE onset relative to study treatment is not reasonable. 
 There is another obvious cause of the AE. 
10.5.5 
Severity Assessment 
For events reported on the AE eCRF, a blinded Investigator will determine the severity 
classification based on his/her clinical experience and by using the following definitions of severity 
(note: a “severe” AE is not the same as a SAE): 
 Mild: Symptoms are barely noticeable or do not make the subject uncomfortable. The AE 
does not influence performance or functioning. Prescription drugs are not ordinarily needed 
for relief of symptom(s). 
 Moderate: Symptoms are of sufficient severity to make the subject uncomfortable. 
Performance of daily activities is influenced. Treatment of symptom(s) with prescription 
drugs or therapies may be needed. 
 Severe: Symptoms are of sufficient severity to cause the subject severe discomfort. 
Performance of daily activities is compromised. Treatment for symptom(s) with prescription 
drugs or therapies may be needed. 
The maximal severity for the AE will be recorded, even if the AE presented as being less severe 
at some point during the event.  
10.5.6 
Safety Reporting 
It is the PI’s responsibility to oversee the safety of the investigation at his/her site, including careful 
assessment and appropriate reporting of all safety events. The site should follow all applicable 
governance, including FDA regulations, FDA guidance, and IRB requirements for notification of 
all types of AEs. The PI or designee must report to ethica CRO any of the following events: 
 SAEs (see section 10.5.2) - using the SAE Report Form 
 Pregnancies - using the Unanticipated Problem Reporting Form 
 New findings/updates in relation to already reported events 

   
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These events must be reported immediately but no later than within 24 hours of first becoming 
aware of them by completing, signing, and dating the applicable form, verifying the accuracy of 
the information recorded in the form with the source documents and the eCRF, and sending the 
applicable form to the CRO by e-mail.  
10.5.6.1 All Adverse Events 
All AEs, whether serious or not, will be recorded from the time of IP injection until the last study 
visit. A blinded Investigator will assess all AEs and record details of seriousness, severity, date of 
onset, date of resolution or stop date, and action taken with study treatment, and relationship to the 
IP. 
If an AE occurs, the first concern will be the safety of the study subjects. All Treatment-Related 
AEs will be followed until the event has resolved or stabilized or until follow-up is no longer 
possible or the blinded Investigator deems it unnecessary. 
If the Sponsor determines that an AE presents an unreasonable risk to subjects, the Sponsor will 
terminate participation in the study as soon as possible (i.e., within 5 working days after the Study 
Sponsor makes this determination and not later than 15 days after the Study Sponsor first receives 
notice of the event).   
The Sponsor is responsible for ensuring that reporting of AEs to the relevant governing authorities 
is within the time frame applicable according to international and local law. 
In the event that adjudication of a safety issue is required, an independent committee will be 
convened. The committee will be comprised of three medical doctors, one dermatologist, and two 
plastic surgeons.  
10.5.6.2 Serious Adverse Events (SAEs) 
All SAEs that occur after the time of IP injection through 7 days after subject completion of the 
study must be reported to ethica CRO within 24 hours of awareness. Initial report must be made 
by completing the paper SAE Report Form with all available information and providing it to ethica 
CRO by email. It is the site’s responsibility to perform the following: 
 Obtain and maintain all pertinent medical records, information, and medical judgments from 
colleagues who assisted in the treatment and follow-up of the subject. 
 Provide ethica CRO with a complete, written case history, including copies of 
pseudonymized supporting reports (e.g., progress notes, laboratory reports) and a statement 
as to whether the event was or was not related to study treatment. 
 With the assistance of the CRO, notify the governing IRB of the SAE in accordance with the 
requirements of SAE reporting stipulated by the governing IRB. 
Serious Adverse Event Reporting: The PI will report SAEs by email using the paper SAE 
report form within 24 hours of awareness and complete the eCRF within 48 hours of awareness. 
SAE reports should be scanned and emailed to the ethica CRO Clinical Project Manager. 
ethica CRO will handle the SAE report according to the process described in the SMMP. Any 
missing or additional relevant follow-up information concerning the SAE should be sent to 
ethica CRO as soon as possible, together with the following information, at a minimum: initial 
report, AE, date of occurrence, subject identification, study ID, and site number; this will allow 
the follow-up information to be linked to the initial SAE report. Specific information may be 
requested by opening queries in the eCRF or via e-mail communication. 

   
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10.5.6.3 Adverse Events of Special Interest (AESI) Reporting 
AESI are important medical events that may be consistent with botulinum toxin effects, such as: 
 Swallowing or breathing difficulties 
 Asthenia 
 Generalized muscle weakness 
 Diplopia 
 Dysphagia 
 Dysphonia 
 Dysarthria 
All AESIs need to be reported within 24 hours of awareness using the SAE/UADE/AESI report 
form and recorded in the eCRF within 48 hours of awareness. ethica CRO will handle the AESI 
report according to the process described in the SMMP. 
The report must include date of IP injection, symptoms that were observed, time to onset and 
resolution, and any intervention(s) that were implemented. All AESIs will be evaluated carefully 
by the Sponsor and the study medical monitor. Follow-up actions will be decided on case-by-case 
basis and documented. 
The study Sponsor will handle the AESI report according to the process described in the SMMP, 
including evaluation of the AESI, and reporting of the AESI to the FDA, all reviewing IRBs, and 
participating Investigators within 10 working days of awareness. 
As the AESI are considered as reportable event to the FDA, the Sponsor will provide further 
information to the PI within 7 working days of receipt of the AESI report form to allow the PI to 
report the event to the reviewing IRB as applicable.  
10.5.6.4 Unexpected Adverse Drug Reaction (UADR) Reporting 
A UADR is a treatment-related adverse reaction where the nature or severity is not consistent with 
the applicable product information in the Investigator's Brochure. An AE will be considered as a 
UADR if it is a treatment-related event not associated with the following Expected Adverse Drug 
Reactions: 
 Headache 
 Facial paresis (eyelid ptosis, brow ptosis) 
 Blepharospasm 
 Injection site pain 
 Injection site hematoma 
 Injection site reaction 
 Eyelid edema 
 Nausea 
Unanticipated Adverse Drug Events occurring during a treatment must be documented in the 
appropriate CRF AE page.  If the event meets one of the seriousness criteria, it will be handled 
like any other SAE and the Sponsor must be informed of this Serious UADR and any follow-up 
information by scanning and emailing the completed SAE reporting form within 24 hours of 
becoming aware of the occurrence of the SAE to the ethica CRO Clinical Project Manager. 

   
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The Sponsor will conduct an evaluation of the UADR and report results of such evaluation to FDA 
and to all reviewing IRBs and participating Investigators within 10 working days after the Sponsor 
first receives notice of the event. 
10.5.6.5 Other Reportable Information 
Certain information, although not considered an SAE, must be recorded, reported, and followed 
up.  This includes the following:  
 Breach of confidentiality. 
 Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
 Complaint of a participant when the complaint indicates unexpected risks, or the complaint 
cannot be resolved by the research team. 
 Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants 
at increased risk or affects the rights or welfare of subjects. 
 Pregnancy after receiving study treatment.  If a pregnancy is confirmed, the subject will 
remain in the study and will be followed to term even if the study has completed.     
10.5.7 
Pregnancy 
The PI must report pregnancy to the CRO within 24 hours of learning of it using the Unanticipated 
Problems Reporting Form and send it to the same e-mail address as for SAE reporting. Pregnancy 
complications such as spontaneous abortion/miscarriage, elective abortion due to a congenital 
abnormality, or a complication of pregnancy or a congenital abnormality diagnosed at any time 
during the pregnancy or postpartum are considered SAEs and must be reported as such. An elective 
abortion of a normal pregnancy without complications is not considered an SAE. 
Every effort should be made to gather information regarding the pregnancy outcome and condition 
of the infant. It is the responsibility of the PI to obtain this information within 28 calendar days 
after the initial notification and approximately 28 calendar days postpartum. The need for safety 
follow-up until birth will not delay study database lock. If the study is completed and/or the study 
database is locked before the postpartum follow-up is expected, the PI will notify the CRO of the 
outcome of the pregnancy only via e-mail and the Unanticipated Problems Reporting Form will 
be processed accordingly. 
In addition to the above, if the PI determines that the pregnancy meets seriousness criteria, it must 
be reported also as an SAE (in addition to reporting the pregnancy itself). 

   
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11 STUDY COMPLETION / SUBJECT COMPLETION / WITHDRAWAL  
11.1 
Study Completion 
The Investigator will provide a summary of the study’s outcome to the IRB within 3 months 
following the Investigator’s completion, termination, or discontinuation of participation in the 
study and will forward a copy of this summary to the Sponsor. 
At the completion of the study, the Investigator will return all remaining drugs not used in the 
study along with all clinical supplies to the Sponsor, unless otherwise directed by the Sponsor, in 
accordance with Good Clinical Practices. 
11.2 
Subject Completion 
A subject will be considered to have completed the study if he/she has completed all assessments 
and applicable study visits or experienced an event that precludes further study participation. 
11.3 
Withdrawal 
Approximately 150 subjects will be enrolled to ensure that a minimum of 135 evaluable subjects 
complete the study. If a subject withdraws from the study, he or she will not be replaced. 
A subject will be withdrawn (i.e., dropouts) from the study for any of the following reasons: 
- Lost to follow-up; 
- Deemed ineligible (following screening) at Visit 1; 
- Subject request/Withdrawal of Informed Consent: A subject may withdraw consent any 
time without negative implication to the subject. The withdrawal will be documented in 
source documents and the Case Report Form (CRF); 
- Non-compliant in the judgment of the Investigator; 
- Adverse event that requires intervention in region injected; 
- Termination of study by the Sponsor; 
- The PI believes that for safety reasons (e.g., AE, concurrent illness) it is in the best interests 
of the subject to be withdrawn from study participation; 
- The subject’s attending physician requests that the subject be withdrawn from the study; 
- The PI or the Sponsor, for any reason, stops the study or stops the subject’s participation 
in the study; 
Protocol deviations will not lead to automatic withdrawal unless they indicate a significant risk to 
the subject’s safety. All major protocol deviations must be discussed promptly with the Medical 
Monitor. 
A subject may be withdrawn from the study, in consultation with the Medical Monitor, for any of 
the following reasons: 
- Lack of compliance to study procedures; 
- A major protocol deviation or violation; 
- Poor visit attendance. 
If a subject decides to withdraw from the study, or should the PI decide to withdraw the subject, 
the PI (or designate) will complete and report the observations up to the time of withdrawal. 

   
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Unless withdrawn during a study visit, subjects who are withdrawn from the study will be 
requested to come in to complete an Early Termination Visit as soon as reasonably possible so that 
a complete evaluation at the time of the subject’s withdrawal should be made. Additionally, 
subjects who withdraw from the study will be requested to allow continued safety monitoring, 
either via telephone interviews or clinic visits, whichever is more appropriate. 
The reason and date of withdrawal must be noted on the eCRF. If the reason for withdrawal is an 
AE or an abnormal laboratory test result, monitoring will continue until resolution or until an 
appropriate medical judgment concerning the cause or importance has been made. The specific 
event or test result(s) must be recorded on the eCRF. 
11.4 
Termination of Study 
11.4.1 
Termination by Sponsor 
The Sponsor may terminate the study at any time for any of the following reasons: 
 Failure to enroll subjects 
 Inaccurate or incomplete data 
 Unsafe or unethical practices 
 Questionable safety of the study drug 
 Administrative decision 
The Investigator/Institution will be promptly informed by the Sponsor in writing of termination of 
the study and reason(s) for termination. The Investigator must inform the IRB promptly and 
provide a detailed written explanation of the termination and must also promptly notify all 
participating subjects of the termination of the study within 24 hours and assure that all appropriate 
therapy and follow-up for subjects is provided. 
11.4.2 
Termination by Investigator 
If the Investigator terminates the study prematurely, the Investigator will: 
 Provide the IRB and the Sponsor with a written statement describing why the study was 
terminated prematurely. Prompt compliance with this requirement is essential so that the 
Sponsor may comply with regulatory obligations. 
 Notify all participating subjects of the termination within 24 hours and ensure that all 
appropriate therapy and follow-up for subjects is provided. 
 Return all CRFs, and related study materials to the Sponsor. 
 
 
 

   
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12 STATISTICAL METHODS 
12.1 
Primary Endpoint 
The primary effectiveness endpoint will be duration of effect, defined as the number of days from 
Treatment Day (Baseline) to the day that GLS severity (Investigator assessment) at maximum 
frown returns to the Baseline value. Although the trial is not powered for inferential analysis, this 
will be the most influential outcome in the overall assessment of the effectiveness of 
prabotulinumtoxinA 40 Units, compared to prabotulinumtoxinA 20 Units, in treating moderate to 
severe glabellar lines. Analysis will be performed using the modified Intent-To-Treat (mITT) 
population. 
Duration of effect will be described by Kaplan-Meier curves and the respective median times with 
associated 2-sided 95% confidence interval (CI) for each treatment group. Statistical analyses of 
treatment group differences will be done using Cox proportional hazards regression with time to 
return to Baseline as the dependent variable, treatment group as the independent variable, and age, 
gender, and Baseline GLS score (Investigator assessment) at maximum frown as covariates.  
Statistical significance will be established at the 0.025 level with one-sided hypothesis testing. 
12.2 
Secondary Endpoints 
Secondary effectiveness endpoints will be used to provide additional evidence of 
prabotulinumtoxinA 40 Units superiority to prabotulinumtoxinA 20 Units. As duration of effect 
outcomes, secondary effectiveness endpoints will be assessed as described above for the primary 
endpoint. The mITT population will be used for summaries and comparisons. Secondary 
endpoints, in order of importance, will be: 
1. Duration of effect, defined as the number of days from Treatment Day (Baseline) to the day 
that GLS severity (subject assessment) at maximum frown returns to the Baseline value. 
2. Duration of effect in GAIS responders (score of 2 or 1) as assessed by Investigator. 
3. Duration of effect in GAIS responders (score of 2 or 1) as assessed by subject. 
4. Duration of effect in SSS responders (score of 2 or 1) as assessed by subjects. 
12.3 
Tertiary Endpoints 
Tertiary effectiveness endpoints will be used to compare prabotulinumtoxinA 40 Units to 
onabotulinumtoxinA 20 Units, as well prabotulinumtoxinA 20 Units to onabotulinumtoxinA 20 
Units. As duration of effect outcomes, tertiary effectiveness endpoints will be assessed as 
described above for the primary endpoint. The mITT population will be used for summaries and 
comparisons. Tertiary endpoints, in order of importance, will be: 
1. Duration of effect, defined as the number of days from Treatment Day (Baseline) to the day 
that GLS severity (Investigator assessment) at maximum frown returns to the Baseline value. 
2. Duration of effect, defined as the number of days from Treatment Day (Baseline) to the day 
that GLS severity (subject assessment) at maximum frown returns to the Baseline value. 
3. Duration of effect in GAIS responders (score of 2 or 1) as assessed by Investigator. 
4. Duration of effect in GAIS responders (score of 2 or 1) as assessed by subject. 
5. Duration of effect in SSS responders (score of 2 or 1) as assessed by subjects. 

   
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12.4 
Exploratory Effectiveness Endpoints 
Exploratory effectiveness endpoints will be evaluated for signals of effectiveness to explore 
whether any should be elevated in importance for subsequent trials. These endpoints will be 
assessed using either logistic regression (for binary endpoints) or survival analysis-type methods 
as described above. Comparisons will be made between all treatment groups. Chi-square tests of 
association or Fisher’s exact tests will be used to compare treatment group differences in 
proportion of subjects returning to Baseline at each time point in the study. Exploratory endpoints 
will be: 
1. GLS score of 0 or 1 (maximum frown) as assessed by Investigator and subject at each visit. 
2. GAIS response (score of 2 or 1) as assessed by Investigator and subject at each visit. 
3. SSS response (score of 2 or 1) as assessed by subjects at each visit. 
4. 1-point or greater, 2-point or greater, and 3-point or greater improvement on the GLS 
(maximum frown) as assessed by Investigator at each visit. 
5. 1-point or greater, 2-point or greater, and 3-point or greater improvement on the GLS 
(maximum frown) as assessed by subject at each visit. 
6. Duration of effect in responders with a 1-point or greater, 2-point or greater, and 3-point or 
greater improvement on the GLS (maximum frown) as assessed by Investigator at each visit. 
7. Duration of effect in responders with a 1-point or greater, 2-point or greater, and 3-point or 
greater improvement on the GLS (maximum frown) as assessed subject at each visit. 
8. Duration of effect in GLS responders (responder = ≥1-point improvement on GLS at Day 
30) as assessed by Investigator. 
9. Duration of effect in GLS responders (responder = ≥1-point improvement on GLS at Day 
30) as assessed by subject. 
10. Onset of effect as assessed by subjects through the 7-Day Subject Diary. 
12.5 
Safety Endpoints 
Safety endpoints will include incidence of treatment-emergent and treatment-related AEs and 
changes from Baseline in ECG parameters, safety laboratory parameters, physical exams, and vital 
signs. The SAFT Population will be used for descriptive summaries of the safety endpoints.  
12.5.1 
Adverse Events (AEs) 
AEs will be coded to system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA). The number and percentage (incidence) of 
subjects reporting an AE and the number of AEs will be summarized. 
A treatment-emergent AE will be defined as AEs that started at or after the first injection. 
The following AE incidence tables will be provided for treatment-emergent AEs: 
 All AEs by SOC and PT 
 Related AEs by SOC and PT 
 All AEs by PT sorted by decreasing frequency among all subjects 
 Related AEs by PT sorted by decreasing frequency among all subjects 
 All SAEs by seriousness criterion 
 Related SAEs by seriousness criterion 

   
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 All SAEs by SOC and PT 
 Related SAEs by SOC and PT 
Treatment-related AEs will be defined as possibly, probably, or definitely related. Two-sided 
Wilson 95% confidence intervals will be calculated for the overall incidence of AEs and SAEs. 
12.5.2 
Laboratory Variables 
The number and percentage of subjects with a clinically significant laboratory abnormality 
(Investigator opinion) will be summarized for each laboratory test with available normal ranges. 
Descriptive statistics will be used to summarize observed values and changes from Baseline. Shift 
tables and other tabular and graphical methods may be used to present results for laboratory tests 
of interest. Listings will be provided with flags indicating clinically significant abnormalities. 
12.5.3 
Vital Signs 
The number and percentage of subjects with a clinically significant vital sign abnormality 
(Investigator opinion) will be summarized for each parameter; percentages will be based on 
subjects with non-missing values.  
Descriptive statistics will be used to summarize observed values and changes from Baseline. 
Tabular and graphical methods may be used to present results for parameters of interest. Listings 
will be provided with flags indicating clinically significant abnormalities. 
12.5.4 
12-Lead Electrocardiograms 
The number and percentage of subjects with a clinically significant ECG abnormality (Investigator 
opinion) will be summarized for each parameter; percentages will be based on subjects with non-
missing values.  
Descriptive statistics will be used to summarize results and changes from Baseline. Tabular and 
graphical methods may be used to present results for parameters of interest. Listings will be 
provided with flags indicating clinically significant abnormalities. 
12.6 
Analysis Populations 
Three analysis populations are defined: Modified Intent-to-Treat (mITT) Population, Per Protocol 
(PP) Population, and Safety (SAFT) Population. All analysis populations will be defined and 
determined prior to database closure and unblinding for the final analysis.  
12.6.1 
Modified Intent-to-Treat Population 
The mITT Population is defined as all subjects who were randomized, received their injection of 
IP, and have at least one post-dosing assessment for the primary effectiveness endpoint. The ITT 
principle will be followed in that subjects in the mITT population will be analyzed according to 
the treatment assigned as per the randomization schedule. The mITT Population will be the 
primary population used for effectiveness analyses of primary, secondary, tertiary, and exploratory 
effectiveness endpoints. 
12.6.2 
Per Protocol Population 
The PP Population is defined as treated subjects who complete the entire study up to the final visit 
with no protocol deviations that could affect effectiveness assessments. The decision whether a 
protocol violation/deviation is relevant for the exclusion of subjects from the PP Population will 
be made in a data review meeting prior to breaking the study blind. The PP Population will be used 
for supportive effectiveness analyses. 

   
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12.6.3 
Safety Population 
The SAFT Population will be used for safety analysis and will consist of all randomized subjects 
who received treatment with the IP and will be analyzed as per treatment received. The SAFT 
population will be the primary population for safety analyses. 
12.7 
Sample Size Considerations 
This study is not powered for inferential analyses. A total of 150 subjects will be randomized to 
the study, 50 subjects in each of the three treatment arms; 20U onabotulinumtoxinA, 20U 
prabotulinumtoxinA and 40U prabotulinumtoxinA. 
Assuming 50 subjects per treatment group, exponential distributions for failure and censoring 
times, a median duration of effect of 4 months in the reference group, and an annual censoring rate 
of 10%, the study will have 80% power to detect a hazard ratio of 0.47 based on a one-sided 
hypothesis test of the primary effectiveness endpoint with alpha = 0.025. As such, it is the opinion 
of the study Sponsor that 50 subjects per group (total sample size n=150) will be sufficient to 
address the objectives of this study. 
12.8 
General Considerations 
Data will be listed by subject number. Data will be summarized by treatment and study visit, where 
applicable. For categorical parameters, the number and percentage of subjects/observations in each 
category will be presented; percentages will be based on the number of subjects in the relevant 
analysis population in each treatment group. For continuous parameters, descriptive statistics will 
include n (number of subjects or observations), mean, standard deviation, median, and range. A 
full description of the statistical methods planned for this study will be provided in the Statistical 
Analysis Plan (SAP). All programs for data output and analyses will be written in SAS version 9.4 
or higher (SAS Institute, Inc., Cary, NC). 
Missing Values: For the mITT analysis of primary, secondary, tertiary, and exploratory duration 
of effectiveness endpoints, in the case of a missed visit, subjects will be considered to have returned 
to Baseline if they are confirmed to have returned to Baseline at the next non-missed visit. Subjects 
will be considered to have to have returned to Baseline if they fail to attend 2 consecutive visits or 
drop out of the study. For missing observations for exploratory endpoints other than duration of 
effect data will be analyzed as observed without imputation. 
Discontinuation and Drop-Outs: Dropouts will not be replaced. Subject disposition will 
summarize the number of subjects who were randomized and who discontinued from the study 
(including reasons for discontinuation). 
Interim Analysis: An interim analysis will be conducted when >90% of subjects have completed 
Visit 8 (Day 120) to evaluate response to exposure (efficacy, duration) and adverse events. For 
assessment of the primary effectiveness endpoint, 95% CIs will be presented but statistical 
analyses will not be conducted and a statistical penalty for the final analysis will not be employed. 
While data by treatment group will be presented, individual subjects will not be unblinded. 
Poolability of Investigative Sites: Data from all investigative sites will be pooled based on the 
assumption of clinical comparability: the same protocol will be used for all sites, all sites will be 
monitored for protocol compliance, and the same data collection instrument and methodology will 
be used across all sites. 
Impact of COVID-19: Any material disruption to the study due to COVID-19 will be addressed, 
as appropriate, in post-hoc sensitivity analyses. 

   
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13 ETHICAL ASPECTS 
13.1 
Informed Consent 
This study will be conducted in compliance with 21 CFR Part 50. Written informed consent will 
be obtained from each subject before any study procedures or assessments are done and after the 
aims, methods, anticipated benefits, potential hazards, compensation and/or honoraria and 
insurance arrangements are explained. Subjects will also be explained that they are free to refuse 
entry into the study and free to withdraw from the study at any time without prejudice to future 
treatment. The study coordinator will present study specifics to potential participants and will lead 
the consenting process. 
The subject’s willingness to participate in the study will be documented in writing on the consent 
form, which will be signed and dated by the subject. The site will keep the original consent forms 
and copies will be given to the subjects. 
See also Section 10.1.  
13.2 
Health Authorities and IRBs 
Before starting this study, the protocol will be submitted to the FDA and IRB for evaluation. As 
required, the study will not start before approval is obtained from the IRB and the FDA. 
In accordance with 21 CFR 56, the protocol (including amendments), any advertisement, and 
informed consent form will be reviewed and approved by a properly instituted Institutional Review 
Board (IRB) for each study center. The Sponsor will supply relevant material for the Investigator 
to submit to the IRB for review and approval. The IRB will comply with applicable requirements, 
defined in the U.S. Code of Regulations, Title 21, Part 56. The study will not begin at an 
investigational site until an IRB has approved the protocol and the Informed Consent form. 
The Investigator will inform the IRB of any UADE. The Investigator will provide the IRB with 
progress reports at intervals specified by the IRB (but in no event less often than yearly), and a 
final report within 3 months following the completion, termination, or discontinuation of the 
Investigator’s participation in the study. 
13.3 
Confidentiality Regarding Study Subjects 
The PI must ensure that the privacy of the subjects, including their personal identity and all 
personal medical information, will be maintained at all times. In eCRFs and other documents 
submitted to the Sponsor, subjects will not be identified by their names, but by an identification 
code (e.g., subject or screen number).  
The site monitor, properly authorized persons on behalf of the Sponsor, or competent authorities 
may scrutinize personal medical information for the purpose of verifying data recorded on the 
eCRF. Personal medical information will always be treated as confidential, according to local 
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14 STUDY MANAGEMENT & ADMINISTRATION 
14.1 
Protocol Amendments 
No amendments to the protocol will be implemented without the prior written consent of the 
Sponsor. Should an amendment be necessary, the reviewing IRB and FDA may require review 
and approval prior to its implementation. 
14.2 
Monitoring and Quality Assurance 
14.2.1 
Information to Study Personnel 
The PI, with the assistance of the CRO, is responsible for ensuring that all study personnel are 
qualified for their designated roles and for providing information about the study to all staff 
members involved in the study or in any element of subject management, both before starting the 
practical performance of the study and during the course of the study (e.g., when new staff become 
involved). 
The CRO site monitor is responsible for initiating the site, conducting interim monitoring visits, 
ensuring site compliance with the protocol, and closing out the site at the end of the study. 
Additional information available during the study should be given as agreed upon, either by the PI 
or the site monitor, and always when new staff members become involved in the study. 
14.2.2 
Study Monitoring 
The CRO clinical monitors will conduct on-site and/or remote interim monitoring visits at each 
study site in order to ensure compliance to the protocol, applicable regulations, and ICH-GCP, and 
to ensure safety of the subjects and maintenance of adequate and accurate clinical records. A 
dedicated close-out visit will also be conducted at each site. 
Monitoring functions will be performed in compliance with GCP and the study specific Monitoring 
Plan. The PI agrees to allow the site monitors, and other authorized Sponsor personnel, access to 
the clinical supplies, the investigational agent dispensing and storage area, subject medical records, 
laboratory data, and other source documentation of the study subjects. 
Source Document worksheets for all subjects and eCRFs will be reviewed in detail by the site 
monitor to ensure data integrity. If errors or omissions are found in the course of a data audit, or if 
clarification of data is required, the eCRFs and/or worksheets in question will be corrected by the 
study coordinator and confirmed/signed for by the PI, as appropriate. Data clarification or query 
forms may be generated for omissions or clarifications, to be completed and returned to the site 
monitor. 
The dates of monitoring visits will be recorded by the site monitor in a sign-in log to be kept at the 
site. The Sponsor expects that, during monitoring visits, the study coordinator and PI will be 
available, the source documentation will be available, and a suitable environment for on-site visits 
will be provided for review of study-related documents. 
The PI and assisting staff must agree to cooperate with the site monitor to resolve any problems, 
errors, or possible misunderstandings concerning any data discrepancies detected in the course of 
these monitoring visits. 
As part of the supervision of the study progress other Sponsor personnel may accompany the site 
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14.2.3 
Audit and Inspection 
According to ICH Guidelines on GCP, the Sponsor (or its designate) may audit the investigational 
site to compare raw data, source data, and associated records with the interim (if applicable) or 
final report of the study to assure that data have been accurately reported. 
The PI must accept that regulatory authorities may conduct an inspection to verify compliance of 
the study with GCP. The PI should notify the Sponsor and the CRO no later than 24 hours upon 
notification of being audited by the FDA or IRB. 
14.3 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or GCP. The 
noncompliance may be either on the part of the subject, the PI, or the study site staff. As a result 
of deviations, corrective actions are to be developed by the site and implemented promptly. It is 
the responsibility of the site to use continuous vigilance to identify and promptly report deviations 
to the CRO.  
All deviations from the protocol must be addressed in study subject source documents. A 
completed copy of the Protocol Deviation Form must be maintained in the regulatory file, as well 
as in the subject’s source document. Protocol deviations must be sent to the IRB per its guidelines. 
The protocol must be rigorously adhered to; however, exceptions will be made in emergency 
situations when the protection, safety, and well-being of the subject requires immediate 
intervention based on the judgment of an Investigator.  
Protocol deviations are termed as Major or Minor, as defined below: 
 Minor Protocol Deviation: any difference or departure in the conduct of a study from the 
criteria and/or procedures prescribed in the IRB approved protocol which does not affect 
the subject’s rights, safety, welfare, and/or the integrity of the study and resultant data. 
deviations may result from action or inaction of the subject, investigator, or staff.  
1. Deviation has no substantive effect on the risks to research subjects; 
2. Deviation has no substantive effect on the value of the data collected (i.e., the 
deviation does not confound the scientific analysis of the results); 
3. Deviation did not result from willful or knowing misconduct on the part of the 
investigator(s) and; 
4. The deviation did not result in or require any substantive action to be taken or result 
in any change to the subject’s condition or status (i.e., did not affect the subject’s 
participation in any way, did not result in a change to the subject’s emotional or 
clinical condition, did not cause an adverse experience or require a change to the 
clinical care of the subject, etc.) 
 Major Protocol Deviation: Any difference or departure from the criteria and/or 
procedures prescribed in the IRB approved protocol that affects the subject’s rights, safety, 
welfare, increases the risk/benefit ratio, or compromises the integrity of the study’s data. 
1. Deviation resulted in or required a substantive action to be taken or resulted in a 
change to the subject’s condition or status; 
2. Deviation has harmed or posed a significant risk of substantive harm to research 
subjects; 
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4. Deviation is evidence of willful or knowing misconduct on the part of the 
investigator(s); 
5. Deviation involves serious or continuing noncompliance with federal, state, or local 
research regulations; 
6. There have been repeated minor protocol deviations from the same 
investigator/research staff; 
7. There has been a failure to follow action ordered to correct minor protocol deviations. 
14.4 
COVID-19 and Potential Study Interruption 
Guidance for managing COVID-19 study interruption is provided in Appendix A. 

   
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15 DATA HANDLING AND RECORD KEEPING 
15.1 
Source Data  
The site is required to maintain adequate and accurate medical records designed to record all 
observations and other data pertinent to the study for each study subject. Source documentation is 
generally considered to be the document on which the information or data point was first recorded. 
Source documentation may include a subject’s medical records, hospital charts, clinic charts, and 
the site’s study files as well as the results of diagnostic tests such as X-rays, laboratory tests, and 
electrocardiograms. 
Source Document Worksheets will be prepared by the CRO for this purpose and serve as part of 
the source record for a subject's study-related data. The Source Document Worksheets will allow 
for the collection of the following information and allow for verification of subject identity 
throughout the study: 
a. Subject’s name; 
b. Subject’s contact information; 
c. The date that the subject entered the study and the subject number assigned; 
d. The study title and/or the protocol number of the study and the Sponsor’s name; 
e. A statement of the ICF process and the date that informed consent, HIPAA, and California 
Experimental Research Subject’s Bill of Rights (if applicable) were signed; 
f. Records of previous aesthetic treatments and/or therapies; 
g. Dates of all subject visits; 
h. Effectiveness evaluations; 
i. Safety evaluations; 
j. All prescription and non-prescription concurrent medications, therapies, and treatments (up 
to 14 days prior to enrollment through the final study visit) and any changes to the list of 
medications; 
k. Occurrence and status of any AEs; 
l. The date the subject exited the study, and a notation as to whether the subject completed the 
study or reason for discontinuation; 
m. The results of urine pregnancy testing, if performed. 
Pertinent records related to the study (e.g., the subject’s medical chart) will be made available to 
the Sponsor representative on request with due precaution to protect the privacy of the subject. If 
applicable (i.e., SAE reporting), personal identifying information (except subject initials) will be 
redacted on any photocopies of relevant medical records and replaced with the unique subject 
number before submission to the Sponsor. The PI will protect the confidentiality of all subjects’ 
records within applicable federal, state, and local laws. 
A subject identification code list will be maintained in order to allow unambiguous identification 
of each subject included in the study. This list should contain the subject’s full name, date of birth, 
dates of participation and identification number as per local regulations. 
The PI must agree to supply all details to Sponsor auditor(s) and/or regulatory authorities, ensuring 
the data is held confidentially at the site after completion of the study. A note will be made in the 

   
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hospital or clinical medical records, if appropriate, that the subject is participating in a clinical 
study. 
The eCRF and subjects’ medical records will be reviewed by the CRO, representatives from the 
study Sponsor, the IRB, and/or the FDA to the extent permitted by regulations. 
15.2 
Case Report Form 
In this study the case report form will be an eCRF. The study coordinator must complete the eCRF 
for each subject within a timely manner of the visit occurring. 
The site monitor will review the completed eCRF for accuracy, completeness, and consistency 
with source documentation (i.e., medical records, source document worksheets, etc.). The site 
monitor will submit requests for correction/clarification of data (e.g., queries) as well as the data 
manager to the study coordinator when inconsistencies are identified during monitoring and source 
data verification or during the data review and edit check process.  
All corrections and alterations of eCRF data must be made by the study coordinator in a timely 
manner and according to the instructions provided. Completed eCRFs for each visit (i.e., those 
reviewed by the CRO and with no remaining queries) should then be reviewed and electronically 
signed by the PI. In order to review and electronically sign the eCRF, the PI will have his/her own 
login that will allow them to view only the data that they have generated. 
A full audit trail detailing corrections and alterations made to the eCRF will be maintained. 
Upon study completion, a softcopy of the eCRF for each subject will be provided to the site. 
15.3 
Archiving of Study Documentation 
An Investigator or Sponsor may withdraw from the responsibility to maintain records for the 
period required and transfer custody of the records to any other person who will accept 
responsibility for them under 812.140 and including the requirements of 812.145. Notice of a 
transfer shall be given to FDA no later than 10 working days after transfer occurs. 
Custody of the records may be transferred to another responsible party, acceptable to the Sponsor, 
who agrees to abide by the retention policies. Written notice of transfer must be submitted to the 
Sponsor. The Investigator must contact the Sponsor prior to disposing of any study records. 
An Investigator or Sponsor shall maintain the records required by the U.S. Code of Federal 
Regulations, Title 21, Part 812.140 during the investigation and for a period of 2 years after the 
latter of the following two dates: The date on which the investigation is terminated or completed, 
or the date that the records are no longer required for purposes of supporting a premarket approval 
application or a notice of completion of a product development protocol. 
Completed eCRFs will be transferred to the Sponsor. The Investigator will retain copies of each 
eCRF. All source documents, records, and reports will be retained by the study site in accordance 
with 21 CFR 812.140 (d). 
All primary data or copies thereof (e.g., laboratory records, CRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original study observations, and are 
necessary for the reconstruction and evaluation of any study report, will be retained at the study 
site. 
 
 

   
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16 FINANCING AND INSURANCE 
A separate financial agreement (Clinical Trial Agreement) will be made between Evolus, Inc. and 
the PI at each site. 
The study is covered under a Evolus, Inc. liability insurance policy. The certificate of insurance 
will be provided upon request. 

   
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17 REPORTING AND PUBLICATION OF RESULTS 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the Study Sponsor. Any 
Investigator involved with this study is obligated to provide the Sponsor with complete test results 
and all data derived from the study. 
The Investigator agrees to the unrestricted use of results of the study for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals by the Sponsor. If required, the authorities will be notified of the Investigator's name, 
address, qualifications, and extent of involvement. 
This study will be posted on www.clinicaltrials.gov. Authorship and manuscript composition will 
reflect joint cooperation between Investigators and Sponsor personnel. As this study involves 
multiple centers, no individual publication will be allowed prior to completion of the final report 
of the multicenter study except as agreed with the Sponsor. 
 
 

   
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18 REFERENCES 
 
1. Kaufman-Janette J et. al.  Botulinum Toxin Type A for Glabellar Frown Lines: What Impact of Higher Doses 
on Outcomes? Toxins 2021, 13:494.  doi: 10.3390/toxins13070494. 
2. Beer KR, et. al.  Efficacy and Safety of PrabotulinumtoxinA for the Treatment of Glabellar Lines in Adult 
Subjects: Results From 2 Identical Phase III Studies.  Dermatol Surg 2019;00:1–13  DOI: 
10.1097/DSS.0000000000001903 
3. Rzany B-J, et. al.  A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Phase III, 
Non-Inferiority Study Comparing PrabotulinumtoxinA and OnabotulinumtoxinA for the Treatment of 
Moderate to Severe Glabellar Lines in Adult Patients.  Aesth Surg J 2019, 1–16  DOI: 10.1093/asj/sjz110 
4. Lorenc ZP, et. al.  The Second of Two One-Year, Multicenter, Open-Label, Repeat-Dose, Phase II Safety 
Studies of PrabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients.  
Aesth Surg J 2021, 1–16 DOI: 10.1093/asj/sjaa382 
5. Kaufman-Janette J, et. al.  The First of Two One-Year, Multicenter, Open-Label, Repeat-Dose, Phase II 
Safety Studies of PrabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult 
Patients.  Aesth Surg J 2021, 1-14  DOI: 10.1093/asj/sjaa383 
 
 
 
 
 

   
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19 APPENDICES 
APPENDIX A: ADJUSTMENT OF VISITS AND ASSESSMENTS DUE TO 
COVID-19 
1. General Guidance 
Subject safety and preserving the integrity of the data are of the highest priority. Any federal, state, 
and local rules, guidances, or laws shall be followed.  
Study visits and procedures should be followed per-protocol whenever possible. Any specific 
changes in study conduct that deviate from the protocol should be communicated to the sponsor 
via reporting to the site’s Clinical Research Associate (CRA), Clinical Project Manager (CPM), 
and IRB, as applicable. All protocol deviations which occur as a result of COVID-19 disruptions 
(including remote visits), will be differentiated from other deviations, and must be documented on 
the appropriate reporting forms/source document, and clearly annotated “protocol deviations due 
to COVID-19 illness/restrictions/etc.”. If the subject is unable or unwilling to come to the site due 
to COVID-19, the PI needs to ask for the reasons and document them in the source documents. 
The PI is responsible for ensuring subjects’ safety and for monitoring all active subjects per 
protocol. PI must ensure that study subjects are kept informed of changes to the study and 
monitoring plans that could impact them. 
Should a subject develop any symptoms that could be related to COVID-19 or any other acute 
infection disease, the subject will be instructed to: 
 Contact the PI as soon as possible 
 Contact their general physician to be examined and determine the course of action 
according to the standard of care. 
The PI or designee will follow-up with the subject as needed but at least within 72 hours of 
awareness to obtain an update on the subject’s health and to obtain information on whether 
COVID-19 has been diagnosed or not. If the subject has been diagnosed with COVID-19, the event 
will be reported as an AE. 
2. Adjustment of Study Visits 
Telemedicine is understood as a possible solution due to COVID-19 disruption and it is not 
mandatory; if the situation allows it, study visits should be done in person. 
On-site Study Visit: If the local situation allows for conduct of on-site study visits, the PI and 
study personnel must take all necessary steps/precautionary measures at the site to minimize or 
eliminate immediate hazards of viral transmission within and/or outside the clinical site premises.  
Before any research activities occur on-site, both subjects and research staff should be screened 
for symptoms or risk of COVID-19 infection. Subjects should be pre-screened by phone before 
their on-site study visit. 
If the local situation only allows for completion of some study procedures, the PI will prioritize 
the research activities that absolutely require an in-person visit in order to maintain the viability 
and integrity of the research (e.g., Treatment Visit). The PI may consider conducting the other 
assessments (e.g., medical history review, directed questionnaire) using telemedicine to minimize 

   
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subject time on site and risk of exposure at the site. However, all efforts should be made to conduct 
all assessments at the scheduled visits, if possible. 
Remote Study Visit: If the local situation does not allow for an on-site study visit to be conducted 
or if a subject does not wish to come to the study site due to COVID-19 disruption, a remote study 
visit may be conducted via video conferencing in lieu of an on-site visit. Phone call may also be 
used to perform some assessments if a subject has no video conferencing capabilities. 
The PI or study personnel who will conduct remote visits must be trained on how to conduct real-
time video conferencing visits. Also, procedures should be put in place to maintain the subject’s 
privacy, as would be done for a clinical visit: 
 
Before the scheduled date of the visit: 
o The site personnel should determine if the subject can accommodate for video 
conferencing (e.g., internet access, PC, smartphone, video conference apps, etc.). 
o The PI or site personnel conducting the remote visit should obtain the subject’s verbal 
consent before proceeding with the visit and document it in the source document. The 
PI or personnel should also explain to the subject how the visit will be conducted. 
o A test call may also be completed with the subject prior to the appointment. 
 
On the day of the scheduled visit:  
o Both the investigator/site delegate and the subject should confirm their respective 
identities with one another before engaging in a real-time video conference visit. For 
example, the site personnel will state their name and role and the subject may be 
identified by using two subject identifiers (e.g., name and date of birth) and a photo 
ID. 
o The date and time of the real-time video interaction, the location of the subject, and 
the location of the PI or site personnel conducting the remote visit should be 
documented in the source document. 
o Remote collection of data by PI or delegate will be conducted as described in Section 
3 below. 
3. Adjustment of Study Assessments 
Informed consent: The following process will be followed for consenting a prospective subject 
remotely: 
 Each subject will be provided with a copy of the IRB-approved consent form to aid in the 
consent discussion before the consent process begins. The consent form may be provided 
to a prospective subject by mail or e-mail.  
 The PI and/or site delegate will participate in the consent process via video conference. All 
parties must introduce themselves and their role in the consenting process.  
 The consent form provided to the subject will be reviewed in detail and the subject will be 
invited to ask any questions and to have them addressed by the study team.   
 If the subject is interested in joining the research study, the subject will be asked to sign 
the consent document. The personnel conducting the consent process must verify that the 

   
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subject physically signed the consent document by viewing via video conference and then 
obtain a photo or scanned copy of the signed consent form before proceeding with study 
assessments. 
 In order to obtain the required signatures from the PI and person conducting the consent 
process on the same day, the site will either sign a separate copy of the informed consent 
form or ask the subject to send a copy of the signed ICF by e-mail.  
 The site should ensure to obtain all signature pages from the subject and to document the 
consent process in the source document. The site should also file in the source document 
all signed components as one combined document and provide a copy to the subject.  
Inclusion/Exclusion Criteria: The list of inclusion/exclusion criteria may be reviewed via video 
conference or phone call with the subject to confirm that they are eligible for the study. 
For potential subjects in a high-risk population for COVID-19 (e.g., 60 years old and older, with 
comorbidities such as diabetes, cardiovascular disease, respiratory system issues, etc.), deferring 
participation should be considered to minimize risks of exposure. 
UPT (if applicable): UPTs cannot be conducted remotely.  
Demographics: Demographic information may be collected via video conference or phone call 
from the subject at a remote screening visit. 
Medical History and Concomitant Medications: Medical history and concomitant medications 
may be reviewed via video conference or phone call at each remote visit. 
Randomization: Randomization is performed before treatment. Therefore, subjects will be 
required to present themselves at the clinic for randomization.  
IP Treatment Session: IP cannot be administered remotely. Therefore, subjects will be required 
to present themselves at the clinic for the IP treatment session. 
Vital Signs, Physical Exam, Safety Laboratories, ECG: Subjects will be required to present 
themselves at the clinic for assessment of vital signs, physical examinations, clinical labs, and 
ECGs.  
Brow Area Photography: Subjects will be required to present themselves at the clinic for 
photography sessions of the brow area. 
Directed Review of Systems: Subjects will be required to present themselves at the clinic for the 
directed review of systems. 
Adverse Events: AEs may be reviewed remotely via video conference or phone call with the 
subject at each remote study visit. Any AE/SAE (including suspected / confirmed COVID-19 
cases) elicited by a subject during a remote visit / phone call must be immediately captured, and 
all attempts should be done to capture the necessary clinical and medical information. Reporting 
of AEs and SAEs to the Sponsor and IRB should follow the protocol procedure and IRB 
requirements. 
Investigator Assessments (GLS, GAIS): The primary effectiveness endpoint will be based on 
the GLS as assessed by the Investigator. As such, the Investigator assessment of the GLS cannot 
be conducted remotely and subjects will be asked to travel to the clinic in order for the Investigator 
to perform a live GLS assessment. If this is impossible, GLS may be conducted remotely via video 

   
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conference; however, such data collected will not be part of the primary effectiveness endpoint 
analysis and will be used as supportive data only. The GAIS may be conducted remotely via video 
conference or phone call with the subject. 
Subject Assessments (GLS, GAIS, Subject Satisfaction, Clinical Interview, Directed 
Questionnaire): All subject assessments may be conducted remotely via video conference or 
phone call with the subject at each remote visit. Subjects will be interviewed by the study 
coordinator who will record responses into the source document worksheets. In order to perform 
the GAIS, the subject’s Baseline photo will also be provided by email. 
 
 

   
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APPENDIX B: DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
 
A. INTRODUCTION 
1.         The World Medical Association has developed the Declaration of Helsinki as a statement of ethical 
principles to provide guidance to physicians and other participants in medical research involving 
human subjects. Medical research involving human subjects includes research on identifiable 
human material or identifiable data.  
2.         It is the duty of the physician to promote and safeguard the health of the people. The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty.  
3.        The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my patient will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act only in the patient's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the patient."  
4.         Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects.  
5.         In medical research on human subjects, considerations related to the well-being of the human subject 
should take precedence over the interests of science and society.  
6.         The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of 
disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously 
be challenged through research for their effectiveness, efficiency, accessibility, and quality.  
7.         In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic 
procedures involve risks and burdens.  
8.         Medical research is subject to ethical standards that promote respect for all human beings and protect 
their health and rights. Some research populations are vulnerable and need special protection. The 
particular needs of the economically and medically disadvantaged must be recognized. Special 
attention is also required for those who cannot give or refuse consent for themselves, for those who 
may be subject to giving consent under duress, for those who will not benefit personally from the 
research and for those for whom the research is combined with care. 
9.        Research Investigators should be aware of the ethical, legal and regulatory requirements for research 
on human subjects in their own countries as well as applicable international requirements. No 
national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of 
the protections for human subjects set forth in this Declaration. 

   
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B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10. 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of 
the human subject.  
11. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and on adequate laboratory and, where appropriate, animal experimentation.  
12. 
Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected.  
13. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol. This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical 
review committee, which must be independent of the investigator, the sponsor or any other kind of 
undue influence. This independent committee should be in conformity with the laws and 
regulations of the country in which the research experiment is performed. The committee has the 
right to monitor ongoing trials. The researcher has the obligation to provide monitoring information 
to the committee, especially any serious adverse events. The researcher should also submit to the 
committee, for review, information regarding funding, sponsors, institutional affiliations, other 
potential conflicts of interest and incentives for subjects.  
14. 
The research protocol should always contain a statement of the ethical considerations involved and 
should indicate that there is compliance with the principles enunciated in this Declaration.  
15. 
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the subject 
of the research, even though the subject has given consent.  
16. 
Every medical research project involving human subjects should be preceded by careful assessment 
of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. 
This does not preclude the participation of healthy volunteers in medical research. The design of 
all studies should be publicly available.  
17. 
Physicians should abstain from engaging in research projects involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians should cease any investigation if the risks are found to outweigh the potential 
benefits or if there is conclusive proof of positive and beneficial results. 
18. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject. This is especially important when 
the human subjects are healthy volunteers.  
19. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research.  
20. 
The subjects must be volunteers and informed participants in the research project.  
21. 
The right of research subjects to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's 
information and to minimize the impact of the study on the subject's physical and mental integrity 
and on the personality of the subject.  
22. 
In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. 

   
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The subject should be informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal. After ensuring that the subject has understood 
the information, the physician should then obtain the subject's freely-given informed consent, 
preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be 
formally documented and witnessed.  
23. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under duress. 
In that case the informed consent should be obtained by a well-informed physician who is not 
engaged in the investigation and who is completely independent of this relationship.  
24. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from the 
legally authorized representative in accordance with applicable law. These groups should not be 
included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons.  
25. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to the 
consent of the legally authorized representative.  
26. 
Research on individuals from whom it is not possible to obtain consent, including proxy or advance 
consent, should be done only if the physical/mental condition that prevents obtaining informed 
consent is a necessary characteristic of the research population. The specific reasons for involving 
research subjects with a condition that renders them unable to give informed consent should be 
stated in the experimental protocol for consideration and approval of the review committee. The 
protocol should state that consent to remain in the research should be obtained as soon as possible 
from the individual or a legally authorized surrogate.  
27. 
Both authors and publishers have ethical obligations. In publication of the results of research, the 
investigators are obliged to preserve the accuracy of the results. Negative as well as positive results 
should be published or otherwise publicly available. Sources of funding, institutional affiliations 
and any possible conflicts of interest should be declared in the publication. Reports of 
experimentation not in accordance with the principles laid down in this Declaration should not be 
accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL 
CARE 
28. 
The physician may combine medical research with medical care, only to the extent that the research 
is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is 
combined with medical care, additional standards apply to protect the patients who are research 
subjects.  
29. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method exists.  
30. 
At the conclusion of the study, every patient entered into the study should be assured of access to 
the best proven prophylactic, diagnostic and therapeutic methods identified by the study.  
31. 
The physician should fully inform the patient which aspects of the care are related to the research. 
The refusal of a patient to participate in a study must never interfere with the patient-physician 
relationship.  
32. 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not 

   
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exist or have been ineffective, the physician, with informed consent from the patient, must be free 
to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating suffering. Where 
possible, these measures should be made the object of research, designed to evaluate their safety 
and efficacy. In all cases, new information should be recorded and, where appropriate, published. 
The other relevant guidelines of this Declaration should be followed.  
 

   
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APPENDIX C: GLABELLAR LINE SCALE (GLS) AT MAXIMUM 
FROWN 
 
 
 
 

   
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APPENDIX D: GLOBAL AESTHETIC IMPROVEMENT SCALE (GAIS) 
GAIS Grade 
Score 
Description 
Much Improved 
2 
Marked improvement in appearance 
Improved 
1 
Improved in appearance, but would like more 
No Change 
0 
The appearance is essentially the same as the original condition 
Worse 
-1 
The appearance is worse than the original condition 
Much Worse 
-2 
The appearance is much worse that the original condition 
 
 
 
APPENDIX E: SUBJECT SATISFACTION SCALE (SSS) 
SSS Grade 
Score 
Description 
Very Satisfied 
2 
I am very satisfied with the treatment 
Satisfied 
1 
I am satisfied with the treatment 
Indifferent 
0 
I am indifferent with the treatment 
Unsatisfied 
-1 
I am unsatisfied with the treatment 
Very Unsatisfied 
-2 
I am very unsatisfied with the treatment